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An Atypical Syphilis Presentation
Syphilis is a chronic systemic infection that has been allotted the epithet “the great imitator” for its gross and histologic similarity to numerous other skin pathologies. Well-characterized for centuries, syphilis features diverse clinical manifestations including a number of cutaneous symptoms.1
RELATED AUDIOCAST: The Syphilis Epidemic: Dermatologists on the Frontline of Treatment and Diagnosis
The primary stage of infection is classically defined by an asymptomatic chancre at the inoculation site. The secondary stage results from the systemic dissemination of the infection and typically is characterized by cutaneous eruptions, regional lymphadenopathy, and flulike symptoms. This stage gained its notoriety as the great imitator owing to its ability to present with a variety of papulosquamous eruptions. The secondary stage is followed by an asymptomatic latent period that may last months to years, followed by the tertiary stage, which is characterized by the neurologic, cardiovascular, and/or gummatous manifestations that represent the major sources of morbidity and mortality associated with syphilis. It is during the primary, secondary, and early latent stages that the infection is communicable.1
Case Report
A 40-year-old man presented with multiple intensely pruritic, scattered, erythematous and slightly violaceous, flat-topped papules on the scrotum (Figure 1A) and penile shaft (Figure 1B) of 1 week’s duration. Some of these lesions were annular in appearance. The patient denied any other dermatologic concerns and showed no other skin lesions. A shave biopsy of the right side of the penile shaft was performed, revealing minimal papillary dermis and superficial perivascular dermatitis with substantial perivascular plasmalymphocytic infiltration. The epidermal layer was mildly acanthotic with parakeratosis. A tentative diagnosis of secondary syphilis of unknown latency was made and confirmatory laboratory studies were ordered.
Within weeks, the patient developed a painful 7-mm white patch on the right lower mucosal lip followed several days later by the appearance of a painful lesion on the hard palate (Figure 2 [arrow indicates palatal lesion]) and odynophagia. He presented to the emergency department roughly 3 weeks from the time of index presentation and was started empirically on amoxicillin 500 mg 3 times daily for 10 days for suspicion of strep throat. At a scheduled follow-up with his dermatologist 1 week later, physical examination showed complete resolution of the mucosal lip patch and genital lesions. A round erythematous patch on the right hard palate consistent with a resolving mucosal patch also was noted. A diagnosis of secondary syphilitic infection was made with a rapid plasma reagin (RPR) titer of 1:32 (reference range, <1:1) and positive Treponema antibodies. The patient was treated with a single dose of intramuscular benzathine penicillin G 2.4 million U to prevent the development of tertiary syphilis.
Comment
Incidence
Syphilis has been well characterized since the early 15th century, though its geographic origin remains a topic of controversy.2 Although acquired syphilis infections represented a major source of morbidity and mortality in the early 20th century, the prevalence of syphilis in the United States declined substantially thereafter due to improved public health management.2 Syphilis was relatively rare in the United States by the year 1956, with fewer than 7000 cases of primary and secondary disease reported annually.3 The incidence of primary and secondary syphilis infections in the United States increased gradually until 1990 before declining precipitously and reaching an unprecedented low of 2.2 cases per 100,000 individuals in 2000.4 These shifts ultimately have resulted in decreased clinical familiarity with the disease presentation of syphilis among many health care providers. Since 2000, the incidence of syphilis infection has increased in the United States, with the greatest increases seen in men who have sex with men, intravenous drug users, and human immunodeficiency virus–infected individuals.5-7
RELATED ARTICLE: Syphilis and the Dermatologist
Pathogenesis and Transmission
The causative agent in syphilis infection is the bacterium Treponema pallidum, a member of the family Spirochaetaceae, which is distinguished by its thin, regularly coiled form and distinctive corkscrew motility.8 Syphilis is communicated primarily by sexual contact or in utero exposure during the primary and secondary stages of maternal infection.9 At the time of presentation, our patient denied having any new sexual partners or practices. He reported a monogamous heterosexual relationship within the months preceding presentation, suggesting historical inaccuracy on the part of the patient or probable infidelity in the reported relationship as an alternative means of infection transmission. Untreated individuals may be contagious for longer than 1 year,9 making transmission patterns difficult to track clinically.
Presentation
The clinical presentation of infection with T pallidum results from dual humoral and cell-mediated inflammatory responses in the host. The primary stage is classically defined by a single chancre, which develops at the inoculation site(s) 9 to 90 days following exposure. The chancre typically begins as a small papule that rapidly develops into a painless ulcer characterized by an indurated border, red base, bordering edema, and a diameter of 2 cm or less. Indolent regional lymphadenopathy often is observed in conjunction with the primary chancre.10 Our case is notable for the absence of a primary syphilitic lesion and lack of adenopathy. The primary chancre of syphilis typically resolves within 3 to 6 weeks of onset regardless of whether the patient is treated,4 thus suggesting the rare possibility that our patient developed a painless primary chancre without realizing it.
The secondary stage of syphilis infection arises weeks to months after resolution of the primary chancre and is triggered by hematogenous and lymphatic dissemination of the bacteria. The symptoms of secondary syphilis are primarily flulike and may include headache, malaise, fatigue, sore throat, arthralgia, and low-grade fever.9 Nontender regional lymphadenopathy and splenomegaly also have been reported.11 Our patient denied any systemic concerns throughout the duration of his illness, with the exception of odynophagia in association with ulceration of the oral mucosa. Abnormal laboratory findings in secondary syphilis are nonspecific and may include an elevated erythrocyte sedimentation rate and/or an increased white blood cell count with absolute lymphocytosis.12 Laboratory studies drawn at the time of presentation showed no such abnormalities in our patient.
The cutaneous signs of secondary syphilis arise concurrently with systemic manifestations and are a common finding, with lesions of the skin or oral mucosa present in up to 80% of patients,13 as in our case. Oral lesions classically involve ulcerations at the tip and sides of the tongue,12 which is distinct from our patient who developed oral lesions of the mucosal lip and hard palate.
Secondary syphilis classically features a copper-colored maculopapular rash with sharply delineated margins typically present on the palmar and plantar surfaces.14 Verrucous lesions appearing as moist exophytic plaques on the genitals, intertriginous areas, and/or perineum also have been described and are referred to as condyloma lata in the setting of secondary syphilis.15 In contrast to these classic findings, our patient demonstrated lichenoid lesions on the genitalia and white mucosal patches on the oral mucosa. Our case also was highly unusual because of the intense pruritus associated with the genital lesions, which starkly contrasts most secondary-stage cutaneous lesions that are classically asymptomatic.14 Additionally, our case was distinctive due to the lack of palmar or plantar involvement, which is considered a characteristic feature of secondary cutaneous syphilis.1 Finally, our case was notable for the presence of multiple annular cutaneous lesions, which indicated a late secondary-stage infection during which involution of the lesions produced endarteritis as deeper vessels became involved. A 20-year retrospective study by Abell et al11 demonstrated that 40% of syphilitic rashes are macular, 40% are maculopapular, 10% are papular (as in our case), and the remaining 10% are not easily grouped within these categories.
Differential Diagnosis
It has been estimated that approximately 8% of cutaneous syphilitic lesions demonstrate morphology and distributions suggestive of other dermatologic conditions, including atopic dermatitis, pityriasis rosea, psoriasis, drug-induced eruptions, erythema multiforme, mycosis fungoides, and far more uncommonly lichenoid lesions,16,17 as in our case.
Histopathology
It has been demonstrated that the gross appearance of the secondary syphilitic lesion depends both on the degree of inflammatory infiltrate and the extent of vascular involvement producing ischemia of the skin.1 Our case presented with small, flat-topped, papular lesions that grossly resembled lichen planus and were ultimately shown to be the product of dense lymphomononuclear infiltration extending perivascularly and throughout the superficial and deep dermis.
Biopsy of a lesion is one means of diagnosis, though the histologic appearance of secondary syphilis can mimic many other diseases. In primary and secondary syphilis, skin biopsy characteristically shows central thinning or ulceration of the epidermal layer with heavy dermal lymphocyte infiltration, lymphovascular proliferation with endarteritis, small-vessel thrombosis, and dermal necrosis. Lichen planus–type dermatitis is histologically characterized by hyperkeratosis, irregular epidermal hyperplasia, and a dermoepidermal junction that may be obscured by a dense lymphomononuclear infiltrate.9 The specimen taken from our patient showed minimal infiltrate in the papillary dermis, suggesting a diagnosis of secondary syphilis with lichenoid features. Despite a gross appearance consistent with lichen planus, the biopsy lacked the hydropic degeneration of the basal layer and keratinocyte necrosis that typically characterize this condition.
Diagnosis
Serologic testing for syphilis infection is comprised of nontreponemal and treponemal studies. Nontreponemal testing, which includes the RPR and VDRL test, detects antibodies to cardiolipin-lecithin antigen, a lipid component of the cell membranes of T pallidum. Because the specificity of these tests is fairly low, they typically are used only for screening and monitoring of disease progression and/or response to treatment. Approximately 25% of cases in the United States of primary syphilis are not detected by nontreponemal testing, whereas a nonreactive test nearly always excludes a diagnosis of secondary or latent-stage syphilitic infection.9 Indeed, nontreponemal studies show the highest antibody titers during the late secondary and early latent stages of infection with declining titers thereafter, even in the absence of antibiotic treatment. In our case, diagnosis was made by biopsy and RPR was used for staging; RPR was reactive at a dilution of 1:32, indicative of secondary or early latent infection.
Treponemal testing, which includes the fluorescent treponemal antibody absorption test, and multiplex flow immunoassay detects antibodies that are specific to syphilis infection. Treponemal antibodies are detectable earlier in the course of infection than nontreponemal antibodies and remain permanently detectable even following treatment. Because of its high specificity, treponemal testing often is used to confirm diagnosis after positive screening with nontreponemal tests.4 Positive fluorescent treponemal antibody absorption testing and positive multiplex flow immunoassay may be used to confirm the diagnosis of T pallidum infection.
The tertiary stage of syphilis infection can occur years after conclusion of the secondary stage and is comprised of one or more of the following: gummas, aortic dilatation or dissection, and neurosyphilitic manifestations such as tabes dorsalis or general paresis.1 It is of vital importance to identify syphilis infection prior to the onset of the tertiary stage to prevent substantial morbidity and mortality.
Treatment
Our patient’s symptoms abated after empiric treatment with amoxicillin for presumed streptococcal throat infection after he presented to the emergency department with odynophagia, which is not surprising given the moderate-spectrum coverage of this β-lactam antibiotic as well as the near-complete susceptibility of Treponema spirochetes to amoxicillin in primary and secondary syphilis with notably lower efficacy in latent or tertiary disease. It was essential to treat the patient with a single dose of intramuscular benzathine penicillin G 2.4 million U, which has been shown to reliably prevent recurrence of infection or progression to tertiary syphilis.18
Conclusion
We present a rare case of lichenoid secondary syphilis in the absence of lesions on the palmar and plantar surfaces. The patient lacked any other cutaneous or systemic manifestations, except for odynophagia in association with oral mucosal lesions. He denied any new sexual partners and did not recall having a primary chancre. Also strikingly unusual in this case was the intense pruritus associated with the genital eruption, which is unlike the classic lack of symptoms experienced in the great majority of eruptions due to secondary syphilis. A clinical appreciation of the many cutaneous manifestations of syphilis infection remains critical to early identification of the disease prior to progression to the tertiary stage and its devastating sequelae.
- Dourmishev LA, Assen L. Syphilis: uncommon presentations in adults. Clin Dermatol. 2005;23:555-564.
- Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51:700-708.
- Kilmarx PH, St Louis ME. The evolving epidemiology of syphilis. Am J Public Health. 1995;85(8, pt 1):1053-1054.
- Patton ME, Su JR, Nelson R, et al. Primary and secondary syphilis—United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63:402-406.
- Coffin LS, Newberry A, Hagan H, et al. Syphilis in drug users in low and middle income countries. Int J Drug Policy. 2010;21:20-27.
- Gao L, Zhang L, Jin Q. Meta-analysis: prevalence of HIV infection and syphilis among MSM in China. Sex Transm Infect. 2009;85:354-358.
- Karp G, Schlaeffer F, Jotkowitz A, et al. Syphilis and HIV co-infection. Eur J Int Med. 2009;20:9-13.
- Hol EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. J Clin Invest. 2011;121:4584-4592.
- Schnirring-Judge M, Gustaferro C, Terol C. Vesiculobullous syphilis: a case involving an unusual cutaneous manifestation of secondary syphilis. J Foot Ankle Surg. 2011;50:96-101.
- Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician. 2003;68:283-290.
- Abell E, Marks R, Jones W. Secondary syphilis: a clinicopathological review. Br J Dermatol. 1975;93:53-61.
- Fiumara N. The treponematoses. Int Dermatol. 1992;1:953-974.
- Martin DH, Mroczkowski TF. Dermatological manifestations of sexually transmitted diseases other than HIV. Infect Dis Clin North Am. 1994;8:533-583.
- Morton RS. The treponematoses. In: Champion RH, Bourton JL, Burns DA, et al. Rook’s Textbook of Dermatology. 6th ed. London, United Kingdom: Blackwell Science; 1998:1237-1275.
- Rosen T, Hwong H. Pedal interdigital condylomata lata: a rare sign of secondary syphilis. Sex Transm Dis. 2001;28:184-186.
- Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373-377.
- Tang MBY, Yosipovitch G, Tan SH. Secondary syphilis presenting as a lichen planus-like rash. J Eur Acad Dermatol Venereol. 2004;18:185-187.
- Onoda Y. Clinical evaluation of amoxicillin in the treatment of syphilis. J Int Med. 1979;7:539-545.
Syphilis is a chronic systemic infection that has been allotted the epithet “the great imitator” for its gross and histologic similarity to numerous other skin pathologies. Well-characterized for centuries, syphilis features diverse clinical manifestations including a number of cutaneous symptoms.1
RELATED AUDIOCAST: The Syphilis Epidemic: Dermatologists on the Frontline of Treatment and Diagnosis
The primary stage of infection is classically defined by an asymptomatic chancre at the inoculation site. The secondary stage results from the systemic dissemination of the infection and typically is characterized by cutaneous eruptions, regional lymphadenopathy, and flulike symptoms. This stage gained its notoriety as the great imitator owing to its ability to present with a variety of papulosquamous eruptions. The secondary stage is followed by an asymptomatic latent period that may last months to years, followed by the tertiary stage, which is characterized by the neurologic, cardiovascular, and/or gummatous manifestations that represent the major sources of morbidity and mortality associated with syphilis. It is during the primary, secondary, and early latent stages that the infection is communicable.1
Case Report
A 40-year-old man presented with multiple intensely pruritic, scattered, erythematous and slightly violaceous, flat-topped papules on the scrotum (Figure 1A) and penile shaft (Figure 1B) of 1 week’s duration. Some of these lesions were annular in appearance. The patient denied any other dermatologic concerns and showed no other skin lesions. A shave biopsy of the right side of the penile shaft was performed, revealing minimal papillary dermis and superficial perivascular dermatitis with substantial perivascular plasmalymphocytic infiltration. The epidermal layer was mildly acanthotic with parakeratosis. A tentative diagnosis of secondary syphilis of unknown latency was made and confirmatory laboratory studies were ordered.
Within weeks, the patient developed a painful 7-mm white patch on the right lower mucosal lip followed several days later by the appearance of a painful lesion on the hard palate (Figure 2 [arrow indicates palatal lesion]) and odynophagia. He presented to the emergency department roughly 3 weeks from the time of index presentation and was started empirically on amoxicillin 500 mg 3 times daily for 10 days for suspicion of strep throat. At a scheduled follow-up with his dermatologist 1 week later, physical examination showed complete resolution of the mucosal lip patch and genital lesions. A round erythematous patch on the right hard palate consistent with a resolving mucosal patch also was noted. A diagnosis of secondary syphilitic infection was made with a rapid plasma reagin (RPR) titer of 1:32 (reference range, <1:1) and positive Treponema antibodies. The patient was treated with a single dose of intramuscular benzathine penicillin G 2.4 million U to prevent the development of tertiary syphilis.
Comment
Incidence
Syphilis has been well characterized since the early 15th century, though its geographic origin remains a topic of controversy.2 Although acquired syphilis infections represented a major source of morbidity and mortality in the early 20th century, the prevalence of syphilis in the United States declined substantially thereafter due to improved public health management.2 Syphilis was relatively rare in the United States by the year 1956, with fewer than 7000 cases of primary and secondary disease reported annually.3 The incidence of primary and secondary syphilis infections in the United States increased gradually until 1990 before declining precipitously and reaching an unprecedented low of 2.2 cases per 100,000 individuals in 2000.4 These shifts ultimately have resulted in decreased clinical familiarity with the disease presentation of syphilis among many health care providers. Since 2000, the incidence of syphilis infection has increased in the United States, with the greatest increases seen in men who have sex with men, intravenous drug users, and human immunodeficiency virus–infected individuals.5-7
RELATED ARTICLE: Syphilis and the Dermatologist
Pathogenesis and Transmission
The causative agent in syphilis infection is the bacterium Treponema pallidum, a member of the family Spirochaetaceae, which is distinguished by its thin, regularly coiled form and distinctive corkscrew motility.8 Syphilis is communicated primarily by sexual contact or in utero exposure during the primary and secondary stages of maternal infection.9 At the time of presentation, our patient denied having any new sexual partners or practices. He reported a monogamous heterosexual relationship within the months preceding presentation, suggesting historical inaccuracy on the part of the patient or probable infidelity in the reported relationship as an alternative means of infection transmission. Untreated individuals may be contagious for longer than 1 year,9 making transmission patterns difficult to track clinically.
Presentation
The clinical presentation of infection with T pallidum results from dual humoral and cell-mediated inflammatory responses in the host. The primary stage is classically defined by a single chancre, which develops at the inoculation site(s) 9 to 90 days following exposure. The chancre typically begins as a small papule that rapidly develops into a painless ulcer characterized by an indurated border, red base, bordering edema, and a diameter of 2 cm or less. Indolent regional lymphadenopathy often is observed in conjunction with the primary chancre.10 Our case is notable for the absence of a primary syphilitic lesion and lack of adenopathy. The primary chancre of syphilis typically resolves within 3 to 6 weeks of onset regardless of whether the patient is treated,4 thus suggesting the rare possibility that our patient developed a painless primary chancre without realizing it.
The secondary stage of syphilis infection arises weeks to months after resolution of the primary chancre and is triggered by hematogenous and lymphatic dissemination of the bacteria. The symptoms of secondary syphilis are primarily flulike and may include headache, malaise, fatigue, sore throat, arthralgia, and low-grade fever.9 Nontender regional lymphadenopathy and splenomegaly also have been reported.11 Our patient denied any systemic concerns throughout the duration of his illness, with the exception of odynophagia in association with ulceration of the oral mucosa. Abnormal laboratory findings in secondary syphilis are nonspecific and may include an elevated erythrocyte sedimentation rate and/or an increased white blood cell count with absolute lymphocytosis.12 Laboratory studies drawn at the time of presentation showed no such abnormalities in our patient.
The cutaneous signs of secondary syphilis arise concurrently with systemic manifestations and are a common finding, with lesions of the skin or oral mucosa present in up to 80% of patients,13 as in our case. Oral lesions classically involve ulcerations at the tip and sides of the tongue,12 which is distinct from our patient who developed oral lesions of the mucosal lip and hard palate.
Secondary syphilis classically features a copper-colored maculopapular rash with sharply delineated margins typically present on the palmar and plantar surfaces.14 Verrucous lesions appearing as moist exophytic plaques on the genitals, intertriginous areas, and/or perineum also have been described and are referred to as condyloma lata in the setting of secondary syphilis.15 In contrast to these classic findings, our patient demonstrated lichenoid lesions on the genitalia and white mucosal patches on the oral mucosa. Our case also was highly unusual because of the intense pruritus associated with the genital lesions, which starkly contrasts most secondary-stage cutaneous lesions that are classically asymptomatic.14 Additionally, our case was distinctive due to the lack of palmar or plantar involvement, which is considered a characteristic feature of secondary cutaneous syphilis.1 Finally, our case was notable for the presence of multiple annular cutaneous lesions, which indicated a late secondary-stage infection during which involution of the lesions produced endarteritis as deeper vessels became involved. A 20-year retrospective study by Abell et al11 demonstrated that 40% of syphilitic rashes are macular, 40% are maculopapular, 10% are papular (as in our case), and the remaining 10% are not easily grouped within these categories.
Differential Diagnosis
It has been estimated that approximately 8% of cutaneous syphilitic lesions demonstrate morphology and distributions suggestive of other dermatologic conditions, including atopic dermatitis, pityriasis rosea, psoriasis, drug-induced eruptions, erythema multiforme, mycosis fungoides, and far more uncommonly lichenoid lesions,16,17 as in our case.
Histopathology
It has been demonstrated that the gross appearance of the secondary syphilitic lesion depends both on the degree of inflammatory infiltrate and the extent of vascular involvement producing ischemia of the skin.1 Our case presented with small, flat-topped, papular lesions that grossly resembled lichen planus and were ultimately shown to be the product of dense lymphomononuclear infiltration extending perivascularly and throughout the superficial and deep dermis.
Biopsy of a lesion is one means of diagnosis, though the histologic appearance of secondary syphilis can mimic many other diseases. In primary and secondary syphilis, skin biopsy characteristically shows central thinning or ulceration of the epidermal layer with heavy dermal lymphocyte infiltration, lymphovascular proliferation with endarteritis, small-vessel thrombosis, and dermal necrosis. Lichen planus–type dermatitis is histologically characterized by hyperkeratosis, irregular epidermal hyperplasia, and a dermoepidermal junction that may be obscured by a dense lymphomononuclear infiltrate.9 The specimen taken from our patient showed minimal infiltrate in the papillary dermis, suggesting a diagnosis of secondary syphilis with lichenoid features. Despite a gross appearance consistent with lichen planus, the biopsy lacked the hydropic degeneration of the basal layer and keratinocyte necrosis that typically characterize this condition.
Diagnosis
Serologic testing for syphilis infection is comprised of nontreponemal and treponemal studies. Nontreponemal testing, which includes the RPR and VDRL test, detects antibodies to cardiolipin-lecithin antigen, a lipid component of the cell membranes of T pallidum. Because the specificity of these tests is fairly low, they typically are used only for screening and monitoring of disease progression and/or response to treatment. Approximately 25% of cases in the United States of primary syphilis are not detected by nontreponemal testing, whereas a nonreactive test nearly always excludes a diagnosis of secondary or latent-stage syphilitic infection.9 Indeed, nontreponemal studies show the highest antibody titers during the late secondary and early latent stages of infection with declining titers thereafter, even in the absence of antibiotic treatment. In our case, diagnosis was made by biopsy and RPR was used for staging; RPR was reactive at a dilution of 1:32, indicative of secondary or early latent infection.
Treponemal testing, which includes the fluorescent treponemal antibody absorption test, and multiplex flow immunoassay detects antibodies that are specific to syphilis infection. Treponemal antibodies are detectable earlier in the course of infection than nontreponemal antibodies and remain permanently detectable even following treatment. Because of its high specificity, treponemal testing often is used to confirm diagnosis after positive screening with nontreponemal tests.4 Positive fluorescent treponemal antibody absorption testing and positive multiplex flow immunoassay may be used to confirm the diagnosis of T pallidum infection.
The tertiary stage of syphilis infection can occur years after conclusion of the secondary stage and is comprised of one or more of the following: gummas, aortic dilatation or dissection, and neurosyphilitic manifestations such as tabes dorsalis or general paresis.1 It is of vital importance to identify syphilis infection prior to the onset of the tertiary stage to prevent substantial morbidity and mortality.
Treatment
Our patient’s symptoms abated after empiric treatment with amoxicillin for presumed streptococcal throat infection after he presented to the emergency department with odynophagia, which is not surprising given the moderate-spectrum coverage of this β-lactam antibiotic as well as the near-complete susceptibility of Treponema spirochetes to amoxicillin in primary and secondary syphilis with notably lower efficacy in latent or tertiary disease. It was essential to treat the patient with a single dose of intramuscular benzathine penicillin G 2.4 million U, which has been shown to reliably prevent recurrence of infection or progression to tertiary syphilis.18
Conclusion
We present a rare case of lichenoid secondary syphilis in the absence of lesions on the palmar and plantar surfaces. The patient lacked any other cutaneous or systemic manifestations, except for odynophagia in association with oral mucosal lesions. He denied any new sexual partners and did not recall having a primary chancre. Also strikingly unusual in this case was the intense pruritus associated with the genital eruption, which is unlike the classic lack of symptoms experienced in the great majority of eruptions due to secondary syphilis. A clinical appreciation of the many cutaneous manifestations of syphilis infection remains critical to early identification of the disease prior to progression to the tertiary stage and its devastating sequelae.
Syphilis is a chronic systemic infection that has been allotted the epithet “the great imitator” for its gross and histologic similarity to numerous other skin pathologies. Well-characterized for centuries, syphilis features diverse clinical manifestations including a number of cutaneous symptoms.1
RELATED AUDIOCAST: The Syphilis Epidemic: Dermatologists on the Frontline of Treatment and Diagnosis
The primary stage of infection is classically defined by an asymptomatic chancre at the inoculation site. The secondary stage results from the systemic dissemination of the infection and typically is characterized by cutaneous eruptions, regional lymphadenopathy, and flulike symptoms. This stage gained its notoriety as the great imitator owing to its ability to present with a variety of papulosquamous eruptions. The secondary stage is followed by an asymptomatic latent period that may last months to years, followed by the tertiary stage, which is characterized by the neurologic, cardiovascular, and/or gummatous manifestations that represent the major sources of morbidity and mortality associated with syphilis. It is during the primary, secondary, and early latent stages that the infection is communicable.1
Case Report
A 40-year-old man presented with multiple intensely pruritic, scattered, erythematous and slightly violaceous, flat-topped papules on the scrotum (Figure 1A) and penile shaft (Figure 1B) of 1 week’s duration. Some of these lesions were annular in appearance. The patient denied any other dermatologic concerns and showed no other skin lesions. A shave biopsy of the right side of the penile shaft was performed, revealing minimal papillary dermis and superficial perivascular dermatitis with substantial perivascular plasmalymphocytic infiltration. The epidermal layer was mildly acanthotic with parakeratosis. A tentative diagnosis of secondary syphilis of unknown latency was made and confirmatory laboratory studies were ordered.
Within weeks, the patient developed a painful 7-mm white patch on the right lower mucosal lip followed several days later by the appearance of a painful lesion on the hard palate (Figure 2 [arrow indicates palatal lesion]) and odynophagia. He presented to the emergency department roughly 3 weeks from the time of index presentation and was started empirically on amoxicillin 500 mg 3 times daily for 10 days for suspicion of strep throat. At a scheduled follow-up with his dermatologist 1 week later, physical examination showed complete resolution of the mucosal lip patch and genital lesions. A round erythematous patch on the right hard palate consistent with a resolving mucosal patch also was noted. A diagnosis of secondary syphilitic infection was made with a rapid plasma reagin (RPR) titer of 1:32 (reference range, <1:1) and positive Treponema antibodies. The patient was treated with a single dose of intramuscular benzathine penicillin G 2.4 million U to prevent the development of tertiary syphilis.
Comment
Incidence
Syphilis has been well characterized since the early 15th century, though its geographic origin remains a topic of controversy.2 Although acquired syphilis infections represented a major source of morbidity and mortality in the early 20th century, the prevalence of syphilis in the United States declined substantially thereafter due to improved public health management.2 Syphilis was relatively rare in the United States by the year 1956, with fewer than 7000 cases of primary and secondary disease reported annually.3 The incidence of primary and secondary syphilis infections in the United States increased gradually until 1990 before declining precipitously and reaching an unprecedented low of 2.2 cases per 100,000 individuals in 2000.4 These shifts ultimately have resulted in decreased clinical familiarity with the disease presentation of syphilis among many health care providers. Since 2000, the incidence of syphilis infection has increased in the United States, with the greatest increases seen in men who have sex with men, intravenous drug users, and human immunodeficiency virus–infected individuals.5-7
RELATED ARTICLE: Syphilis and the Dermatologist
Pathogenesis and Transmission
The causative agent in syphilis infection is the bacterium Treponema pallidum, a member of the family Spirochaetaceae, which is distinguished by its thin, regularly coiled form and distinctive corkscrew motility.8 Syphilis is communicated primarily by sexual contact or in utero exposure during the primary and secondary stages of maternal infection.9 At the time of presentation, our patient denied having any new sexual partners or practices. He reported a monogamous heterosexual relationship within the months preceding presentation, suggesting historical inaccuracy on the part of the patient or probable infidelity in the reported relationship as an alternative means of infection transmission. Untreated individuals may be contagious for longer than 1 year,9 making transmission patterns difficult to track clinically.
Presentation
The clinical presentation of infection with T pallidum results from dual humoral and cell-mediated inflammatory responses in the host. The primary stage is classically defined by a single chancre, which develops at the inoculation site(s) 9 to 90 days following exposure. The chancre typically begins as a small papule that rapidly develops into a painless ulcer characterized by an indurated border, red base, bordering edema, and a diameter of 2 cm or less. Indolent regional lymphadenopathy often is observed in conjunction with the primary chancre.10 Our case is notable for the absence of a primary syphilitic lesion and lack of adenopathy. The primary chancre of syphilis typically resolves within 3 to 6 weeks of onset regardless of whether the patient is treated,4 thus suggesting the rare possibility that our patient developed a painless primary chancre without realizing it.
The secondary stage of syphilis infection arises weeks to months after resolution of the primary chancre and is triggered by hematogenous and lymphatic dissemination of the bacteria. The symptoms of secondary syphilis are primarily flulike and may include headache, malaise, fatigue, sore throat, arthralgia, and low-grade fever.9 Nontender regional lymphadenopathy and splenomegaly also have been reported.11 Our patient denied any systemic concerns throughout the duration of his illness, with the exception of odynophagia in association with ulceration of the oral mucosa. Abnormal laboratory findings in secondary syphilis are nonspecific and may include an elevated erythrocyte sedimentation rate and/or an increased white blood cell count with absolute lymphocytosis.12 Laboratory studies drawn at the time of presentation showed no such abnormalities in our patient.
The cutaneous signs of secondary syphilis arise concurrently with systemic manifestations and are a common finding, with lesions of the skin or oral mucosa present in up to 80% of patients,13 as in our case. Oral lesions classically involve ulcerations at the tip and sides of the tongue,12 which is distinct from our patient who developed oral lesions of the mucosal lip and hard palate.
Secondary syphilis classically features a copper-colored maculopapular rash with sharply delineated margins typically present on the palmar and plantar surfaces.14 Verrucous lesions appearing as moist exophytic plaques on the genitals, intertriginous areas, and/or perineum also have been described and are referred to as condyloma lata in the setting of secondary syphilis.15 In contrast to these classic findings, our patient demonstrated lichenoid lesions on the genitalia and white mucosal patches on the oral mucosa. Our case also was highly unusual because of the intense pruritus associated with the genital lesions, which starkly contrasts most secondary-stage cutaneous lesions that are classically asymptomatic.14 Additionally, our case was distinctive due to the lack of palmar or plantar involvement, which is considered a characteristic feature of secondary cutaneous syphilis.1 Finally, our case was notable for the presence of multiple annular cutaneous lesions, which indicated a late secondary-stage infection during which involution of the lesions produced endarteritis as deeper vessels became involved. A 20-year retrospective study by Abell et al11 demonstrated that 40% of syphilitic rashes are macular, 40% are maculopapular, 10% are papular (as in our case), and the remaining 10% are not easily grouped within these categories.
Differential Diagnosis
It has been estimated that approximately 8% of cutaneous syphilitic lesions demonstrate morphology and distributions suggestive of other dermatologic conditions, including atopic dermatitis, pityriasis rosea, psoriasis, drug-induced eruptions, erythema multiforme, mycosis fungoides, and far more uncommonly lichenoid lesions,16,17 as in our case.
Histopathology
It has been demonstrated that the gross appearance of the secondary syphilitic lesion depends both on the degree of inflammatory infiltrate and the extent of vascular involvement producing ischemia of the skin.1 Our case presented with small, flat-topped, papular lesions that grossly resembled lichen planus and were ultimately shown to be the product of dense lymphomononuclear infiltration extending perivascularly and throughout the superficial and deep dermis.
Biopsy of a lesion is one means of diagnosis, though the histologic appearance of secondary syphilis can mimic many other diseases. In primary and secondary syphilis, skin biopsy characteristically shows central thinning or ulceration of the epidermal layer with heavy dermal lymphocyte infiltration, lymphovascular proliferation with endarteritis, small-vessel thrombosis, and dermal necrosis. Lichen planus–type dermatitis is histologically characterized by hyperkeratosis, irregular epidermal hyperplasia, and a dermoepidermal junction that may be obscured by a dense lymphomononuclear infiltrate.9 The specimen taken from our patient showed minimal infiltrate in the papillary dermis, suggesting a diagnosis of secondary syphilis with lichenoid features. Despite a gross appearance consistent with lichen planus, the biopsy lacked the hydropic degeneration of the basal layer and keratinocyte necrosis that typically characterize this condition.
Diagnosis
Serologic testing for syphilis infection is comprised of nontreponemal and treponemal studies. Nontreponemal testing, which includes the RPR and VDRL test, detects antibodies to cardiolipin-lecithin antigen, a lipid component of the cell membranes of T pallidum. Because the specificity of these tests is fairly low, they typically are used only for screening and monitoring of disease progression and/or response to treatment. Approximately 25% of cases in the United States of primary syphilis are not detected by nontreponemal testing, whereas a nonreactive test nearly always excludes a diagnosis of secondary or latent-stage syphilitic infection.9 Indeed, nontreponemal studies show the highest antibody titers during the late secondary and early latent stages of infection with declining titers thereafter, even in the absence of antibiotic treatment. In our case, diagnosis was made by biopsy and RPR was used for staging; RPR was reactive at a dilution of 1:32, indicative of secondary or early latent infection.
Treponemal testing, which includes the fluorescent treponemal antibody absorption test, and multiplex flow immunoassay detects antibodies that are specific to syphilis infection. Treponemal antibodies are detectable earlier in the course of infection than nontreponemal antibodies and remain permanently detectable even following treatment. Because of its high specificity, treponemal testing often is used to confirm diagnosis after positive screening with nontreponemal tests.4 Positive fluorescent treponemal antibody absorption testing and positive multiplex flow immunoassay may be used to confirm the diagnosis of T pallidum infection.
The tertiary stage of syphilis infection can occur years after conclusion of the secondary stage and is comprised of one or more of the following: gummas, aortic dilatation or dissection, and neurosyphilitic manifestations such as tabes dorsalis or general paresis.1 It is of vital importance to identify syphilis infection prior to the onset of the tertiary stage to prevent substantial morbidity and mortality.
Treatment
Our patient’s symptoms abated after empiric treatment with amoxicillin for presumed streptococcal throat infection after he presented to the emergency department with odynophagia, which is not surprising given the moderate-spectrum coverage of this β-lactam antibiotic as well as the near-complete susceptibility of Treponema spirochetes to amoxicillin in primary and secondary syphilis with notably lower efficacy in latent or tertiary disease. It was essential to treat the patient with a single dose of intramuscular benzathine penicillin G 2.4 million U, which has been shown to reliably prevent recurrence of infection or progression to tertiary syphilis.18
Conclusion
We present a rare case of lichenoid secondary syphilis in the absence of lesions on the palmar and plantar surfaces. The patient lacked any other cutaneous or systemic manifestations, except for odynophagia in association with oral mucosal lesions. He denied any new sexual partners and did not recall having a primary chancre. Also strikingly unusual in this case was the intense pruritus associated with the genital eruption, which is unlike the classic lack of symptoms experienced in the great majority of eruptions due to secondary syphilis. A clinical appreciation of the many cutaneous manifestations of syphilis infection remains critical to early identification of the disease prior to progression to the tertiary stage and its devastating sequelae.
- Dourmishev LA, Assen L. Syphilis: uncommon presentations in adults. Clin Dermatol. 2005;23:555-564.
- Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51:700-708.
- Kilmarx PH, St Louis ME. The evolving epidemiology of syphilis. Am J Public Health. 1995;85(8, pt 1):1053-1054.
- Patton ME, Su JR, Nelson R, et al. Primary and secondary syphilis—United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63:402-406.
- Coffin LS, Newberry A, Hagan H, et al. Syphilis in drug users in low and middle income countries. Int J Drug Policy. 2010;21:20-27.
- Gao L, Zhang L, Jin Q. Meta-analysis: prevalence of HIV infection and syphilis among MSM in China. Sex Transm Infect. 2009;85:354-358.
- Karp G, Schlaeffer F, Jotkowitz A, et al. Syphilis and HIV co-infection. Eur J Int Med. 2009;20:9-13.
- Hol EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. J Clin Invest. 2011;121:4584-4592.
- Schnirring-Judge M, Gustaferro C, Terol C. Vesiculobullous syphilis: a case involving an unusual cutaneous manifestation of secondary syphilis. J Foot Ankle Surg. 2011;50:96-101.
- Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician. 2003;68:283-290.
- Abell E, Marks R, Jones W. Secondary syphilis: a clinicopathological review. Br J Dermatol. 1975;93:53-61.
- Fiumara N. The treponematoses. Int Dermatol. 1992;1:953-974.
- Martin DH, Mroczkowski TF. Dermatological manifestations of sexually transmitted diseases other than HIV. Infect Dis Clin North Am. 1994;8:533-583.
- Morton RS. The treponematoses. In: Champion RH, Bourton JL, Burns DA, et al. Rook’s Textbook of Dermatology. 6th ed. London, United Kingdom: Blackwell Science; 1998:1237-1275.
- Rosen T, Hwong H. Pedal interdigital condylomata lata: a rare sign of secondary syphilis. Sex Transm Dis. 2001;28:184-186.
- Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373-377.
- Tang MBY, Yosipovitch G, Tan SH. Secondary syphilis presenting as a lichen planus-like rash. J Eur Acad Dermatol Venereol. 2004;18:185-187.
- Onoda Y. Clinical evaluation of amoxicillin in the treatment of syphilis. J Int Med. 1979;7:539-545.
- Dourmishev LA, Assen L. Syphilis: uncommon presentations in adults. Clin Dermatol. 2005;23:555-564.
- Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51:700-708.
- Kilmarx PH, St Louis ME. The evolving epidemiology of syphilis. Am J Public Health. 1995;85(8, pt 1):1053-1054.
- Patton ME, Su JR, Nelson R, et al. Primary and secondary syphilis—United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63:402-406.
- Coffin LS, Newberry A, Hagan H, et al. Syphilis in drug users in low and middle income countries. Int J Drug Policy. 2010;21:20-27.
- Gao L, Zhang L, Jin Q. Meta-analysis: prevalence of HIV infection and syphilis among MSM in China. Sex Transm Infect. 2009;85:354-358.
- Karp G, Schlaeffer F, Jotkowitz A, et al. Syphilis and HIV co-infection. Eur J Int Med. 2009;20:9-13.
- Hol EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. J Clin Invest. 2011;121:4584-4592.
- Schnirring-Judge M, Gustaferro C, Terol C. Vesiculobullous syphilis: a case involving an unusual cutaneous manifestation of secondary syphilis. J Foot Ankle Surg. 2011;50:96-101.
- Brown DL, Frank JE. Diagnosis and management of syphilis. Am Fam Physician. 2003;68:283-290.
- Abell E, Marks R, Jones W. Secondary syphilis: a clinicopathological review. Br J Dermatol. 1975;93:53-61.
- Fiumara N. The treponematoses. Int Dermatol. 1992;1:953-974.
- Martin DH, Mroczkowski TF. Dermatological manifestations of sexually transmitted diseases other than HIV. Infect Dis Clin North Am. 1994;8:533-583.
- Morton RS. The treponematoses. In: Champion RH, Bourton JL, Burns DA, et al. Rook’s Textbook of Dermatology. 6th ed. London, United Kingdom: Blackwell Science; 1998:1237-1275.
- Rosen T, Hwong H. Pedal interdigital condylomata lata: a rare sign of secondary syphilis. Sex Transm Dis. 2001;28:184-186.
- Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373-377.
- Tang MBY, Yosipovitch G, Tan SH. Secondary syphilis presenting as a lichen planus-like rash. J Eur Acad Dermatol Venereol. 2004;18:185-187.
- Onoda Y. Clinical evaluation of amoxicillin in the treatment of syphilis. J Int Med. 1979;7:539-545.
Practice Points
- Syphilis retains its reputation as “the great imitator” due to its wide variability in clinical presentation and propensity for misdiagnosis.
- Lichenoid syphilis is a well-described cutaneous presentation of secondary syphilis, though the characteristics of these lesions remain highly variable and require a high degree of clinical suspicion.
- Treponema pallidum is partially susceptible to most β-lactam antibiotics in primary and early secondary stages of infection; thus, use of these medications can obscure symptoms without adequately treating the infection.
Novel oral orphan drug tames pemphigus
GENEVA – An oral reversible Bruton tyrosine kinase inhibitor known as PRN1008 showed promising efficacy and safety for the treatment of pemphigus vulgaris in an interim analysis of an ongoing small-to-date, open-label phase 2 study, according to DeDee Murrell, MD.
PRN1008 is a designer drug intended as an alternative to the long-standing standard therapy for pemphigus, months to years of moderate- or high-dose systemic corticosteroids, with all the debilitating side effects that sledgehammer approach often brings, she said at the annual congress of the European Academy of Dermatology and Venereology.
Thus, PRN1008 inhibits a range of inflammatory cellular activities in mast cells, neutrophils, and other cells activated in autoimmune diseases, without killing those cells or directly affecting T cells. And – like corticosteroids – it works quickly, according to Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
“The development of an oral, fast-acting treatment that could safely and effectively modulate B-cell function without depleting B cells would be a major advance in treating autoimmune diseases like pemphigus, vasculitis, immune thrombocytopenic purpura, multiple sclerosis, and rheumatoid arthritis,” she said.
Also, PRN1008 was designed to provide durable inhibition of BTK, coupled with rapid systemic clearance of the drug in order to minimize side effects.
The ongoing phase 2 multicenter international study, known as Believe-PV, to date includes 12 patients with biopsy-proven mild to moderate pemphigus vulgaris. Five patients were newly diagnosed and treatment naive, while seven had relapsing disease. All were placed on fixed-dose PRN1008 at 400 mg b.i.d. for 12 weeks with low-dose prednisone as needed, then followed for an additional 12 weeks off PRN1008 to evaluate the durability of responses.
The primary study endpoint was control of disease activity by week 4 on a background of little or no prednisone, which 5 of 12 patients achieved. The secondary endpoint of complete clinical remission at 12 weeks was achieved in half of patients. Total pemphigus disease activity index (PDAI) scores dropped throughout the study period, reaching a mean 70% reduction at 12 weeks from a baseline of 20 points. Scores on the autoimmune bullous quality of life metric improved by 43%.
Eight of the 11 individuals who completed the study had control of disease activity by week 4 and/or complete clinical remission at 12 weeks. Those results are comparable with those typically seen with high-dose steroids at 12 weeks, the dermatologist noted.
Levels of anti–desmoglein-1 and/or -3 autoantibodies, which were elevated at baseline in 10 of 12 subjects, decreased during treatment with PRN1008.
Seventy-five percent of Bruton tyrosine kinase receptors were occupied by PRN1008 by day 2 of the study, confirming earlier studies in canine models of pemphigus. It turns out that pemphigus foliaceus is as common in dogs as atopic dermatitis is in humans, according to Dr. Murrell.
Side effects were limited to mild headache in two patients. One patient developed serious grade 3 cellulitis. She was taken off the study medication, although it was deemed unlikely that the infection was treatment related because she had had a recent history of multiple episodes of cellulitis.
During the second 12-week phase of the trial, after discontinuation of PRN1008, most patients retained their on-treatment reduction in total PDAI scores.
Dr. Murrell noted that the gradient of improvement in PDAI scores seen with PRN1008 in the Believe-PV study was quite similar to that seen in a recent 90-patient French randomized trial of rituximab (Rituxan) for the treatment of pemphigus. That’s of considerable interest, she said, because rituximab is a much more powerful drug, which drastically depletes the B-cell population. Moreover, the gradient of improvement in the rituximab-treated patients in the French trial was achieved with the aid of moderate-dose prednisone at 1 or 1.5 mg/kg per day, while PRN1008-treated patients in Believe-PV were taking on average only 0.2 mg/kg per day.
Asked if she thinks PRN1008 has a future as a stand-alone treatment for pemphigus or is better suited as an adjunct to systemic corticosteroids, Dr. Murrell said she believes the drug can be used effectively without steroids. However, since it’s recommended that patients be screened for tuberculosis before going on rituximab, and PRN1008 also targets B cells, she and her coinvestigators followed the same practice in Believe-PV. And because it takes a couple of weeks for the results of the Quantiferon-TB Gold In-Tube test to come back, it would be unethical for patients newly diagnosed with pemphigus to go untreated and in pain during that period, they get corticosteroids, at least initially.
Dr. Murrell reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008.
GENEVA – An oral reversible Bruton tyrosine kinase inhibitor known as PRN1008 showed promising efficacy and safety for the treatment of pemphigus vulgaris in an interim analysis of an ongoing small-to-date, open-label phase 2 study, according to DeDee Murrell, MD.
PRN1008 is a designer drug intended as an alternative to the long-standing standard therapy for pemphigus, months to years of moderate- or high-dose systemic corticosteroids, with all the debilitating side effects that sledgehammer approach often brings, she said at the annual congress of the European Academy of Dermatology and Venereology.
Thus, PRN1008 inhibits a range of inflammatory cellular activities in mast cells, neutrophils, and other cells activated in autoimmune diseases, without killing those cells or directly affecting T cells. And – like corticosteroids – it works quickly, according to Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
“The development of an oral, fast-acting treatment that could safely and effectively modulate B-cell function without depleting B cells would be a major advance in treating autoimmune diseases like pemphigus, vasculitis, immune thrombocytopenic purpura, multiple sclerosis, and rheumatoid arthritis,” she said.
Also, PRN1008 was designed to provide durable inhibition of BTK, coupled with rapid systemic clearance of the drug in order to minimize side effects.
The ongoing phase 2 multicenter international study, known as Believe-PV, to date includes 12 patients with biopsy-proven mild to moderate pemphigus vulgaris. Five patients were newly diagnosed and treatment naive, while seven had relapsing disease. All were placed on fixed-dose PRN1008 at 400 mg b.i.d. for 12 weeks with low-dose prednisone as needed, then followed for an additional 12 weeks off PRN1008 to evaluate the durability of responses.
The primary study endpoint was control of disease activity by week 4 on a background of little or no prednisone, which 5 of 12 patients achieved. The secondary endpoint of complete clinical remission at 12 weeks was achieved in half of patients. Total pemphigus disease activity index (PDAI) scores dropped throughout the study period, reaching a mean 70% reduction at 12 weeks from a baseline of 20 points. Scores on the autoimmune bullous quality of life metric improved by 43%.
Eight of the 11 individuals who completed the study had control of disease activity by week 4 and/or complete clinical remission at 12 weeks. Those results are comparable with those typically seen with high-dose steroids at 12 weeks, the dermatologist noted.
Levels of anti–desmoglein-1 and/or -3 autoantibodies, which were elevated at baseline in 10 of 12 subjects, decreased during treatment with PRN1008.
Seventy-five percent of Bruton tyrosine kinase receptors were occupied by PRN1008 by day 2 of the study, confirming earlier studies in canine models of pemphigus. It turns out that pemphigus foliaceus is as common in dogs as atopic dermatitis is in humans, according to Dr. Murrell.
Side effects were limited to mild headache in two patients. One patient developed serious grade 3 cellulitis. She was taken off the study medication, although it was deemed unlikely that the infection was treatment related because she had had a recent history of multiple episodes of cellulitis.
During the second 12-week phase of the trial, after discontinuation of PRN1008, most patients retained their on-treatment reduction in total PDAI scores.
Dr. Murrell noted that the gradient of improvement in PDAI scores seen with PRN1008 in the Believe-PV study was quite similar to that seen in a recent 90-patient French randomized trial of rituximab (Rituxan) for the treatment of pemphigus. That’s of considerable interest, she said, because rituximab is a much more powerful drug, which drastically depletes the B-cell population. Moreover, the gradient of improvement in the rituximab-treated patients in the French trial was achieved with the aid of moderate-dose prednisone at 1 or 1.5 mg/kg per day, while PRN1008-treated patients in Believe-PV were taking on average only 0.2 mg/kg per day.
Asked if she thinks PRN1008 has a future as a stand-alone treatment for pemphigus or is better suited as an adjunct to systemic corticosteroids, Dr. Murrell said she believes the drug can be used effectively without steroids. However, since it’s recommended that patients be screened for tuberculosis before going on rituximab, and PRN1008 also targets B cells, she and her coinvestigators followed the same practice in Believe-PV. And because it takes a couple of weeks for the results of the Quantiferon-TB Gold In-Tube test to come back, it would be unethical for patients newly diagnosed with pemphigus to go untreated and in pain during that period, they get corticosteroids, at least initially.
Dr. Murrell reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008.
GENEVA – An oral reversible Bruton tyrosine kinase inhibitor known as PRN1008 showed promising efficacy and safety for the treatment of pemphigus vulgaris in an interim analysis of an ongoing small-to-date, open-label phase 2 study, according to DeDee Murrell, MD.
PRN1008 is a designer drug intended as an alternative to the long-standing standard therapy for pemphigus, months to years of moderate- or high-dose systemic corticosteroids, with all the debilitating side effects that sledgehammer approach often brings, she said at the annual congress of the European Academy of Dermatology and Venereology.
Thus, PRN1008 inhibits a range of inflammatory cellular activities in mast cells, neutrophils, and other cells activated in autoimmune diseases, without killing those cells or directly affecting T cells. And – like corticosteroids – it works quickly, according to Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
“The development of an oral, fast-acting treatment that could safely and effectively modulate B-cell function without depleting B cells would be a major advance in treating autoimmune diseases like pemphigus, vasculitis, immune thrombocytopenic purpura, multiple sclerosis, and rheumatoid arthritis,” she said.
Also, PRN1008 was designed to provide durable inhibition of BTK, coupled with rapid systemic clearance of the drug in order to minimize side effects.
The ongoing phase 2 multicenter international study, known as Believe-PV, to date includes 12 patients with biopsy-proven mild to moderate pemphigus vulgaris. Five patients were newly diagnosed and treatment naive, while seven had relapsing disease. All were placed on fixed-dose PRN1008 at 400 mg b.i.d. for 12 weeks with low-dose prednisone as needed, then followed for an additional 12 weeks off PRN1008 to evaluate the durability of responses.
The primary study endpoint was control of disease activity by week 4 on a background of little or no prednisone, which 5 of 12 patients achieved. The secondary endpoint of complete clinical remission at 12 weeks was achieved in half of patients. Total pemphigus disease activity index (PDAI) scores dropped throughout the study period, reaching a mean 70% reduction at 12 weeks from a baseline of 20 points. Scores on the autoimmune bullous quality of life metric improved by 43%.
Eight of the 11 individuals who completed the study had control of disease activity by week 4 and/or complete clinical remission at 12 weeks. Those results are comparable with those typically seen with high-dose steroids at 12 weeks, the dermatologist noted.
Levels of anti–desmoglein-1 and/or -3 autoantibodies, which were elevated at baseline in 10 of 12 subjects, decreased during treatment with PRN1008.
Seventy-five percent of Bruton tyrosine kinase receptors were occupied by PRN1008 by day 2 of the study, confirming earlier studies in canine models of pemphigus. It turns out that pemphigus foliaceus is as common in dogs as atopic dermatitis is in humans, according to Dr. Murrell.
Side effects were limited to mild headache in two patients. One patient developed serious grade 3 cellulitis. She was taken off the study medication, although it was deemed unlikely that the infection was treatment related because she had had a recent history of multiple episodes of cellulitis.
During the second 12-week phase of the trial, after discontinuation of PRN1008, most patients retained their on-treatment reduction in total PDAI scores.
Dr. Murrell noted that the gradient of improvement in PDAI scores seen with PRN1008 in the Believe-PV study was quite similar to that seen in a recent 90-patient French randomized trial of rituximab (Rituxan) for the treatment of pemphigus. That’s of considerable interest, she said, because rituximab is a much more powerful drug, which drastically depletes the B-cell population. Moreover, the gradient of improvement in the rituximab-treated patients in the French trial was achieved with the aid of moderate-dose prednisone at 1 or 1.5 mg/kg per day, while PRN1008-treated patients in Believe-PV were taking on average only 0.2 mg/kg per day.
Asked if she thinks PRN1008 has a future as a stand-alone treatment for pemphigus or is better suited as an adjunct to systemic corticosteroids, Dr. Murrell said she believes the drug can be used effectively without steroids. However, since it’s recommended that patients be screened for tuberculosis before going on rituximab, and PRN1008 also targets B cells, she and her coinvestigators followed the same practice in Believe-PV. And because it takes a couple of weeks for the results of the Quantiferon-TB Gold In-Tube test to come back, it would be unethical for patients newly diagnosed with pemphigus to go untreated and in pain during that period, they get corticosteroids, at least initially.
Dr. Murrell reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008.
AT THE EADV CONGRESS
Key clinical point:
Major finding: Five of 12 pemphigus vulgaris patients achieved control of disease activity within the first 4 weeks on the investigational oral Bruton tyrosine kinase inhibitor PRN1008.
Data source: An interim analysis of the first 12 patients with pemphigus vulgaris in an ongoing multicenter, international open-label, phase 2 clinical trial.
Disclosures: The study presenter reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008 and sponsored the Believe-PV trial.
More states allowing pharmacists to administer vaccines to younger patients
.
Since the 1990s, states have made laws to increase access to immunization services by giving pharmacists authority to give vaccines, said Cason D. Schmit, JD, of Texas A&M University at College Station, and Matthew S. Penn, JD, director of the Public Health Law Program at the Centers for Disease Control and Prevention, Atlanta. This has the advantage of pharmacies being open longer hours than most physicians’ offices, in addition to the opportunities for immunizing people in rural locations as well as those people without a regular physician.
Yet barriers to pharmacists’ providing immunization services remain because of some state laws. Laws in nine states that prevent pharmacists from vaccinating patients younger than age 18 years keep pharmacists from administering any of the vaccines listed in the 2016 Advisory Committee of Immunization Practices child immunization schedule. The two states in which pharmacists can vaccinate patients as young as 14 years allow the pharmacists to administer only the recommended booster for meningococcal vaccine and annual influenza vaccines for children. And the 15 states with minimum patient age restrictions for 7- to 12-year-oldss allow pharmacists to administer only the four vaccines ACIP recommends on the 2016 schedule for children (meningococcal, Tdap, human papillomavirus, and annual influenza vaccines).
Read more in the Journal of the American Pharmacists Association (2017 Nov-Dec;57[6]:661-9).
.
Since the 1990s, states have made laws to increase access to immunization services by giving pharmacists authority to give vaccines, said Cason D. Schmit, JD, of Texas A&M University at College Station, and Matthew S. Penn, JD, director of the Public Health Law Program at the Centers for Disease Control and Prevention, Atlanta. This has the advantage of pharmacies being open longer hours than most physicians’ offices, in addition to the opportunities for immunizing people in rural locations as well as those people without a regular physician.
Yet barriers to pharmacists’ providing immunization services remain because of some state laws. Laws in nine states that prevent pharmacists from vaccinating patients younger than age 18 years keep pharmacists from administering any of the vaccines listed in the 2016 Advisory Committee of Immunization Practices child immunization schedule. The two states in which pharmacists can vaccinate patients as young as 14 years allow the pharmacists to administer only the recommended booster for meningococcal vaccine and annual influenza vaccines for children. And the 15 states with minimum patient age restrictions for 7- to 12-year-oldss allow pharmacists to administer only the four vaccines ACIP recommends on the 2016 schedule for children (meningococcal, Tdap, human papillomavirus, and annual influenza vaccines).
Read more in the Journal of the American Pharmacists Association (2017 Nov-Dec;57[6]:661-9).
.
Since the 1990s, states have made laws to increase access to immunization services by giving pharmacists authority to give vaccines, said Cason D. Schmit, JD, of Texas A&M University at College Station, and Matthew S. Penn, JD, director of the Public Health Law Program at the Centers for Disease Control and Prevention, Atlanta. This has the advantage of pharmacies being open longer hours than most physicians’ offices, in addition to the opportunities for immunizing people in rural locations as well as those people without a regular physician.
Yet barriers to pharmacists’ providing immunization services remain because of some state laws. Laws in nine states that prevent pharmacists from vaccinating patients younger than age 18 years keep pharmacists from administering any of the vaccines listed in the 2016 Advisory Committee of Immunization Practices child immunization schedule. The two states in which pharmacists can vaccinate patients as young as 14 years allow the pharmacists to administer only the recommended booster for meningococcal vaccine and annual influenza vaccines for children. And the 15 states with minimum patient age restrictions for 7- to 12-year-oldss allow pharmacists to administer only the four vaccines ACIP recommends on the 2016 schedule for children (meningococcal, Tdap, human papillomavirus, and annual influenza vaccines).
Read more in the Journal of the American Pharmacists Association (2017 Nov-Dec;57[6]:661-9).
FROM THE JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION
Novel ADC shows promise in metastatic triple-negative breast cancer
SAN ANTONIO – A novel antibody drug conjugate has shown promise in metastatic triple-negative breast cancer (TNBC), according to new findings presented at the San Antonio Breast Cancer Symposium.
Sacituzumab govitecan, a novel antibody-drug conjugate, demonstrated significant clinical activity when used as a single agent among patients with relapsed/refractory disease who had already received multiple lines of therapy. The objective response rate in a cohort of more than 100 patients was 34%, and that included 3 complete responses and 34 partial responses.
“Sacituzumab govitecan demonstrated significant single-agent activity in this population,” said lead author Aditya Bardia, MD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
“Metastatic triple-negative breast cancer is an aggressive disease with a poor prognosis that tends to affect young women,” said Dr. Bardia. “Visceral and brain metastases are very common. Currently there is no single standard chemotherapy for relapsed or refractory metastatic triple-negative breast cancer.”
He noted that the response rates to standard chemotherapy are low and that median progression-free survival is in the range of 2-3 months. The response rate to standard chemotherapy first line and beyond, based on available data, is in the range of 6-15%.
“Consequently, there is a large unmet need in the breast cancer community,” said Dr. Bardia.
Sacituzumab govitecan (IMMU-132) is an antitrophoblastic cell-surface antigen (anti–Trop-2) and humanized antibody-SN-38 conjugate, which is the active metabolite of the topoisomerase I inhibitor irinotecan. Trop-2 is highly expressed in most epithelial cancers, including TNBC. A phase 1/2 basket trial was previously conducted in a cohort with multiple, advanced epithelial cancers and showed encouraging activity.
Dr. Bardia and his group also published preliminary results earlier this year in patients with metastatic TNBC, which showed an objective response rate of 30%, and last year, sacituzumab govitecan was granted Breakthrough Designation by the Food and Drug Administration. In the current study, the authors expanded the cohort and looked at a more defined population (third-line setting or greater in metastatic TNBC).
In this study, 110 patients who had metastatic TNBC (109 female, 1 male) and had received two or more lines of therapy for metastatic disease were enrolled between July 2013 and February 2017. The cohort included 53 patients from the investigators’ previously reported study in metastatic TNBC (n=69 total). As of this study’s cutoff date (June 30, 2017), 66 patients had died, 30 were in long term follow up, and 14 were still on treatment.
All patients were treated at the 10 mg/kg dose level, receiving 14.5 median doses (range, 1-88) over a median duration of 4.9 months. Treatment was administered on day 1 and 8 in a 21 day cycle, until progression or unacceptable toxicity.
Within the cohort of this heavily pretreated group, 41% received sacituzumab govitecan as third-line therapy while 59% received it at fourth line or more. The majority of patients had previously received taxanes or anthracyclines, and of note, 75% had previously received prior platinum, and 17% had previously received checkpoint inhibitors.
The clinical benefit rate, calculated using the rate of complete and partial response and stable disease greater than 6 months, was 45%. Responses were durable, with a median duration of 7.6 months by local assessment and 9.1 months by central review.
The median progression-free survival was 5.5 months (95% confidence interval, 4.8-6.6) and median overall survival was 12.7 months (95% CI, 10.8-13.6). Of the long term responders, nine have been progression free for more than a year, and four for more than 2 years. At the time of data cutoff, 12 responders were still receiving treatment.
Of note, Dr. Bardia said, patients stayed on sacituzumab govitecan longer than they had stayed on their most recent previous therapy.
The authors also conducted an exploratory subset analysis but found no difference in response when looking at age, prior regimens, onset of metastasis, the presence of visceral involvement at study entry, or Trop-2 expression.
Response among patients who had previously received checkpoint inhibitors was 47%, but Dr. Bardia cautions that “these numbers are small.”
Treatment with sacituzumab govitecan was well tolerated overall, with 2 patients discontinuing the drug because of related toxicity, and no antidrug antibodies detected. Grade 3 or greater toxicity included neutropenia (39%), leukopenia (14%), and anemia (10%); the incidence of febrile neutropenia was low (7%). There was a high rate of gastrointestinal related toxicity, but the majority were grade 1-2, and the rate of grade 3-4 “was in the single digits, ranging from 5-8%,” said Dr. Bardia. There were no drug-related deaths.
Given the high unmet medical need among patients with metastatic TNBC, data from this trial is being sent to the FDA to be considered for accelerated approval, and a global confirmatory randomized Phase 3 is now underway. “The ASCENT trial is recruiting in the United States right now,” said Dr. Bardia; this trial will include patients with metastatic TNBC who will receive either sacituzumab govitecan or physician’s choice of standard therapy.
Additional studies including rational combinations are currently being evaluated for metastatic TNBC and other breast cancer subsets.
SOURCE: Bardia A et al. Abstract GS1-07.
SAN ANTONIO – A novel antibody drug conjugate has shown promise in metastatic triple-negative breast cancer (TNBC), according to new findings presented at the San Antonio Breast Cancer Symposium.
Sacituzumab govitecan, a novel antibody-drug conjugate, demonstrated significant clinical activity when used as a single agent among patients with relapsed/refractory disease who had already received multiple lines of therapy. The objective response rate in a cohort of more than 100 patients was 34%, and that included 3 complete responses and 34 partial responses.
“Sacituzumab govitecan demonstrated significant single-agent activity in this population,” said lead author Aditya Bardia, MD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
“Metastatic triple-negative breast cancer is an aggressive disease with a poor prognosis that tends to affect young women,” said Dr. Bardia. “Visceral and brain metastases are very common. Currently there is no single standard chemotherapy for relapsed or refractory metastatic triple-negative breast cancer.”
He noted that the response rates to standard chemotherapy are low and that median progression-free survival is in the range of 2-3 months. The response rate to standard chemotherapy first line and beyond, based on available data, is in the range of 6-15%.
“Consequently, there is a large unmet need in the breast cancer community,” said Dr. Bardia.
Sacituzumab govitecan (IMMU-132) is an antitrophoblastic cell-surface antigen (anti–Trop-2) and humanized antibody-SN-38 conjugate, which is the active metabolite of the topoisomerase I inhibitor irinotecan. Trop-2 is highly expressed in most epithelial cancers, including TNBC. A phase 1/2 basket trial was previously conducted in a cohort with multiple, advanced epithelial cancers and showed encouraging activity.
Dr. Bardia and his group also published preliminary results earlier this year in patients with metastatic TNBC, which showed an objective response rate of 30%, and last year, sacituzumab govitecan was granted Breakthrough Designation by the Food and Drug Administration. In the current study, the authors expanded the cohort and looked at a more defined population (third-line setting or greater in metastatic TNBC).
In this study, 110 patients who had metastatic TNBC (109 female, 1 male) and had received two or more lines of therapy for metastatic disease were enrolled between July 2013 and February 2017. The cohort included 53 patients from the investigators’ previously reported study in metastatic TNBC (n=69 total). As of this study’s cutoff date (June 30, 2017), 66 patients had died, 30 were in long term follow up, and 14 were still on treatment.
All patients were treated at the 10 mg/kg dose level, receiving 14.5 median doses (range, 1-88) over a median duration of 4.9 months. Treatment was administered on day 1 and 8 in a 21 day cycle, until progression or unacceptable toxicity.
Within the cohort of this heavily pretreated group, 41% received sacituzumab govitecan as third-line therapy while 59% received it at fourth line or more. The majority of patients had previously received taxanes or anthracyclines, and of note, 75% had previously received prior platinum, and 17% had previously received checkpoint inhibitors.
The clinical benefit rate, calculated using the rate of complete and partial response and stable disease greater than 6 months, was 45%. Responses were durable, with a median duration of 7.6 months by local assessment and 9.1 months by central review.
The median progression-free survival was 5.5 months (95% confidence interval, 4.8-6.6) and median overall survival was 12.7 months (95% CI, 10.8-13.6). Of the long term responders, nine have been progression free for more than a year, and four for more than 2 years. At the time of data cutoff, 12 responders were still receiving treatment.
Of note, Dr. Bardia said, patients stayed on sacituzumab govitecan longer than they had stayed on their most recent previous therapy.
The authors also conducted an exploratory subset analysis but found no difference in response when looking at age, prior regimens, onset of metastasis, the presence of visceral involvement at study entry, or Trop-2 expression.
Response among patients who had previously received checkpoint inhibitors was 47%, but Dr. Bardia cautions that “these numbers are small.”
Treatment with sacituzumab govitecan was well tolerated overall, with 2 patients discontinuing the drug because of related toxicity, and no antidrug antibodies detected. Grade 3 or greater toxicity included neutropenia (39%), leukopenia (14%), and anemia (10%); the incidence of febrile neutropenia was low (7%). There was a high rate of gastrointestinal related toxicity, but the majority were grade 1-2, and the rate of grade 3-4 “was in the single digits, ranging from 5-8%,” said Dr. Bardia. There were no drug-related deaths.
Given the high unmet medical need among patients with metastatic TNBC, data from this trial is being sent to the FDA to be considered for accelerated approval, and a global confirmatory randomized Phase 3 is now underway. “The ASCENT trial is recruiting in the United States right now,” said Dr. Bardia; this trial will include patients with metastatic TNBC who will receive either sacituzumab govitecan or physician’s choice of standard therapy.
Additional studies including rational combinations are currently being evaluated for metastatic TNBC and other breast cancer subsets.
SOURCE: Bardia A et al. Abstract GS1-07.
SAN ANTONIO – A novel antibody drug conjugate has shown promise in metastatic triple-negative breast cancer (TNBC), according to new findings presented at the San Antonio Breast Cancer Symposium.
Sacituzumab govitecan, a novel antibody-drug conjugate, demonstrated significant clinical activity when used as a single agent among patients with relapsed/refractory disease who had already received multiple lines of therapy. The objective response rate in a cohort of more than 100 patients was 34%, and that included 3 complete responses and 34 partial responses.
“Sacituzumab govitecan demonstrated significant single-agent activity in this population,” said lead author Aditya Bardia, MD, of Harvard Medical School and Massachusetts General Hospital Cancer Center.
“Metastatic triple-negative breast cancer is an aggressive disease with a poor prognosis that tends to affect young women,” said Dr. Bardia. “Visceral and brain metastases are very common. Currently there is no single standard chemotherapy for relapsed or refractory metastatic triple-negative breast cancer.”
He noted that the response rates to standard chemotherapy are low and that median progression-free survival is in the range of 2-3 months. The response rate to standard chemotherapy first line and beyond, based on available data, is in the range of 6-15%.
“Consequently, there is a large unmet need in the breast cancer community,” said Dr. Bardia.
Sacituzumab govitecan (IMMU-132) is an antitrophoblastic cell-surface antigen (anti–Trop-2) and humanized antibody-SN-38 conjugate, which is the active metabolite of the topoisomerase I inhibitor irinotecan. Trop-2 is highly expressed in most epithelial cancers, including TNBC. A phase 1/2 basket trial was previously conducted in a cohort with multiple, advanced epithelial cancers and showed encouraging activity.
Dr. Bardia and his group also published preliminary results earlier this year in patients with metastatic TNBC, which showed an objective response rate of 30%, and last year, sacituzumab govitecan was granted Breakthrough Designation by the Food and Drug Administration. In the current study, the authors expanded the cohort and looked at a more defined population (third-line setting or greater in metastatic TNBC).
In this study, 110 patients who had metastatic TNBC (109 female, 1 male) and had received two or more lines of therapy for metastatic disease were enrolled between July 2013 and February 2017. The cohort included 53 patients from the investigators’ previously reported study in metastatic TNBC (n=69 total). As of this study’s cutoff date (June 30, 2017), 66 patients had died, 30 were in long term follow up, and 14 were still on treatment.
All patients were treated at the 10 mg/kg dose level, receiving 14.5 median doses (range, 1-88) over a median duration of 4.9 months. Treatment was administered on day 1 and 8 in a 21 day cycle, until progression or unacceptable toxicity.
Within the cohort of this heavily pretreated group, 41% received sacituzumab govitecan as third-line therapy while 59% received it at fourth line or more. The majority of patients had previously received taxanes or anthracyclines, and of note, 75% had previously received prior platinum, and 17% had previously received checkpoint inhibitors.
The clinical benefit rate, calculated using the rate of complete and partial response and stable disease greater than 6 months, was 45%. Responses were durable, with a median duration of 7.6 months by local assessment and 9.1 months by central review.
The median progression-free survival was 5.5 months (95% confidence interval, 4.8-6.6) and median overall survival was 12.7 months (95% CI, 10.8-13.6). Of the long term responders, nine have been progression free for more than a year, and four for more than 2 years. At the time of data cutoff, 12 responders were still receiving treatment.
Of note, Dr. Bardia said, patients stayed on sacituzumab govitecan longer than they had stayed on their most recent previous therapy.
The authors also conducted an exploratory subset analysis but found no difference in response when looking at age, prior regimens, onset of metastasis, the presence of visceral involvement at study entry, or Trop-2 expression.
Response among patients who had previously received checkpoint inhibitors was 47%, but Dr. Bardia cautions that “these numbers are small.”
Treatment with sacituzumab govitecan was well tolerated overall, with 2 patients discontinuing the drug because of related toxicity, and no antidrug antibodies detected. Grade 3 or greater toxicity included neutropenia (39%), leukopenia (14%), and anemia (10%); the incidence of febrile neutropenia was low (7%). There was a high rate of gastrointestinal related toxicity, but the majority were grade 1-2, and the rate of grade 3-4 “was in the single digits, ranging from 5-8%,” said Dr. Bardia. There were no drug-related deaths.
Given the high unmet medical need among patients with metastatic TNBC, data from this trial is being sent to the FDA to be considered for accelerated approval, and a global confirmatory randomized Phase 3 is now underway. “The ASCENT trial is recruiting in the United States right now,” said Dr. Bardia; this trial will include patients with metastatic TNBC who will receive either sacituzumab govitecan or physician’s choice of standard therapy.
Additional studies including rational combinations are currently being evaluated for metastatic TNBC and other breast cancer subsets.
SOURCE: Bardia A et al. Abstract GS1-07.
REPORTING FROM SABCS 2017
Key clinical point: Sacituzumab govitecan demonstrated significant clinical activity when used as a single agent among heavily pretreated patients with relapsed/refractory metastatic TNBC.
Major finding: The objective response rate was 34% and clinical benefit was 45%.
Data source: Single-arm, open-label trial that included 110 patients with relapsed/refractory metastatic TNBC who had received two or more lines of therapy.
Disclosures:. Immunomedics, which makes sacituzumab govitecan, funded the study. Dr. Bardia reported institutional funding but had no other disclosures.
Source: Bardia A et al. Abstract GS1-07.
Parents taking photos of kids’ lesions for telederm diagnosis looks promising
, said Daniel M. O’Connor, MD, of the Children’s Hospital of Philadelphia, and his associates.
Skin conditions make up 10%-30% of the approximately 200 million pediatric outpatient visits each year, Dr. O’Connor and his colleagues said. But there are fewer than 300 board-certified U.S. pediatric dermatologists for the nation’s nearly 75 million children. So, the possibility of using photos taken by parents for distant pediatric dermatologists to assess is an attractive one.
Concordance between photograph-based vs. in-person diagnosis was 83%. In three cases, diagnoses could not be made by the remote dermatologist because of poor photograph quality. When those cases were excluded, concordance was 89% between photograph-based vs. in-person diagnosis. Concordance for birthmarks was 100%, 92% for rashes, and 64% for alopecia-related diagnoses. Of four cases that were misdiagnosed, there were three cases of alopecia and one nodule.
Half the parents received a simple, three-step instruction sheet on smartphone photography. There was no statistical difference in diagnostic concordance between the parents who received the instruction sheet and those who didn’t.
“When dealing with categories with low concordance, such as alopecia and nodules and tumors, teledermatology practitioners may need to be cautious about attempting definitive diagnoses in some cases, and may need to refer patients for in-person consultation,” Dr. O’Connor and his associates wrote. “For these cases, teledermatology may still serve as a triage tool. For example, patients with suspicious nodules could be referred for expedited appointments in specialty clinics, whereas patients with isolated alopecia could be scheduled for routine visits. Conversely, in diagnostic categories with high concordance, such as birthmarks and rashes, certain cases could be definitively diagnosed and treated exclusively using teledermatology (for example, mild acne).”
Read more in JAMA Dermatology (2017 Nov 15. doi: 10.1001/jamadermatol.2017.4280).
, said Daniel M. O’Connor, MD, of the Children’s Hospital of Philadelphia, and his associates.
Skin conditions make up 10%-30% of the approximately 200 million pediatric outpatient visits each year, Dr. O’Connor and his colleagues said. But there are fewer than 300 board-certified U.S. pediatric dermatologists for the nation’s nearly 75 million children. So, the possibility of using photos taken by parents for distant pediatric dermatologists to assess is an attractive one.
Concordance between photograph-based vs. in-person diagnosis was 83%. In three cases, diagnoses could not be made by the remote dermatologist because of poor photograph quality. When those cases were excluded, concordance was 89% between photograph-based vs. in-person diagnosis. Concordance for birthmarks was 100%, 92% for rashes, and 64% for alopecia-related diagnoses. Of four cases that were misdiagnosed, there were three cases of alopecia and one nodule.
Half the parents received a simple, three-step instruction sheet on smartphone photography. There was no statistical difference in diagnostic concordance between the parents who received the instruction sheet and those who didn’t.
“When dealing with categories with low concordance, such as alopecia and nodules and tumors, teledermatology practitioners may need to be cautious about attempting definitive diagnoses in some cases, and may need to refer patients for in-person consultation,” Dr. O’Connor and his associates wrote. “For these cases, teledermatology may still serve as a triage tool. For example, patients with suspicious nodules could be referred for expedited appointments in specialty clinics, whereas patients with isolated alopecia could be scheduled for routine visits. Conversely, in diagnostic categories with high concordance, such as birthmarks and rashes, certain cases could be definitively diagnosed and treated exclusively using teledermatology (for example, mild acne).”
Read more in JAMA Dermatology (2017 Nov 15. doi: 10.1001/jamadermatol.2017.4280).
, said Daniel M. O’Connor, MD, of the Children’s Hospital of Philadelphia, and his associates.
Skin conditions make up 10%-30% of the approximately 200 million pediatric outpatient visits each year, Dr. O’Connor and his colleagues said. But there are fewer than 300 board-certified U.S. pediatric dermatologists for the nation’s nearly 75 million children. So, the possibility of using photos taken by parents for distant pediatric dermatologists to assess is an attractive one.
Concordance between photograph-based vs. in-person diagnosis was 83%. In three cases, diagnoses could not be made by the remote dermatologist because of poor photograph quality. When those cases were excluded, concordance was 89% between photograph-based vs. in-person diagnosis. Concordance for birthmarks was 100%, 92% for rashes, and 64% for alopecia-related diagnoses. Of four cases that were misdiagnosed, there were three cases of alopecia and one nodule.
Half the parents received a simple, three-step instruction sheet on smartphone photography. There was no statistical difference in diagnostic concordance between the parents who received the instruction sheet and those who didn’t.
“When dealing with categories with low concordance, such as alopecia and nodules and tumors, teledermatology practitioners may need to be cautious about attempting definitive diagnoses in some cases, and may need to refer patients for in-person consultation,” Dr. O’Connor and his associates wrote. “For these cases, teledermatology may still serve as a triage tool. For example, patients with suspicious nodules could be referred for expedited appointments in specialty clinics, whereas patients with isolated alopecia could be scheduled for routine visits. Conversely, in diagnostic categories with high concordance, such as birthmarks and rashes, certain cases could be definitively diagnosed and treated exclusively using teledermatology (for example, mild acne).”
Read more in JAMA Dermatology (2017 Nov 15. doi: 10.1001/jamadermatol.2017.4280).
FROM JAMA DERMATOLOGY
Flare of nonradiographic axial SpA occurs often after adalimumab withdrawal for remission
Patients with nonradiographic axial spondyloarthritis (nr-axSpA) who enter remission on adalimumab are likely to relapse if the medication is withdrawn – and many won’t attain remission again, even if the drug is restarted.
However, the findings of the ABILITY-3 trial do offer an intriguing potential, Robert Landewé, MD, PhD, said at the annual meeting of the American College of Rheumatology. About 30% of the study group did maintain remission after adalimumab (Humira) withdrawal, suggesting that at least a portion of these patients can stay in good clinical shape off TNF inhibition.
ABILITY-3 is the successor to ABILITY-1, the 2012 placebo-controlled study that established adalimumab as an effective treatment for nr-axSpA. Adalimumab is approved in the United States for the treatment of ankylosing spondylitis (radiographic axSpA), but not for nr-axSpA.
ABILITY-3 assessed the impact of withdrawing adalimumab from nr-axSpA patients who had attained remission on the medication. It enrolled 673 adults with active disease at baseline and an inadequate response to at least two nonsteroidal anti-inflammatory drugs.
The study commenced with open-label adalimumab at 40 mg every other week for 28 weeks. At that point, the 305 patients who had attained disease remission were randomized to either continued adalimumab at the same dose and schedule or to placebo. Randomized treatment continued for 40 more weeks. Any patient who experienced a flare resumed the drug as rescue therapy. The investigators calculated the number of patients with a disease flare at week 68 as the primary endpoint. The study also examined a number of secondary endpoints, including response measures, time to flare, functional status, quality of life, and remission.
At baseline, patients were a mean of 35 years old, with a mean disease duration of about 7 years. Most (88%) were HLA-B27 positive, and about 60% had elevated C-reactive protein levels.
At 68 weeks, patients who discontinued adalimumab were 77% more likely to have experienced a disease flare than were those who stayed on the drug (83% vs. 57% or 70% vs. 47% with nonresponder imputation; relative risk, 1.77). A time-to-flare analysis found a significant 67% reduction in the risk of flare among those continuing to take adalimumab.
While those who experienced a disease flare were allowed to resume adalimumab, it appeared to be far less effective at that point. After 12 weeks of rescue therapy, only 57% had regained remission, leaving 43% with persistent active disease.
Nearly all of the secondary endpoints were in favor of continuing therapy, Dr. Landewé said, including the Ankylosing Spondyloarthritis Disease Activity Score-inactive disease (ASDAS-ID), ASDAS-major improvement, ASDAS-clinically important improvement; the Assessment in Spondyloarthritis International Society (ASAS) 20% and 40% rates; the ASAS 5/6 and ASAS-partial response rates; the Bath Ankylosing Spondylitis Disease Activity Index 50; and the Bath Ankylosing Spondylitis Functional Index. Only health-related quality of life as measured by the Health Assessment Questionnaire for the Spondyloarthropathies did not significantly improve to a greater extent among those staying on adalimumab.
There were no new or concerning safety signals, Dr. Landewé said. In the placebo-controlled period, there were 10 serious adverse events in the placebo group and 1 – a case of ureterolithiasis – in the adalimumab group. There was one malignancy, which occurred in the placebo group. No patient died during the study.
“These results support the continuation of adalimumab therapy after achieving a sustained remission,” Dr. Landewé said. “But it will be an important research goal to identify predictors for the population in whom treatment may be safely discontinued.”
AbbVie sponsored the study. Dr. Landewé reported relationships with numerous pharmaceutical companies, including AbbVie.
Patients with nonradiographic axial spondyloarthritis (nr-axSpA) who enter remission on adalimumab are likely to relapse if the medication is withdrawn – and many won’t attain remission again, even if the drug is restarted.
However, the findings of the ABILITY-3 trial do offer an intriguing potential, Robert Landewé, MD, PhD, said at the annual meeting of the American College of Rheumatology. About 30% of the study group did maintain remission after adalimumab (Humira) withdrawal, suggesting that at least a portion of these patients can stay in good clinical shape off TNF inhibition.
ABILITY-3 is the successor to ABILITY-1, the 2012 placebo-controlled study that established adalimumab as an effective treatment for nr-axSpA. Adalimumab is approved in the United States for the treatment of ankylosing spondylitis (radiographic axSpA), but not for nr-axSpA.
ABILITY-3 assessed the impact of withdrawing adalimumab from nr-axSpA patients who had attained remission on the medication. It enrolled 673 adults with active disease at baseline and an inadequate response to at least two nonsteroidal anti-inflammatory drugs.
The study commenced with open-label adalimumab at 40 mg every other week for 28 weeks. At that point, the 305 patients who had attained disease remission were randomized to either continued adalimumab at the same dose and schedule or to placebo. Randomized treatment continued for 40 more weeks. Any patient who experienced a flare resumed the drug as rescue therapy. The investigators calculated the number of patients with a disease flare at week 68 as the primary endpoint. The study also examined a number of secondary endpoints, including response measures, time to flare, functional status, quality of life, and remission.
At baseline, patients were a mean of 35 years old, with a mean disease duration of about 7 years. Most (88%) were HLA-B27 positive, and about 60% had elevated C-reactive protein levels.
At 68 weeks, patients who discontinued adalimumab were 77% more likely to have experienced a disease flare than were those who stayed on the drug (83% vs. 57% or 70% vs. 47% with nonresponder imputation; relative risk, 1.77). A time-to-flare analysis found a significant 67% reduction in the risk of flare among those continuing to take adalimumab.
While those who experienced a disease flare were allowed to resume adalimumab, it appeared to be far less effective at that point. After 12 weeks of rescue therapy, only 57% had regained remission, leaving 43% with persistent active disease.
Nearly all of the secondary endpoints were in favor of continuing therapy, Dr. Landewé said, including the Ankylosing Spondyloarthritis Disease Activity Score-inactive disease (ASDAS-ID), ASDAS-major improvement, ASDAS-clinically important improvement; the Assessment in Spondyloarthritis International Society (ASAS) 20% and 40% rates; the ASAS 5/6 and ASAS-partial response rates; the Bath Ankylosing Spondylitis Disease Activity Index 50; and the Bath Ankylosing Spondylitis Functional Index. Only health-related quality of life as measured by the Health Assessment Questionnaire for the Spondyloarthropathies did not significantly improve to a greater extent among those staying on adalimumab.
There were no new or concerning safety signals, Dr. Landewé said. In the placebo-controlled period, there were 10 serious adverse events in the placebo group and 1 – a case of ureterolithiasis – in the adalimumab group. There was one malignancy, which occurred in the placebo group. No patient died during the study.
“These results support the continuation of adalimumab therapy after achieving a sustained remission,” Dr. Landewé said. “But it will be an important research goal to identify predictors for the population in whom treatment may be safely discontinued.”
AbbVie sponsored the study. Dr. Landewé reported relationships with numerous pharmaceutical companies, including AbbVie.
Patients with nonradiographic axial spondyloarthritis (nr-axSpA) who enter remission on adalimumab are likely to relapse if the medication is withdrawn – and many won’t attain remission again, even if the drug is restarted.
However, the findings of the ABILITY-3 trial do offer an intriguing potential, Robert Landewé, MD, PhD, said at the annual meeting of the American College of Rheumatology. About 30% of the study group did maintain remission after adalimumab (Humira) withdrawal, suggesting that at least a portion of these patients can stay in good clinical shape off TNF inhibition.
ABILITY-3 is the successor to ABILITY-1, the 2012 placebo-controlled study that established adalimumab as an effective treatment for nr-axSpA. Adalimumab is approved in the United States for the treatment of ankylosing spondylitis (radiographic axSpA), but not for nr-axSpA.
ABILITY-3 assessed the impact of withdrawing adalimumab from nr-axSpA patients who had attained remission on the medication. It enrolled 673 adults with active disease at baseline and an inadequate response to at least two nonsteroidal anti-inflammatory drugs.
The study commenced with open-label adalimumab at 40 mg every other week for 28 weeks. At that point, the 305 patients who had attained disease remission were randomized to either continued adalimumab at the same dose and schedule or to placebo. Randomized treatment continued for 40 more weeks. Any patient who experienced a flare resumed the drug as rescue therapy. The investigators calculated the number of patients with a disease flare at week 68 as the primary endpoint. The study also examined a number of secondary endpoints, including response measures, time to flare, functional status, quality of life, and remission.
At baseline, patients were a mean of 35 years old, with a mean disease duration of about 7 years. Most (88%) were HLA-B27 positive, and about 60% had elevated C-reactive protein levels.
At 68 weeks, patients who discontinued adalimumab were 77% more likely to have experienced a disease flare than were those who stayed on the drug (83% vs. 57% or 70% vs. 47% with nonresponder imputation; relative risk, 1.77). A time-to-flare analysis found a significant 67% reduction in the risk of flare among those continuing to take adalimumab.
While those who experienced a disease flare were allowed to resume adalimumab, it appeared to be far less effective at that point. After 12 weeks of rescue therapy, only 57% had regained remission, leaving 43% with persistent active disease.
Nearly all of the secondary endpoints were in favor of continuing therapy, Dr. Landewé said, including the Ankylosing Spondyloarthritis Disease Activity Score-inactive disease (ASDAS-ID), ASDAS-major improvement, ASDAS-clinically important improvement; the Assessment in Spondyloarthritis International Society (ASAS) 20% and 40% rates; the ASAS 5/6 and ASAS-partial response rates; the Bath Ankylosing Spondylitis Disease Activity Index 50; and the Bath Ankylosing Spondylitis Functional Index. Only health-related quality of life as measured by the Health Assessment Questionnaire for the Spondyloarthropathies did not significantly improve to a greater extent among those staying on adalimumab.
There were no new or concerning safety signals, Dr. Landewé said. In the placebo-controlled period, there were 10 serious adverse events in the placebo group and 1 – a case of ureterolithiasis – in the adalimumab group. There was one malignancy, which occurred in the placebo group. No patient died during the study.
“These results support the continuation of adalimumab therapy after achieving a sustained remission,” Dr. Landewé said. “But it will be an important research goal to identify predictors for the population in whom treatment may be safely discontinued.”
AbbVie sponsored the study. Dr. Landewé reported relationships with numerous pharmaceutical companies, including AbbVie.
REPORTING FROM ACR 2017
Key clinical point:
Major finding: Withdrawing adalimumab increased the risk of flare by 77%.
Study details: The study randomized 305 patients in remission to placebo or 40 mg adalimumab every other week.
Disclosures: AbbVie sponsored the study. The presenter reported relationships with numerous pharmaceutical companies, including AbbVie.
Source: Landewé R et al. ACR 2017 Abstract 1787
Urinary tract agents: A safety review in pregnancy
The reported frequency of use in pregnancy and during breastfeeding for most of these agents is very low or completely absent.
The five subclasses of urinary tract agents are analgesics, antispasmodics, urinary acidifiers, urinary alkalinizers, and urinary germicides. With the exception of the three urinary germicides, anti-infectives are not covered in this column.
Analgesics
The analgesic subclass includes pentosan and phenazopyridine. Pentosan (Elmiron), a heparinlike compound, is an oral drug that is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis. Systemic absorption is low, at about 6%. Because of the high molecular weight (4,000-6,000), it does not appear to cross the placenta, at least in the first half of pregnancy. A 1975 reference described its use in five women with preeclampsia. Each patient received 100 mg intramuscularly every 8 hours for about 5 days in the last weeks of pregnancy. No maternal benefit from the therapy was observed. There was apparently no fetal harm, but the neonatal outcomes were not described.
There are substantial – more than 900 – human pregnancy exposures in the first trimester with phenazopyridine. The exposures were not related to an increased risk of embryo-fetal harm and so use of the drug in pregnancy can be classified as compatible. However, the low molecular weight (about 214 for the free base) suggests that the drug will cross to the embryo and fetus.
Antispasmodics
The eight antispasmodics are darifenacin (Enablex), fesoterodine (Toviaz), flavoxate, mirabegron (Myrbetriq), oxybutynin (Ditropan XL), solifenacin (Vesicare), tolterodine (Detrol LA), and trospium.
These agents are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The molecular weights range between 342 and 508, suggesting that all will cross the human placenta. There are no human pregnancy data for six of these agents and very limited data for flavoxate and oxybutynin. There is no evidence of embryo-fetal harm from these two drugs, but only one case involved exposure in the first trimester.
In seven of these drugs, the animal data suggested low risk. There was no embryo harm from doses that were equal to or less than 10 times the human dose based on body surface area (BSA) or area under the concentration curve (AUC). Solifenacin did cause embryo toxicity in pregnant mice. There was no embryo toxicity in pregnant rats and rabbits, but the maximum doses used were very low. Overall, the available data suggest that exposure to an antispasmodic in pregnancy is low risk for embryo, fetal, and newborn harm.
Urinary acidifiers
Ammonium chloride is a urinary acidifier as well as a respiratory expectorant. There is a large amount of data related to when the drug was used as an expectorant. There was no evidence that this use was associated with large categories of major or minor malformations. However, there were possible associations with three individual defects: inguinal hernia, cataract, and any benign tumor. No reports describing its use as a urinary acidifier have been located. When large amounts are consumed near term, the drug may cause acidosis in the mother and fetus. The molecular weight (about 53) suggests that it will cross the placenta.
Urinary alkalinizers
Potassium citrate (Urocit-K) is indicated for the management of renal tubular acidosis with calcium stones, hypocitraturic calcium oxalate with nephrolithiasis of any etiology, and uric acid lithiasis with or without calcium stones. The molecular weight (about 307) suggests it will cross the placenta. Only one case of its use in pregnancy has been located. The newborn had an unspecified defect but no other information was provided. The animal data in four species suggest low risk.
Urinary germicides
There are three urinary germicides: methenamine, methylene blue, and nitrofurantoin. Methenamine is available as methenamine mandelate (molecular weight abut 292) and methenamine hippurate (molecular weight about 319). Both are metabolized to formaldehyde (molecular weight about 30), the active agent. The molecular weights suggest that all will cross the placenta. The use of methenamine during pregnancy has been reported in more than 750 pregnancies. There have been no embryo or fetal adverse effects attributed to the drug.
The human data involving oral methylene blue, a weak urinary germicide, is limited to 55 exposures. There were three infants with birth defects (type not specified). Several reports have described the use of intra-amniotic injections to assist in the diagnosis of suspected membrane rupture. This use has resulted in newborns with hemolytic anemia, hyperbilirubinemia with or without Heinz body formation, blue staining of the skin, and methemoglobinemia. Fetal deaths have also been described. Recommendations to avoid the intra-amniotic use of methylene blue were issued more than 10 years ago. Moreover, the use of oral methylene blue as a urinary germicide is no longer recommended.
The low molecular weight (about 238) of nitrofurantoin suggests that it will cross the placenta. It is commonly used in pregnancy for the treatment or prophylaxis of urinary tract infections. The large amount of human data indicates that the risk of drug-induced birth defects is low. Several cohort studies have found no increased risk for birth defects. However, some case-control studies have found increased risks for hypoplastic left heart syndrome and oral clefts. A 2015 review concluded that this difference was due to the increased sensitivity of case-control studies to detect adverse effects (J Obstet Gynaecol Can. 2015 Feb;37[2]:150-6).
Use of the drug close to term may cause hemolytic anemia in newborns who are glucose-6-phosphate dehydrogenase (G6PD) deficient. Although rare, this may also occur in newborns who are not G6PD deficient. The best course is to avoid use of the drug close to delivery. As for use of the drug in the first trimester, ACOG’s Committee on Obstetric Practice stated in Committee Opinion No. 717 that nitrofurantoin was still thought to be appropriate when no other suitable alternative antibiotics were available (Obstet Gynecol. 2017 Sept;130[3]:666-7).
Breastfeeding
Except for methenamine and nitrofurantoin, there are no data related to the use of the urinary tract drugs during breastfeeding. Peak levels of methenamine occur at 1 hour, but no reports of adverse effects on nursing infants have been located. Several reports have described the use of nitrofurantoin during breastfeeding. Minor diarrhea was noted in two infants. However, breastfeeding an infant with G6PD deficiency could lead to hemolytic anemia.
Phenazopyridine should be used with caution especially for an infant younger than 1 month or with G6PD deficiency because of the risk for methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia.
Although there have been no reports of the use of mirabegron during lactation, the characteristics of the drug – low molecular weight (about 397), long elimination half life (50 hours), and moderate plasma protein binding (about 71%) – suggest that the drug will be excreted into milk, potentially in clinically significant amounts. There is also concern with use of tolterodine (molecular weight about 476) because both the primary drug and its equipotent metabolite may be excreted into milk.
Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
The reported frequency of use in pregnancy and during breastfeeding for most of these agents is very low or completely absent.
The five subclasses of urinary tract agents are analgesics, antispasmodics, urinary acidifiers, urinary alkalinizers, and urinary germicides. With the exception of the three urinary germicides, anti-infectives are not covered in this column.
Analgesics
The analgesic subclass includes pentosan and phenazopyridine. Pentosan (Elmiron), a heparinlike compound, is an oral drug that is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis. Systemic absorption is low, at about 6%. Because of the high molecular weight (4,000-6,000), it does not appear to cross the placenta, at least in the first half of pregnancy. A 1975 reference described its use in five women with preeclampsia. Each patient received 100 mg intramuscularly every 8 hours for about 5 days in the last weeks of pregnancy. No maternal benefit from the therapy was observed. There was apparently no fetal harm, but the neonatal outcomes were not described.
There are substantial – more than 900 – human pregnancy exposures in the first trimester with phenazopyridine. The exposures were not related to an increased risk of embryo-fetal harm and so use of the drug in pregnancy can be classified as compatible. However, the low molecular weight (about 214 for the free base) suggests that the drug will cross to the embryo and fetus.
Antispasmodics
The eight antispasmodics are darifenacin (Enablex), fesoterodine (Toviaz), flavoxate, mirabegron (Myrbetriq), oxybutynin (Ditropan XL), solifenacin (Vesicare), tolterodine (Detrol LA), and trospium.
These agents are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The molecular weights range between 342 and 508, suggesting that all will cross the human placenta. There are no human pregnancy data for six of these agents and very limited data for flavoxate and oxybutynin. There is no evidence of embryo-fetal harm from these two drugs, but only one case involved exposure in the first trimester.
In seven of these drugs, the animal data suggested low risk. There was no embryo harm from doses that were equal to or less than 10 times the human dose based on body surface area (BSA) or area under the concentration curve (AUC). Solifenacin did cause embryo toxicity in pregnant mice. There was no embryo toxicity in pregnant rats and rabbits, but the maximum doses used were very low. Overall, the available data suggest that exposure to an antispasmodic in pregnancy is low risk for embryo, fetal, and newborn harm.
Urinary acidifiers
Ammonium chloride is a urinary acidifier as well as a respiratory expectorant. There is a large amount of data related to when the drug was used as an expectorant. There was no evidence that this use was associated with large categories of major or minor malformations. However, there were possible associations with three individual defects: inguinal hernia, cataract, and any benign tumor. No reports describing its use as a urinary acidifier have been located. When large amounts are consumed near term, the drug may cause acidosis in the mother and fetus. The molecular weight (about 53) suggests that it will cross the placenta.
Urinary alkalinizers
Potassium citrate (Urocit-K) is indicated for the management of renal tubular acidosis with calcium stones, hypocitraturic calcium oxalate with nephrolithiasis of any etiology, and uric acid lithiasis with or without calcium stones. The molecular weight (about 307) suggests it will cross the placenta. Only one case of its use in pregnancy has been located. The newborn had an unspecified defect but no other information was provided. The animal data in four species suggest low risk.
Urinary germicides
There are three urinary germicides: methenamine, methylene blue, and nitrofurantoin. Methenamine is available as methenamine mandelate (molecular weight abut 292) and methenamine hippurate (molecular weight about 319). Both are metabolized to formaldehyde (molecular weight about 30), the active agent. The molecular weights suggest that all will cross the placenta. The use of methenamine during pregnancy has been reported in more than 750 pregnancies. There have been no embryo or fetal adverse effects attributed to the drug.
The human data involving oral methylene blue, a weak urinary germicide, is limited to 55 exposures. There were three infants with birth defects (type not specified). Several reports have described the use of intra-amniotic injections to assist in the diagnosis of suspected membrane rupture. This use has resulted in newborns with hemolytic anemia, hyperbilirubinemia with or without Heinz body formation, blue staining of the skin, and methemoglobinemia. Fetal deaths have also been described. Recommendations to avoid the intra-amniotic use of methylene blue were issued more than 10 years ago. Moreover, the use of oral methylene blue as a urinary germicide is no longer recommended.
The low molecular weight (about 238) of nitrofurantoin suggests that it will cross the placenta. It is commonly used in pregnancy for the treatment or prophylaxis of urinary tract infections. The large amount of human data indicates that the risk of drug-induced birth defects is low. Several cohort studies have found no increased risk for birth defects. However, some case-control studies have found increased risks for hypoplastic left heart syndrome and oral clefts. A 2015 review concluded that this difference was due to the increased sensitivity of case-control studies to detect adverse effects (J Obstet Gynaecol Can. 2015 Feb;37[2]:150-6).
Use of the drug close to term may cause hemolytic anemia in newborns who are glucose-6-phosphate dehydrogenase (G6PD) deficient. Although rare, this may also occur in newborns who are not G6PD deficient. The best course is to avoid use of the drug close to delivery. As for use of the drug in the first trimester, ACOG’s Committee on Obstetric Practice stated in Committee Opinion No. 717 that nitrofurantoin was still thought to be appropriate when no other suitable alternative antibiotics were available (Obstet Gynecol. 2017 Sept;130[3]:666-7).
Breastfeeding
Except for methenamine and nitrofurantoin, there are no data related to the use of the urinary tract drugs during breastfeeding. Peak levels of methenamine occur at 1 hour, but no reports of adverse effects on nursing infants have been located. Several reports have described the use of nitrofurantoin during breastfeeding. Minor diarrhea was noted in two infants. However, breastfeeding an infant with G6PD deficiency could lead to hemolytic anemia.
Phenazopyridine should be used with caution especially for an infant younger than 1 month or with G6PD deficiency because of the risk for methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia.
Although there have been no reports of the use of mirabegron during lactation, the characteristics of the drug – low molecular weight (about 397), long elimination half life (50 hours), and moderate plasma protein binding (about 71%) – suggest that the drug will be excreted into milk, potentially in clinically significant amounts. There is also concern with use of tolterodine (molecular weight about 476) because both the primary drug and its equipotent metabolite may be excreted into milk.
Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
The reported frequency of use in pregnancy and during breastfeeding for most of these agents is very low or completely absent.
The five subclasses of urinary tract agents are analgesics, antispasmodics, urinary acidifiers, urinary alkalinizers, and urinary germicides. With the exception of the three urinary germicides, anti-infectives are not covered in this column.
Analgesics
The analgesic subclass includes pentosan and phenazopyridine. Pentosan (Elmiron), a heparinlike compound, is an oral drug that is indicated for the relief of bladder pain or discomfort associated with interstitial cystitis. Systemic absorption is low, at about 6%. Because of the high molecular weight (4,000-6,000), it does not appear to cross the placenta, at least in the first half of pregnancy. A 1975 reference described its use in five women with preeclampsia. Each patient received 100 mg intramuscularly every 8 hours for about 5 days in the last weeks of pregnancy. No maternal benefit from the therapy was observed. There was apparently no fetal harm, but the neonatal outcomes were not described.
There are substantial – more than 900 – human pregnancy exposures in the first trimester with phenazopyridine. The exposures were not related to an increased risk of embryo-fetal harm and so use of the drug in pregnancy can be classified as compatible. However, the low molecular weight (about 214 for the free base) suggests that the drug will cross to the embryo and fetus.
Antispasmodics
The eight antispasmodics are darifenacin (Enablex), fesoterodine (Toviaz), flavoxate, mirabegron (Myrbetriq), oxybutynin (Ditropan XL), solifenacin (Vesicare), tolterodine (Detrol LA), and trospium.
These agents are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. The molecular weights range between 342 and 508, suggesting that all will cross the human placenta. There are no human pregnancy data for six of these agents and very limited data for flavoxate and oxybutynin. There is no evidence of embryo-fetal harm from these two drugs, but only one case involved exposure in the first trimester.
In seven of these drugs, the animal data suggested low risk. There was no embryo harm from doses that were equal to or less than 10 times the human dose based on body surface area (BSA) or area under the concentration curve (AUC). Solifenacin did cause embryo toxicity in pregnant mice. There was no embryo toxicity in pregnant rats and rabbits, but the maximum doses used were very low. Overall, the available data suggest that exposure to an antispasmodic in pregnancy is low risk for embryo, fetal, and newborn harm.
Urinary acidifiers
Ammonium chloride is a urinary acidifier as well as a respiratory expectorant. There is a large amount of data related to when the drug was used as an expectorant. There was no evidence that this use was associated with large categories of major or minor malformations. However, there were possible associations with three individual defects: inguinal hernia, cataract, and any benign tumor. No reports describing its use as a urinary acidifier have been located. When large amounts are consumed near term, the drug may cause acidosis in the mother and fetus. The molecular weight (about 53) suggests that it will cross the placenta.
Urinary alkalinizers
Potassium citrate (Urocit-K) is indicated for the management of renal tubular acidosis with calcium stones, hypocitraturic calcium oxalate with nephrolithiasis of any etiology, and uric acid lithiasis with or without calcium stones. The molecular weight (about 307) suggests it will cross the placenta. Only one case of its use in pregnancy has been located. The newborn had an unspecified defect but no other information was provided. The animal data in four species suggest low risk.
Urinary germicides
There are three urinary germicides: methenamine, methylene blue, and nitrofurantoin. Methenamine is available as methenamine mandelate (molecular weight abut 292) and methenamine hippurate (molecular weight about 319). Both are metabolized to formaldehyde (molecular weight about 30), the active agent. The molecular weights suggest that all will cross the placenta. The use of methenamine during pregnancy has been reported in more than 750 pregnancies. There have been no embryo or fetal adverse effects attributed to the drug.
The human data involving oral methylene blue, a weak urinary germicide, is limited to 55 exposures. There were three infants with birth defects (type not specified). Several reports have described the use of intra-amniotic injections to assist in the diagnosis of suspected membrane rupture. This use has resulted in newborns with hemolytic anemia, hyperbilirubinemia with or without Heinz body formation, blue staining of the skin, and methemoglobinemia. Fetal deaths have also been described. Recommendations to avoid the intra-amniotic use of methylene blue were issued more than 10 years ago. Moreover, the use of oral methylene blue as a urinary germicide is no longer recommended.
The low molecular weight (about 238) of nitrofurantoin suggests that it will cross the placenta. It is commonly used in pregnancy for the treatment or prophylaxis of urinary tract infections. The large amount of human data indicates that the risk of drug-induced birth defects is low. Several cohort studies have found no increased risk for birth defects. However, some case-control studies have found increased risks for hypoplastic left heart syndrome and oral clefts. A 2015 review concluded that this difference was due to the increased sensitivity of case-control studies to detect adverse effects (J Obstet Gynaecol Can. 2015 Feb;37[2]:150-6).
Use of the drug close to term may cause hemolytic anemia in newborns who are glucose-6-phosphate dehydrogenase (G6PD) deficient. Although rare, this may also occur in newborns who are not G6PD deficient. The best course is to avoid use of the drug close to delivery. As for use of the drug in the first trimester, ACOG’s Committee on Obstetric Practice stated in Committee Opinion No. 717 that nitrofurantoin was still thought to be appropriate when no other suitable alternative antibiotics were available (Obstet Gynecol. 2017 Sept;130[3]:666-7).
Breastfeeding
Except for methenamine and nitrofurantoin, there are no data related to the use of the urinary tract drugs during breastfeeding. Peak levels of methenamine occur at 1 hour, but no reports of adverse effects on nursing infants have been located. Several reports have described the use of nitrofurantoin during breastfeeding. Minor diarrhea was noted in two infants. However, breastfeeding an infant with G6PD deficiency could lead to hemolytic anemia.
Phenazopyridine should be used with caution especially for an infant younger than 1 month or with G6PD deficiency because of the risk for methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia.
Although there have been no reports of the use of mirabegron during lactation, the characteristics of the drug – low molecular weight (about 397), long elimination half life (50 hours), and moderate plasma protein binding (about 71%) – suggest that the drug will be excreted into milk, potentially in clinically significant amounts. There is also concern with use of tolterodine (molecular weight about 476) because both the primary drug and its equipotent metabolite may be excreted into milk.
Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
VIDEO: Good responses with antibody-drug conjugate in third-line metastatic TNBC therapy
SAN ANTONIO – Fully one-third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) had a response to therapy with a novel antibody-drug conjugate called sacituzumab govitecan. The conjugate consists of the active metabolites of the topoisomerase I inhibitor irinotecan linked to a humanized monoclonal antibody target Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
Aditya Bardia, MD, from Massachusetts General Hospital in Boston, previously reported results of a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
In this video interview, he discusses the conjugate’s activity in the third-line or greater setting for patients with metastatic TNBC, with an overall response rate of 34%, including some complete responses according to independent reviewers, and describes planned clinical trials pitting the agent against standard-of-care single-drug therapies.
The trial was supported by Immunomedics. Dr. Bardia reported institutional funding from the company, but no other conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Fully one-third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) had a response to therapy with a novel antibody-drug conjugate called sacituzumab govitecan. The conjugate consists of the active metabolites of the topoisomerase I inhibitor irinotecan linked to a humanized monoclonal antibody target Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
Aditya Bardia, MD, from Massachusetts General Hospital in Boston, previously reported results of a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
In this video interview, he discusses the conjugate’s activity in the third-line or greater setting for patients with metastatic TNBC, with an overall response rate of 34%, including some complete responses according to independent reviewers, and describes planned clinical trials pitting the agent against standard-of-care single-drug therapies.
The trial was supported by Immunomedics. Dr. Bardia reported institutional funding from the company, but no other conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Fully one-third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) had a response to therapy with a novel antibody-drug conjugate called sacituzumab govitecan. The conjugate consists of the active metabolites of the topoisomerase I inhibitor irinotecan linked to a humanized monoclonal antibody target Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
Aditya Bardia, MD, from Massachusetts General Hospital in Boston, previously reported results of a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
In this video interview, he discusses the conjugate’s activity in the third-line or greater setting for patients with metastatic TNBC, with an overall response rate of 34%, including some complete responses according to independent reviewers, and describes planned clinical trials pitting the agent against standard-of-care single-drug therapies.
The trial was supported by Immunomedics. Dr. Bardia reported institutional funding from the company, but no other conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM SABCS 2017
Promising add-on therapy for neonatal seizures found active in safety study
WASHINGTON – presented at the annual meeting of the American Epilepsy Society.
“This is an early-phase trial, but it did associate bumetanide with an additional reduction in seizure burden relative to phenobarbital alone,” reported Janet S. Soul, MD, director of the fetal-neonatal neurology program at Boston Children’s Hospital. She added, “The adverse events observed were not substantially different in the group that received the experimental agent.”
Of the 111 neonates with documented seizures enrolled at four participating hospitals, 43 proceeded to randomization if their seizures proved to be refractory to standard doses of phenobarbital. After randomization, the next dose of phenobarbital was administered either with placebo or with 0.1, 0.2, or 0.3 mg/kg of bumetanide. Seizure burden was evaluated at 0-2, 2-4, and 0-4 hours after study-drug administration and compared with the burden during the 2 hours before treatment.
All three doses were active, reducing the seizure burden by a median of 41%-75% in a dose-dependent manner. Whether assessed in the first 2 hours or the first 4 hours, the efficacy of bumetanide was significantly greater in those with the greatest, relative to the least, baseline seizure burden (P = .01 for hours 0-2; P = .04 for hours 0-4). The median seizure burden during the baseline period was higher in the 27 children randomized to bumetanide (114 minutes) relative to those randomized to placebo (33 minutes), although researchers attributed this to random effects in a small study.
The evidence of antiseizure activity from bumetanide as an add-on to phenobarbital is consistent with its mechanism of action, which is blockading the chloride transporter NKCC1. In the immature neurons of neonates, NKCC1 is highly expressed, and there is basic scientific evidence that this impairs the efficacy of gamma-aminobutyric acid–receptor agonists like phenobarbital, according to Dr. Soul. The hypothesis driving the study of bumetanide is that blockading NKCC1 would improve the efficacy of phenobarbital while adding its own antiseizure effects, which together could potentially provide synergistic benefit.
The efficacy and the safety of this study are somewhat discordant with a previously published study evaluating bumetanide in 14 neonates with hypoxic-ischemic encephalopathy (HIE) seizures (Lancet Neurol 2015;14:469-77). Even though there were seizure reductions in five children in this other series, which did not include a control arm, there were three cases of hearing loss considered potentially related to bumetanide. The authors of that study concluded that efficacy was not shown.
There were also three cases of hearing loss in the randomized trial presented by Dr. Soul, but one occurred in the placebo group. Although the potential for ototoxicity “still needs to be addressed” in the next set of studies, Dr. Soul noted that hearing loss in children with epilepsy is common and has numerous potential etiologies. Based on these data, she concluded, “All serious adverse events were related to severe HIE with multiorgan dysfunction and/or withdrawal of care for poor prognosis.”
Among nonserious adverse events, diuresis was the only one found significantly more common in the bumetanide group (P = .02).
Phenobarbital has been a standard in the treatment of neonatal seizures for several decades despite the substantial proportion of children who do not achieve an adequate response, according to Dr. Soul. She noted that bumetanide is one of several agents being evaluated as an adjunctive agent. For example, a phase 2 crossover trial with levetiracetam is now underway. She suggested that there is reason for optimism about gaining new treatments for neonates in an area in which she believes there are unmet needs.
“I think we may see a phase 2 trial with bumetanide within a year or 2,” Dr. Soul said. If bumetanide moves forward, she expects its role to be primarily for the treatment of acute seizures caused by HIE, stroke, or hemorrhage. She is less optimistic about its benefit for seizures caused by other etiologies, such as brain malformations.
SOURCE: Soul J Abstract 2.426
WASHINGTON – presented at the annual meeting of the American Epilepsy Society.
“This is an early-phase trial, but it did associate bumetanide with an additional reduction in seizure burden relative to phenobarbital alone,” reported Janet S. Soul, MD, director of the fetal-neonatal neurology program at Boston Children’s Hospital. She added, “The adverse events observed were not substantially different in the group that received the experimental agent.”
Of the 111 neonates with documented seizures enrolled at four participating hospitals, 43 proceeded to randomization if their seizures proved to be refractory to standard doses of phenobarbital. After randomization, the next dose of phenobarbital was administered either with placebo or with 0.1, 0.2, or 0.3 mg/kg of bumetanide. Seizure burden was evaluated at 0-2, 2-4, and 0-4 hours after study-drug administration and compared with the burden during the 2 hours before treatment.
All three doses were active, reducing the seizure burden by a median of 41%-75% in a dose-dependent manner. Whether assessed in the first 2 hours or the first 4 hours, the efficacy of bumetanide was significantly greater in those with the greatest, relative to the least, baseline seizure burden (P = .01 for hours 0-2; P = .04 for hours 0-4). The median seizure burden during the baseline period was higher in the 27 children randomized to bumetanide (114 minutes) relative to those randomized to placebo (33 minutes), although researchers attributed this to random effects in a small study.
The evidence of antiseizure activity from bumetanide as an add-on to phenobarbital is consistent with its mechanism of action, which is blockading the chloride transporter NKCC1. In the immature neurons of neonates, NKCC1 is highly expressed, and there is basic scientific evidence that this impairs the efficacy of gamma-aminobutyric acid–receptor agonists like phenobarbital, according to Dr. Soul. The hypothesis driving the study of bumetanide is that blockading NKCC1 would improve the efficacy of phenobarbital while adding its own antiseizure effects, which together could potentially provide synergistic benefit.
The efficacy and the safety of this study are somewhat discordant with a previously published study evaluating bumetanide in 14 neonates with hypoxic-ischemic encephalopathy (HIE) seizures (Lancet Neurol 2015;14:469-77). Even though there were seizure reductions in five children in this other series, which did not include a control arm, there were three cases of hearing loss considered potentially related to bumetanide. The authors of that study concluded that efficacy was not shown.
There were also three cases of hearing loss in the randomized trial presented by Dr. Soul, but one occurred in the placebo group. Although the potential for ototoxicity “still needs to be addressed” in the next set of studies, Dr. Soul noted that hearing loss in children with epilepsy is common and has numerous potential etiologies. Based on these data, she concluded, “All serious adverse events were related to severe HIE with multiorgan dysfunction and/or withdrawal of care for poor prognosis.”
Among nonserious adverse events, diuresis was the only one found significantly more common in the bumetanide group (P = .02).
Phenobarbital has been a standard in the treatment of neonatal seizures for several decades despite the substantial proportion of children who do not achieve an adequate response, according to Dr. Soul. She noted that bumetanide is one of several agents being evaluated as an adjunctive agent. For example, a phase 2 crossover trial with levetiracetam is now underway. She suggested that there is reason for optimism about gaining new treatments for neonates in an area in which she believes there are unmet needs.
“I think we may see a phase 2 trial with bumetanide within a year or 2,” Dr. Soul said. If bumetanide moves forward, she expects its role to be primarily for the treatment of acute seizures caused by HIE, stroke, or hemorrhage. She is less optimistic about its benefit for seizures caused by other etiologies, such as brain malformations.
SOURCE: Soul J Abstract 2.426
WASHINGTON – presented at the annual meeting of the American Epilepsy Society.
“This is an early-phase trial, but it did associate bumetanide with an additional reduction in seizure burden relative to phenobarbital alone,” reported Janet S. Soul, MD, director of the fetal-neonatal neurology program at Boston Children’s Hospital. She added, “The adverse events observed were not substantially different in the group that received the experimental agent.”
Of the 111 neonates with documented seizures enrolled at four participating hospitals, 43 proceeded to randomization if their seizures proved to be refractory to standard doses of phenobarbital. After randomization, the next dose of phenobarbital was administered either with placebo or with 0.1, 0.2, or 0.3 mg/kg of bumetanide. Seizure burden was evaluated at 0-2, 2-4, and 0-4 hours after study-drug administration and compared with the burden during the 2 hours before treatment.
All three doses were active, reducing the seizure burden by a median of 41%-75% in a dose-dependent manner. Whether assessed in the first 2 hours or the first 4 hours, the efficacy of bumetanide was significantly greater in those with the greatest, relative to the least, baseline seizure burden (P = .01 for hours 0-2; P = .04 for hours 0-4). The median seizure burden during the baseline period was higher in the 27 children randomized to bumetanide (114 minutes) relative to those randomized to placebo (33 minutes), although researchers attributed this to random effects in a small study.
The evidence of antiseizure activity from bumetanide as an add-on to phenobarbital is consistent with its mechanism of action, which is blockading the chloride transporter NKCC1. In the immature neurons of neonates, NKCC1 is highly expressed, and there is basic scientific evidence that this impairs the efficacy of gamma-aminobutyric acid–receptor agonists like phenobarbital, according to Dr. Soul. The hypothesis driving the study of bumetanide is that blockading NKCC1 would improve the efficacy of phenobarbital while adding its own antiseizure effects, which together could potentially provide synergistic benefit.
The efficacy and the safety of this study are somewhat discordant with a previously published study evaluating bumetanide in 14 neonates with hypoxic-ischemic encephalopathy (HIE) seizures (Lancet Neurol 2015;14:469-77). Even though there were seizure reductions in five children in this other series, which did not include a control arm, there were three cases of hearing loss considered potentially related to bumetanide. The authors of that study concluded that efficacy was not shown.
There were also three cases of hearing loss in the randomized trial presented by Dr. Soul, but one occurred in the placebo group. Although the potential for ototoxicity “still needs to be addressed” in the next set of studies, Dr. Soul noted that hearing loss in children with epilepsy is common and has numerous potential etiologies. Based on these data, she concluded, “All serious adverse events were related to severe HIE with multiorgan dysfunction and/or withdrawal of care for poor prognosis.”
Among nonserious adverse events, diuresis was the only one found significantly more common in the bumetanide group (P = .02).
Phenobarbital has been a standard in the treatment of neonatal seizures for several decades despite the substantial proportion of children who do not achieve an adequate response, according to Dr. Soul. She noted that bumetanide is one of several agents being evaluated as an adjunctive agent. For example, a phase 2 crossover trial with levetiracetam is now underway. She suggested that there is reason for optimism about gaining new treatments for neonates in an area in which she believes there are unmet needs.
“I think we may see a phase 2 trial with bumetanide within a year or 2,” Dr. Soul said. If bumetanide moves forward, she expects its role to be primarily for the treatment of acute seizures caused by HIE, stroke, or hemorrhage. She is less optimistic about its benefit for seizures caused by other etiologies, such as brain malformations.
SOURCE: Soul J Abstract 2.426
REPORTING FROM AES 2017
Key clinical point: Bumetanide is associated with antiseizure activity as add-on therapy to phenobarbital for neonatal seizures.
Major finding: Relative to pretreatment, there was greater reduction in seizure burden (P = .01) at 4 hours in those with the highest seizure burden.
Data source: Randomized, double-blind phase 1/2 trial.
Disclosures: Dr. Soul reports no potential conflicts of interest related to this topic.
Source: Soul J et al. Abstract 2.426
Alcohol use, abuse rise after bariatric surgery
ORLANDO –
Following any of several methods of bariatric surgery, patients showed a statistically significant 8% higher rate of new onset alcohol abuse, and a relative 50% increased rate of significant alcohol use, compared with rates before surgery, Prandeet Wander, MD, said at the World Congress of Gastroenterology at ACG 2017.
Her meta-analysis identified prospective, retrospective, and cross-sectional studies of alcohol use that included more than 100 bariatric surgery patients and that had follow-up beyond 1 year. Patients could have undergone Roux-en-Y gastric bypass, sleeve gastrectomy, or laparoscopic adjustable gastric banding. Comparator populations had to be either the surgery patients prior to the procedure or the controls matched by age and body mass index.
The 28 included studies enrolled 15,714 patients who averaged 43 years old, with more than three quarters women. Follow-up averaged 2.6 years. The most common surgery was Roux-en-Y, used in 23 studies, followed by banding in 12 studies, and sleeves in 8 studies (some studies used more than one type of surgery).
Nineteen of the studies examined the prevalence of “significant alcohol abuse” following surgery in a total of 4,552 patients, with 23% of patients overall showing this behavior. Five studies, involving 2,698 patients, documented the rate of new-onset alcohol abuse after surgery, with an overall rate of 8% that was statistically significant. All five studies individually showed increased incidence of alcohol abuse, with rates that ranged from 4% to 8%.
The analysis that showed a relative 50% higher rate of “significant” alcohol use after surgery, compared with the same patients before their surgery used data from 11 studies with 3,370 patients. Five of these 11 studies individually showed a statistically significant increase in alcohol use, 1 showed a significant, 34% relative decrease, and the remaining 5 studies did not show statistically significant changes, with 3 studies trending toward an increased rate and two trending toward a decreased rate after surgery.
None of the 28 included studies had a randomized control arm, and the studies collectively ran in six countries, including the United States, and hence involved different societal norms of alcohol use. Changes in alcohol absorption and metabolism following bariatric surgery may play roles in the observed effects, as might undiagnosed depression or substance use by patients who undergo this surgery, Dr. Wander suggested.
SOURCE: Wander P et al. World Congress of Gastroenterology, abstract 10.
ORLANDO –
Following any of several methods of bariatric surgery, patients showed a statistically significant 8% higher rate of new onset alcohol abuse, and a relative 50% increased rate of significant alcohol use, compared with rates before surgery, Prandeet Wander, MD, said at the World Congress of Gastroenterology at ACG 2017.
Her meta-analysis identified prospective, retrospective, and cross-sectional studies of alcohol use that included more than 100 bariatric surgery patients and that had follow-up beyond 1 year. Patients could have undergone Roux-en-Y gastric bypass, sleeve gastrectomy, or laparoscopic adjustable gastric banding. Comparator populations had to be either the surgery patients prior to the procedure or the controls matched by age and body mass index.
The 28 included studies enrolled 15,714 patients who averaged 43 years old, with more than three quarters women. Follow-up averaged 2.6 years. The most common surgery was Roux-en-Y, used in 23 studies, followed by banding in 12 studies, and sleeves in 8 studies (some studies used more than one type of surgery).
Nineteen of the studies examined the prevalence of “significant alcohol abuse” following surgery in a total of 4,552 patients, with 23% of patients overall showing this behavior. Five studies, involving 2,698 patients, documented the rate of new-onset alcohol abuse after surgery, with an overall rate of 8% that was statistically significant. All five studies individually showed increased incidence of alcohol abuse, with rates that ranged from 4% to 8%.
The analysis that showed a relative 50% higher rate of “significant” alcohol use after surgery, compared with the same patients before their surgery used data from 11 studies with 3,370 patients. Five of these 11 studies individually showed a statistically significant increase in alcohol use, 1 showed a significant, 34% relative decrease, and the remaining 5 studies did not show statistically significant changes, with 3 studies trending toward an increased rate and two trending toward a decreased rate after surgery.
None of the 28 included studies had a randomized control arm, and the studies collectively ran in six countries, including the United States, and hence involved different societal norms of alcohol use. Changes in alcohol absorption and metabolism following bariatric surgery may play roles in the observed effects, as might undiagnosed depression or substance use by patients who undergo this surgery, Dr. Wander suggested.
SOURCE: Wander P et al. World Congress of Gastroenterology, abstract 10.
ORLANDO –
Following any of several methods of bariatric surgery, patients showed a statistically significant 8% higher rate of new onset alcohol abuse, and a relative 50% increased rate of significant alcohol use, compared with rates before surgery, Prandeet Wander, MD, said at the World Congress of Gastroenterology at ACG 2017.
Her meta-analysis identified prospective, retrospective, and cross-sectional studies of alcohol use that included more than 100 bariatric surgery patients and that had follow-up beyond 1 year. Patients could have undergone Roux-en-Y gastric bypass, sleeve gastrectomy, or laparoscopic adjustable gastric banding. Comparator populations had to be either the surgery patients prior to the procedure or the controls matched by age and body mass index.
The 28 included studies enrolled 15,714 patients who averaged 43 years old, with more than three quarters women. Follow-up averaged 2.6 years. The most common surgery was Roux-en-Y, used in 23 studies, followed by banding in 12 studies, and sleeves in 8 studies (some studies used more than one type of surgery).
Nineteen of the studies examined the prevalence of “significant alcohol abuse” following surgery in a total of 4,552 patients, with 23% of patients overall showing this behavior. Five studies, involving 2,698 patients, documented the rate of new-onset alcohol abuse after surgery, with an overall rate of 8% that was statistically significant. All five studies individually showed increased incidence of alcohol abuse, with rates that ranged from 4% to 8%.
The analysis that showed a relative 50% higher rate of “significant” alcohol use after surgery, compared with the same patients before their surgery used data from 11 studies with 3,370 patients. Five of these 11 studies individually showed a statistically significant increase in alcohol use, 1 showed a significant, 34% relative decrease, and the remaining 5 studies did not show statistically significant changes, with 3 studies trending toward an increased rate and two trending toward a decreased rate after surgery.
None of the 28 included studies had a randomized control arm, and the studies collectively ran in six countries, including the United States, and hence involved different societal norms of alcohol use. Changes in alcohol absorption and metabolism following bariatric surgery may play roles in the observed effects, as might undiagnosed depression or substance use by patients who undergo this surgery, Dr. Wander suggested.
SOURCE: Wander P et al. World Congress of Gastroenterology, abstract 10.
REPORTING FROM WORLD CONGRESS OF GASTROENTEROLOGY
Key clinical point: Following bariatric surgery patients have increased alcohol use and abuse.
Major finding: Alcohol abuse rose by 8%; significant alcohol use rose by a relative 50%.
Study details: Meta-analysis of 28 reports with 15,714 patients
Disclosures: Dr. Wander had no disclosures.
Source: Wander P et al. World Congress of Gastroenterology, abstract 10.