Cutis

To the Editor:

A 38-year-old woman was diagnosed with common variable immune deficiency (CVID) by an immunologist at an outside institution 1 year prior to the current presentation. The diagnosis was based on history of severe recurrent sinopulmonary tract, inner ear, Clostridium difficile, urinary tract, and herpes zoster infections of approximately 6 years’ duration, as well as persistently low IgG, IgA, and IgM levels of 530 mg/dL (reference range, 690–1400 mg/dL), 29 mg/dL (reference range, 88–410 mg/dL), and 30 mg/dL (reference range, 34–210 mg/dL), respectively, with failure to respond to vaccinations (ie, Haemophilus influenzae type B, Streptococcus pneumoniae, diphtheria IgG antibody, tetanus antibody). She was started on replacement intravenous immunoglobulin (IVIG) 40 g monthly (400 mg/kg) for CVID. She had a family history of CVID diagnosed in her son and sister.

One year after the CVID diagnosis, she was diagnosed with Sweet syndrome (SS) by a physician at our institution via biopsy of a lesion on the left arm (Figure 1) that showed dense dermal infiltrate of neutrophils with scattered background apoptotic nuclear debris without evidence of vasculitis (Figure 2). Gram stain and microbial biopsy cultures were negative for mycobacterial, fungal, and bacterial organisms. Cutaneous lesions failed to respond to courses of intravenous antibiotics. Sarcoidosis workup was unremarkable and was pursued to exclude the association with SS. Other negative testing included antinuclear antibody, human immunodeficiency virus, rheumatoid factor, thyroid-stimulating hormone, Ro and La autoantibodies, cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, antimitochondrial antibody, and urinalysis. Occult malignancy was excluded with negative bone marrow biopsy; cerebrospinal fluid analysis; esophagogastroduodenoscopy; colonoscopy; and computed tomography of the chest, abdomen, and pelvis.

Sweet syndrome flares in this patient began with a prodromal syndrome of fever, chills, fatigue, diarrhea, and severe local neuropathic pain. Cutaneous lesions erupted 2 days later, most frequently on the arms and fingers. Preemptive treatment with prednisone 30 to 40 mg when the prodrome was present did not arrest cutaneous lesion development. Flares initially occurred every 3 to 5 weeks.

She initially was successfully treated with high-dose prednisone 100 mg daily during SS flares. Prolonged low-dose prednisone maintenance (10–20 mg) and hydroxychloroquine failed to control her frequent exacerbations. Dapsone was intolerable secondary to an adverse reaction. She continued to have frequent exacerbations of the SS requiring hospitalizations.

During SS flares, CVID was stable with infrequent systemic infections. Although a causal relationship between CVID and SS was unclear, an empiric increase in IVIG dose was made by her immunologist to test if it would decrease the frequency of the cutaneous flares. Subsequently, the IVIG dose was increased to 60 g monthly followed by 200 g monthly after approximately 4 months with a partial initial response in the beginning of therapy for the first 6 months. However, episodes resumed with increasing frequency with cutaneous lesion flares every 2 to 3 weeks. In a 3-month period, the patient had at least 4 hospitalizations for SS flares. Finally, 18 months after the diagnosis of SS was made, she was started on metronomic cyclophosphamide at a daily oral dose of 100 mg, later reduced to 50 mg daily after she developed mild neutropenia. She was continued on monthly IVIG replacement at a higher dose of 200 g divided over 2 days for CVID throughout the course of the disease and to the present time. Since then, the frequency of SS flares has notably reduced. She required 1 hospitalization after cyclophosphamide was initiated. She uses short-pulse prednisone (1 mg/kg) for 3 to 5 days when new skin lesions appear in addition to cyclophosphamide.

Common variable immune deficiency, the most common primary immunodeficiency, initially can present in adulthood.^1,2 Its hallmarks include low levels of serum immunoglobulin, most notably IgG with most patients having concurrent deficiencies of IgA and IgM, and impaired antibody responses with recurrent or atypical infections. It has been associated with autoimmune diseases, granulomatous disease, and inflammatory disorders.² Failure to mount protective levels of antibody titer after vaccination demonstrates the deficiency of antibody production.¹ Lack of recognition of this clinical spectrum may lead to delayed diagnosis and more importantly stalls the initiation of immunoglobulin replacement therapy.¹ The customary dose of immunoglobulin replacement is 400 mg/kg given in a single monthly infusion²; however, doses should be individualized and based on clinical response.¹

Sweet syndrome is characterized by the constellation of pyrexia; leukocytosis; and eruption of painful, edematous, dermal, and neutrophil-dense plaques that occur in the setting of infection or malignancy or are drug induced.^3,4 Although not fully elucidated, the pathogenesis is thought to involve the effects of cytokines that precipitate neutrophil activation and infiltration inducing a hypersensitivity reaction and escalation of the immunologic cascade.³ Because SS can represent a paraneoplastic phenomenon or a dermal manifestation of a solid neoplasm or hematologic dyscrasia, it is important to rule out occult malignancy.³ The mainstay of treatment is systemic corticosteroids to which classical SS lesions readily respond. Alternatively, topical or intralesional corticosteroids may be used as adjuvant therapy. Alternate first-line treatments include potassium iodide and colchicine. Second-line therapies include indomethacin, cyclosporine, dapsone, and other immunosuppressive agents.⁵ The lesions may become superinfected with bacterial pathogens requiring antimicrobials.³ Spontaneous resolution seldom occurs. The risk for relapse is lifelong following spontaneous or therapy-induced clinical remission.³ There is a growing body of literature of SS-associated conditions.

Common variable immune deficiency is a collection of disorders resulting in antibody deficiency and recurrent infections.⁶ Despite the humeral defects in CVID, patients paradoxically may develop various autoimmune, hematologic, and inflammatory disorders.⁷ Sweet syndrome, first described in 1964, is a constellation of fever, neutrophilia, and neutrophilic dermatosis of unknown pathogenesis.⁸ Copresentation of CVID and SS has not been commonly reported. O’Regan et al⁸ described a 17-year-old adolescent boy with both SS and CVID but SS preceded the diagnosis of CVID. In our case, the patient presented with CVID first and then manifested SS 1 year later.

Common variable immune deficiency is the most frequent symptomatic primary immunodeficiency in adults. Because adults with CVID have varied manifestations, CVID is thought to be late-onset antibody failure. The genetic basis of these disorders has not been identified in the majority of individuals. More than 100 genetic defects have been ascribed to primary immunodeficiencies,⁹ though none are consistently found to be associated with CVID. The majority of CVID cases are sporadic, but the positive family history in our patient suggests a familial form. Approximately 10% to 20% of patients have an identified heritable cause of CVID.¹⁰ Our patient’s diagnosis of CVID was confirmed by meeting the diagnostic triad set by the European Society for Immunodeficiencies¹¹ of marked reduction of IgG and IgA or IgM plus onset after 2 years of age, recurrent infections, and defective vaccination response. Additional complications including autoimmunity, malignancy, and granulomatous inflammation were extensively ruled out.

The etiology of SS is unknown and its pathogenesis not fully elucidated, though it is presumed to be a hypersensitivity reaction.¹² Sweet syndrome can be classified into 3 major subtypes: classical or idiopathic, malignancy associated, or drug induced.³ Our patient’s presentation is consistent with the classical variant, as malignancy was ruled out and the patient was not on any medication other than IVIG at the time of diagnosis. The treatment of SS consists of systemic steroids, initially high dose followed by a prolonged taper over 4 to 6 weeks.³ This treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and decreased synthesis during and for a variable time after drug administration.¹³ In refractory cases, intravenous pulse administration of methylprednisolone sodium succinate for 3 to 5 days may enhance the response to standard therapies.⁵

The concurrent development of neutrophilic dermatoses/SS in an individual with CVID has not been fully described. There is a credible association of SS with infections, inflammatory bowel disease, pregnancy, malignancy, and medications, as well as a possible association with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease.⁵ The association between immunoglobulin deficiencies and SS is markedly unusual. Despite regular IVIG replacement, adequate treatment of CVID did not seem to modulate SS flares in our patient. A case report in a pediatric patient does not provide specific guidance regarding treatment options.⁸

A particularly challenging aspect of our case was tailoring a treatment regimen to suppress SS flares. We have attained partial response to the refractory cutaneous lesions (decreased frequency and amplitude of outbreaks) with IVIG replacement 200 g every 4 weeks in combination with metronomic cyclophosphamide 50 mg daily (use of a repetitive, low-dose daily chemotherapy regimen to minimize side effects). Intermittent SS flares were managed acutely with pulse high-dose steroids. We report a case of SS with CVID, raising the plausibility of correlated pathogenesis. However, the exact mechanisms remain undefined.

To the Editor:

A 38-year-old woman was diagnosed with common variable immune deficiency (CVID) by an immunologist at an outside institution 1 year prior to the current presentation. The diagnosis was based on history of severe recurrent sinopulmonary tract, inner ear, Clostridium difficile, urinary tract, and herpes zoster infections of approximately 6 years’ duration, as well as persistently low IgG, IgA, and IgM levels of 530 mg/dL (reference range, 690–1400 mg/dL), 29 mg/dL (reference range, 88–410 mg/dL), and 30 mg/dL (reference range, 34–210 mg/dL), respectively, with failure to respond to vaccinations (ie, Haemophilus influenzae type B, Streptococcus pneumoniae, diphtheria IgG antibody, tetanus antibody). She was started on replacement intravenous immunoglobulin (IVIG) 40 g monthly (400 mg/kg) for CVID. She had a family history of CVID diagnosed in her son and sister.

One year after the CVID diagnosis, she was diagnosed with Sweet syndrome (SS) by a physician at our institution via biopsy of a lesion on the left arm (Figure 1) that showed dense dermal infiltrate of neutrophils with scattered background apoptotic nuclear debris without evidence of vasculitis (Figure 2). Gram stain and microbial biopsy cultures were negative for mycobacterial, fungal, and bacterial organisms. Cutaneous lesions failed to respond to courses of intravenous antibiotics. Sarcoidosis workup was unremarkable and was pursued to exclude the association with SS. Other negative testing included antinuclear antibody, human immunodeficiency virus, rheumatoid factor, thyroid-stimulating hormone, Ro and La autoantibodies, cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, antimitochondrial antibody, and urinalysis. Occult malignancy was excluded with negative bone marrow biopsy; cerebrospinal fluid analysis; esophagogastroduodenoscopy; colonoscopy; and computed tomography of the chest, abdomen, and pelvis.

Sweet syndrome flares in this patient began with a prodromal syndrome of fever, chills, fatigue, diarrhea, and severe local neuropathic pain. Cutaneous lesions erupted 2 days later, most frequently on the arms and fingers. Preemptive treatment with prednisone 30 to 40 mg when the prodrome was present did not arrest cutaneous lesion development. Flares initially occurred every 3 to 5 weeks.

She initially was successfully treated with high-dose prednisone 100 mg daily during SS flares. Prolonged low-dose prednisone maintenance (10–20 mg) and hydroxychloroquine failed to control her frequent exacerbations. Dapsone was intolerable secondary to an adverse reaction. She continued to have frequent exacerbations of the SS requiring hospitalizations.

During SS flares, CVID was stable with infrequent systemic infections. Although a causal relationship between CVID and SS was unclear, an empiric increase in IVIG dose was made by her immunologist to test if it would decrease the frequency of the cutaneous flares. Subsequently, the IVIG dose was increased to 60 g monthly followed by 200 g monthly after approximately 4 months with a partial initial response in the beginning of therapy for the first 6 months. However, episodes resumed with increasing frequency with cutaneous lesion flares every 2 to 3 weeks. In a 3-month period, the patient had at least 4 hospitalizations for SS flares. Finally, 18 months after the diagnosis of SS was made, she was started on metronomic cyclophosphamide at a daily oral dose of 100 mg, later reduced to 50 mg daily after she developed mild neutropenia. She was continued on monthly IVIG replacement at a higher dose of 200 g divided over 2 days for CVID throughout the course of the disease and to the present time. Since then, the frequency of SS flares has notably reduced. She required 1 hospitalization after cyclophosphamide was initiated. She uses short-pulse prednisone (1 mg/kg) for 3 to 5 days when new skin lesions appear in addition to cyclophosphamide.

Common variable immune deficiency, the most common primary immunodeficiency, initially can present in adulthood.^1,2 Its hallmarks include low levels of serum immunoglobulin, most notably IgG with most patients having concurrent deficiencies of IgA and IgM, and impaired antibody responses with recurrent or atypical infections. It has been associated with autoimmune diseases, granulomatous disease, and inflammatory disorders.² Failure to mount protective levels of antibody titer after vaccination demonstrates the deficiency of antibody production.¹ Lack of recognition of this clinical spectrum may lead to delayed diagnosis and more importantly stalls the initiation of immunoglobulin replacement therapy.¹ The customary dose of immunoglobulin replacement is 400 mg/kg given in a single monthly infusion²; however, doses should be individualized and based on clinical response.¹

Sweet syndrome is characterized by the constellation of pyrexia; leukocytosis; and eruption of painful, edematous, dermal, and neutrophil-dense plaques that occur in the setting of infection or malignancy or are drug induced.^3,4 Although not fully elucidated, the pathogenesis is thought to involve the effects of cytokines that precipitate neutrophil activation and infiltration inducing a hypersensitivity reaction and escalation of the immunologic cascade.³ Because SS can represent a paraneoplastic phenomenon or a dermal manifestation of a solid neoplasm or hematologic dyscrasia, it is important to rule out occult malignancy.³ The mainstay of treatment is systemic corticosteroids to which classical SS lesions readily respond. Alternatively, topical or intralesional corticosteroids may be used as adjuvant therapy. Alternate first-line treatments include potassium iodide and colchicine. Second-line therapies include indomethacin, cyclosporine, dapsone, and other immunosuppressive agents.⁵ The lesions may become superinfected with bacterial pathogens requiring antimicrobials.³ Spontaneous resolution seldom occurs. The risk for relapse is lifelong following spontaneous or therapy-induced clinical remission.³ There is a growing body of literature of SS-associated conditions.

Common variable immune deficiency is a collection of disorders resulting in antibody deficiency and recurrent infections.⁶ Despite the humeral defects in CVID, patients paradoxically may develop various autoimmune, hematologic, and inflammatory disorders.⁷ Sweet syndrome, first described in 1964, is a constellation of fever, neutrophilia, and neutrophilic dermatosis of unknown pathogenesis.⁸ Copresentation of CVID and SS has not been commonly reported. O’Regan et al⁸ described a 17-year-old adolescent boy with both SS and CVID but SS preceded the diagnosis of CVID. In our case, the patient presented with CVID first and then manifested SS 1 year later.

Common variable immune deficiency is the most frequent symptomatic primary immunodeficiency in adults. Because adults with CVID have varied manifestations, CVID is thought to be late-onset antibody failure. The genetic basis of these disorders has not been identified in the majority of individuals. More than 100 genetic defects have been ascribed to primary immunodeficiencies,⁹ though none are consistently found to be associated with CVID. The majority of CVID cases are sporadic, but the positive family history in our patient suggests a familial form. Approximately 10% to 20% of patients have an identified heritable cause of CVID.¹⁰ Our patient’s diagnosis of CVID was confirmed by meeting the diagnostic triad set by the European Society for Immunodeficiencies¹¹ of marked reduction of IgG and IgA or IgM plus onset after 2 years of age, recurrent infections, and defective vaccination response. Additional complications including autoimmunity, malignancy, and granulomatous inflammation were extensively ruled out.

The etiology of SS is unknown and its pathogenesis not fully elucidated, though it is presumed to be a hypersensitivity reaction.¹² Sweet syndrome can be classified into 3 major subtypes: classical or idiopathic, malignancy associated, or drug induced.³ Our patient’s presentation is consistent with the classical variant, as malignancy was ruled out and the patient was not on any medication other than IVIG at the time of diagnosis. The treatment of SS consists of systemic steroids, initially high dose followed by a prolonged taper over 4 to 6 weeks.³ This treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and decreased synthesis during and for a variable time after drug administration.¹³ In refractory cases, intravenous pulse administration of methylprednisolone sodium succinate for 3 to 5 days may enhance the response to standard therapies.⁵

The concurrent development of neutrophilic dermatoses/SS in an individual with CVID has not been fully described. There is a credible association of SS with infections, inflammatory bowel disease, pregnancy, malignancy, and medications, as well as a possible association with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease.⁵ The association between immunoglobulin deficiencies and SS is markedly unusual. Despite regular IVIG replacement, adequate treatment of CVID did not seem to modulate SS flares in our patient. A case report in a pediatric patient does not provide specific guidance regarding treatment options.⁸

A particularly challenging aspect of our case was tailoring a treatment regimen to suppress SS flares. We have attained partial response to the refractory cutaneous lesions (decreased frequency and amplitude of outbreaks) with IVIG replacement 200 g every 4 weeks in combination with metronomic cyclophosphamide 50 mg daily (use of a repetitive, low-dose daily chemotherapy regimen to minimize side effects). Intermittent SS flares were managed acutely with pulse high-dose steroids. We report a case of SS with CVID, raising the plausibility of correlated pathogenesis. However, the exact mechanisms remain undefined.

To the Editor:

A 38-year-old woman was diagnosed with common variable immune deficiency (CVID) by an immunologist at an outside institution 1 year prior to the current presentation. The diagnosis was based on history of severe recurrent sinopulmonary tract, inner ear, Clostridium difficile, urinary tract, and herpes zoster infections of approximately 6 years’ duration, as well as persistently low IgG, IgA, and IgM levels of 530 mg/dL (reference range, 690–1400 mg/dL), 29 mg/dL (reference range, 88–410 mg/dL), and 30 mg/dL (reference range, 34–210 mg/dL), respectively, with failure to respond to vaccinations (ie, Haemophilus influenzae type B, Streptococcus pneumoniae, diphtheria IgG antibody, tetanus antibody). She was started on replacement intravenous immunoglobulin (IVIG) 40 g monthly (400 mg/kg) for CVID. She had a family history of CVID diagnosed in her son and sister.

One year after the CVID diagnosis, she was diagnosed with Sweet syndrome (SS) by a physician at our institution via biopsy of a lesion on the left arm (Figure 1) that showed dense dermal infiltrate of neutrophils with scattered background apoptotic nuclear debris without evidence of vasculitis (Figure 2). Gram stain and microbial biopsy cultures were negative for mycobacterial, fungal, and bacterial organisms. Cutaneous lesions failed to respond to courses of intravenous antibiotics. Sarcoidosis workup was unremarkable and was pursued to exclude the association with SS. Other negative testing included antinuclear antibody, human immunodeficiency virus, rheumatoid factor, thyroid-stimulating hormone, Ro and La autoantibodies, cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, antimitochondrial antibody, and urinalysis. Occult malignancy was excluded with negative bone marrow biopsy; cerebrospinal fluid analysis; esophagogastroduodenoscopy; colonoscopy; and computed tomography of the chest, abdomen, and pelvis.

Sweet syndrome flares in this patient began with a prodromal syndrome of fever, chills, fatigue, diarrhea, and severe local neuropathic pain. Cutaneous lesions erupted 2 days later, most frequently on the arms and fingers. Preemptive treatment with prednisone 30 to 40 mg when the prodrome was present did not arrest cutaneous lesion development. Flares initially occurred every 3 to 5 weeks.

She initially was successfully treated with high-dose prednisone 100 mg daily during SS flares. Prolonged low-dose prednisone maintenance (10–20 mg) and hydroxychloroquine failed to control her frequent exacerbations. Dapsone was intolerable secondary to an adverse reaction. She continued to have frequent exacerbations of the SS requiring hospitalizations.

During SS flares, CVID was stable with infrequent systemic infections. Although a causal relationship between CVID and SS was unclear, an empiric increase in IVIG dose was made by her immunologist to test if it would decrease the frequency of the cutaneous flares. Subsequently, the IVIG dose was increased to 60 g monthly followed by 200 g monthly after approximately 4 months with a partial initial response in the beginning of therapy for the first 6 months. However, episodes resumed with increasing frequency with cutaneous lesion flares every 2 to 3 weeks. In a 3-month period, the patient had at least 4 hospitalizations for SS flares. Finally, 18 months after the diagnosis of SS was made, she was started on metronomic cyclophosphamide at a daily oral dose of 100 mg, later reduced to 50 mg daily after she developed mild neutropenia. She was continued on monthly IVIG replacement at a higher dose of 200 g divided over 2 days for CVID throughout the course of the disease and to the present time. Since then, the frequency of SS flares has notably reduced. She required 1 hospitalization after cyclophosphamide was initiated. She uses short-pulse prednisone (1 mg/kg) for 3 to 5 days when new skin lesions appear in addition to cyclophosphamide.

Common variable immune deficiency, the most common primary immunodeficiency, initially can present in adulthood.^1,2 Its hallmarks include low levels of serum immunoglobulin, most notably IgG with most patients having concurrent deficiencies of IgA and IgM, and impaired antibody responses with recurrent or atypical infections. It has been associated with autoimmune diseases, granulomatous disease, and inflammatory disorders.² Failure to mount protective levels of antibody titer after vaccination demonstrates the deficiency of antibody production.¹ Lack of recognition of this clinical spectrum may lead to delayed diagnosis and more importantly stalls the initiation of immunoglobulin replacement therapy.¹ The customary dose of immunoglobulin replacement is 400 mg/kg given in a single monthly infusion²; however, doses should be individualized and based on clinical response.¹

Sweet syndrome is characterized by the constellation of pyrexia; leukocytosis; and eruption of painful, edematous, dermal, and neutrophil-dense plaques that occur in the setting of infection or malignancy or are drug induced.^3,4 Although not fully elucidated, the pathogenesis is thought to involve the effects of cytokines that precipitate neutrophil activation and infiltration inducing a hypersensitivity reaction and escalation of the immunologic cascade.³ Because SS can represent a paraneoplastic phenomenon or a dermal manifestation of a solid neoplasm or hematologic dyscrasia, it is important to rule out occult malignancy.³ The mainstay of treatment is systemic corticosteroids to which classical SS lesions readily respond. Alternatively, topical or intralesional corticosteroids may be used as adjuvant therapy. Alternate first-line treatments include potassium iodide and colchicine. Second-line therapies include indomethacin, cyclosporine, dapsone, and other immunosuppressive agents.⁵ The lesions may become superinfected with bacterial pathogens requiring antimicrobials.³ Spontaneous resolution seldom occurs. The risk for relapse is lifelong following spontaneous or therapy-induced clinical remission.³ There is a growing body of literature of SS-associated conditions.

Common variable immune deficiency is a collection of disorders resulting in antibody deficiency and recurrent infections.⁶ Despite the humeral defects in CVID, patients paradoxically may develop various autoimmune, hematologic, and inflammatory disorders.⁷ Sweet syndrome, first described in 1964, is a constellation of fever, neutrophilia, and neutrophilic dermatosis of unknown pathogenesis.⁸ Copresentation of CVID and SS has not been commonly reported. O’Regan et al⁸ described a 17-year-old adolescent boy with both SS and CVID but SS preceded the diagnosis of CVID. In our case, the patient presented with CVID first and then manifested SS 1 year later.

Common variable immune deficiency is the most frequent symptomatic primary immunodeficiency in adults. Because adults with CVID have varied manifestations, CVID is thought to be late-onset antibody failure. The genetic basis of these disorders has not been identified in the majority of individuals. More than 100 genetic defects have been ascribed to primary immunodeficiencies,⁹ though none are consistently found to be associated with CVID. The majority of CVID cases are sporadic, but the positive family history in our patient suggests a familial form. Approximately 10% to 20% of patients have an identified heritable cause of CVID.¹⁰ Our patient’s diagnosis of CVID was confirmed by meeting the diagnostic triad set by the European Society for Immunodeficiencies¹¹ of marked reduction of IgG and IgA or IgM plus onset after 2 years of age, recurrent infections, and defective vaccination response. Additional complications including autoimmunity, malignancy, and granulomatous inflammation were extensively ruled out.

The etiology of SS is unknown and its pathogenesis not fully elucidated, though it is presumed to be a hypersensitivity reaction.¹² Sweet syndrome can be classified into 3 major subtypes: classical or idiopathic, malignancy associated, or drug induced.³ Our patient’s presentation is consistent with the classical variant, as malignancy was ruled out and the patient was not on any medication other than IVIG at the time of diagnosis. The treatment of SS consists of systemic steroids, initially high dose followed by a prolonged taper over 4 to 6 weeks.³ This treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and decreased synthesis during and for a variable time after drug administration.¹³ In refractory cases, intravenous pulse administration of methylprednisolone sodium succinate for 3 to 5 days may enhance the response to standard therapies.⁵

The concurrent development of neutrophilic dermatoses/SS in an individual with CVID has not been fully described. There is a credible association of SS with infections, inflammatory bowel disease, pregnancy, malignancy, and medications, as well as a possible association with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease.⁵ The association between immunoglobulin deficiencies and SS is markedly unusual. Despite regular IVIG replacement, adequate treatment of CVID did not seem to modulate SS flares in our patient. A case report in a pediatric patient does not provide specific guidance regarding treatment options.⁸

A particularly challenging aspect of our case was tailoring a treatment regimen to suppress SS flares. We have attained partial response to the refractory cutaneous lesions (decreased frequency and amplitude of outbreaks) with IVIG replacement 200 g every 4 weeks in combination with metronomic cyclophosphamide 50 mg daily (use of a repetitive, low-dose daily chemotherapy regimen to minimize side effects). Intermittent SS flares were managed acutely with pulse high-dose steroids. We report a case of SS with CVID, raising the plausibility of correlated pathogenesis. However, the exact mechanisms remain undefined.

Facial symmetry plays a role in attractiveness, but a small degree of asymmetry is normal and more common than symmetry. Mild asymmetry has been noted in the general population, even in the absence of pathology such as trauma or craniosynostosis.^1,2 Asymmetry may be static or dynamic and is thought to arise from a multitude of developmental factors, including skeletal, neurologic, and soft tissue changes, as well as photoaging.^3-5 Cosmetic and reconstructive surgical procedures strive to achieve facial symmetry. Patients often are unaware of their preexisting facial asymmetry.⁶ Anecdotally, we have found patients tend to be more cognizant of preexisting facial asymmetry following a notable change in facial appearance (eg, surgery). In counseling patients who are considering reconstructive or cosmetic surgery, it is beneficial to identify any preexisting facial asymmetries and discuss if they are within normal limits. The current literature, however, lacks thresholds for what is considered normal in many cases. In this study, we reviewed 100 faces without unilateral or orbital pathology or diplopia to describe the occurrence of facial asymmetries, including larger hemiface and hemiface with greater excursion of motion upon smiling (interpreted to signify stronger seventh cranial nerve), hemiface with more rhytides at rest, higher globe, higher earlobe, and higher lip.

Methods

One hundred oculofacial surgery patients without unilateral or orbital pathology or diplopia were included in this retrospective evaluation of static and dynamic facial asymmetry via facial photography (100 participants). Three graders were provided standard frontal and frontal smiling photographs with overlying facial grids to aid in assessing larger hemiface and hemiface with stronger seventh cranial nerve, which was judged in smiling photographs by assessing the excursion and the vector of motion; more rhytides at rest; higher globe; higher earlobe; and higher lip. Difference in globe height was measured relative to interpupillary distance (IPD) and recorded as the ratio of difference in globe height to IPD. The data were analyzed to see if there were any correlations among the 6 variables. This study was approved by the Duke University Health System (Durham, North Carolina) institutional review board.

Results

One hundred photographs were analyzed including 82 women aged 42 to 85 years and 18 men aged 22 to 88 years (overall average age, 61.64 years). The average difference in globe height was 1.2% of IPD; the maximum was 4.4% of IPD. The difference in globe height was verified by 3 graders via 2 different methods. Fifty-four patients were found to have a larger right hemiface, 36 had a larger left hemiface, and 10 had symmetrically sized hemifaces. Nearly half of patients were judged to have greater seventh cranial nerve action on the left (n=47), approximately one-quarter had greater action on the right (n=28), and another quarter were judged to have equal action (n=25). Most patients had static facial asymmetry; 72 had rhytides more pronounced on one hemiface compared to the other, 79 with a difference in globe height, and 68 with a difference in lip height. In approximately 40% of photographs, the graders were unable to judge earlobe height difference; therefore, this data was not analyzed. There was no correlation among the 6 variables.

Discussion

Facial asymmetry has long been a topic of interest in the plastic and reconstructive surgery fields. Ercan et al⁷ used statistical shape analysis to study facial asymmetry in young healthy subjects and found the left hemiface to be larger than the right hemiface in both sexes. Smith⁴ evaluated facial asymmetry in healthy college students and found the left hemiface to be larger in males and the right hemiface to be larger in females. Our group was predominantly female, but we found the right hemiface to be larger in both females and males, similar to the findings of Lepich et al.⁸

We also found that most patients had static and dynamic facial asymmetry despite no known unilateral pathology. The present literature lacks normative values to help determine what degree of asymmetry should be considered pathologic. Vertical orbital dystopia is defined as an inequality in the horizontal levels of the whole orbits.⁹ It has been hypothesized that most vertical dystopia is caused by congenital malformations, but no threshold has been set for the difference in height that qualifies as dystopia.¹⁰ Regarding the difference we found in globe height relative to IPD, if one takes the mean IPD of 63.36 mm (based on a study of 3976 American adults aged 17–51 years)¹¹ and makes the assumption that our patients have this IPD, then one can extrapolate that on average there was a difference of 0.76 mm between the 2 globe heights. Likewise, nearly all patients (n=96) had less than a 2-mm difference (21 had symmetric globe heights, 46 had a difference in globe height of <1 mm, and 29 had a difference of >1 mm and <2 mm). Four patients had a difference greater than 2 mm, with the largest difference being 2.75 mm. A limitation of this retrospective study is the need to extrapolate these distances, as our patients were not photographed with rulers.

Hafezi et al¹² looked at the facial asymmetry in patients without history of trauma or nasal fracture who were seeking rhinoplasty. They noted vertical orbital dystopia in this patient population, but the degree of dystopia was not quantified.¹² We believe our data highlight the importance of counseling patients about preexisting facial asymmetry with normative values in mind. Patients may be dissatisfied by new or preexisting asymmetry following surgery, even if such asymmetries are less objectively apparent than in the patient’s preoperative appearance. Even when patients are already acutely aware of their facial asymmetries, they should learn that facial asymmetries, to varying degrees, are natural and not necessarily unattractive. In fact, a 2006 study of ocular adnexal asymmetry in 102 models with magazine photograph analysis found small amounts of asymmetry to be the norm. Specifically, the authors found an average difference in globe height of 1.2 mm, slightly greater than the average found among our patients.¹³ Our data will help to establish normative values for asymmetry in normal faces.

Facial symmetry plays a role in attractiveness, but a small degree of asymmetry is normal and more common than symmetry. Mild asymmetry has been noted in the general population, even in the absence of pathology such as trauma or craniosynostosis.^1,2 Asymmetry may be static or dynamic and is thought to arise from a multitude of developmental factors, including skeletal, neurologic, and soft tissue changes, as well as photoaging.^3-5 Cosmetic and reconstructive surgical procedures strive to achieve facial symmetry. Patients often are unaware of their preexisting facial asymmetry.⁶ Anecdotally, we have found patients tend to be more cognizant of preexisting facial asymmetry following a notable change in facial appearance (eg, surgery). In counseling patients who are considering reconstructive or cosmetic surgery, it is beneficial to identify any preexisting facial asymmetries and discuss if they are within normal limits. The current literature, however, lacks thresholds for what is considered normal in many cases. In this study, we reviewed 100 faces without unilateral or orbital pathology or diplopia to describe the occurrence of facial asymmetries, including larger hemiface and hemiface with greater excursion of motion upon smiling (interpreted to signify stronger seventh cranial nerve), hemiface with more rhytides at rest, higher globe, higher earlobe, and higher lip.

Methods

One hundred oculofacial surgery patients without unilateral or orbital pathology or diplopia were included in this retrospective evaluation of static and dynamic facial asymmetry via facial photography (100 participants). Three graders were provided standard frontal and frontal smiling photographs with overlying facial grids to aid in assessing larger hemiface and hemiface with stronger seventh cranial nerve, which was judged in smiling photographs by assessing the excursion and the vector of motion; more rhytides at rest; higher globe; higher earlobe; and higher lip. Difference in globe height was measured relative to interpupillary distance (IPD) and recorded as the ratio of difference in globe height to IPD. The data were analyzed to see if there were any correlations among the 6 variables. This study was approved by the Duke University Health System (Durham, North Carolina) institutional review board.

Results

One hundred photographs were analyzed including 82 women aged 42 to 85 years and 18 men aged 22 to 88 years (overall average age, 61.64 years). The average difference in globe height was 1.2% of IPD; the maximum was 4.4% of IPD. The difference in globe height was verified by 3 graders via 2 different methods. Fifty-four patients were found to have a larger right hemiface, 36 had a larger left hemiface, and 10 had symmetrically sized hemifaces. Nearly half of patients were judged to have greater seventh cranial nerve action on the left (n=47), approximately one-quarter had greater action on the right (n=28), and another quarter were judged to have equal action (n=25). Most patients had static facial asymmetry; 72 had rhytides more pronounced on one hemiface compared to the other, 79 with a difference in globe height, and 68 with a difference in lip height. In approximately 40% of photographs, the graders were unable to judge earlobe height difference; therefore, this data was not analyzed. There was no correlation among the 6 variables.

Discussion

Facial asymmetry has long been a topic of interest in the plastic and reconstructive surgery fields. Ercan et al⁷ used statistical shape analysis to study facial asymmetry in young healthy subjects and found the left hemiface to be larger than the right hemiface in both sexes. Smith⁴ evaluated facial asymmetry in healthy college students and found the left hemiface to be larger in males and the right hemiface to be larger in females. Our group was predominantly female, but we found the right hemiface to be larger in both females and males, similar to the findings of Lepich et al.⁸

We also found that most patients had static and dynamic facial asymmetry despite no known unilateral pathology. The present literature lacks normative values to help determine what degree of asymmetry should be considered pathologic. Vertical orbital dystopia is defined as an inequality in the horizontal levels of the whole orbits.⁹ It has been hypothesized that most vertical dystopia is caused by congenital malformations, but no threshold has been set for the difference in height that qualifies as dystopia.¹⁰ Regarding the difference we found in globe height relative to IPD, if one takes the mean IPD of 63.36 mm (based on a study of 3976 American adults aged 17–51 years)¹¹ and makes the assumption that our patients have this IPD, then one can extrapolate that on average there was a difference of 0.76 mm between the 2 globe heights. Likewise, nearly all patients (n=96) had less than a 2-mm difference (21 had symmetric globe heights, 46 had a difference in globe height of <1 mm, and 29 had a difference of >1 mm and <2 mm). Four patients had a difference greater than 2 mm, with the largest difference being 2.75 mm. A limitation of this retrospective study is the need to extrapolate these distances, as our patients were not photographed with rulers.

Hafezi et al¹² looked at the facial asymmetry in patients without history of trauma or nasal fracture who were seeking rhinoplasty. They noted vertical orbital dystopia in this patient population, but the degree of dystopia was not quantified.¹² We believe our data highlight the importance of counseling patients about preexisting facial asymmetry with normative values in mind. Patients may be dissatisfied by new or preexisting asymmetry following surgery, even if such asymmetries are less objectively apparent than in the patient’s preoperative appearance. Even when patients are already acutely aware of their facial asymmetries, they should learn that facial asymmetries, to varying degrees, are natural and not necessarily unattractive. In fact, a 2006 study of ocular adnexal asymmetry in 102 models with magazine photograph analysis found small amounts of asymmetry to be the norm. Specifically, the authors found an average difference in globe height of 1.2 mm, slightly greater than the average found among our patients.¹³ Our data will help to establish normative values for asymmetry in normal faces.

Facial symmetry plays a role in attractiveness, but a small degree of asymmetry is normal and more common than symmetry. Mild asymmetry has been noted in the general population, even in the absence of pathology such as trauma or craniosynostosis.^1,2 Asymmetry may be static or dynamic and is thought to arise from a multitude of developmental factors, including skeletal, neurologic, and soft tissue changes, as well as photoaging.^3-5 Cosmetic and reconstructive surgical procedures strive to achieve facial symmetry. Patients often are unaware of their preexisting facial asymmetry.⁶ Anecdotally, we have found patients tend to be more cognizant of preexisting facial asymmetry following a notable change in facial appearance (eg, surgery). In counseling patients who are considering reconstructive or cosmetic surgery, it is beneficial to identify any preexisting facial asymmetries and discuss if they are within normal limits. The current literature, however, lacks thresholds for what is considered normal in many cases. In this study, we reviewed 100 faces without unilateral or orbital pathology or diplopia to describe the occurrence of facial asymmetries, including larger hemiface and hemiface with greater excursion of motion upon smiling (interpreted to signify stronger seventh cranial nerve), hemiface with more rhytides at rest, higher globe, higher earlobe, and higher lip.

Methods

One hundred oculofacial surgery patients without unilateral or orbital pathology or diplopia were included in this retrospective evaluation of static and dynamic facial asymmetry via facial photography (100 participants). Three graders were provided standard frontal and frontal smiling photographs with overlying facial grids to aid in assessing larger hemiface and hemiface with stronger seventh cranial nerve, which was judged in smiling photographs by assessing the excursion and the vector of motion; more rhytides at rest; higher globe; higher earlobe; and higher lip. Difference in globe height was measured relative to interpupillary distance (IPD) and recorded as the ratio of difference in globe height to IPD. The data were analyzed to see if there were any correlations among the 6 variables. This study was approved by the Duke University Health System (Durham, North Carolina) institutional review board.

Results

One hundred photographs were analyzed including 82 women aged 42 to 85 years and 18 men aged 22 to 88 years (overall average age, 61.64 years). The average difference in globe height was 1.2% of IPD; the maximum was 4.4% of IPD. The difference in globe height was verified by 3 graders via 2 different methods. Fifty-four patients were found to have a larger right hemiface, 36 had a larger left hemiface, and 10 had symmetrically sized hemifaces. Nearly half of patients were judged to have greater seventh cranial nerve action on the left (n=47), approximately one-quarter had greater action on the right (n=28), and another quarter were judged to have equal action (n=25). Most patients had static facial asymmetry; 72 had rhytides more pronounced on one hemiface compared to the other, 79 with a difference in globe height, and 68 with a difference in lip height. In approximately 40% of photographs, the graders were unable to judge earlobe height difference; therefore, this data was not analyzed. There was no correlation among the 6 variables.

Discussion

Facial asymmetry has long been a topic of interest in the plastic and reconstructive surgery fields. Ercan et al⁷ used statistical shape analysis to study facial asymmetry in young healthy subjects and found the left hemiface to be larger than the right hemiface in both sexes. Smith⁴ evaluated facial asymmetry in healthy college students and found the left hemiface to be larger in males and the right hemiface to be larger in females. Our group was predominantly female, but we found the right hemiface to be larger in both females and males, similar to the findings of Lepich et al.⁸

We also found that most patients had static and dynamic facial asymmetry despite no known unilateral pathology. The present literature lacks normative values to help determine what degree of asymmetry should be considered pathologic. Vertical orbital dystopia is defined as an inequality in the horizontal levels of the whole orbits.⁹ It has been hypothesized that most vertical dystopia is caused by congenital malformations, but no threshold has been set for the difference in height that qualifies as dystopia.¹⁰ Regarding the difference we found in globe height relative to IPD, if one takes the mean IPD of 63.36 mm (based on a study of 3976 American adults aged 17–51 years)¹¹ and makes the assumption that our patients have this IPD, then one can extrapolate that on average there was a difference of 0.76 mm between the 2 globe heights. Likewise, nearly all patients (n=96) had less than a 2-mm difference (21 had symmetric globe heights, 46 had a difference in globe height of <1 mm, and 29 had a difference of >1 mm and <2 mm). Four patients had a difference greater than 2 mm, with the largest difference being 2.75 mm. A limitation of this retrospective study is the need to extrapolate these distances, as our patients were not photographed with rulers.

Hafezi et al¹² looked at the facial asymmetry in patients without history of trauma or nasal fracture who were seeking rhinoplasty. They noted vertical orbital dystopia in this patient population, but the degree of dystopia was not quantified.¹² We believe our data highlight the importance of counseling patients about preexisting facial asymmetry with normative values in mind. Patients may be dissatisfied by new or preexisting asymmetry following surgery, even if such asymmetries are less objectively apparent than in the patient’s preoperative appearance. Even when patients are already acutely aware of their facial asymmetries, they should learn that facial asymmetries, to varying degrees, are natural and not necessarily unattractive. In fact, a 2006 study of ocular adnexal asymmetry in 102 models with magazine photograph analysis found small amounts of asymmetry to be the norm. Specifically, the authors found an average difference in globe height of 1.2 mm, slightly greater than the average found among our patients.¹³ Our data will help to establish normative values for asymmetry in normal faces.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 19-year-old man first presented to our outpatient dermatology clinic for evaluation of a rash on the elbows and knees of 2 to 3 months’ duration. The lesions were asymptomatic. A review of symptoms including joint pain was largely negative. His medical history was remarkable for terminal ileitis, Crohn disease, anal fissure, rhabdomyolysis, and viral gastroenteritis. Physical examination revealed a well-nourished man with red, scaly, indurated papules and plaques involving approximately 0.5% of the body surface area. A diagnosis of plaque psoriasis was made, and he was treated with topical corticosteroids for 2 weeks and as needed thereafter.

The patient remained stable for 5 years before presenting again to the dermatology clinic for psoriasis that had now spread to the scalp. Clinical examination revealed a very thin, faintly erythematous, scaly patch associated with increased hair density of the right frontal and parietal scalp (Figure). The patient denied any trauma or injury to the area or application of hair dye. We prescribed clobetasol solution 0.05% twice daily to the affected area of the scalp for 2 weeks, which resulted in minimal resolution of the psoriatic scalp lesion.

Comment

The scalp is a site of predilection in psoriasis, as approximately 80% of psoriasis patients report involvement of the scalp.¹ Scalp involvement can dramatically affect a patient’s quality of life and often poses considerable therapeutic challenges for dermatologists.¹ Alopecia in the setting of scalp psoriasis is common but is not well understood.² First described by Shuster³ in 1972, psoriatic alopecia is associated with diminished hair density, follicular miniaturization, sebaceous gland atrophy, and an increased number of dystrophic bulbs in psoriatic plaques.⁴ It clinically presents as pink scaly plaques consistent with psoriasis with overlying alopecia. There are few instances of psoriatic alopecia reported as cicatricial hair loss and generalized telogen effluvium.² It is known that a higher proportion of telogen and catagen hairs exist in patients with psoriatic alopecia.⁵ Additionally, psoriasis patients have more dystrophic hairs in affected and unaffected skin despite no differences in skin when compared to unaffected patients. Many patients achieve hair regrowth following treatment of psoriasis.²

We described a patient with scalp psoriasis who had increased and preserved hair density. Our case suggests that while most patients with scalp psoriasis experience psoriatic alopecia of the lesional skin, some may unconventionally experience increased hair density, which is contradictory to propositions that the friction associated with the application of topical treatments results in breakage of telogen hairs.² Additionally, the presence of increased hair density in scalp psoriasis can further complicate antipsoriatic treatment by making the scalp inaccessible and topical therapies even more difficult to apply.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Case Report

A 60-year-old man with a history of Hodgkin lymphoma that had been treated with chemotherapy 6 years prior presented to our dermatology clinic with a persistent pruritic rash on the back, abdomen, and bilateral arms and legs. The eruption initially began as localized discrete lesions on the lower back 1 year prior to the current presentation; at that time a diagnosis of psoriasis was made at an outside dermatology clinic, and treatment with mometasone furoate cream was initiated. Despite the patient’s compliance with this treatment, the lesions did not resolve and began spreading to the arms, legs, chest, and abdomen. His current medications included lisinopril, escitalopram, aspirin, and omeprazole.

On presentation to our clinic, physical examination revealed round, scaly, pink plaques and tumors of variable sizes (3–10 cm) distributed asymmetrically on the chest, back, abdomen, arms, and legs (Figure 1). The lesions were grouped in well-defined areas encompassing approximately 30% of the body surface area. No lymphadenopathy was appreciated. In vivo reflectance confocal microscopy (RCM) performed on one of the lesions revealed disarray of the epidermis with small, weakly refractile, round to oval cells scattered within the spinous layer and dermoepidermal junction (Figure 2). Additionally, these weakly refractile, round to oval cells also were seen in vesiclelike dark spaces, and hyporefractile basal cells were appreciated surrounding the dermal papillae. Mycosis fungoides (MF) was diagnosed following correlation of the RCM findings with the clinical picture.

A biopsy was performed, with pathologic examination confirming the diagnosis of tumor-stage MF. Parakeratosis with epidermotropism of lymphocytes was noted along the basal layer and into the spinous layer of the epidermis (Figure 3). Underlying the epidermis there was a dense mononuclear infiltrate and conspicuous eosinophils extending to the deeper reticular dermis. The infiltrating cells had cerebriform nuclei and large pale cytoplasm. On immunostaining, the lymphocytes were positive for CD3 and CD4, and negative for CD5, CD7, and CD8. The patient was referred to the oncology department for disease management. Staging workup including computed tomography, flow cytometry, and T-cell receptor gene rearrangement were consistent with tumor-stage MF (T3N0M0B0).

Comment

Clinical Presentation of MF
Mycosis fungoides, a non-Hodgkin lymphoma of T-cell origin, is the most commonly diagnosed cutaneous lymphoma worldwide.¹ It has an annual incidence of approximately 0.36 per 100,000 persons, and this number continues to rise.^2,3 The median age of diagnosis is 55 to 60 years, and MF occurs twice as often in men versus women.⁴

The clinical presentation of MF varies and is classified by stages including patches, plaques, tumors, and erythroderma.⁵ Classically, MF is slowly progressive and begins as pruritic erythematous patches that have a predilection for non–sun-exposed areas of the skin. Over time, these patches may evolve into plaques and tumors. Early or patch-stage MF often presents as well-demarcated lesions of various sizes and shapes that tend to enlarge.⁶ These lesions may resemble eczema or psoriasis if there is scaling, such as in our patient. At the tumor stage, flat or dome-shaped nodules that may vary in color and are deeper than plaques begin to appear. Ulcerations, which were absent in our case, may often be seen.

Because of the diverse clinical manifestations of MF, which can mimic other common dermatoses, diagnosis often is challenging for clinicians. Furthermore, histology can yield nonspecific diagnostic results and may even resemble chronic inflammatory dermatoses.⁷ As a result, patients frequently are subjected to multiple skin biopsies to establish the diagnosis,⁸ and diagnosis may be delayed, with the median time from onset of skin symptoms to diagnosis being approximately 6 years.⁹

Reflectance Confocal Microscopy
In vivo RCM is a noninvasive technique that allows visualization of the skin at a cellular level and recently has been evaluated as a diagnostic tool for many skin conditions.^10,11 Reflectance confocal microscopy findings have been well established for many cutaneous malignancies as well as inflammatory conditions such as psoriasis and atopic dermatitis.^12,13 Specifically, 2 preliminary descriptive studies utilized RCM to visualize the characteristic features of MF in vivo.^14,15 These studies reported the histopathologic correlation of RCM findings in biopsy-proven MF lesions. Consistent in all stages of MF is the presence of small, weakly refractile, round to oval cells within the spinous layer that correlate with atypical lymphocytes, in addition to hyporefractile basal cells surrounding the dermal papillae. Patch-stage MF lesions have more subtle epidermal findings compared to plaque-stage lesions, which tend to have more prominent vesiclelike dark spaces filled with collections of monomorphous, weakly refractile, round to oval cells corresponding with Pautrier microabscesses and evidence of spongiosis.^14,15 The first descriptive study of RCM in the diagnosis of MF failed to identify features of tumor-stage MF that would distinguish it from patch- or plaque-stage disease. The investigators also stated that deep nodular collections of atypical lymphocytes seen on histopathology in tumor-stage MF were missed on RCM evaluation.¹⁴ Furthermore, the second descriptive study of RCM and MF, which included 2 patients with tumor-stage disease, also failed to differentiate tumor-stage MF from the patch or plaque stages.¹⁵

Because of these 2 descriptive studies, a pilot study was conducted to determine the applicability and reproducibility of RCM findings for MF diagnosis.¹⁶ Two blinded confocalists were asked to diagnose RCM images as MF when compared to either normal skin or a variety of lymphoproliferative disorders. Of 15 patients, the confocalists correctly diagnosed MF in 84% and 90% of cases, respectively. Additionally, they reported the specificity and sensitivity of the following RCM features in the diagnosis of MF: spongiosis, 88.9% and 94.7%; loss of demarcation, 88.9% and 94.7%; disarray of the epidermis, 77.8% and 89.5%; hyporefractile rings, 88.9% and 78.9%; junctional atypical lymphocytes, 100% and 73.7%; and vesiclelike structures (Pautrier microabscesses), 100% and 73.7%. Importantly, this study did not evaluate the specificity and sensitivity of MF diagnosis compared to other eczematous or inflammatory conditions that may share similar RCM findings; therefore, these results are not generalizable, and many of the RCM findings characteristically seen in MF are not specific to its diagnosis.¹⁶

One study assessed the diagnostic accuracy of RCM in evaluating erythematosquamous diseases including MF, psoriasis, contact dermatitis, discoid lupus, and subacute cutaneous lupus.¹⁷ In this study, 3 blinded confocalists achieved a 95.41% and 92.89% specificity and 89.13% and 63.33% sensitivity for psoriasis and MF, respectively. Typical features of psoriasis on RCM included parakeratosis, reduction or absence of the granular layer, papillomatosis, acanthosis with normal honeycomb pattern of the epidermis, and dilated vessels in the upper dermis. Features that were more specific to MF included epidermotropic atypical lymphocytes, interface dermatitis, pleomorphic tumor cells, and dendritic cells.¹⁷ However, atypical lymphocytes and interface dermatitis also may be seen in cutaneous lupus; therefore, additional studies are still needed to validate RCM’s utility in differentiating between erythematosquamous skin diseases, including psoriasis, cutaneous lupus, and MF. Currently, RCM findings must be interpreted in conjunction with the clinical and histologic picture.

Importantly, RCM also is limited when evaluating MF due to its limited depth of visualization, as it allows imaging only to the superficial papillary dermis. Furthermore, any infiltrative process such as epidermal hyperplasia, spongiosis, or scaling, which can be seen in MF, may further impair the imaging quality of the deeper dermis.

Conclusion

Despite its limitations, RCM has the potential to be advantageous in evaluating skin lesions suspicious for MF in real time and is a promising technology for a quick noninvasive bedside adjunct tool. Its utility in selecting the optimal site for biopsy for better yield of histopathologic results in suspected MF cases has been demonstrated.¹⁶ However, large-scale studies still are needed to evaluate RCM in the diagnosis of the wide diversity of MF lesions as well as its efficacy in selecting optimal biopsy sites.

Vitamin D receptors are found in every cell of the body and have been shown to play a role in bone, neural, and cardiovascular health; immune regulation; and possibly cancer prevention via the regulation of cell differentiation, proliferation, and apoptosis.¹ Although it is controversial, vitamin D deficiency has been associated with various forms of nonscarring hair loss,^2-4 including telogen effluvium, androgenetic alopecia, and alopecia areata. We describe a notable case of nonscarring alopecia associated with vitamin D deficiency in which vitamin D replacement therapy promoted hair regrowth.

Case Report

An otherwise healthy 34-year-old black woman presented to the Hair and Nail Clinic at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) for evaluation of progressive hair loss of 4 years’ duration that began shortly after her fourth child was born. Although she denied any history of excessive shedding, she stated that she used to have shoulder-length hair and somehow it had become extremely short without shaving or cutting the hair (Figure 1). Her current medications included a progestin intrauterine device and biotin 10 mg once daily, the latter of which she had taken for several months for the hair loss without any improvement.

On physical examination, the patient was noted to have diffusely thinning, short, brittle hair. Trichoscopy was notable for hairs of varying diameters, with some fractured at the level of the follicular ostia but no yellow dots at the follicular openings or exclamation point hairs. No scarring or erythema was seen on the scalp. The patient refused several of our team’s recommendations for scalp biopsy due to needle phobia. A hair growth window was made that showed good regrowth at 2 weeks after the initial presentation. Initial blood work revealed a total serum 25-hydroxyvitamin D level of 12 ng/mL (optimal, >30 ng/mL). Complete blood cell count, hormonal panel, zinc level, iron level, and thyroid studies were all normal.

The patient was started on vitamin D₃ replacement therapy 50,000 IU once weekly for 4 weeks followed by 1000 IU once daily for 6 months. No other topical or systemic treatments were administered for the nonscarring alopecia. At a follow-up visit 6 months later, the patient’s vitamin D level was 36 ng/mL, and she had noticeable hair regrowth (Figure 2). At this time, the diagnosis of nonscarring alopecia associated with vitamin D deficiency was made.

Comment

Vitamin D is a fat-soluble vitamin that can be obtained via sun exposure, food sources (eg, fish, vitamin D–fortified foods), and direct supplementation.⁵ It has been estimated that nearly 1 billion individuals worldwide⁶ and approximately 41.6% of US adults are vitamin D deficient.⁷ Certainly not all of these individuals will present with alopecia, but in patients with hair loss, we suggest that vitamin D deficiency is an important factor to consider. Risk factors for vitamin D deficiency include older age, obesity, darker skin types, residence in northern latitudes, and malabsorption syndromes.⁷

Pathogenesis
Vitamin D is thought to play a role in the normal initiation and completion of the hair cycle as well as the differentiation of the follicular and interfollicular epidermis. The vitamin D receptor (VDR) is thought to induce the development of mature anagen hairs via the canonical WNT-β-catenin and hedgehog signaling pathways.⁸ In the absence of VDRs, the stem cells in the bulge of the hair follicle have an impaired ability to replicate, and as a result, VDR-deficient mice have shown near-total hair loss.^9-12 We propose that vitamin D deficiency can not only be a trigger for hair loss but also can perpetuate hair loss and poor regrowth.

Diagnosis and Prevention of Vitamin D Deficiency
In the skin, 7-dehydrocholesterol is converted to previtamin D₃ via UVB light, followed by subsequent conversion to vitamin D₃. Dietary sources are in the form of either vitamin D₂ or D₃, both of which are converted in the liver to 25-hydroxyvitamin D, the major circulating metabolite. In the kidneys, 25-hydroxyvitamin D is then converted to 1,25-dihydroxyvitamin D, the biologically active form. Paradoxically, serum levels of 1,25-dihydroxyvitamin D can be normal or high in the setting of vitamin D deficiency; therefore, serum total 25-hydroxyvitamin D is the best way to assess a patient’s vitamin D status.^5,13

The optimal serum 25-hydroxyvitamin D level is controversial. Recommendations range between 20 to 40 ng/mL¹⁴ and 30 to 50 ng/mL.^13,15,16 Vitamin D levels higher than 50 ng/mL have been correlated with an increased risk of bone fractures and certain cancers.^16-18 Vitamin D toxicity usually is noted in serum levels greater than 88 ng/mL; symptoms of toxicity include hypercalcemia, nausea, vomiting, and muscle weakness. For nondeficient patients, the National Academy of Medicine (formerly the Institute of Medicine) recommended an upper limit of 4000 IU daily.¹⁴ The optimal dose in preventing vitamin D deficiency ranges from 600 to 1000 IU daily.^13-15

Treatment of Vitamin D Deficiency
In the setting of vitamin D deficiency, the amount required for repletion often is dependent on each individual’s ability to absorb and convert to 25-hydroxyvitamin D. Typically every 100 IU of vitamin D correlates with a 0.7 to 1.0 ng/mL increase in serum 25-hydroxyvitamin D levels.¹⁹ There are multiple dosing regimens used to achieve the desired serum 25-hydroxyvitamin D levels in deficient patients. One recommendation from the Endocrine Society is 50,000 IU once weekly for 6 to 8 weeks (single doses >50,000 IU typically are not recommended due to increased risk for toxicity), followed by 600 to 1000 IU once daily in children and 1500 to 2000 IU once daily in adults thereafter.¹³ In patients with vitamin D deficiency, reassessment of serum 25-hydroxyvitamin D levels is recommended after 3 to 4 months of treatment, and adjustments to the repletion regimen should be made as needed.^15,16 Generally, vitamin D₃ is recommended over vitamin D₂ due to enhanced efficacy in raising serum 25-hydroxyvitamin D levels.²⁰

Vitamin D Deficiency in Alopecia
Although most recommendations are given in the interest of optimizing bone health, in the setting of alopecia, we set a similar serum 25-hydroxyvitamin D goal of greater than 30 ng/mL. We recommend treatment with vitamin D₃ and practice the following repletion protocol: 50,000 IU once weekly for 4 weeks, followed by 1000 IU once daily for at least 8 weeks for serum 25-hydroxyvitamin D levels less than 20 ng/mL. For serum hydroxyvitamin D levels between 20 and 29 ng/mL, we recommend 1000 IU once daily for at least 12 weeks. We recheck blood levels again in 3 months. If levels fail to normalize, we will refer the patient to endocrinology. If levels return to normal, we transition to a daily multivitamin with vitamin D (400–800 IU) once daily and refer the patient back to the primary care physician for long-term monitoring.

Vitamin D receptors are found in every cell of the body and have been shown to play a role in bone, neural, and cardiovascular health; immune regulation; and possibly cancer prevention via the regulation of cell differentiation, proliferation, and apoptosis.¹ Although it is controversial, vitamin D deficiency has been associated with various forms of nonscarring hair loss,^2-4 including telogen effluvium, androgenetic alopecia, and alopecia areata. We describe a notable case of nonscarring alopecia associated with vitamin D deficiency in which vitamin D replacement therapy promoted hair regrowth.

Case Report

An otherwise healthy 34-year-old black woman presented to the Hair and Nail Clinic at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) for evaluation of progressive hair loss of 4 years’ duration that began shortly after her fourth child was born. Although she denied any history of excessive shedding, she stated that she used to have shoulder-length hair and somehow it had become extremely short without shaving or cutting the hair (Figure 1). Her current medications included a progestin intrauterine device and biotin 10 mg once daily, the latter of which she had taken for several months for the hair loss without any improvement.

On physical examination, the patient was noted to have diffusely thinning, short, brittle hair. Trichoscopy was notable for hairs of varying diameters, with some fractured at the level of the follicular ostia but no yellow dots at the follicular openings or exclamation point hairs. No scarring or erythema was seen on the scalp. The patient refused several of our team’s recommendations for scalp biopsy due to needle phobia. A hair growth window was made that showed good regrowth at 2 weeks after the initial presentation. Initial blood work revealed a total serum 25-hydroxyvitamin D level of 12 ng/mL (optimal, >30 ng/mL). Complete blood cell count, hormonal panel, zinc level, iron level, and thyroid studies were all normal.

The patient was started on vitamin D₃ replacement therapy 50,000 IU once weekly for 4 weeks followed by 1000 IU once daily for 6 months. No other topical or systemic treatments were administered for the nonscarring alopecia. At a follow-up visit 6 months later, the patient’s vitamin D level was 36 ng/mL, and she had noticeable hair regrowth (Figure 2). At this time, the diagnosis of nonscarring alopecia associated with vitamin D deficiency was made.

Comment

Vitamin D is a fat-soluble vitamin that can be obtained via sun exposure, food sources (eg, fish, vitamin D–fortified foods), and direct supplementation.⁵ It has been estimated that nearly 1 billion individuals worldwide⁶ and approximately 41.6% of US adults are vitamin D deficient.⁷ Certainly not all of these individuals will present with alopecia, but in patients with hair loss, we suggest that vitamin D deficiency is an important factor to consider. Risk factors for vitamin D deficiency include older age, obesity, darker skin types, residence in northern latitudes, and malabsorption syndromes.⁷

Pathogenesis
Vitamin D is thought to play a role in the normal initiation and completion of the hair cycle as well as the differentiation of the follicular and interfollicular epidermis. The vitamin D receptor (VDR) is thought to induce the development of mature anagen hairs via the canonical WNT-β-catenin and hedgehog signaling pathways.⁸ In the absence of VDRs, the stem cells in the bulge of the hair follicle have an impaired ability to replicate, and as a result, VDR-deficient mice have shown near-total hair loss.^9-12 We propose that vitamin D deficiency can not only be a trigger for hair loss but also can perpetuate hair loss and poor regrowth.

Diagnosis and Prevention of Vitamin D Deficiency
In the skin, 7-dehydrocholesterol is converted to previtamin D₃ via UVB light, followed by subsequent conversion to vitamin D₃. Dietary sources are in the form of either vitamin D₂ or D₃, both of which are converted in the liver to 25-hydroxyvitamin D, the major circulating metabolite. In the kidneys, 25-hydroxyvitamin D is then converted to 1,25-dihydroxyvitamin D, the biologically active form. Paradoxically, serum levels of 1,25-dihydroxyvitamin D can be normal or high in the setting of vitamin D deficiency; therefore, serum total 25-hydroxyvitamin D is the best way to assess a patient’s vitamin D status.^5,13

The optimal serum 25-hydroxyvitamin D level is controversial. Recommendations range between 20 to 40 ng/mL¹⁴ and 30 to 50 ng/mL.^13,15,16 Vitamin D levels higher than 50 ng/mL have been correlated with an increased risk of bone fractures and certain cancers.^16-18 Vitamin D toxicity usually is noted in serum levels greater than 88 ng/mL; symptoms of toxicity include hypercalcemia, nausea, vomiting, and muscle weakness. For nondeficient patients, the National Academy of Medicine (formerly the Institute of Medicine) recommended an upper limit of 4000 IU daily.¹⁴ The optimal dose in preventing vitamin D deficiency ranges from 600 to 1000 IU daily.^13-15

Treatment of Vitamin D Deficiency
In the setting of vitamin D deficiency, the amount required for repletion often is dependent on each individual’s ability to absorb and convert to 25-hydroxyvitamin D. Typically every 100 IU of vitamin D correlates with a 0.7 to 1.0 ng/mL increase in serum 25-hydroxyvitamin D levels.¹⁹ There are multiple dosing regimens used to achieve the desired serum 25-hydroxyvitamin D levels in deficient patients. One recommendation from the Endocrine Society is 50,000 IU once weekly for 6 to 8 weeks (single doses >50,000 IU typically are not recommended due to increased risk for toxicity), followed by 600 to 1000 IU once daily in children and 1500 to 2000 IU once daily in adults thereafter.¹³ In patients with vitamin D deficiency, reassessment of serum 25-hydroxyvitamin D levels is recommended after 3 to 4 months of treatment, and adjustments to the repletion regimen should be made as needed.^15,16 Generally, vitamin D₃ is recommended over vitamin D₂ due to enhanced efficacy in raising serum 25-hydroxyvitamin D levels.²⁰

Vitamin D Deficiency in Alopecia
Although most recommendations are given in the interest of optimizing bone health, in the setting of alopecia, we set a similar serum 25-hydroxyvitamin D goal of greater than 30 ng/mL. We recommend treatment with vitamin D₃ and practice the following repletion protocol: 50,000 IU once weekly for 4 weeks, followed by 1000 IU once daily for at least 8 weeks for serum 25-hydroxyvitamin D levels less than 20 ng/mL. For serum hydroxyvitamin D levels between 20 and 29 ng/mL, we recommend 1000 IU once daily for at least 12 weeks. We recheck blood levels again in 3 months. If levels fail to normalize, we will refer the patient to endocrinology. If levels return to normal, we transition to a daily multivitamin with vitamin D (400–800 IU) once daily and refer the patient back to the primary care physician for long-term monitoring.

Vitamin D receptors are found in every cell of the body and have been shown to play a role in bone, neural, and cardiovascular health; immune regulation; and possibly cancer prevention via the regulation of cell differentiation, proliferation, and apoptosis.¹ Although it is controversial, vitamin D deficiency has been associated with various forms of nonscarring hair loss,^2-4 including telogen effluvium, androgenetic alopecia, and alopecia areata. We describe a notable case of nonscarring alopecia associated with vitamin D deficiency in which vitamin D replacement therapy promoted hair regrowth.

Case Report

An otherwise healthy 34-year-old black woman presented to the Hair and Nail Clinic at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) for evaluation of progressive hair loss of 4 years’ duration that began shortly after her fourth child was born. Although she denied any history of excessive shedding, she stated that she used to have shoulder-length hair and somehow it had become extremely short without shaving or cutting the hair (Figure 1). Her current medications included a progestin intrauterine device and biotin 10 mg once daily, the latter of which she had taken for several months for the hair loss without any improvement.

On physical examination, the patient was noted to have diffusely thinning, short, brittle hair. Trichoscopy was notable for hairs of varying diameters, with some fractured at the level of the follicular ostia but no yellow dots at the follicular openings or exclamation point hairs. No scarring or erythema was seen on the scalp. The patient refused several of our team’s recommendations for scalp biopsy due to needle phobia. A hair growth window was made that showed good regrowth at 2 weeks after the initial presentation. Initial blood work revealed a total serum 25-hydroxyvitamin D level of 12 ng/mL (optimal, >30 ng/mL). Complete blood cell count, hormonal panel, zinc level, iron level, and thyroid studies were all normal.

The patient was started on vitamin D₃ replacement therapy 50,000 IU once weekly for 4 weeks followed by 1000 IU once daily for 6 months. No other topical or systemic treatments were administered for the nonscarring alopecia. At a follow-up visit 6 months later, the patient’s vitamin D level was 36 ng/mL, and she had noticeable hair regrowth (Figure 2). At this time, the diagnosis of nonscarring alopecia associated with vitamin D deficiency was made.

Comment

Vitamin D is a fat-soluble vitamin that can be obtained via sun exposure, food sources (eg, fish, vitamin D–fortified foods), and direct supplementation.⁵ It has been estimated that nearly 1 billion individuals worldwide⁶ and approximately 41.6% of US adults are vitamin D deficient.⁷ Certainly not all of these individuals will present with alopecia, but in patients with hair loss, we suggest that vitamin D deficiency is an important factor to consider. Risk factors for vitamin D deficiency include older age, obesity, darker skin types, residence in northern latitudes, and malabsorption syndromes.⁷

Pathogenesis
Vitamin D is thought to play a role in the normal initiation and completion of the hair cycle as well as the differentiation of the follicular and interfollicular epidermis. The vitamin D receptor (VDR) is thought to induce the development of mature anagen hairs via the canonical WNT-β-catenin and hedgehog signaling pathways.⁸ In the absence of VDRs, the stem cells in the bulge of the hair follicle have an impaired ability to replicate, and as a result, VDR-deficient mice have shown near-total hair loss.^9-12 We propose that vitamin D deficiency can not only be a trigger for hair loss but also can perpetuate hair loss and poor regrowth.

Diagnosis and Prevention of Vitamin D Deficiency
In the skin, 7-dehydrocholesterol is converted to previtamin D₃ via UVB light, followed by subsequent conversion to vitamin D₃. Dietary sources are in the form of either vitamin D₂ or D₃, both of which are converted in the liver to 25-hydroxyvitamin D, the major circulating metabolite. In the kidneys, 25-hydroxyvitamin D is then converted to 1,25-dihydroxyvitamin D, the biologically active form. Paradoxically, serum levels of 1,25-dihydroxyvitamin D can be normal or high in the setting of vitamin D deficiency; therefore, serum total 25-hydroxyvitamin D is the best way to assess a patient’s vitamin D status.^5,13

The optimal serum 25-hydroxyvitamin D level is controversial. Recommendations range between 20 to 40 ng/mL¹⁴ and 30 to 50 ng/mL.^13,15,16 Vitamin D levels higher than 50 ng/mL have been correlated with an increased risk of bone fractures and certain cancers.^16-18 Vitamin D toxicity usually is noted in serum levels greater than 88 ng/mL; symptoms of toxicity include hypercalcemia, nausea, vomiting, and muscle weakness. For nondeficient patients, the National Academy of Medicine (formerly the Institute of Medicine) recommended an upper limit of 4000 IU daily.¹⁴ The optimal dose in preventing vitamin D deficiency ranges from 600 to 1000 IU daily.^13-15

Treatment of Vitamin D Deficiency
In the setting of vitamin D deficiency, the amount required for repletion often is dependent on each individual’s ability to absorb and convert to 25-hydroxyvitamin D. Typically every 100 IU of vitamin D correlates with a 0.7 to 1.0 ng/mL increase in serum 25-hydroxyvitamin D levels.¹⁹ There are multiple dosing regimens used to achieve the desired serum 25-hydroxyvitamin D levels in deficient patients. One recommendation from the Endocrine Society is 50,000 IU once weekly for 6 to 8 weeks (single doses >50,000 IU typically are not recommended due to increased risk for toxicity), followed by 600 to 1000 IU once daily in children and 1500 to 2000 IU once daily in adults thereafter.¹³ In patients with vitamin D deficiency, reassessment of serum 25-hydroxyvitamin D levels is recommended after 3 to 4 months of treatment, and adjustments to the repletion regimen should be made as needed.^15,16 Generally, vitamin D₃ is recommended over vitamin D₂ due to enhanced efficacy in raising serum 25-hydroxyvitamin D levels.²⁰

Vitamin D Deficiency in Alopecia
Although most recommendations are given in the interest of optimizing bone health, in the setting of alopecia, we set a similar serum 25-hydroxyvitamin D goal of greater than 30 ng/mL. We recommend treatment with vitamin D₃ and practice the following repletion protocol: 50,000 IU once weekly for 4 weeks, followed by 1000 IU once daily for at least 8 weeks for serum 25-hydroxyvitamin D levels less than 20 ng/mL. For serum hydroxyvitamin D levels between 20 and 29 ng/mL, we recommend 1000 IU once daily for at least 12 weeks. We recheck blood levels again in 3 months. If levels fail to normalize, we will refer the patient to endocrinology. If levels return to normal, we transition to a daily multivitamin with vitamin D (400–800 IU) once daily and refer the patient back to the primary care physician for long-term monitoring.

Social media has become a prominent source of medical information for patients, including those with dermatologic conditions.^1,2 Physicians, patients, and pharmaceutical companies can use social media platforms to communicate with each other and share knowledge and advertisements related to conditions. Social media can influence patients’ perceptions of their disease and serve as a modality to acquire medical treatments.³ Furthermore, social media posts from illicit pharmacies can result in patients buying harmful medications without physician oversight.^4,5 Examination of the content and sources of social media posts related to acne may be useful in determining those who are primarily utilizing social media and for what purpose. The goal of this systematic review was to identify sources of acne-related social media posts to determine communication trends to gain a better understanding of the potential impact social media may have on patient care.

Methods

Social media posts were identified (May 2008 to May 2016) using the search terms acne and treatment across all social media platforms available through a commercial social media data aggregating software (Crimson Hexagon). Information from relevant posts was extracted and compiled into a spreadsheet that included the content, post date, social media platform, and hyperlink. To further analyze the data, the first 100 posts on acne treatment from May 2008 to May 2016 were selected and manually classified by the following types of communication: (1) patient-to-patient (eg, testimonies of patients’ medical experiences); (2) professional-to-patient (eg, clinical knowledge or experience provided by a medical provider and/or cited article in reference to relevant treatments); (3) pharmaceutical company–to-patient (eg, information from reputable drug manufacturers regarding drug activity and adverse effects); (4) illicit pharmacy–to-patient (eg, pharmacies with advertisements calling patients to buy a drug online or offering discrete shipping without a prescription)^4,5; or (5) other-to-patient (eg, posts that did not contain enough detail to be classified).

Results

Hundreds of thousands of social media posts discussing acne treatment were identified over the 8-year study period (Figure 1). The social media data aggregator extracted posts from various blogs, website comment sections, and online forums, as well as major social media platforms (ie, Facebook, Twitter, Google+, Tumblr). The first 100 posts selected for further analysis included 0 from 2008, 6 from 2009, 36 from 2010, 15 from 2011, 7 from 2012, 8 from 2013, 12 from 2014, 11 from 2015, and 5 from 2016. From this sample, 65 posts were considered to have an illicit source; conversely, 18 posts were from patients and 7 posts were from pharmaceutical companies (Figure 2).

Comment

This study demonstrated that discussion of acne treatment is prevalent in social media. Although our research underrepresents the social media interest in specific acne treatments, as only posts mentioning the terms acne and treatment were evaluated to gain insights into how social media platforms are being used by individuals with cutaneous disease. As such, even with this potential underrepresentation, our study demonstrated a high incidence of illicit marketing of prescription acne medications across multiple social media platforms (Figure 2). The sale of dermatologic pharmaceuticals (eg, isotretinoin) without a prescription is recognized by the US Government as a problem that is rapidly growing.^4,5 Illicit pharmacies pose as legitimate pharmacies that can provide prescription medications to consumers without a prescription.^5,6 The fact that these illicit pharmacy–to-patient posts were the most abundant in our study may speak to their relative success on social media platforms in encouraging patients to purchase prescription medications without physician oversight. These findings should concern health care providers, as the procurement of prescription medications without a prescription may put patients at risk.

Social media has become a prominent source of medical information for patients, including those with dermatologic conditions.^1,2 Physicians, patients, and pharmaceutical companies can use social media platforms to communicate with each other and share knowledge and advertisements related to conditions. Social media can influence patients’ perceptions of their disease and serve as a modality to acquire medical treatments.³ Furthermore, social media posts from illicit pharmacies can result in patients buying harmful medications without physician oversight.^4,5 Examination of the content and sources of social media posts related to acne may be useful in determining those who are primarily utilizing social media and for what purpose. The goal of this systematic review was to identify sources of acne-related social media posts to determine communication trends to gain a better understanding of the potential impact social media may have on patient care.

Methods

Social media posts were identified (May 2008 to May 2016) using the search terms acne and treatment across all social media platforms available through a commercial social media data aggregating software (Crimson Hexagon). Information from relevant posts was extracted and compiled into a spreadsheet that included the content, post date, social media platform, and hyperlink. To further analyze the data, the first 100 posts on acne treatment from May 2008 to May 2016 were selected and manually classified by the following types of communication: (1) patient-to-patient (eg, testimonies of patients’ medical experiences); (2) professional-to-patient (eg, clinical knowledge or experience provided by a medical provider and/or cited article in reference to relevant treatments); (3) pharmaceutical company–to-patient (eg, information from reputable drug manufacturers regarding drug activity and adverse effects); (4) illicit pharmacy–to-patient (eg, pharmacies with advertisements calling patients to buy a drug online or offering discrete shipping without a prescription)^4,5; or (5) other-to-patient (eg, posts that did not contain enough detail to be classified).

Results

Hundreds of thousands of social media posts discussing acne treatment were identified over the 8-year study period (Figure 1). The social media data aggregator extracted posts from various blogs, website comment sections, and online forums, as well as major social media platforms (ie, Facebook, Twitter, Google+, Tumblr). The first 100 posts selected for further analysis included 0 from 2008, 6 from 2009, 36 from 2010, 15 from 2011, 7 from 2012, 8 from 2013, 12 from 2014, 11 from 2015, and 5 from 2016. From this sample, 65 posts were considered to have an illicit source; conversely, 18 posts were from patients and 7 posts were from pharmaceutical companies (Figure 2).

Comment

This study demonstrated that discussion of acne treatment is prevalent in social media. Although our research underrepresents the social media interest in specific acne treatments, as only posts mentioning the terms acne and treatment were evaluated to gain insights into how social media platforms are being used by individuals with cutaneous disease. As such, even with this potential underrepresentation, our study demonstrated a high incidence of illicit marketing of prescription acne medications across multiple social media platforms (Figure 2). The sale of dermatologic pharmaceuticals (eg, isotretinoin) without a prescription is recognized by the US Government as a problem that is rapidly growing.^4,5 Illicit pharmacies pose as legitimate pharmacies that can provide prescription medications to consumers without a prescription.^5,6 The fact that these illicit pharmacy–to-patient posts were the most abundant in our study may speak to their relative success on social media platforms in encouraging patients to purchase prescription medications without physician oversight. These findings should concern health care providers, as the procurement of prescription medications without a prescription may put patients at risk.

Social media has become a prominent source of medical information for patients, including those with dermatologic conditions.^1,2 Physicians, patients, and pharmaceutical companies can use social media platforms to communicate with each other and share knowledge and advertisements related to conditions. Social media can influence patients’ perceptions of their disease and serve as a modality to acquire medical treatments.³ Furthermore, social media posts from illicit pharmacies can result in patients buying harmful medications without physician oversight.^4,5 Examination of the content and sources of social media posts related to acne may be useful in determining those who are primarily utilizing social media and for what purpose. The goal of this systematic review was to identify sources of acne-related social media posts to determine communication trends to gain a better understanding of the potential impact social media may have on patient care.

Methods

Social media posts were identified (May 2008 to May 2016) using the search terms acne and treatment across all social media platforms available through a commercial social media data aggregating software (Crimson Hexagon). Information from relevant posts was extracted and compiled into a spreadsheet that included the content, post date, social media platform, and hyperlink. To further analyze the data, the first 100 posts on acne treatment from May 2008 to May 2016 were selected and manually classified by the following types of communication: (1) patient-to-patient (eg, testimonies of patients’ medical experiences); (2) professional-to-patient (eg, clinical knowledge or experience provided by a medical provider and/or cited article in reference to relevant treatments); (3) pharmaceutical company–to-patient (eg, information from reputable drug manufacturers regarding drug activity and adverse effects); (4) illicit pharmacy–to-patient (eg, pharmacies with advertisements calling patients to buy a drug online or offering discrete shipping without a prescription)^4,5; or (5) other-to-patient (eg, posts that did not contain enough detail to be classified).

Results

Hundreds of thousands of social media posts discussing acne treatment were identified over the 8-year study period (Figure 1). The social media data aggregator extracted posts from various blogs, website comment sections, and online forums, as well as major social media platforms (ie, Facebook, Twitter, Google+, Tumblr). The first 100 posts selected for further analysis included 0 from 2008, 6 from 2009, 36 from 2010, 15 from 2011, 7 from 2012, 8 from 2013, 12 from 2014, 11 from 2015, and 5 from 2016. From this sample, 65 posts were considered to have an illicit source; conversely, 18 posts were from patients and 7 posts were from pharmaceutical companies (Figure 2).

Comment

This study demonstrated that discussion of acne treatment is prevalent in social media. Although our research underrepresents the social media interest in specific acne treatments, as only posts mentioning the terms acne and treatment were evaluated to gain insights into how social media platforms are being used by individuals with cutaneous disease. As such, even with this potential underrepresentation, our study demonstrated a high incidence of illicit marketing of prescription acne medications across multiple social media platforms (Figure 2). The sale of dermatologic pharmaceuticals (eg, isotretinoin) without a prescription is recognized by the US Government as a problem that is rapidly growing.^4,5 Illicit pharmacies pose as legitimate pharmacies that can provide prescription medications to consumers without a prescription.^5,6 The fact that these illicit pharmacy–to-patient posts were the most abundant in our study may speak to their relative success on social media platforms in encouraging patients to purchase prescription medications without physician oversight. These findings should concern health care providers, as the procurement of prescription medications without a prescription may put patients at risk.

Rosacea is a chronic skin condition that can be classified into 4 subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Erythematotelangiectatic rosacea is characterized by redness of the face and excessive blushing. Papulopustular rosacea is a more severe form of disease that is characterized by papules and pustules of the central face. If left untreated, these subtypes may progress to phymatous rosacea, which is characterized by skin thickening, fibrosis, and cosmetic disfigurement. Ocular rosacea is characterized by redness and irritation of the eyes.¹ Rosacea patients often are burdened with embarrassment, social anxiety, and psychiatric comorbidities.

The Patient Health Questionnaire 9 (PHQ-9) is a validated and reliable self-administered tool for diagnosis of depression and designation of depression severity. This instrument could prove useful in screening for depression in rosacea patients given the high incidence of psychiatric comorbidities in this patient population.² The PHQ-9 consists of 9 questions that assess for criteria used to define depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).³ The questionnaire is brief, easy to administer, and has 88% specificity and sensitivity.⁴

Other studies have evaluated the relationship between rosacea and psychiatric illness, but the PHQ-9 was not used as a screening tool.^7,8 Rosacea patients are at increased risk for having psychiatrist-diagnosed depression.⁵ In one assessment, a positive correlation between rosacea and psychiatric illness was noted using the Dermatology Life Quality Index, the rejection scale of the Questionnaire on Experience with Skin Complaints, and the German version of the Hospital Anxiety and Depression Scale.⁶ Interpretation of Rosacea Quality of Life and Dermatology Life Quality Index scores indicated that rosacea has a negative impact on quality of life.⁷

The purpose of this study was to examine the relationship between self-assessed rosacea severity scores and level of depression using the validated rosacea self-assessment tool and the PHQ-9 questionnaire, respectively.

Methods

Study Population
Study participants were adult patients from the Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) dermatology clinic from January 2011 to December 2014 who had received a diagnosis of rosacea (International Classification of Diseases, Ninth Revision [ICD-9] code 695.3) from a Wake Forest dermatologist. Institutional review board approval was obtained prior to initiation of the study. Data collection occurred from October 2014 through February 2015. A total of 478 patients met criteria for participation in the study and were identified from the Wake Forest Baptist Hospital Transitional Data Warehouse and the electronic medical record. Because rosacea typically is not diagnosed in children and the data measures are not validated in children, this demographic group was excluded from participation.

Of 478 eligible patients who were invited to participate via mail or telephone, 46 completed the rosacea self-assessment tool and PHQ-9 survey in person. A total of 432 patients were mailed a presurvey recruitment letter notifying them that they would be receiving a survey in the mail unless they contacted the study team to decline participation. An email address and telephone number for the study team was provided. Twenty patients declined to participate in the study; surveys were then mailed to the remaining 412 patients. Sixteen of the mailed surveys were returned by the post office due to an incorrect address. A total of 195 surveys (149 through mail and 46 in person) were completed and analyzed. All survey respondents completed the validated rosacea self-assessment tool (Figure 1); of them, 183 completed the PHQ-9. Participants in this study received compensation for travel expenses and time.

Results

There is a direct relationship between rosacea severity and depression when comparing across the following levels of depression: nondepressed, minimal depression symptoms, minor depression, major depression (moderate), and major depression (severe)(P=.006; F=5.18; N=183)(Figures 2 and 3). There was no statistically significant difference in rosacea severity between the moderate and severe major depression groups.

Most patients reported they were nondepressed (68.9%). As measured by the PHQ-9, 31.1% of patients experienced some level of depression: 21.9% reported minimal depression symptoms, 7.1% reported minor depression, 1.1% reported major depression (moderate), and 1.1% reported major depression (severe)(Table).

Comment

There is a direct relationship between rosacea severity and level of depression. In our study, nearly one-third of patients reported some degree of depression. The reason for this correlation may be due to disease stigmatization and decreased quality of life due to the somatic symptoms of rosacea. Our study reinforced the results of other studies evaluating the psychosocial impact of rosacea.^8,9 Depression is associated with poor treatment adherence and poor outcomes in rosacea patients; therefore, depression may serve as an important outcome measure.¹⁰ The psychosocial impact of rosacea can be severe, but with disease improvement, there often is an improvement in the patient’s psychosocial status.⁷

There are several limitations to our study. The study population consisted of patients at a university dermatology clinic who may not be representative of patients in the general population; however, our hospital system does not require referral and provides care to a large percentage of the surrounding community.

Clinical implementation of the validated rosacea self-assessment tool and PHQ-9 may have several benefits. Patient-assessed rosacea severity and psychosocial impact obtained via use of these tools would provide physicians with information to fine-tune rosacea treatment regimens. Patients with the greatest social impact may require a more aggressive treatment approach. Early detection of depression in the rosacea population is important in informing treatment strategy and improving outcomes. Physicians should pay close attention to signs of depression in rosacea patients and determine if psychiatric treatment or referral for psychiatric evaluation is indicated. The correlation between rosacea and depression underscores the importance of treating this highly impactful disease; however, the low number of responders from the major depression (moderate) subgroup prevented us from making any strong conclusion about this specific subgroup.

Rosacea is a chronic skin condition that can be classified into 4 subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Erythematotelangiectatic rosacea is characterized by redness of the face and excessive blushing. Papulopustular rosacea is a more severe form of disease that is characterized by papules and pustules of the central face. If left untreated, these subtypes may progress to phymatous rosacea, which is characterized by skin thickening, fibrosis, and cosmetic disfigurement. Ocular rosacea is characterized by redness and irritation of the eyes.¹ Rosacea patients often are burdened with embarrassment, social anxiety, and psychiatric comorbidities.

The Patient Health Questionnaire 9 (PHQ-9) is a validated and reliable self-administered tool for diagnosis of depression and designation of depression severity. This instrument could prove useful in screening for depression in rosacea patients given the high incidence of psychiatric comorbidities in this patient population.² The PHQ-9 consists of 9 questions that assess for criteria used to define depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).³ The questionnaire is brief, easy to administer, and has 88% specificity and sensitivity.⁴

Other studies have evaluated the relationship between rosacea and psychiatric illness, but the PHQ-9 was not used as a screening tool.^7,8 Rosacea patients are at increased risk for having psychiatrist-diagnosed depression.⁵ In one assessment, a positive correlation between rosacea and psychiatric illness was noted using the Dermatology Life Quality Index, the rejection scale of the Questionnaire on Experience with Skin Complaints, and the German version of the Hospital Anxiety and Depression Scale.⁶ Interpretation of Rosacea Quality of Life and Dermatology Life Quality Index scores indicated that rosacea has a negative impact on quality of life.⁷

The purpose of this study was to examine the relationship between self-assessed rosacea severity scores and level of depression using the validated rosacea self-assessment tool and the PHQ-9 questionnaire, respectively.

Methods

Study Population
Study participants were adult patients from the Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) dermatology clinic from January 2011 to December 2014 who had received a diagnosis of rosacea (International Classification of Diseases, Ninth Revision [ICD-9] code 695.3) from a Wake Forest dermatologist. Institutional review board approval was obtained prior to initiation of the study. Data collection occurred from October 2014 through February 2015. A total of 478 patients met criteria for participation in the study and were identified from the Wake Forest Baptist Hospital Transitional Data Warehouse and the electronic medical record. Because rosacea typically is not diagnosed in children and the data measures are not validated in children, this demographic group was excluded from participation.

Of 478 eligible patients who were invited to participate via mail or telephone, 46 completed the rosacea self-assessment tool and PHQ-9 survey in person. A total of 432 patients were mailed a presurvey recruitment letter notifying them that they would be receiving a survey in the mail unless they contacted the study team to decline participation. An email address and telephone number for the study team was provided. Twenty patients declined to participate in the study; surveys were then mailed to the remaining 412 patients. Sixteen of the mailed surveys were returned by the post office due to an incorrect address. A total of 195 surveys (149 through mail and 46 in person) were completed and analyzed. All survey respondents completed the validated rosacea self-assessment tool (Figure 1); of them, 183 completed the PHQ-9. Participants in this study received compensation for travel expenses and time.

Results

There is a direct relationship between rosacea severity and depression when comparing across the following levels of depression: nondepressed, minimal depression symptoms, minor depression, major depression (moderate), and major depression (severe)(P=.006; F=5.18; N=183)(Figures 2 and 3). There was no statistically significant difference in rosacea severity between the moderate and severe major depression groups.

Most patients reported they were nondepressed (68.9%). As measured by the PHQ-9, 31.1% of patients experienced some level of depression: 21.9% reported minimal depression symptoms, 7.1% reported minor depression, 1.1% reported major depression (moderate), and 1.1% reported major depression (severe)(Table).

Comment

There is a direct relationship between rosacea severity and level of depression. In our study, nearly one-third of patients reported some degree of depression. The reason for this correlation may be due to disease stigmatization and decreased quality of life due to the somatic symptoms of rosacea. Our study reinforced the results of other studies evaluating the psychosocial impact of rosacea.^8,9 Depression is associated with poor treatment adherence and poor outcomes in rosacea patients; therefore, depression may serve as an important outcome measure.¹⁰ The psychosocial impact of rosacea can be severe, but with disease improvement, there often is an improvement in the patient’s psychosocial status.⁷

There are several limitations to our study. The study population consisted of patients at a university dermatology clinic who may not be representative of patients in the general population; however, our hospital system does not require referral and provides care to a large percentage of the surrounding community.

Clinical implementation of the validated rosacea self-assessment tool and PHQ-9 may have several benefits. Patient-assessed rosacea severity and psychosocial impact obtained via use of these tools would provide physicians with information to fine-tune rosacea treatment regimens. Patients with the greatest social impact may require a more aggressive treatment approach. Early detection of depression in the rosacea population is important in informing treatment strategy and improving outcomes. Physicians should pay close attention to signs of depression in rosacea patients and determine if psychiatric treatment or referral for psychiatric evaluation is indicated. The correlation between rosacea and depression underscores the importance of treating this highly impactful disease; however, the low number of responders from the major depression (moderate) subgroup prevented us from making any strong conclusion about this specific subgroup.

Rosacea is a chronic skin condition that can be classified into 4 subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Erythematotelangiectatic rosacea is characterized by redness of the face and excessive blushing. Papulopustular rosacea is a more severe form of disease that is characterized by papules and pustules of the central face. If left untreated, these subtypes may progress to phymatous rosacea, which is characterized by skin thickening, fibrosis, and cosmetic disfigurement. Ocular rosacea is characterized by redness and irritation of the eyes.¹ Rosacea patients often are burdened with embarrassment, social anxiety, and psychiatric comorbidities.

The Patient Health Questionnaire 9 (PHQ-9) is a validated and reliable self-administered tool for diagnosis of depression and designation of depression severity. This instrument could prove useful in screening for depression in rosacea patients given the high incidence of psychiatric comorbidities in this patient population.² The PHQ-9 consists of 9 questions that assess for criteria used to define depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).³ The questionnaire is brief, easy to administer, and has 88% specificity and sensitivity.⁴

Other studies have evaluated the relationship between rosacea and psychiatric illness, but the PHQ-9 was not used as a screening tool.^7,8 Rosacea patients are at increased risk for having psychiatrist-diagnosed depression.⁵ In one assessment, a positive correlation between rosacea and psychiatric illness was noted using the Dermatology Life Quality Index, the rejection scale of the Questionnaire on Experience with Skin Complaints, and the German version of the Hospital Anxiety and Depression Scale.⁶ Interpretation of Rosacea Quality of Life and Dermatology Life Quality Index scores indicated that rosacea has a negative impact on quality of life.⁷

The purpose of this study was to examine the relationship between self-assessed rosacea severity scores and level of depression using the validated rosacea self-assessment tool and the PHQ-9 questionnaire, respectively.

Methods

Study Population
Study participants were adult patients from the Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) dermatology clinic from January 2011 to December 2014 who had received a diagnosis of rosacea (International Classification of Diseases, Ninth Revision [ICD-9] code 695.3) from a Wake Forest dermatologist. Institutional review board approval was obtained prior to initiation of the study. Data collection occurred from October 2014 through February 2015. A total of 478 patients met criteria for participation in the study and were identified from the Wake Forest Baptist Hospital Transitional Data Warehouse and the electronic medical record. Because rosacea typically is not diagnosed in children and the data measures are not validated in children, this demographic group was excluded from participation.

Of 478 eligible patients who were invited to participate via mail or telephone, 46 completed the rosacea self-assessment tool and PHQ-9 survey in person. A total of 432 patients were mailed a presurvey recruitment letter notifying them that they would be receiving a survey in the mail unless they contacted the study team to decline participation. An email address and telephone number for the study team was provided. Twenty patients declined to participate in the study; surveys were then mailed to the remaining 412 patients. Sixteen of the mailed surveys were returned by the post office due to an incorrect address. A total of 195 surveys (149 through mail and 46 in person) were completed and analyzed. All survey respondents completed the validated rosacea self-assessment tool (Figure 1); of them, 183 completed the PHQ-9. Participants in this study received compensation for travel expenses and time.

Results

There is a direct relationship between rosacea severity and depression when comparing across the following levels of depression: nondepressed, minimal depression symptoms, minor depression, major depression (moderate), and major depression (severe)(P=.006; F=5.18; N=183)(Figures 2 and 3). There was no statistically significant difference in rosacea severity between the moderate and severe major depression groups.

Most patients reported they were nondepressed (68.9%). As measured by the PHQ-9, 31.1% of patients experienced some level of depression: 21.9% reported minimal depression symptoms, 7.1% reported minor depression, 1.1% reported major depression (moderate), and 1.1% reported major depression (severe)(Table).

Comment

There is a direct relationship between rosacea severity and level of depression. In our study, nearly one-third of patients reported some degree of depression. The reason for this correlation may be due to disease stigmatization and decreased quality of life due to the somatic symptoms of rosacea. Our study reinforced the results of other studies evaluating the psychosocial impact of rosacea.^8,9 Depression is associated with poor treatment adherence and poor outcomes in rosacea patients; therefore, depression may serve as an important outcome measure.¹⁰ The psychosocial impact of rosacea can be severe, but with disease improvement, there often is an improvement in the patient’s psychosocial status.⁷

There are several limitations to our study. The study population consisted of patients at a university dermatology clinic who may not be representative of patients in the general population; however, our hospital system does not require referral and provides care to a large percentage of the surrounding community.

Clinical implementation of the validated rosacea self-assessment tool and PHQ-9 may have several benefits. Patient-assessed rosacea severity and psychosocial impact obtained via use of these tools would provide physicians with information to fine-tune rosacea treatment regimens. Patients with the greatest social impact may require a more aggressive treatment approach. Early detection of depression in the rosacea population is important in informing treatment strategy and improving outcomes. Physicians should pay close attention to signs of depression in rosacea patients and determine if psychiatric treatment or referral for psychiatric evaluation is indicated. The correlation between rosacea and depression underscores the importance of treating this highly impactful disease; however, the low number of responders from the major depression (moderate) subgroup prevented us from making any strong conclusion about this specific subgroup.

Acne vulgaris is prevalent in the general population, with 40 to 50 million affected individuals in the United States.¹ Severe inflammation and injury can lead to disfiguring scarring, which has a considerable impact on quality of life.² Numerous therapeutic options for acne scarring are available, including microneedling with and without platelet-rich plasma (PRP), lasers, chemical peels, and dermal fillers, with different modalities suited to individual patients and scar characteristics. This article reviews updates in treatment options for acne scarring.

Microneedling

Microneedling, also known as percutaneous collagen induction or collagen induction therapy, has been utilized for more than 2 decades.³ Dermatologic indications for microneedling include skin rejuvenation,^4-6 atrophic acne scarring,^7-9 and androgenic alopecia.^10,11 Microneedling also has been used to enhance skin penetration of topically applied drugs.^12-15 Fernandes¹⁶ described percutaneous collagen induction as the skin’s natural response to injury. Microneedling creates small wounds as fine needles puncture the epidermis and dermis, resulting in a cascade of growth factors that lead to tissue proliferation, regeneration, and a collagen remodeling phase that can last for several months.^8,16

Microneedling has gained popularity in the treatment of acne scarring.⁷ Alam et al⁹ conducted a split-face randomized clinical trial (RCT) to evaluate acne scarring after 3 microneedling sessions performed at 2-week intervals. Twenty participants with acne scarring on both sides of the face were enrolled in the study and one side of the face was randomized for treatment. Participants had at least two 5×5-cm areas of acne scarring graded as 2 (moderately atrophic scars) to 4 (hyperplastic or papular scars) on the quantitative Global Acne Scarring Classification system. A roller device with a 1.0-mm depth was used on participants with fine, less sebaceous skin and a 2.0-mm device for all others. Two blinded investigators assessed acne scars at baseline and at 3 and 6 months after treatment. Scar improvement was measured using the quantitative Goodman and Baron scale, which provides a score according to type and number of scars.¹⁷ Mean scar scores were significantly reduced at 6 months compared to baseline on the treatment side (P=.03) but not the control side. Participants experienced minimal pain associated with microneedling therapy, rated 1.08 of 10, and adverse effects were limited to mild transient erythema and edema.⁹ Several other clinical trials have demonstrated clinical improvements with microneedling.^18-20

The benefits of microneedling also have been observed on a histologic level. One group of investigators explored the effects of microneedling on dermal collagen in the treatment of various atrophic acne scars in 10 participants.⁷ After 6 treatment sessions performed at 2-week intervals, dermal collagen was assessed via punch biopsy. A roller device with a needle depth of 1.5 mm was used for all patients. At 1 month after treatment compared to baseline, mean (SD) levels of type I collagen were significantly increased (67.1% [4.2%] vs 70.4% [5.4%]; P=.01) as well as at 3 months after treatment compared to baseline for type III collagen (61.4% [3.6%] vs 74.3% [7.4%]; P=.01), type VII collagen (15.2% [2.1%] vs 21.3% [1.2%]; P=.03), and newly synthesized collagen (14.5% [5.8%] vs 19.5% [3.2%]; P=.02). Total elastin levels were significantly decreased at 3 months after treatment compared to baseline (51.3% [6.7%] vs 46.9% [4.3%]; P=.04). Adverse effects were limited to transient erythema and edema.⁷

Microneedling With Platelet-Rich Plasma

Microneedling has been combined with platelet-rich plasma (PRP) in the treatment of atrophic acne scars.²¹ In addition to inducing new collagen synthesis, microneedling aids in the absorption of PRP, an autologous concentrate of platelets that is obtained through peripheral venipuncture. The concentrate is centrifuged into 3 layers: (1) platelet-poor plasma, (2) PRP, and (3) erythrocytes.²² Platelet-rich plasma contains growth factors such as platelet-derived growth factor, transforming growth factor (TGF), and vascular endothelial growth factor, as well as cell adhesion molecules.^22,23 The application of PRP is thought to result in upregulated protein synthesis, greater collagen remodeling, and accelerated wound healing.²¹

Several studies have shown that the addition of PRP to microneedling can improve treatment outcome (Table 1).^24-27 Severity of acne scarring can be improved, such as reduced scar depth, by using both modalities synergistically (Figure).²⁴ Asif et al²⁶ compared microneedling with PRP to microneedling with distilled water in the treatment of 50 patients with atrophic acne scars graded 2 to 4 (mild to severe acne scarring) on the Goodman’s Qualitative classification and equal Goodman’s Qualitative and Quantitative scores on both halves of the face.^17,28 The right side of the face was treated with a 1.5-mm microneedling roller with intradermal and topical PRP, while the left side was treated with distilled water (placebo) delivered intradermally. Patients underwent 3 treatment sessions at 1-month intervals. The area treated with microneedling and PRP showed a 62.20% improvement from baseline after 3 treatments, while the placebo-treated area showed a 45.84% improvement on the Goodman and Baron quantitative scale.²⁶

Chawla²⁵ compared microneedling with topical PRP to microneedling with topical vitamin C in a split-face study of 30 participants with atrophic acne scarring graded 2 to 4 on the Goodman and Baron scale. A 1.5-mm roller device was used. Patients underwent 4 treatment sessions at 1-month intervals, and treatment efficacy was evaluated using the qualitative Goodman and Baron scale.²⁸ Participants experienced positive outcomes overall with both treatments. Notably, 18.5% (5/27) on the microneedling with PRP side demonstrated excellent response compared to 7.4% (2/27) on the microneedling with vitamin C side.²⁵

Laser Treatment

Laser skin resurfacing has shown to be efficacious in the treatment of both acne vulgaris and acne scarring. Various lasers have been utilized, including nonfractional CO₂ and erbium-doped:YAG (Er:YAG) lasers, as well as ablative fractional lasers (AFLs) and nonablative fractional lasers (NAFLs).²⁹

One retrospective study of 58 patients compared the use of 2 resurfacing lasers—10,600-nm nonfractional CO₂ and 2940-nm Er:YAG—and 2 fractional lasers—1550-nm NAFL and 10,600-nm AFL—in the treatment of atrophic acne scars.²⁹ A retrospective photographic analysis was performed by 6 blinded dermatologists to evaluate clinical improvement on a scale of 0 (no improvement) to 10 (excellent improvement). The mean improvement scores of the CO₂, Er:YAG, AFL, and NAFL groups were 6.0, 5.8, 2.2, and 5.2, respectively, and the mean number of treatments was 1.6, 1.1, 4.0, and 3.4, respectively. Thus, patients in the fractional laser groups required more treatments; however, those in the resurfacing laser groups had longer recovery times, pain, erythema, and postinflammatory hyperpigmentation. The investigators concluded that 3 consecutive AFL treatments could be as effective as a single resurfacing treatment with lower risk for complications.²⁹

A split-face RCT compared the use of the fractional Er:YAG laser on one side of the face to microneedling with a 2.0-mm needle on the other side for treatment of atrophic acne scars.³⁰ Thirty patients underwent 5 treatments at 1-month intervals. At 3-month follow-up, the areas treated with the Er:YAG laser showed 70% improvement from baseline compared to 30% improvement in the areas treated with microneedling (P<.001). Histologically, the Er:YAG laser showed a higher increase in dermal collagen than microneedling (P<.001). Furthermore, the Er:YAG laser yielded significantly lower pain scores (P<.001); however, patients reported higher rates of erythema, swelling, superficial crusting, and total downtime.³⁰

Lasers With PRP
More recent studies have examined the use of laser therapy in addition to PRP for the treatment of acne scars (Table 2).^31-34 Abdel Aal et al³³ examined the use of the ablative fractional CO₂ laser with and without intradermal PRP in a split-face study of 30 participants with various types of acne scarring (ie, boxcar, ice pick, and rolling scars). Participants underwent 2 treatments at 4-week intervals. Evaluations were performed by 2 blinded dermatologists 6 months after the final laser treatment using the qualitative Goodman and Baron scale.²⁸ Both treatments yielded improvement in scarring, but the PRP-treated side showed shorter durations of postprocedure erythema (P=.0052) as well as higher patient satisfaction scores (P<.001) than laser therapy alone.³³

In another split-face study, Gawdat et al³² examined combination treatment with the ablative fractional CO₂ laser and PRP in 30 participants with atrophic acne scars graded 2 to 4 on the qualitative Goodman and Baron scale.²⁸ Participants were randomized to 2 different treatment groups: In group 1, half of the face was treated with the fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and intradermal saline. In group 2, half of the face was treated with fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and topical PRP. All patients underwent 3 treatment sessions at 1-month intervals with assessment occurring a 6-month follow-up using the qualitative Goodman and Baron Scale.²⁸ In all participants, areas treated with the combined laser and PRP showed significant improvement in scarring (P=.03) and reduced recovery time (P=.02) compared to areas treated with laser therapy only. Patients receiving intradermal or topical PRP showed no statistically significant differences in improvement of scarring or recovery time; however, areas treated with topical PRP had significantly lower pain levels (P=.005).³²

Lee et al³¹ conducted a split-face study of 14 patients with moderate to severe acne scarring treated with an ablative fractional CO₂ laser followed by intradermal PRP or intradermal normal saline injections. Patients underwent 2 treatment sessions at 4-week intervals. Photographs taken at baseline and 4 months posttreatment were evaluated by 2 blinded dermatologists for clinical improvement using a quartile grading system. Erythema was assessed using a skin color measuring device. A blinded dermatologist assessed patients for adverse events. At 4-month follow-up, mean (SD) clinical improvement on the side receiving intradermal PRP was significantly better than the control side (2.7 [0.7] vs 2.3 [0.5]; P=.03). Erythema on posttreatment day 4 was significantly less on the side treated with PRP (P=.01). No adverse events were reported.³¹

Another split-face study compared the use of intradermal PRP to intradermal normal saline following fractional CO₂ laser treatment.³⁴ Twenty-five participants with moderate to severe acne scars completed 2 treatment sessions at 4-week intervals. Additionally, skin biopsies were collected to evaluate collagen production using immunohistochemistry, quantitative polymerase chain reaction, and western blot techniques. Experimental fibroblasts and keratinocytes were isolated and cultured. The cultures were irradiated with a fractional CO₂ laser and treated with PRP or platelet-poor plasma. Cultures were evaluated at 30 minutes, 24 hours, and 48 hours. Participants reported 75% improvement of acne scarring from baseline in the side treated with PRP compared to 50% improvement of acne scarring from baseline in the control group (P<.001). On days 7 and 84, participants reported greater improvement on the side treated with PRP (P=.03 and P=.02, respectively). On day 28, skin biopsy evaluation yielded higher levels of TGF-β1 (P=.02), TGF-β3 (P=.004), c-myc (P=.004), type I collagen (P=.03), and type III collagen (P=.03) on the PRP-treated side compared to the control side. Transforming growth factor β increases collagen and fibroblast production, while c-myc leads to cell cycle progression.^35-37 Similarly, TGF-β1, TGF-β3, types I andIII collagen, and p-Akt were increased in all cultures treated with PRP and platelet-poor plasma in a dose-dependent manner.³⁴ p-Akt is thought to regulate wound healing³⁸; however, PRP-treated keratinocytes yielded increased epidermal growth factor receptor and decreased keratin-16 at 48 hours, which suggests PRP plays a role in increasing epithelization and reducing laser-induced keratinocyte damage.³⁹ Adverse effects (eg, erythema, edema, oozing) were less frequent in the PRP-treated side.³⁴

Chemical Peels

Chemical peels are widely used in the treatment of acne scarring.⁴⁰ Peels improve scarring through destruction of the epidermal and/or dermal layers, leading to skin exfoliation, rejuvenation, and remodeling. Superficial peeling agents, which extend to the dermoepidermal junction, include resorcinol, tretinoin, glycolic acid, lactic acid, salicylic acid, and trichloroacetic acid (TCA) 10% to 35%.⁴¹ Medium-depth peeling agents extend to the upper reticular dermis and include phenol, TCA 35% to 50%, and Jessner solution (resorcinol, lactic acid, and salicylic acid in ethanol) followed by TCA 35%.⁴¹ Finally, the effects of deep peeling agents reach the mid reticular dermis and include the Baker-Gordon or Litton phenol formulas.⁴¹ Deep peels are associated with higher rates of adverse outcomes including infection, dyschromia, and scarring.^41,42

An RCT was performed to evaluate the use of a deep phenol 60% peel compared to microneedling with a 1.5-mm roller device plus a TCA 20% peel in the treatment of atrophic acne scars.⁴³ Twenty-four patients were randomly and evenly assigned to both treatment groups. The phenol group underwent a single treatment session, while the microneedling plus TCA group underwent 4 treatment sessions at 6-week intervals. Both groups were instructed to use daily topical tretinoin and hydroquinone 2% in the 2 weeks prior to treatment. Posttreatment results were evaluated using a quartile grading scale. Scarring improved from baseline by 75.12% (P<.001) in the phenol group and 69.43% (P<.001) in the microneedling plus TCA group, with no significant difference between groups. Adverse effects in the phenol group included erythema and hyperpigmentation, while adverse events in the microneedling plus TCA group included transient pain, edema, erythema, and desquamation.⁴³

Another study compared the use of a TCA 15% peel with microneedling to PRP with microneedling and microneedling alone in the treatment of atrophic acne scars.⁴⁴ Twenty-four patients were randomly assigned to the 3 treatment groups (8 to each group) and underwent 6 treatment sessions with 2-week intervals. A roller device with a 1.5-mm needle was used for microneedling. Microneedling plus TCA and microneedling plus PRP were significantly more effective than microneedling alone (P=.011 and P=.015, respectively); however, the TCA 15% peel with microneedling resulted in the largest increase in epidermal thickening. The investigators concluded that combined use of a TCA 15% peel and microneedling was the most effective in treating atrophic acne scarring.⁴⁴

Dermal Fillers

Dermal or subcutaneous fillers are used to increase volume in depressed scars and stimulate the skin’s natural production.⁴⁵ Tissue augmentation methods commonly are used for larger rolling acne scars. Options for filler materials include autologous fat, bovine, or human collagen derivatives; hyaluronic acid; and polymethyl methacrylate microspheres with collagen.⁴⁵ Newer fillers are formulated with lidocaine to decrease pain associated with the procedure.⁴⁶ Hyaluronic acid fillers provide natural volume correction and have limited potential to elicit an immune response due to their derivation from bacterial fermentation. Fillers using polymethyl methacrylate microspheres with collagen are permanent and effective, which may lead to reduced patient costs; however, they often are not a first choice for treatment.^45,46 Furthermore, if dermal fillers consist of bovine collagen, it is necessary to perform skin testing for allergy prior to use. Autologous fat transfer also has become popular for treatment of acne scarring, especially because there is no risk of allergic reaction, as the patient’s own fat is used for correction.⁴⁶ However, this method requires a high degree of skill, and results are unpredictable, generally lasting from 6 months to several years.

Therapies on the horizon include autologous cell therapy. A multicenter, double-blinded, placebo-controlled RCT examined the use of an autologous fibroblast filler in the treatment of bilateral, depressed, and distensible acne scars that were graded as moderate to severe.⁴⁷ Autologous fat fibroblasts were harvested from full-thickness postauricular punch biopsies. In this split-face study, 99 participants were treated with an intradermal autologous fibroblast filler on one cheek and a protein-free cell-culture medium on the contralateral cheek. Participants received an average of 5.9 mL of both autologous fat fibroblasts and cell-culture medium over 3 treatment sessions at 2-week intervals. The autologous fat fibroblasts were associated with greater improvement compared to cell-culture medium based on participant (43% vs 18%), evaluator (59% vs 42%), and independent photographic viewer’s assessment.⁴⁷

Conclusion

Acne scarring is a burden affecting millions of Americans. It often has a negative impact on quality of life and can lead to low self-esteem in patients. Numerous trials have indicated that microneedling is beneficial in the treatment of acne scarring, and emerging evidence indicates that the addition of PRP provides measurable benefits. Similarly, the addition of PRP to laser therapy may reduce recovery time as well as the commonly associated adverse events of erythema and pain. Chemical peels provide the advantage of being easily and efficiently performed in the office setting. Finally, the wide range of available dermal fillers can be tailored to treat specific types of acne scars. Autologous dermal fillers recently have been used and show promising benefits. It is important to consider desired outcome, cost, and adverse events when discussing therapeutic options for acne scarring with patients. The numerous therapeutic options warrant further research and well-designed RCTs to ensure optimal patient outcomes.

Acne vulgaris is prevalent in the general population, with 40 to 50 million affected individuals in the United States.¹ Severe inflammation and injury can lead to disfiguring scarring, which has a considerable impact on quality of life.² Numerous therapeutic options for acne scarring are available, including microneedling with and without platelet-rich plasma (PRP), lasers, chemical peels, and dermal fillers, with different modalities suited to individual patients and scar characteristics. This article reviews updates in treatment options for acne scarring.

Microneedling

Microneedling, also known as percutaneous collagen induction or collagen induction therapy, has been utilized for more than 2 decades.³ Dermatologic indications for microneedling include skin rejuvenation,^4-6 atrophic acne scarring,^7-9 and androgenic alopecia.^10,11 Microneedling also has been used to enhance skin penetration of topically applied drugs.^12-15 Fernandes¹⁶ described percutaneous collagen induction as the skin’s natural response to injury. Microneedling creates small wounds as fine needles puncture the epidermis and dermis, resulting in a cascade of growth factors that lead to tissue proliferation, regeneration, and a collagen remodeling phase that can last for several months.^8,16

Microneedling has gained popularity in the treatment of acne scarring.⁷ Alam et al⁹ conducted a split-face randomized clinical trial (RCT) to evaluate acne scarring after 3 microneedling sessions performed at 2-week intervals. Twenty participants with acne scarring on both sides of the face were enrolled in the study and one side of the face was randomized for treatment. Participants had at least two 5×5-cm areas of acne scarring graded as 2 (moderately atrophic scars) to 4 (hyperplastic or papular scars) on the quantitative Global Acne Scarring Classification system. A roller device with a 1.0-mm depth was used on participants with fine, less sebaceous skin and a 2.0-mm device for all others. Two blinded investigators assessed acne scars at baseline and at 3 and 6 months after treatment. Scar improvement was measured using the quantitative Goodman and Baron scale, which provides a score according to type and number of scars.¹⁷ Mean scar scores were significantly reduced at 6 months compared to baseline on the treatment side (P=.03) but not the control side. Participants experienced minimal pain associated with microneedling therapy, rated 1.08 of 10, and adverse effects were limited to mild transient erythema and edema.⁹ Several other clinical trials have demonstrated clinical improvements with microneedling.^18-20

The benefits of microneedling also have been observed on a histologic level. One group of investigators explored the effects of microneedling on dermal collagen in the treatment of various atrophic acne scars in 10 participants.⁷ After 6 treatment sessions performed at 2-week intervals, dermal collagen was assessed via punch biopsy. A roller device with a needle depth of 1.5 mm was used for all patients. At 1 month after treatment compared to baseline, mean (SD) levels of type I collagen were significantly increased (67.1% [4.2%] vs 70.4% [5.4%]; P=.01) as well as at 3 months after treatment compared to baseline for type III collagen (61.4% [3.6%] vs 74.3% [7.4%]; P=.01), type VII collagen (15.2% [2.1%] vs 21.3% [1.2%]; P=.03), and newly synthesized collagen (14.5% [5.8%] vs 19.5% [3.2%]; P=.02). Total elastin levels were significantly decreased at 3 months after treatment compared to baseline (51.3% [6.7%] vs 46.9% [4.3%]; P=.04). Adverse effects were limited to transient erythema and edema.⁷

Microneedling With Platelet-Rich Plasma

Microneedling has been combined with platelet-rich plasma (PRP) in the treatment of atrophic acne scars.²¹ In addition to inducing new collagen synthesis, microneedling aids in the absorption of PRP, an autologous concentrate of platelets that is obtained through peripheral venipuncture. The concentrate is centrifuged into 3 layers: (1) platelet-poor plasma, (2) PRP, and (3) erythrocytes.²² Platelet-rich plasma contains growth factors such as platelet-derived growth factor, transforming growth factor (TGF), and vascular endothelial growth factor, as well as cell adhesion molecules.^22,23 The application of PRP is thought to result in upregulated protein synthesis, greater collagen remodeling, and accelerated wound healing.²¹

Several studies have shown that the addition of PRP to microneedling can improve treatment outcome (Table 1).^24-27 Severity of acne scarring can be improved, such as reduced scar depth, by using both modalities synergistically (Figure).²⁴ Asif et al²⁶ compared microneedling with PRP to microneedling with distilled water in the treatment of 50 patients with atrophic acne scars graded 2 to 4 (mild to severe acne scarring) on the Goodman’s Qualitative classification and equal Goodman’s Qualitative and Quantitative scores on both halves of the face.^17,28 The right side of the face was treated with a 1.5-mm microneedling roller with intradermal and topical PRP, while the left side was treated with distilled water (placebo) delivered intradermally. Patients underwent 3 treatment sessions at 1-month intervals. The area treated with microneedling and PRP showed a 62.20% improvement from baseline after 3 treatments, while the placebo-treated area showed a 45.84% improvement on the Goodman and Baron quantitative scale.²⁶

Chawla²⁵ compared microneedling with topical PRP to microneedling with topical vitamin C in a split-face study of 30 participants with atrophic acne scarring graded 2 to 4 on the Goodman and Baron scale. A 1.5-mm roller device was used. Patients underwent 4 treatment sessions at 1-month intervals, and treatment efficacy was evaluated using the qualitative Goodman and Baron scale.²⁸ Participants experienced positive outcomes overall with both treatments. Notably, 18.5% (5/27) on the microneedling with PRP side demonstrated excellent response compared to 7.4% (2/27) on the microneedling with vitamin C side.²⁵

Laser Treatment

Laser skin resurfacing has shown to be efficacious in the treatment of both acne vulgaris and acne scarring. Various lasers have been utilized, including nonfractional CO₂ and erbium-doped:YAG (Er:YAG) lasers, as well as ablative fractional lasers (AFLs) and nonablative fractional lasers (NAFLs).²⁹

One retrospective study of 58 patients compared the use of 2 resurfacing lasers—10,600-nm nonfractional CO₂ and 2940-nm Er:YAG—and 2 fractional lasers—1550-nm NAFL and 10,600-nm AFL—in the treatment of atrophic acne scars.²⁹ A retrospective photographic analysis was performed by 6 blinded dermatologists to evaluate clinical improvement on a scale of 0 (no improvement) to 10 (excellent improvement). The mean improvement scores of the CO₂, Er:YAG, AFL, and NAFL groups were 6.0, 5.8, 2.2, and 5.2, respectively, and the mean number of treatments was 1.6, 1.1, 4.0, and 3.4, respectively. Thus, patients in the fractional laser groups required more treatments; however, those in the resurfacing laser groups had longer recovery times, pain, erythema, and postinflammatory hyperpigmentation. The investigators concluded that 3 consecutive AFL treatments could be as effective as a single resurfacing treatment with lower risk for complications.²⁹

A split-face RCT compared the use of the fractional Er:YAG laser on one side of the face to microneedling with a 2.0-mm needle on the other side for treatment of atrophic acne scars.³⁰ Thirty patients underwent 5 treatments at 1-month intervals. At 3-month follow-up, the areas treated with the Er:YAG laser showed 70% improvement from baseline compared to 30% improvement in the areas treated with microneedling (P<.001). Histologically, the Er:YAG laser showed a higher increase in dermal collagen than microneedling (P<.001). Furthermore, the Er:YAG laser yielded significantly lower pain scores (P<.001); however, patients reported higher rates of erythema, swelling, superficial crusting, and total downtime.³⁰

Lasers With PRP
More recent studies have examined the use of laser therapy in addition to PRP for the treatment of acne scars (Table 2).^31-34 Abdel Aal et al³³ examined the use of the ablative fractional CO₂ laser with and without intradermal PRP in a split-face study of 30 participants with various types of acne scarring (ie, boxcar, ice pick, and rolling scars). Participants underwent 2 treatments at 4-week intervals. Evaluations were performed by 2 blinded dermatologists 6 months after the final laser treatment using the qualitative Goodman and Baron scale.²⁸ Both treatments yielded improvement in scarring, but the PRP-treated side showed shorter durations of postprocedure erythema (P=.0052) as well as higher patient satisfaction scores (P<.001) than laser therapy alone.³³

In another split-face study, Gawdat et al³² examined combination treatment with the ablative fractional CO₂ laser and PRP in 30 participants with atrophic acne scars graded 2 to 4 on the qualitative Goodman and Baron scale.²⁸ Participants were randomized to 2 different treatment groups: In group 1, half of the face was treated with the fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and intradermal saline. In group 2, half of the face was treated with fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and topical PRP. All patients underwent 3 treatment sessions at 1-month intervals with assessment occurring a 6-month follow-up using the qualitative Goodman and Baron Scale.²⁸ In all participants, areas treated with the combined laser and PRP showed significant improvement in scarring (P=.03) and reduced recovery time (P=.02) compared to areas treated with laser therapy only. Patients receiving intradermal or topical PRP showed no statistically significant differences in improvement of scarring or recovery time; however, areas treated with topical PRP had significantly lower pain levels (P=.005).³²

Lee et al³¹ conducted a split-face study of 14 patients with moderate to severe acne scarring treated with an ablative fractional CO₂ laser followed by intradermal PRP or intradermal normal saline injections. Patients underwent 2 treatment sessions at 4-week intervals. Photographs taken at baseline and 4 months posttreatment were evaluated by 2 blinded dermatologists for clinical improvement using a quartile grading system. Erythema was assessed using a skin color measuring device. A blinded dermatologist assessed patients for adverse events. At 4-month follow-up, mean (SD) clinical improvement on the side receiving intradermal PRP was significantly better than the control side (2.7 [0.7] vs 2.3 [0.5]; P=.03). Erythema on posttreatment day 4 was significantly less on the side treated with PRP (P=.01). No adverse events were reported.³¹

Another split-face study compared the use of intradermal PRP to intradermal normal saline following fractional CO₂ laser treatment.³⁴ Twenty-five participants with moderate to severe acne scars completed 2 treatment sessions at 4-week intervals. Additionally, skin biopsies were collected to evaluate collagen production using immunohistochemistry, quantitative polymerase chain reaction, and western blot techniques. Experimental fibroblasts and keratinocytes were isolated and cultured. The cultures were irradiated with a fractional CO₂ laser and treated with PRP or platelet-poor plasma. Cultures were evaluated at 30 minutes, 24 hours, and 48 hours. Participants reported 75% improvement of acne scarring from baseline in the side treated with PRP compared to 50% improvement of acne scarring from baseline in the control group (P<.001). On days 7 and 84, participants reported greater improvement on the side treated with PRP (P=.03 and P=.02, respectively). On day 28, skin biopsy evaluation yielded higher levels of TGF-β1 (P=.02), TGF-β3 (P=.004), c-myc (P=.004), type I collagen (P=.03), and type III collagen (P=.03) on the PRP-treated side compared to the control side. Transforming growth factor β increases collagen and fibroblast production, while c-myc leads to cell cycle progression.^35-37 Similarly, TGF-β1, TGF-β3, types I andIII collagen, and p-Akt were increased in all cultures treated with PRP and platelet-poor plasma in a dose-dependent manner.³⁴ p-Akt is thought to regulate wound healing³⁸; however, PRP-treated keratinocytes yielded increased epidermal growth factor receptor and decreased keratin-16 at 48 hours, which suggests PRP plays a role in increasing epithelization and reducing laser-induced keratinocyte damage.³⁹ Adverse effects (eg, erythema, edema, oozing) were less frequent in the PRP-treated side.³⁴

Chemical Peels

Chemical peels are widely used in the treatment of acne scarring.⁴⁰ Peels improve scarring through destruction of the epidermal and/or dermal layers, leading to skin exfoliation, rejuvenation, and remodeling. Superficial peeling agents, which extend to the dermoepidermal junction, include resorcinol, tretinoin, glycolic acid, lactic acid, salicylic acid, and trichloroacetic acid (TCA) 10% to 35%.⁴¹ Medium-depth peeling agents extend to the upper reticular dermis and include phenol, TCA 35% to 50%, and Jessner solution (resorcinol, lactic acid, and salicylic acid in ethanol) followed by TCA 35%.⁴¹ Finally, the effects of deep peeling agents reach the mid reticular dermis and include the Baker-Gordon or Litton phenol formulas.⁴¹ Deep peels are associated with higher rates of adverse outcomes including infection, dyschromia, and scarring.^41,42

An RCT was performed to evaluate the use of a deep phenol 60% peel compared to microneedling with a 1.5-mm roller device plus a TCA 20% peel in the treatment of atrophic acne scars.⁴³ Twenty-four patients were randomly and evenly assigned to both treatment groups. The phenol group underwent a single treatment session, while the microneedling plus TCA group underwent 4 treatment sessions at 6-week intervals. Both groups were instructed to use daily topical tretinoin and hydroquinone 2% in the 2 weeks prior to treatment. Posttreatment results were evaluated using a quartile grading scale. Scarring improved from baseline by 75.12% (P<.001) in the phenol group and 69.43% (P<.001) in the microneedling plus TCA group, with no significant difference between groups. Adverse effects in the phenol group included erythema and hyperpigmentation, while adverse events in the microneedling plus TCA group included transient pain, edema, erythema, and desquamation.⁴³

Another study compared the use of a TCA 15% peel with microneedling to PRP with microneedling and microneedling alone in the treatment of atrophic acne scars.⁴⁴ Twenty-four patients were randomly assigned to the 3 treatment groups (8 to each group) and underwent 6 treatment sessions with 2-week intervals. A roller device with a 1.5-mm needle was used for microneedling. Microneedling plus TCA and microneedling plus PRP were significantly more effective than microneedling alone (P=.011 and P=.015, respectively); however, the TCA 15% peel with microneedling resulted in the largest increase in epidermal thickening. The investigators concluded that combined use of a TCA 15% peel and microneedling was the most effective in treating atrophic acne scarring.⁴⁴

Dermal Fillers

Dermal or subcutaneous fillers are used to increase volume in depressed scars and stimulate the skin’s natural production.⁴⁵ Tissue augmentation methods commonly are used for larger rolling acne scars. Options for filler materials include autologous fat, bovine, or human collagen derivatives; hyaluronic acid; and polymethyl methacrylate microspheres with collagen.⁴⁵ Newer fillers are formulated with lidocaine to decrease pain associated with the procedure.⁴⁶ Hyaluronic acid fillers provide natural volume correction and have limited potential to elicit an immune response due to their derivation from bacterial fermentation. Fillers using polymethyl methacrylate microspheres with collagen are permanent and effective, which may lead to reduced patient costs; however, they often are not a first choice for treatment.^45,46 Furthermore, if dermal fillers consist of bovine collagen, it is necessary to perform skin testing for allergy prior to use. Autologous fat transfer also has become popular for treatment of acne scarring, especially because there is no risk of allergic reaction, as the patient’s own fat is used for correction.⁴⁶ However, this method requires a high degree of skill, and results are unpredictable, generally lasting from 6 months to several years.

Therapies on the horizon include autologous cell therapy. A multicenter, double-blinded, placebo-controlled RCT examined the use of an autologous fibroblast filler in the treatment of bilateral, depressed, and distensible acne scars that were graded as moderate to severe.⁴⁷ Autologous fat fibroblasts were harvested from full-thickness postauricular punch biopsies. In this split-face study, 99 participants were treated with an intradermal autologous fibroblast filler on one cheek and a protein-free cell-culture medium on the contralateral cheek. Participants received an average of 5.9 mL of both autologous fat fibroblasts and cell-culture medium over 3 treatment sessions at 2-week intervals. The autologous fat fibroblasts were associated with greater improvement compared to cell-culture medium based on participant (43% vs 18%), evaluator (59% vs 42%), and independent photographic viewer’s assessment.⁴⁷

Conclusion

Acne scarring is a burden affecting millions of Americans. It often has a negative impact on quality of life and can lead to low self-esteem in patients. Numerous trials have indicated that microneedling is beneficial in the treatment of acne scarring, and emerging evidence indicates that the addition of PRP provides measurable benefits. Similarly, the addition of PRP to laser therapy may reduce recovery time as well as the commonly associated adverse events of erythema and pain. Chemical peels provide the advantage of being easily and efficiently performed in the office setting. Finally, the wide range of available dermal fillers can be tailored to treat specific types of acne scars. Autologous dermal fillers recently have been used and show promising benefits. It is important to consider desired outcome, cost, and adverse events when discussing therapeutic options for acne scarring with patients. The numerous therapeutic options warrant further research and well-designed RCTs to ensure optimal patient outcomes.

Acne vulgaris is prevalent in the general population, with 40 to 50 million affected individuals in the United States.¹ Severe inflammation and injury can lead to disfiguring scarring, which has a considerable impact on quality of life.² Numerous therapeutic options for acne scarring are available, including microneedling with and without platelet-rich plasma (PRP), lasers, chemical peels, and dermal fillers, with different modalities suited to individual patients and scar characteristics. This article reviews updates in treatment options for acne scarring.

Microneedling

Microneedling, also known as percutaneous collagen induction or collagen induction therapy, has been utilized for more than 2 decades.³ Dermatologic indications for microneedling include skin rejuvenation,^4-6 atrophic acne scarring,^7-9 and androgenic alopecia.^10,11 Microneedling also has been used to enhance skin penetration of topically applied drugs.^12-15 Fernandes¹⁶ described percutaneous collagen induction as the skin’s natural response to injury. Microneedling creates small wounds as fine needles puncture the epidermis and dermis, resulting in a cascade of growth factors that lead to tissue proliferation, regeneration, and a collagen remodeling phase that can last for several months.^8,16

Microneedling has gained popularity in the treatment of acne scarring.⁷ Alam et al⁹ conducted a split-face randomized clinical trial (RCT) to evaluate acne scarring after 3 microneedling sessions performed at 2-week intervals. Twenty participants with acne scarring on both sides of the face were enrolled in the study and one side of the face was randomized for treatment. Participants had at least two 5×5-cm areas of acne scarring graded as 2 (moderately atrophic scars) to 4 (hyperplastic or papular scars) on the quantitative Global Acne Scarring Classification system. A roller device with a 1.0-mm depth was used on participants with fine, less sebaceous skin and a 2.0-mm device for all others. Two blinded investigators assessed acne scars at baseline and at 3 and 6 months after treatment. Scar improvement was measured using the quantitative Goodman and Baron scale, which provides a score according to type and number of scars.¹⁷ Mean scar scores were significantly reduced at 6 months compared to baseline on the treatment side (P=.03) but not the control side. Participants experienced minimal pain associated with microneedling therapy, rated 1.08 of 10, and adverse effects were limited to mild transient erythema and edema.⁹ Several other clinical trials have demonstrated clinical improvements with microneedling.^18-20

The benefits of microneedling also have been observed on a histologic level. One group of investigators explored the effects of microneedling on dermal collagen in the treatment of various atrophic acne scars in 10 participants.⁷ After 6 treatment sessions performed at 2-week intervals, dermal collagen was assessed via punch biopsy. A roller device with a needle depth of 1.5 mm was used for all patients. At 1 month after treatment compared to baseline, mean (SD) levels of type I collagen were significantly increased (67.1% [4.2%] vs 70.4% [5.4%]; P=.01) as well as at 3 months after treatment compared to baseline for type III collagen (61.4% [3.6%] vs 74.3% [7.4%]; P=.01), type VII collagen (15.2% [2.1%] vs 21.3% [1.2%]; P=.03), and newly synthesized collagen (14.5% [5.8%] vs 19.5% [3.2%]; P=.02). Total elastin levels were significantly decreased at 3 months after treatment compared to baseline (51.3% [6.7%] vs 46.9% [4.3%]; P=.04). Adverse effects were limited to transient erythema and edema.⁷

Microneedling With Platelet-Rich Plasma

Microneedling has been combined with platelet-rich plasma (PRP) in the treatment of atrophic acne scars.²¹ In addition to inducing new collagen synthesis, microneedling aids in the absorption of PRP, an autologous concentrate of platelets that is obtained through peripheral venipuncture. The concentrate is centrifuged into 3 layers: (1) platelet-poor plasma, (2) PRP, and (3) erythrocytes.²² Platelet-rich plasma contains growth factors such as platelet-derived growth factor, transforming growth factor (TGF), and vascular endothelial growth factor, as well as cell adhesion molecules.^22,23 The application of PRP is thought to result in upregulated protein synthesis, greater collagen remodeling, and accelerated wound healing.²¹

Several studies have shown that the addition of PRP to microneedling can improve treatment outcome (Table 1).^24-27 Severity of acne scarring can be improved, such as reduced scar depth, by using both modalities synergistically (Figure).²⁴ Asif et al²⁶ compared microneedling with PRP to microneedling with distilled water in the treatment of 50 patients with atrophic acne scars graded 2 to 4 (mild to severe acne scarring) on the Goodman’s Qualitative classification and equal Goodman’s Qualitative and Quantitative scores on both halves of the face.^17,28 The right side of the face was treated with a 1.5-mm microneedling roller with intradermal and topical PRP, while the left side was treated with distilled water (placebo) delivered intradermally. Patients underwent 3 treatment sessions at 1-month intervals. The area treated with microneedling and PRP showed a 62.20% improvement from baseline after 3 treatments, while the placebo-treated area showed a 45.84% improvement on the Goodman and Baron quantitative scale.²⁶

Chawla²⁵ compared microneedling with topical PRP to microneedling with topical vitamin C in a split-face study of 30 participants with atrophic acne scarring graded 2 to 4 on the Goodman and Baron scale. A 1.5-mm roller device was used. Patients underwent 4 treatment sessions at 1-month intervals, and treatment efficacy was evaluated using the qualitative Goodman and Baron scale.²⁸ Participants experienced positive outcomes overall with both treatments. Notably, 18.5% (5/27) on the microneedling with PRP side demonstrated excellent response compared to 7.4% (2/27) on the microneedling with vitamin C side.²⁵

Laser Treatment

Laser skin resurfacing has shown to be efficacious in the treatment of both acne vulgaris and acne scarring. Various lasers have been utilized, including nonfractional CO₂ and erbium-doped:YAG (Er:YAG) lasers, as well as ablative fractional lasers (AFLs) and nonablative fractional lasers (NAFLs).²⁹

One retrospective study of 58 patients compared the use of 2 resurfacing lasers—10,600-nm nonfractional CO₂ and 2940-nm Er:YAG—and 2 fractional lasers—1550-nm NAFL and 10,600-nm AFL—in the treatment of atrophic acne scars.²⁹ A retrospective photographic analysis was performed by 6 blinded dermatologists to evaluate clinical improvement on a scale of 0 (no improvement) to 10 (excellent improvement). The mean improvement scores of the CO₂, Er:YAG, AFL, and NAFL groups were 6.0, 5.8, 2.2, and 5.2, respectively, and the mean number of treatments was 1.6, 1.1, 4.0, and 3.4, respectively. Thus, patients in the fractional laser groups required more treatments; however, those in the resurfacing laser groups had longer recovery times, pain, erythema, and postinflammatory hyperpigmentation. The investigators concluded that 3 consecutive AFL treatments could be as effective as a single resurfacing treatment with lower risk for complications.²⁹

A split-face RCT compared the use of the fractional Er:YAG laser on one side of the face to microneedling with a 2.0-mm needle on the other side for treatment of atrophic acne scars.³⁰ Thirty patients underwent 5 treatments at 1-month intervals. At 3-month follow-up, the areas treated with the Er:YAG laser showed 70% improvement from baseline compared to 30% improvement in the areas treated with microneedling (P<.001). Histologically, the Er:YAG laser showed a higher increase in dermal collagen than microneedling (P<.001). Furthermore, the Er:YAG laser yielded significantly lower pain scores (P<.001); however, patients reported higher rates of erythema, swelling, superficial crusting, and total downtime.³⁰

Lasers With PRP
More recent studies have examined the use of laser therapy in addition to PRP for the treatment of acne scars (Table 2).^31-34 Abdel Aal et al³³ examined the use of the ablative fractional CO₂ laser with and without intradermal PRP in a split-face study of 30 participants with various types of acne scarring (ie, boxcar, ice pick, and rolling scars). Participants underwent 2 treatments at 4-week intervals. Evaluations were performed by 2 blinded dermatologists 6 months after the final laser treatment using the qualitative Goodman and Baron scale.²⁸ Both treatments yielded improvement in scarring, but the PRP-treated side showed shorter durations of postprocedure erythema (P=.0052) as well as higher patient satisfaction scores (P<.001) than laser therapy alone.³³

In another split-face study, Gawdat et al³² examined combination treatment with the ablative fractional CO₂ laser and PRP in 30 participants with atrophic acne scars graded 2 to 4 on the qualitative Goodman and Baron scale.²⁸ Participants were randomized to 2 different treatment groups: In group 1, half of the face was treated with the fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and intradermal saline. In group 2, half of the face was treated with fractional CO₂ laser and intradermal PRP, while the other half was treated with fractional CO₂ laser and topical PRP. All patients underwent 3 treatment sessions at 1-month intervals with assessment occurring a 6-month follow-up using the qualitative Goodman and Baron Scale.²⁸ In all participants, areas treated with the combined laser and PRP showed significant improvement in scarring (P=.03) and reduced recovery time (P=.02) compared to areas treated with laser therapy only. Patients receiving intradermal or topical PRP showed no statistically significant differences in improvement of scarring or recovery time; however, areas treated with topical PRP had significantly lower pain levels (P=.005).³²

Lee et al³¹ conducted a split-face study of 14 patients with moderate to severe acne scarring treated with an ablative fractional CO₂ laser followed by intradermal PRP or intradermal normal saline injections. Patients underwent 2 treatment sessions at 4-week intervals. Photographs taken at baseline and 4 months posttreatment were evaluated by 2 blinded dermatologists for clinical improvement using a quartile grading system. Erythema was assessed using a skin color measuring device. A blinded dermatologist assessed patients for adverse events. At 4-month follow-up, mean (SD) clinical improvement on the side receiving intradermal PRP was significantly better than the control side (2.7 [0.7] vs 2.3 [0.5]; P=.03). Erythema on posttreatment day 4 was significantly less on the side treated with PRP (P=.01). No adverse events were reported.³¹

Another split-face study compared the use of intradermal PRP to intradermal normal saline following fractional CO₂ laser treatment.³⁴ Twenty-five participants with moderate to severe acne scars completed 2 treatment sessions at 4-week intervals. Additionally, skin biopsies were collected to evaluate collagen production using immunohistochemistry, quantitative polymerase chain reaction, and western blot techniques. Experimental fibroblasts and keratinocytes were isolated and cultured. The cultures were irradiated with a fractional CO₂ laser and treated with PRP or platelet-poor plasma. Cultures were evaluated at 30 minutes, 24 hours, and 48 hours. Participants reported 75% improvement of acne scarring from baseline in the side treated with PRP compared to 50% improvement of acne scarring from baseline in the control group (P<.001). On days 7 and 84, participants reported greater improvement on the side treated with PRP (P=.03 and P=.02, respectively). On day 28, skin biopsy evaluation yielded higher levels of TGF-β1 (P=.02), TGF-β3 (P=.004), c-myc (P=.004), type I collagen (P=.03), and type III collagen (P=.03) on the PRP-treated side compared to the control side. Transforming growth factor β increases collagen and fibroblast production, while c-myc leads to cell cycle progression.^35-37 Similarly, TGF-β1, TGF-β3, types I andIII collagen, and p-Akt were increased in all cultures treated with PRP and platelet-poor plasma in a dose-dependent manner.³⁴ p-Akt is thought to regulate wound healing³⁸; however, PRP-treated keratinocytes yielded increased epidermal growth factor receptor and decreased keratin-16 at 48 hours, which suggests PRP plays a role in increasing epithelization and reducing laser-induced keratinocyte damage.³⁹ Adverse effects (eg, erythema, edema, oozing) were less frequent in the PRP-treated side.³⁴

Chemical Peels

Chemical peels are widely used in the treatment of acne scarring.⁴⁰ Peels improve scarring through destruction of the epidermal and/or dermal layers, leading to skin exfoliation, rejuvenation, and remodeling. Superficial peeling agents, which extend to the dermoepidermal junction, include resorcinol, tretinoin, glycolic acid, lactic acid, salicylic acid, and trichloroacetic acid (TCA) 10% to 35%.⁴¹ Medium-depth peeling agents extend to the upper reticular dermis and include phenol, TCA 35% to 50%, and Jessner solution (resorcinol, lactic acid, and salicylic acid in ethanol) followed by TCA 35%.⁴¹ Finally, the effects of deep peeling agents reach the mid reticular dermis and include the Baker-Gordon or Litton phenol formulas.⁴¹ Deep peels are associated with higher rates of adverse outcomes including infection, dyschromia, and scarring.^41,42

An RCT was performed to evaluate the use of a deep phenol 60% peel compared to microneedling with a 1.5-mm roller device plus a TCA 20% peel in the treatment of atrophic acne scars.⁴³ Twenty-four patients were randomly and evenly assigned to both treatment groups. The phenol group underwent a single treatment session, while the microneedling plus TCA group underwent 4 treatment sessions at 6-week intervals. Both groups were instructed to use daily topical tretinoin and hydroquinone 2% in the 2 weeks prior to treatment. Posttreatment results were evaluated using a quartile grading scale. Scarring improved from baseline by 75.12% (P<.001) in the phenol group and 69.43% (P<.001) in the microneedling plus TCA group, with no significant difference between groups. Adverse effects in the phenol group included erythema and hyperpigmentation, while adverse events in the microneedling plus TCA group included transient pain, edema, erythema, and desquamation.⁴³

Another study compared the use of a TCA 15% peel with microneedling to PRP with microneedling and microneedling alone in the treatment of atrophic acne scars.⁴⁴ Twenty-four patients were randomly assigned to the 3 treatment groups (8 to each group) and underwent 6 treatment sessions with 2-week intervals. A roller device with a 1.5-mm needle was used for microneedling. Microneedling plus TCA and microneedling plus PRP were significantly more effective than microneedling alone (P=.011 and P=.015, respectively); however, the TCA 15% peel with microneedling resulted in the largest increase in epidermal thickening. The investigators concluded that combined use of a TCA 15% peel and microneedling was the most effective in treating atrophic acne scarring.⁴⁴

Dermal Fillers

Dermal or subcutaneous fillers are used to increase volume in depressed scars and stimulate the skin’s natural production.⁴⁵ Tissue augmentation methods commonly are used for larger rolling acne scars. Options for filler materials include autologous fat, bovine, or human collagen derivatives; hyaluronic acid; and polymethyl methacrylate microspheres with collagen.⁴⁵ Newer fillers are formulated with lidocaine to decrease pain associated with the procedure.⁴⁶ Hyaluronic acid fillers provide natural volume correction and have limited potential to elicit an immune response due to their derivation from bacterial fermentation. Fillers using polymethyl methacrylate microspheres with collagen are permanent and effective, which may lead to reduced patient costs; however, they often are not a first choice for treatment.^45,46 Furthermore, if dermal fillers consist of bovine collagen, it is necessary to perform skin testing for allergy prior to use. Autologous fat transfer also has become popular for treatment of acne scarring, especially because there is no risk of allergic reaction, as the patient’s own fat is used for correction.⁴⁶ However, this method requires a high degree of skill, and results are unpredictable, generally lasting from 6 months to several years.

Therapies on the horizon include autologous cell therapy. A multicenter, double-blinded, placebo-controlled RCT examined the use of an autologous fibroblast filler in the treatment of bilateral, depressed, and distensible acne scars that were graded as moderate to severe.⁴⁷ Autologous fat fibroblasts were harvested from full-thickness postauricular punch biopsies. In this split-face study, 99 participants were treated with an intradermal autologous fibroblast filler on one cheek and a protein-free cell-culture medium on the contralateral cheek. Participants received an average of 5.9 mL of both autologous fat fibroblasts and cell-culture medium over 3 treatment sessions at 2-week intervals. The autologous fat fibroblasts were associated with greater improvement compared to cell-culture medium based on participant (43% vs 18%), evaluator (59% vs 42%), and independent photographic viewer’s assessment.⁴⁷

Conclusion

Acne scarring is a burden affecting millions of Americans. It often has a negative impact on quality of life and can lead to low self-esteem in patients. Numerous trials have indicated that microneedling is beneficial in the treatment of acne scarring, and emerging evidence indicates that the addition of PRP provides measurable benefits. Similarly, the addition of PRP to laser therapy may reduce recovery time as well as the commonly associated adverse events of erythema and pain. Chemical peels provide the advantage of being easily and efficiently performed in the office setting. Finally, the wide range of available dermal fillers can be tailored to treat specific types of acne scars. Autologous dermal fillers recently have been used and show promising benefits. It is important to consider desired outcome, cost, and adverse events when discussing therapeutic options for acne scarring with patients. The numerous therapeutic options warrant further research and well-designed RCTs to ensure optimal patient outcomes.

Practice Gap

Mohs micrographic surgery (MMS) is a highly curative tissue-sparing skin cancer treatment¹ and is a required component of dermatology residency training. According to the Accreditation Council for Graduate Medical Education, residents must have exposure “either through direct observation or as an assistant in Mohs micrographic surgery, and reconstruction of these defects, to include flaps and grafts.”² The MMS technique allows for complete circumferential peripheral and deep margin assessment of excised specimens; however, the conformation of a 3-dimensional gross tissue specimen into a 2-dimensional specimen as represented on a microscope slide is challenging to conceptualize.

Behavioral science research has shown that analogies and metaphors help integrate topics into a memorable format and produce deeper comprehension.³ As such, analogies can aid in the visualization of these complex spatial concepts. The MMS tissue-processing technique has been compared to flattening a pie pan.⁴ More recently, a peanut butter cup analogy was described as a visualization tool for explaining the various steps of MMS to patients.⁵ Although these analogies may help elucidate certain aspects of the MMS technique, none adequately account for the multilayered anatomy of the skin.

The Technique

To address this need, we developed the cantaloupe analogy, which provides visual representation of the 3 basic skin layers: (1) the rind represents the epidermis; (2) the flesh represents the dermis, and (3) the seed cavity represents the subcutaneous layer (Figures 1 and 2).

Image courtesy of Janna M. Vassantachart, MD.

Image courtesy of Janna M. Vassantachart, MD.

In MMS tissue processing, the peripheral margin of the ovoid excised skin specimen is pressed down into the same plane as the deepest layer through a process called relaxation.⁴ The cantaloupe represents the dome shape of the relaxed tissue, which is then serially sectioned in horizontal layers from deep to superficial (Figure 2). The first slice represents the deepest subcutaneous layer and most peripheral dermal and epidermal layers of the specimen (Figure 3). Using the cantaloupe analogy, subsequent stages (if warranted) would be guided by the location of the residual skin cancer. If the skin cancer is in the epidermis (rind) or dermis (flesh), then a skin specimen from the perimeter of the defect would be indicated. Residual skin cancer extending into the subcutaneous layer (seed cavity) would require a deeper resection.

Image courtesy of Janna M. Vassantachart, MD.

Practice Implications

The cantaloupe provides a simple analogy to conceptualize the transition from the multilayered 3-dimensional skin tissue specimen to the 2-dimensional histologic slide specimen. Use of this cantaloupe analogy will aid dermatology residents and others interested in gaining a clearer understanding of MMS.

Practice Gap

Mohs micrographic surgery (MMS) is a highly curative tissue-sparing skin cancer treatment¹ and is a required component of dermatology residency training. According to the Accreditation Council for Graduate Medical Education, residents must have exposure “either through direct observation or as an assistant in Mohs micrographic surgery, and reconstruction of these defects, to include flaps and grafts.”² The MMS technique allows for complete circumferential peripheral and deep margin assessment of excised specimens; however, the conformation of a 3-dimensional gross tissue specimen into a 2-dimensional specimen as represented on a microscope slide is challenging to conceptualize.

Behavioral science research has shown that analogies and metaphors help integrate topics into a memorable format and produce deeper comprehension.³ As such, analogies can aid in the visualization of these complex spatial concepts. The MMS tissue-processing technique has been compared to flattening a pie pan.⁴ More recently, a peanut butter cup analogy was described as a visualization tool for explaining the various steps of MMS to patients.⁵ Although these analogies may help elucidate certain aspects of the MMS technique, none adequately account for the multilayered anatomy of the skin.

The Technique

To address this need, we developed the cantaloupe analogy, which provides visual representation of the 3 basic skin layers: (1) the rind represents the epidermis; (2) the flesh represents the dermis, and (3) the seed cavity represents the subcutaneous layer (Figures 1 and 2).

Image courtesy of Janna M. Vassantachart, MD.

Image courtesy of Janna M. Vassantachart, MD.

In MMS tissue processing, the peripheral margin of the ovoid excised skin specimen is pressed down into the same plane as the deepest layer through a process called relaxation.⁴ The cantaloupe represents the dome shape of the relaxed tissue, which is then serially sectioned in horizontal layers from deep to superficial (Figure 2). The first slice represents the deepest subcutaneous layer and most peripheral dermal and epidermal layers of the specimen (Figure 3). Using the cantaloupe analogy, subsequent stages (if warranted) would be guided by the location of the residual skin cancer. If the skin cancer is in the epidermis (rind) or dermis (flesh), then a skin specimen from the perimeter of the defect would be indicated. Residual skin cancer extending into the subcutaneous layer (seed cavity) would require a deeper resection.

Image courtesy of Janna M. Vassantachart, MD.

Practice Implications

The cantaloupe provides a simple analogy to conceptualize the transition from the multilayered 3-dimensional skin tissue specimen to the 2-dimensional histologic slide specimen. Use of this cantaloupe analogy will aid dermatology residents and others interested in gaining a clearer understanding of MMS.

Practice Gap

Mohs micrographic surgery (MMS) is a highly curative tissue-sparing skin cancer treatment¹ and is a required component of dermatology residency training. According to the Accreditation Council for Graduate Medical Education, residents must have exposure “either through direct observation or as an assistant in Mohs micrographic surgery, and reconstruction of these defects, to include flaps and grafts.”² The MMS technique allows for complete circumferential peripheral and deep margin assessment of excised specimens; however, the conformation of a 3-dimensional gross tissue specimen into a 2-dimensional specimen as represented on a microscope slide is challenging to conceptualize.

Behavioral science research has shown that analogies and metaphors help integrate topics into a memorable format and produce deeper comprehension.³ As such, analogies can aid in the visualization of these complex spatial concepts. The MMS tissue-processing technique has been compared to flattening a pie pan.⁴ More recently, a peanut butter cup analogy was described as a visualization tool for explaining the various steps of MMS to patients.⁵ Although these analogies may help elucidate certain aspects of the MMS technique, none adequately account for the multilayered anatomy of the skin.

The Technique

To address this need, we developed the cantaloupe analogy, which provides visual representation of the 3 basic skin layers: (1) the rind represents the epidermis; (2) the flesh represents the dermis, and (3) the seed cavity represents the subcutaneous layer (Figures 1 and 2).

Image courtesy of Janna M. Vassantachart, MD.

Image courtesy of Janna M. Vassantachart, MD.

In MMS tissue processing, the peripheral margin of the ovoid excised skin specimen is pressed down into the same plane as the deepest layer through a process called relaxation.⁴ The cantaloupe represents the dome shape of the relaxed tissue, which is then serially sectioned in horizontal layers from deep to superficial (Figure 2). The first slice represents the deepest subcutaneous layer and most peripheral dermal and epidermal layers of the specimen (Figure 3). Using the cantaloupe analogy, subsequent stages (if warranted) would be guided by the location of the residual skin cancer. If the skin cancer is in the epidermis (rind) or dermis (flesh), then a skin specimen from the perimeter of the defect would be indicated. Residual skin cancer extending into the subcutaneous layer (seed cavity) would require a deeper resection.

Image courtesy of Janna M. Vassantachart, MD.

Practice Implications

The cantaloupe provides a simple analogy to conceptualize the transition from the multilayered 3-dimensional skin tissue specimen to the 2-dimensional histologic slide specimen. Use of this cantaloupe analogy will aid dermatology residents and others interested in gaining a clearer understanding of MMS.