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New 52-week EASI, pruritus data strengthen case for dupilumab in adult atopic dermatitis
ORLANDO – Treatment with dupilumab was associated with significantly improved measures of disease severity, including in quality of life and pruritus symptoms, at 16 and 52 weeks in adults with moderate to severe atopic dermatitis (AD) in the phase III CHRONOS trial.
In the CHRONOS study of adults with uncontrolled, moderate to severe AD, patients were treated with the investigational biologic dupilumab (Dupixent), an interleukin-4 and interleukin-13 pathway blocker administered in subcutaneous injections, in combination with topical corticosteroids. At 52 weeks, they had achieved significantly improved measures of overall disease severity, compared with those who received corticosteroids alone, according to Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, who presented the new data from the study in a late-breaking clinical session at the annual meeting of the American Academy of Dermatology.
The new 52-week data presented at AAD show that the mean improvement in the EASI score from baseline was 80% in the 300 mg dupilumab every week plus corticosteroid group (group 1) and 78% in the group treated every 2 weeks (group 2), compared with 46% in the placebo plus corticosteroids group (control) (P less than .0001).
The mean improvement in self-reported itch from baseline, as measured by the Pruritus Numerical Rating Scale, was 54% in the first group, 56% in the second group, compared with 27% in controls (P less than .0001).
In the first group, 65% achieved a 4-point or greater improvement in their Patient Oriented Eczema Measure scores, as did 76% of the second group, compared with 26% of controls (P less than .0001).
At least a 4-point improvement over baseline in Dermatology Life Quality Index scores was seen in 63% of group 1, 80% of group 2, and 30% of controls (P less than .0001).
Adverse events across the study were similar, although the treatment groups had higher incidences of injection site reactions: 19% in group 1 and 15% in group 2, compared with 8% in controls. The treatment groups also had higher rates of conjunctivitis: 19% in group 1 and 14% in group 2, compared with 8% in controls.
Dr. Blauvelt said that patients who were “exited from the trial were continued for follow-up” and that rescue therapies such as cyclosporine, and other systemic agents, were also available. The rate of rescue therapy was about 15% in the first two groups, while half of controls needed rescue therapy. “We considered those patients who needed rescue nonresponders,” he noted.
The dropout rate at week 52 was about 15% across the treatment groups, compared with twice that in controls.
“Atopic dermatitis is the new psoriasis. We’re in an exciting area now, and we’ll be seeing more biologic therapies for moderate to severe atopic dermatitis. We have a tremendous need for this,” Dr. Blauvelt commented.
The Food and Drug Administration is expected to make a decision on approval of dupilumab by March 29, 2017. Dupilumab was designated by the FDA as a breakthrough therapy for uncontrolled, moderate to severe AD in 2014.
Dr. Blauvelt disclosed many pharmaceutical industry relationships, including with Regeneron Pharmaceuticals and Sanofi, which are developing dupilumab. (If approved, Regeneron and Sanofi Genzyme, part of Sanofi, will commercialize dupilumab).
CORRECTION 3/10/17: An earlier version of this article misstated the rates of clear or nearly clear skin.
ORLANDO – Treatment with dupilumab was associated with significantly improved measures of disease severity, including in quality of life and pruritus symptoms, at 16 and 52 weeks in adults with moderate to severe atopic dermatitis (AD) in the phase III CHRONOS trial.
In the CHRONOS study of adults with uncontrolled, moderate to severe AD, patients were treated with the investigational biologic dupilumab (Dupixent), an interleukin-4 and interleukin-13 pathway blocker administered in subcutaneous injections, in combination with topical corticosteroids. At 52 weeks, they had achieved significantly improved measures of overall disease severity, compared with those who received corticosteroids alone, according to Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, who presented the new data from the study in a late-breaking clinical session at the annual meeting of the American Academy of Dermatology.
The new 52-week data presented at AAD show that the mean improvement in the EASI score from baseline was 80% in the 300 mg dupilumab every week plus corticosteroid group (group 1) and 78% in the group treated every 2 weeks (group 2), compared with 46% in the placebo plus corticosteroids group (control) (P less than .0001).
The mean improvement in self-reported itch from baseline, as measured by the Pruritus Numerical Rating Scale, was 54% in the first group, 56% in the second group, compared with 27% in controls (P less than .0001).
In the first group, 65% achieved a 4-point or greater improvement in their Patient Oriented Eczema Measure scores, as did 76% of the second group, compared with 26% of controls (P less than .0001).
At least a 4-point improvement over baseline in Dermatology Life Quality Index scores was seen in 63% of group 1, 80% of group 2, and 30% of controls (P less than .0001).
Adverse events across the study were similar, although the treatment groups had higher incidences of injection site reactions: 19% in group 1 and 15% in group 2, compared with 8% in controls. The treatment groups also had higher rates of conjunctivitis: 19% in group 1 and 14% in group 2, compared with 8% in controls.
Dr. Blauvelt said that patients who were “exited from the trial were continued for follow-up” and that rescue therapies such as cyclosporine, and other systemic agents, were also available. The rate of rescue therapy was about 15% in the first two groups, while half of controls needed rescue therapy. “We considered those patients who needed rescue nonresponders,” he noted.
The dropout rate at week 52 was about 15% across the treatment groups, compared with twice that in controls.
“Atopic dermatitis is the new psoriasis. We’re in an exciting area now, and we’ll be seeing more biologic therapies for moderate to severe atopic dermatitis. We have a tremendous need for this,” Dr. Blauvelt commented.
The Food and Drug Administration is expected to make a decision on approval of dupilumab by March 29, 2017. Dupilumab was designated by the FDA as a breakthrough therapy for uncontrolled, moderate to severe AD in 2014.
Dr. Blauvelt disclosed many pharmaceutical industry relationships, including with Regeneron Pharmaceuticals and Sanofi, which are developing dupilumab. (If approved, Regeneron and Sanofi Genzyme, part of Sanofi, will commercialize dupilumab).
CORRECTION 3/10/17: An earlier version of this article misstated the rates of clear or nearly clear skin.
ORLANDO – Treatment with dupilumab was associated with significantly improved measures of disease severity, including in quality of life and pruritus symptoms, at 16 and 52 weeks in adults with moderate to severe atopic dermatitis (AD) in the phase III CHRONOS trial.
In the CHRONOS study of adults with uncontrolled, moderate to severe AD, patients were treated with the investigational biologic dupilumab (Dupixent), an interleukin-4 and interleukin-13 pathway blocker administered in subcutaneous injections, in combination with topical corticosteroids. At 52 weeks, they had achieved significantly improved measures of overall disease severity, compared with those who received corticosteroids alone, according to Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, who presented the new data from the study in a late-breaking clinical session at the annual meeting of the American Academy of Dermatology.
The new 52-week data presented at AAD show that the mean improvement in the EASI score from baseline was 80% in the 300 mg dupilumab every week plus corticosteroid group (group 1) and 78% in the group treated every 2 weeks (group 2), compared with 46% in the placebo plus corticosteroids group (control) (P less than .0001).
The mean improvement in self-reported itch from baseline, as measured by the Pruritus Numerical Rating Scale, was 54% in the first group, 56% in the second group, compared with 27% in controls (P less than .0001).
In the first group, 65% achieved a 4-point or greater improvement in their Patient Oriented Eczema Measure scores, as did 76% of the second group, compared with 26% of controls (P less than .0001).
At least a 4-point improvement over baseline in Dermatology Life Quality Index scores was seen in 63% of group 1, 80% of group 2, and 30% of controls (P less than .0001).
Adverse events across the study were similar, although the treatment groups had higher incidences of injection site reactions: 19% in group 1 and 15% in group 2, compared with 8% in controls. The treatment groups also had higher rates of conjunctivitis: 19% in group 1 and 14% in group 2, compared with 8% in controls.
Dr. Blauvelt said that patients who were “exited from the trial were continued for follow-up” and that rescue therapies such as cyclosporine, and other systemic agents, were also available. The rate of rescue therapy was about 15% in the first two groups, while half of controls needed rescue therapy. “We considered those patients who needed rescue nonresponders,” he noted.
The dropout rate at week 52 was about 15% across the treatment groups, compared with twice that in controls.
“Atopic dermatitis is the new psoriasis. We’re in an exciting area now, and we’ll be seeing more biologic therapies for moderate to severe atopic dermatitis. We have a tremendous need for this,” Dr. Blauvelt commented.
The Food and Drug Administration is expected to make a decision on approval of dupilumab by March 29, 2017. Dupilumab was designated by the FDA as a breakthrough therapy for uncontrolled, moderate to severe AD in 2014.
Dr. Blauvelt disclosed many pharmaceutical industry relationships, including with Regeneron Pharmaceuticals and Sanofi, which are developing dupilumab. (If approved, Regeneron and Sanofi Genzyme, part of Sanofi, will commercialize dupilumab).
CORRECTION 3/10/17: An earlier version of this article misstated the rates of clear or nearly clear skin.
AT AAD 2017
Key clinical point:
Major finding: At 52 weeks, dupilumab 300 mg administered in a subcutaneous injection once a week or every two weeks plus topical corticosteroids resulted in significantly more clearing compared with topical corticosteroids alone (P less than .0001). Self-reported measures of itch and quality-of-life measures were also higher across treatment groups.
Data source: A phase III trial of 740 adults with moderate to severe AD, randomized to treatment with one of the two regimens or corticosteroids alone.
Disclosures: Dr. Blauvelt disclosed many pharmaceutical industry relationships, including with Regeneron Pharmaceuticals and Sanofi, which are developing dupilumab. (If approved, Regeneron and Sanofi Genzyme, part of Sanofi, will commercialize dupilumab).
When atopic dermatitis is really contact dermatitis
ATLANTA – When patients present with atopic dermatitis that worsens, changes distribution, fails to improve, or immediately rebounds, think contact dermatitis, Luz Fonacier, MD, advised at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
Clinical signs of contact dermatitis include lesions with an atypical distribution/pattern, such as head, eyelid, or cheilitis/perioral predominance, or lesions on the hand or foot. Also elevate your suspicion in patients with therapy-resistant hand eczema, adult- or childhood-onset atopic dermatitis without childhood eczema, as well as in cases of severe or widespread dermatitis prior to initiating a systemic immunosuppressant. The list of potential allergens to consider includes metal (especially nickel, cobalt, and potassium dichromate), fragrances such as formaldehyde and balsam of Peru, preservatives, as well as topical emollients, corticosteroids, antibiotics, and antiseptics.
Dr. Fonacier, professor of medicine at the State University of New York at Stony Brook and section head of allergy at Winthrop University Hospital, Mineola, N.Y., recommends loading acrylates, fragrances, and allergens in an aqueous vehicle immediately before application. She noted that delayed patch test readings are common to metals, topical antibiotics, and topical corticosteroids, and that positive reactions to gold are often not clinically relevant. “The patch test positivity of gold can be as high as 30% in adults and a little bit less in children, but results from two large studies show clinical relevance in only 10%-15% of cases,” she said. A trial of gold avoidance may be warranted in patients with suspected jewelry allergy, facial or eyelid dermatitis, or exposure through gold dental restorations.
She went on to share tips for reading skin patch tests. The first reading should be done after 48 hours, while the second should be done 3, 4, or 7 days after application. “The second reading helps distinguish irritant from allergic responses,” she said. “Thirty percent of negative tests at 48 hours may be positive on delayed readings.” Most true allergic reactions occur between 72 and 96 hours. Allergens that may peak early include thiuram mix, carba mix, and balsam of Peru. Those that disappear after 5 days include balsam of Peru, benzoic acid, disperse blue #124, fragrance mix, mercury, methyldibromo glutaronitrile, phenoxyethanol, and octyl gallate. Delayed patch test reactions after five days include metals (gold potassium dichromate, nickel, and cobalt), topical antibiotics (neomycin and bacitracin) as well as topic corticosteroids.
Resources she recommended to attendees include the American Contact Dermatitis Society and the Contact Dermatitis Institute. Health and safety information about household products can be found here.
Dr. Fonacier disclosed that she has received research and educational grants from Baxter and Genentech. She is also a consultant to Church and Dwight and Regeneron.
ATLANTA – When patients present with atopic dermatitis that worsens, changes distribution, fails to improve, or immediately rebounds, think contact dermatitis, Luz Fonacier, MD, advised at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
Clinical signs of contact dermatitis include lesions with an atypical distribution/pattern, such as head, eyelid, or cheilitis/perioral predominance, or lesions on the hand or foot. Also elevate your suspicion in patients with therapy-resistant hand eczema, adult- or childhood-onset atopic dermatitis without childhood eczema, as well as in cases of severe or widespread dermatitis prior to initiating a systemic immunosuppressant. The list of potential allergens to consider includes metal (especially nickel, cobalt, and potassium dichromate), fragrances such as formaldehyde and balsam of Peru, preservatives, as well as topical emollients, corticosteroids, antibiotics, and antiseptics.
Dr. Fonacier, professor of medicine at the State University of New York at Stony Brook and section head of allergy at Winthrop University Hospital, Mineola, N.Y., recommends loading acrylates, fragrances, and allergens in an aqueous vehicle immediately before application. She noted that delayed patch test readings are common to metals, topical antibiotics, and topical corticosteroids, and that positive reactions to gold are often not clinically relevant. “The patch test positivity of gold can be as high as 30% in adults and a little bit less in children, but results from two large studies show clinical relevance in only 10%-15% of cases,” she said. A trial of gold avoidance may be warranted in patients with suspected jewelry allergy, facial or eyelid dermatitis, or exposure through gold dental restorations.
She went on to share tips for reading skin patch tests. The first reading should be done after 48 hours, while the second should be done 3, 4, or 7 days after application. “The second reading helps distinguish irritant from allergic responses,” she said. “Thirty percent of negative tests at 48 hours may be positive on delayed readings.” Most true allergic reactions occur between 72 and 96 hours. Allergens that may peak early include thiuram mix, carba mix, and balsam of Peru. Those that disappear after 5 days include balsam of Peru, benzoic acid, disperse blue #124, fragrance mix, mercury, methyldibromo glutaronitrile, phenoxyethanol, and octyl gallate. Delayed patch test reactions after five days include metals (gold potassium dichromate, nickel, and cobalt), topical antibiotics (neomycin and bacitracin) as well as topic corticosteroids.
Resources she recommended to attendees include the American Contact Dermatitis Society and the Contact Dermatitis Institute. Health and safety information about household products can be found here.
Dr. Fonacier disclosed that she has received research and educational grants from Baxter and Genentech. She is also a consultant to Church and Dwight and Regeneron.
ATLANTA – When patients present with atopic dermatitis that worsens, changes distribution, fails to improve, or immediately rebounds, think contact dermatitis, Luz Fonacier, MD, advised at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
Clinical signs of contact dermatitis include lesions with an atypical distribution/pattern, such as head, eyelid, or cheilitis/perioral predominance, or lesions on the hand or foot. Also elevate your suspicion in patients with therapy-resistant hand eczema, adult- or childhood-onset atopic dermatitis without childhood eczema, as well as in cases of severe or widespread dermatitis prior to initiating a systemic immunosuppressant. The list of potential allergens to consider includes metal (especially nickel, cobalt, and potassium dichromate), fragrances such as formaldehyde and balsam of Peru, preservatives, as well as topical emollients, corticosteroids, antibiotics, and antiseptics.
Dr. Fonacier, professor of medicine at the State University of New York at Stony Brook and section head of allergy at Winthrop University Hospital, Mineola, N.Y., recommends loading acrylates, fragrances, and allergens in an aqueous vehicle immediately before application. She noted that delayed patch test readings are common to metals, topical antibiotics, and topical corticosteroids, and that positive reactions to gold are often not clinically relevant. “The patch test positivity of gold can be as high as 30% in adults and a little bit less in children, but results from two large studies show clinical relevance in only 10%-15% of cases,” she said. A trial of gold avoidance may be warranted in patients with suspected jewelry allergy, facial or eyelid dermatitis, or exposure through gold dental restorations.
She went on to share tips for reading skin patch tests. The first reading should be done after 48 hours, while the second should be done 3, 4, or 7 days after application. “The second reading helps distinguish irritant from allergic responses,” she said. “Thirty percent of negative tests at 48 hours may be positive on delayed readings.” Most true allergic reactions occur between 72 and 96 hours. Allergens that may peak early include thiuram mix, carba mix, and balsam of Peru. Those that disappear after 5 days include balsam of Peru, benzoic acid, disperse blue #124, fragrance mix, mercury, methyldibromo glutaronitrile, phenoxyethanol, and octyl gallate. Delayed patch test reactions after five days include metals (gold potassium dichromate, nickel, and cobalt), topical antibiotics (neomycin and bacitracin) as well as topic corticosteroids.
Resources she recommended to attendees include the American Contact Dermatitis Society and the Contact Dermatitis Institute. Health and safety information about household products can be found here.
Dr. Fonacier disclosed that she has received research and educational grants from Baxter and Genentech. She is also a consultant to Church and Dwight and Regeneron.
EXPERT ANALYSIS AT THE 2017 AAAAI ANNUAL MEETING
Nemolizumab improves pruritus in atopic dermatitis
Monthly subcutaneous injections of nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, significantly improved pruritus associated with atopic dermatitis (AD) in a small, 3-month phase II trial. The results were published online March 2 in the New England Journal of Medicine.
“Although this trial has limitations, most notably the small number of patients and short duration, it provides evidence supporting the role of interleukin-31 in the pathobiologic mechanism of atopic dermatitis,” said Thomas Ruzicka, MD, of the department of dermatology and allergology, Ludwig Maximilian University, Munich, and his associates.
Pruritus aggravates atopic dermatitis and has been linked to loss of sleep, depression, aggressiveness, body disfiguration, and suicidal thoughts. Existing treatments, including emollients, topical glucocorticoids, calcineurin inhibitors, and oral antihistamines, have limited efficacy and can cause adverse effects when used long term, the investigators noted.
They assessed nemolizumab in a manufacturer-funded multiple-dose trial involving 264 adults in the United States, Europe, and Japan who had refractory moderate to severe atopic dermatitis, inadequately controlled with topical treatments. Study participants were randomly assigned in a double blind fashion to receive 12 weeks of 0.1 mg/kg nemolizumab (53 patients), 0.5 mg/kg nemolizumab (54 patients), 2.0 mg/kg nemolizumab (52 patients), or placebo (53 control subjects) every 4 weeks. Another 52 participants were given 2.0 mg/kg nemolizumab every 8 weeks in an exploratory analysis. All the study participants were permitted to use emollients and localized treatments, and some were permitted by the investigators to use a potent topical glucocorticoid as rescue therapy after week 4.
A total of 216 patients (82%) completed the trial.
The primary efficacy endpoint was the percentage improvement at week 12 in scores on a pruritus visual analogue scale, which patients recorded electronically every day. These scores improved significantly in a dose-dependent manner for active treatment, compared with placebo. Pruritus declined by 43.7% with the 0.1 mg/kg dose (P =.002), 59.8% with the 0.5 mg/kg dose (P less than .001), and 63.1% with the 2.0 mg/kg dose (P less than .001), compared with 20.9% with placebo.
Nemolizumab also bested placebo in several secondary endpoints including scores on a verbal rating of pruritus, the Eczema Area and Severity Index, and the static Investigator’s Global Assessment, the investigators said (N Engl J Med 2017;376:826-35. doi: 10.1056/NEJMoa1606490).
The study population was too small to allow the investigators to draw conclusions regarding adverse events, even before a relatively high number of participants dropped out. However, patients who received active treatment had a higher rate of dermatitis exacerbations and peripheral edema than did those who received placebo.
The group given 0.5 mg/kg nemolizumab every month showed the greatest treatment benefit and the best benefit-to-risk profile, Dr. Ruzicka and his associates said.
This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
In addition to the benefits cited by Ruzicka et al., nemolizumab appeared to work quickly, reducing pruritus by nearly 30% within the first week, compared with a slight placebo effect.
Data from larger and longer-term studies, as well as pediatric trials, are needed to fully understand how nemolizumab and other new agents should be incorporated into the management of AD.
It will be important to assess how quickly disease flares occur when these agents are stopped, and whether the concomitant use of other treatments may enhance their effectiveness or induce longer remissions.
Lynda C. Schneider, MD, is in the division of immunology at Boston Children’s Hospital. She disclosed having received grant support from Astellas, personal fees from Anacor Pharmaceuticals, and other support from the National Eczema Association outside the submitted work. Dr. Schneider made these remarks in an editorial accompanying the study (N Engl J Med. 2017 March 2. doi:10.1056/NEJMe1616072).
In addition to the benefits cited by Ruzicka et al., nemolizumab appeared to work quickly, reducing pruritus by nearly 30% within the first week, compared with a slight placebo effect.
Data from larger and longer-term studies, as well as pediatric trials, are needed to fully understand how nemolizumab and other new agents should be incorporated into the management of AD.
It will be important to assess how quickly disease flares occur when these agents are stopped, and whether the concomitant use of other treatments may enhance their effectiveness or induce longer remissions.
Lynda C. Schneider, MD, is in the division of immunology at Boston Children’s Hospital. She disclosed having received grant support from Astellas, personal fees from Anacor Pharmaceuticals, and other support from the National Eczema Association outside the submitted work. Dr. Schneider made these remarks in an editorial accompanying the study (N Engl J Med. 2017 March 2. doi:10.1056/NEJMe1616072).
In addition to the benefits cited by Ruzicka et al., nemolizumab appeared to work quickly, reducing pruritus by nearly 30% within the first week, compared with a slight placebo effect.
Data from larger and longer-term studies, as well as pediatric trials, are needed to fully understand how nemolizumab and other new agents should be incorporated into the management of AD.
It will be important to assess how quickly disease flares occur when these agents are stopped, and whether the concomitant use of other treatments may enhance their effectiveness or induce longer remissions.
Lynda C. Schneider, MD, is in the division of immunology at Boston Children’s Hospital. She disclosed having received grant support from Astellas, personal fees from Anacor Pharmaceuticals, and other support from the National Eczema Association outside the submitted work. Dr. Schneider made these remarks in an editorial accompanying the study (N Engl J Med. 2017 March 2. doi:10.1056/NEJMe1616072).
Monthly subcutaneous injections of nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, significantly improved pruritus associated with atopic dermatitis (AD) in a small, 3-month phase II trial. The results were published online March 2 in the New England Journal of Medicine.
“Although this trial has limitations, most notably the small number of patients and short duration, it provides evidence supporting the role of interleukin-31 in the pathobiologic mechanism of atopic dermatitis,” said Thomas Ruzicka, MD, of the department of dermatology and allergology, Ludwig Maximilian University, Munich, and his associates.
Pruritus aggravates atopic dermatitis and has been linked to loss of sleep, depression, aggressiveness, body disfiguration, and suicidal thoughts. Existing treatments, including emollients, topical glucocorticoids, calcineurin inhibitors, and oral antihistamines, have limited efficacy and can cause adverse effects when used long term, the investigators noted.
They assessed nemolizumab in a manufacturer-funded multiple-dose trial involving 264 adults in the United States, Europe, and Japan who had refractory moderate to severe atopic dermatitis, inadequately controlled with topical treatments. Study participants were randomly assigned in a double blind fashion to receive 12 weeks of 0.1 mg/kg nemolizumab (53 patients), 0.5 mg/kg nemolizumab (54 patients), 2.0 mg/kg nemolizumab (52 patients), or placebo (53 control subjects) every 4 weeks. Another 52 participants were given 2.0 mg/kg nemolizumab every 8 weeks in an exploratory analysis. All the study participants were permitted to use emollients and localized treatments, and some were permitted by the investigators to use a potent topical glucocorticoid as rescue therapy after week 4.
A total of 216 patients (82%) completed the trial.
The primary efficacy endpoint was the percentage improvement at week 12 in scores on a pruritus visual analogue scale, which patients recorded electronically every day. These scores improved significantly in a dose-dependent manner for active treatment, compared with placebo. Pruritus declined by 43.7% with the 0.1 mg/kg dose (P =.002), 59.8% with the 0.5 mg/kg dose (P less than .001), and 63.1% with the 2.0 mg/kg dose (P less than .001), compared with 20.9% with placebo.
Nemolizumab also bested placebo in several secondary endpoints including scores on a verbal rating of pruritus, the Eczema Area and Severity Index, and the static Investigator’s Global Assessment, the investigators said (N Engl J Med 2017;376:826-35. doi: 10.1056/NEJMoa1606490).
The study population was too small to allow the investigators to draw conclusions regarding adverse events, even before a relatively high number of participants dropped out. However, patients who received active treatment had a higher rate of dermatitis exacerbations and peripheral edema than did those who received placebo.
The group given 0.5 mg/kg nemolizumab every month showed the greatest treatment benefit and the best benefit-to-risk profile, Dr. Ruzicka and his associates said.
This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
Monthly subcutaneous injections of nemolizumab, a humanized monoclonal antibody that inhibits interleukin-31 signaling, significantly improved pruritus associated with atopic dermatitis (AD) in a small, 3-month phase II trial. The results were published online March 2 in the New England Journal of Medicine.
“Although this trial has limitations, most notably the small number of patients and short duration, it provides evidence supporting the role of interleukin-31 in the pathobiologic mechanism of atopic dermatitis,” said Thomas Ruzicka, MD, of the department of dermatology and allergology, Ludwig Maximilian University, Munich, and his associates.
Pruritus aggravates atopic dermatitis and has been linked to loss of sleep, depression, aggressiveness, body disfiguration, and suicidal thoughts. Existing treatments, including emollients, topical glucocorticoids, calcineurin inhibitors, and oral antihistamines, have limited efficacy and can cause adverse effects when used long term, the investigators noted.
They assessed nemolizumab in a manufacturer-funded multiple-dose trial involving 264 adults in the United States, Europe, and Japan who had refractory moderate to severe atopic dermatitis, inadequately controlled with topical treatments. Study participants were randomly assigned in a double blind fashion to receive 12 weeks of 0.1 mg/kg nemolizumab (53 patients), 0.5 mg/kg nemolizumab (54 patients), 2.0 mg/kg nemolizumab (52 patients), or placebo (53 control subjects) every 4 weeks. Another 52 participants were given 2.0 mg/kg nemolizumab every 8 weeks in an exploratory analysis. All the study participants were permitted to use emollients and localized treatments, and some were permitted by the investigators to use a potent topical glucocorticoid as rescue therapy after week 4.
A total of 216 patients (82%) completed the trial.
The primary efficacy endpoint was the percentage improvement at week 12 in scores on a pruritus visual analogue scale, which patients recorded electronically every day. These scores improved significantly in a dose-dependent manner for active treatment, compared with placebo. Pruritus declined by 43.7% with the 0.1 mg/kg dose (P =.002), 59.8% with the 0.5 mg/kg dose (P less than .001), and 63.1% with the 2.0 mg/kg dose (P less than .001), compared with 20.9% with placebo.
Nemolizumab also bested placebo in several secondary endpoints including scores on a verbal rating of pruritus, the Eczema Area and Severity Index, and the static Investigator’s Global Assessment, the investigators said (N Engl J Med 2017;376:826-35. doi: 10.1056/NEJMoa1606490).
The study population was too small to allow the investigators to draw conclusions regarding adverse events, even before a relatively high number of participants dropped out. However, patients who received active treatment had a higher rate of dermatitis exacerbations and peripheral edema than did those who received placebo.
The group given 0.5 mg/kg nemolizumab every month showed the greatest treatment benefit and the best benefit-to-risk profile, Dr. Ruzicka and his associates said.
This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Monthly nemolizumab injections significantly improved pruritus in adults with moderate to severe atopic dermatitis.
Major finding: Pruritus declined by 43.7% with the 0.1-mg/kg dose, 59.8% with the 0.5-mg/kg dose, and 63.1% with the 2.0-mg/kg dose, compared with 20.9% with placebo.
Data source: A manufacturer-funded international randomized double-blind placebo-controlled phase II trial of 216 adults with moderate to severe AD treated for 12 weeks.
Disclosures: This trial was funded by Chugai Pharmaceutical, which also participated in the study design, data collection and analysis, and preparation of the manuscript. Dr. Ruzicka reported receiving research grants and personal fees from Chugai and honoraria from Astellas; his associates reported ties to numerous industry sources.
Late-breaking research presented March 4-5 at AAD meeting
Dermatology News will be on site later this week at the annual meeting of the American Academy of Dermatology in Orlando. Look for the latest news in medical, surgical, and aesthetic dermatology starting Friday, March 3. The late-breaker sessions are on Saturday and Sunday March 4 and 5.
The late-breaking research session on clinical trials on March 4 will highlight:
- 16-week results from two phase III studies of certolizumab for chronic plaque psoriasis.
- Phase III results on the long-term management of moderate to severe atopic dermatitis (AD) with dupilumab plus topical corticosteroids.
Additional late breakers focus on pediatric, procedural, and pathology studies:
- Data from the Pediatric Eczema Elective Registry, on racial/ethnic disparities in health care utilization and school attendance among children with AD.
- Results of a prospective study evaluating the efficacy and systemic absorption of topical timolol for infantile hemangioma.
- Results of a randomized, placebo-controlled, double-blind study of oral tranexamic acid for treating moderate to severe melasma.
- The efficacy of adjuvant treatment with the long-pulsed 1064nm Nd:YAG Laser for toe onychomycosis.
- Risk factors associated with a recent change in the size, shape or color of moles among participants in the AAD SPOTme® Program (2009-2010).
- A survey-based study on the management of longitudinal melanonychia among attending and resident dermatologists.
Dermatology News will be on site later this week at the annual meeting of the American Academy of Dermatology in Orlando. Look for the latest news in medical, surgical, and aesthetic dermatology starting Friday, March 3. The late-breaker sessions are on Saturday and Sunday March 4 and 5.
The late-breaking research session on clinical trials on March 4 will highlight:
- 16-week results from two phase III studies of certolizumab for chronic plaque psoriasis.
- Phase III results on the long-term management of moderate to severe atopic dermatitis (AD) with dupilumab plus topical corticosteroids.
Additional late breakers focus on pediatric, procedural, and pathology studies:
- Data from the Pediatric Eczema Elective Registry, on racial/ethnic disparities in health care utilization and school attendance among children with AD.
- Results of a prospective study evaluating the efficacy and systemic absorption of topical timolol for infantile hemangioma.
- Results of a randomized, placebo-controlled, double-blind study of oral tranexamic acid for treating moderate to severe melasma.
- The efficacy of adjuvant treatment with the long-pulsed 1064nm Nd:YAG Laser for toe onychomycosis.
- Risk factors associated with a recent change in the size, shape or color of moles among participants in the AAD SPOTme® Program (2009-2010).
- A survey-based study on the management of longitudinal melanonychia among attending and resident dermatologists.
Dermatology News will be on site later this week at the annual meeting of the American Academy of Dermatology in Orlando. Look for the latest news in medical, surgical, and aesthetic dermatology starting Friday, March 3. The late-breaker sessions are on Saturday and Sunday March 4 and 5.
The late-breaking research session on clinical trials on March 4 will highlight:
- 16-week results from two phase III studies of certolizumab for chronic plaque psoriasis.
- Phase III results on the long-term management of moderate to severe atopic dermatitis (AD) with dupilumab plus topical corticosteroids.
Additional late breakers focus on pediatric, procedural, and pathology studies:
- Data from the Pediatric Eczema Elective Registry, on racial/ethnic disparities in health care utilization and school attendance among children with AD.
- Results of a prospective study evaluating the efficacy and systemic absorption of topical timolol for infantile hemangioma.
- Results of a randomized, placebo-controlled, double-blind study of oral tranexamic acid for treating moderate to severe melasma.
- The efficacy of adjuvant treatment with the long-pulsed 1064nm Nd:YAG Laser for toe onychomycosis.
- Risk factors associated with a recent change in the size, shape or color of moles among participants in the AAD SPOTme® Program (2009-2010).
- A survey-based study on the management of longitudinal melanonychia among attending and resident dermatologists.
Tips for taming atopic dermatitis and managing expectations
MIAMI – Tactics for managing patients with atopic dermatitis can go a long way to educate patients, set realistic expectations, and devise strategies for existing therapies, even as clinicians await some promising agents expected on the market soon.
“The good news is this is the Age of Eczema. In the last couple of years we’ve seen an explosion in the literature,” Adam Friedman, MD, of the department of dermatology, George Washington University, Washington, D.C., said at the Orlando Dermatology Aesthetic and Clinical Conference. Some of this research is spurring new therapeutics. a phosphodiesterase 4 inhibitor.
Crisaborole ointment, 2% (Eucrisa), a phosphodiesterase 4 inhibitor, was approved by the Food and Drug Administration in December 2016 for treating patients aged 2 years and older with mild to moderate AD, for example. It is a novel, nonsteroidal anti-inflammatory and the first prescription agent approved in the United States for atopic dermatitis in more than 10 years.
Dr. Friedman has no personal experience with crisaborole, which just became available. “But the data look encouraging. From what I’ve seen this may be a nonburning alternative to calcineurin inhibitors. It will be interesting to see how this will fit in our practices.”
Systemic management of pruritus
There’s also promise for patients troubled by one of the top manifestations of AD – the itch. “We have new targeted therapies coming down the pike, some hopefully [gaining approval] in the next few months. We have biologics going after the cytokines of itch. It’s a very, very exciting time right now,” Dr. Friedman said.
Current clinical trials are not only focusing on AD but also specifically on pruritus, he added.
In the meantime, itch can be managed with prescription and over-the-counter topical agents, as well as systemic therapies such as gabapentin, some antidepressants, and the antiemetic aprepitant. Aprepitant is a substance P antagonist (through blocking neurokinin 1 receptor) and can be effective for some patients when taken three times a week, but it is not indicated for itch, Dr. Friedman said. Because of its off label indication “it’s a little tricky getting [insurance] coverage.”
Back to basics
“Even with all the excitement, even with the new therapeutics, you have to stick with the basics,” he said. “Put the lotion on, put the cream on. You have to put moisturizer on wet skin and be cautious with soaps.” He added, “don’t be afraid to ask for help. The National Eczema Association has a wonderful website with research, education, tools – you name it.”
Keeping it real
For regional eczemas like hand dermatitis, what are the options? “Tell patients they can glove up, there are various latex alternatives … but it probably won’t fly in the real world,” Dr. Friedman said. Zinc oxide “works like armor, and patients will probably do well,” but the aesthetics are unacceptable for most, he added. “Newer alternatives, such as those with aluminum magnesium hydroxide stearate, have similar protecting power, but are not opaque and rub on easier.”
A goal of topical therapy is to get rid of the inflammation, and steroids have a long history of evidence supporting their use, but “topical steroid phobia in parents” is a problem, he said. To counter the reluctance or refusal to use topical steroids, he suggested exploring reasons for noncompliance, dispelling any myths, and working with parent to make it easier to apply the steroids to their child.
Interestingly, there is some evidence that a simpler regimen may work well for some patients. “We always say ‘apply twice a day.’ Why? Because all the clinical trials had participants apply steroids twice a day. But there is no evidence to show twice a day is better than once a day, and in fact, a meta-analysis suggests once a day works just as well” (Br J Dermatol. 2005 Jan;152[1]:130-41).
Topical calcineurin inhibitors are another option. In general, Dr. Friedman prescribes these agents for delicate areas, for patients with thin skin, or for patients who use a topical steroid “on and on and on and can’t seem to get off it.” Calcineurin inhibitors can also be used on in-between days during steroid maintenance therapy, he added. When prescribing, warn patients about the initial burn (due to substance P release) that commonly occurs so that they have realistic expectations.
Education remains essential
“I encourage you to educate your patients and empathize with them,” he said. “Show them how to apply a moisturizer. Also, use your nurses and assistants to help with education – really empower them to be part of the process.”
“Explain, explain, explain, so they have realistic expectations,” and know that there is no cure, so that when they experience a flare, they understand that “it’s not that the steroid didn’t work – this is a chronic disease,” added Dr. Friedman, who recommends providing patients with handouts that answer many of their questions.
Maximize moisturizing
When it comes to moisturizing, more is usually better. Effective products contain all the key ingredients: emollients to soften the skin, an occlusive to keep the water there, and a humectant to bond the water. “Just one or two is not going to cut it,” he said.
“Something we now know is that starting early is key,” he pointed out, referring to recent studies that have shown that in babies at high risk for AD, starting moisturizers early can decrease their risk for developing AD later (J Allergy Clin Immunol. 2014 Oct; 134[4]: 818-23).
“Another study that received a ton of press was in JAMA Pediatrics recently,” Dr. Friedman said. The study concluded that the use of different moisturizers to prevent AD in high risk babies was likely to be cost-effective (JAMA Pediatr. 2017 Feb 6;171[2]:e163909. doi: 10.1001/jamapediatrics.2016.3909). Although some news reports claimed starting babies with Vaseline as a moisturizer will prevent AD, “that’s actually not what the study showed. All the over-the-counter moisturizers they used worked, but Vaseline was the least expensive,” Dr. Friedman noted
Help patients select the right soap
Educate patients to avoid “true soaps” such as Dial, Ivory, Irish Spring, or Lever 2000. “Soaps can be a real enemy here. You want lower pH types of soaps. Depending on skin type, our skin is somewhere between 5.5 and 6.5 pH,” Dr. Friedman explained. “The paradigm shift for your patients is to hydrate, not to clean. Showers are okay if they’re not blaring hot. Baths are okay ... but you should not be sitting in a sudsy bath.”
Also, instruct patients to avoid irritating fabrics, dryer sheets, or harsh laundry detergents that could exacerbate AD.
‘You’re not alone’
Sometimes it’s helpful to assure patients with AD that they’re not alone, and that many researchers and clinicians are working on effective treatment strategies. “We’re all familiar with atopic dermatitis because there’s so much of it. The numbers are surprisingly high,” Dr. Friedman said. Compared with the estimated 2.2 million Americans with psoriasis, AD eclipses their numbers substantially, affecting about 17 million people.
Dr. Friedman disclosed that he is a speaker for Amgen, Janssen, and Promius; receives research grants from Valeant; and is a consultant and/or advisory board member for Amgen, Aveeno, Biogen, Encore, Exeltis, Ferndale, Galderma, G&W Laboratories, Intraderm, La Roche-Posay, Loreal, Microcures, Nano Bio-Med, Novartis, Oakstone Institute, Occulus, Onset, Pfizer, Promius, Sanova Works, and Valeant. Dr. Friedman is also an editorial advisory board member for Dermatology News.
MIAMI – Tactics for managing patients with atopic dermatitis can go a long way to educate patients, set realistic expectations, and devise strategies for existing therapies, even as clinicians await some promising agents expected on the market soon.
“The good news is this is the Age of Eczema. In the last couple of years we’ve seen an explosion in the literature,” Adam Friedman, MD, of the department of dermatology, George Washington University, Washington, D.C., said at the Orlando Dermatology Aesthetic and Clinical Conference. Some of this research is spurring new therapeutics. a phosphodiesterase 4 inhibitor.
Crisaborole ointment, 2% (Eucrisa), a phosphodiesterase 4 inhibitor, was approved by the Food and Drug Administration in December 2016 for treating patients aged 2 years and older with mild to moderate AD, for example. It is a novel, nonsteroidal anti-inflammatory and the first prescription agent approved in the United States for atopic dermatitis in more than 10 years.
Dr. Friedman has no personal experience with crisaborole, which just became available. “But the data look encouraging. From what I’ve seen this may be a nonburning alternative to calcineurin inhibitors. It will be interesting to see how this will fit in our practices.”
Systemic management of pruritus
There’s also promise for patients troubled by one of the top manifestations of AD – the itch. “We have new targeted therapies coming down the pike, some hopefully [gaining approval] in the next few months. We have biologics going after the cytokines of itch. It’s a very, very exciting time right now,” Dr. Friedman said.
Current clinical trials are not only focusing on AD but also specifically on pruritus, he added.
In the meantime, itch can be managed with prescription and over-the-counter topical agents, as well as systemic therapies such as gabapentin, some antidepressants, and the antiemetic aprepitant. Aprepitant is a substance P antagonist (through blocking neurokinin 1 receptor) and can be effective for some patients when taken three times a week, but it is not indicated for itch, Dr. Friedman said. Because of its off label indication “it’s a little tricky getting [insurance] coverage.”
Back to basics
“Even with all the excitement, even with the new therapeutics, you have to stick with the basics,” he said. “Put the lotion on, put the cream on. You have to put moisturizer on wet skin and be cautious with soaps.” He added, “don’t be afraid to ask for help. The National Eczema Association has a wonderful website with research, education, tools – you name it.”
Keeping it real
For regional eczemas like hand dermatitis, what are the options? “Tell patients they can glove up, there are various latex alternatives … but it probably won’t fly in the real world,” Dr. Friedman said. Zinc oxide “works like armor, and patients will probably do well,” but the aesthetics are unacceptable for most, he added. “Newer alternatives, such as those with aluminum magnesium hydroxide stearate, have similar protecting power, but are not opaque and rub on easier.”
A goal of topical therapy is to get rid of the inflammation, and steroids have a long history of evidence supporting their use, but “topical steroid phobia in parents” is a problem, he said. To counter the reluctance or refusal to use topical steroids, he suggested exploring reasons for noncompliance, dispelling any myths, and working with parent to make it easier to apply the steroids to their child.
Interestingly, there is some evidence that a simpler regimen may work well for some patients. “We always say ‘apply twice a day.’ Why? Because all the clinical trials had participants apply steroids twice a day. But there is no evidence to show twice a day is better than once a day, and in fact, a meta-analysis suggests once a day works just as well” (Br J Dermatol. 2005 Jan;152[1]:130-41).
Topical calcineurin inhibitors are another option. In general, Dr. Friedman prescribes these agents for delicate areas, for patients with thin skin, or for patients who use a topical steroid “on and on and on and can’t seem to get off it.” Calcineurin inhibitors can also be used on in-between days during steroid maintenance therapy, he added. When prescribing, warn patients about the initial burn (due to substance P release) that commonly occurs so that they have realistic expectations.
Education remains essential
“I encourage you to educate your patients and empathize with them,” he said. “Show them how to apply a moisturizer. Also, use your nurses and assistants to help with education – really empower them to be part of the process.”
“Explain, explain, explain, so they have realistic expectations,” and know that there is no cure, so that when they experience a flare, they understand that “it’s not that the steroid didn’t work – this is a chronic disease,” added Dr. Friedman, who recommends providing patients with handouts that answer many of their questions.
Maximize moisturizing
When it comes to moisturizing, more is usually better. Effective products contain all the key ingredients: emollients to soften the skin, an occlusive to keep the water there, and a humectant to bond the water. “Just one or two is not going to cut it,” he said.
“Something we now know is that starting early is key,” he pointed out, referring to recent studies that have shown that in babies at high risk for AD, starting moisturizers early can decrease their risk for developing AD later (J Allergy Clin Immunol. 2014 Oct; 134[4]: 818-23).
“Another study that received a ton of press was in JAMA Pediatrics recently,” Dr. Friedman said. The study concluded that the use of different moisturizers to prevent AD in high risk babies was likely to be cost-effective (JAMA Pediatr. 2017 Feb 6;171[2]:e163909. doi: 10.1001/jamapediatrics.2016.3909). Although some news reports claimed starting babies with Vaseline as a moisturizer will prevent AD, “that’s actually not what the study showed. All the over-the-counter moisturizers they used worked, but Vaseline was the least expensive,” Dr. Friedman noted
Help patients select the right soap
Educate patients to avoid “true soaps” such as Dial, Ivory, Irish Spring, or Lever 2000. “Soaps can be a real enemy here. You want lower pH types of soaps. Depending on skin type, our skin is somewhere between 5.5 and 6.5 pH,” Dr. Friedman explained. “The paradigm shift for your patients is to hydrate, not to clean. Showers are okay if they’re not blaring hot. Baths are okay ... but you should not be sitting in a sudsy bath.”
Also, instruct patients to avoid irritating fabrics, dryer sheets, or harsh laundry detergents that could exacerbate AD.
‘You’re not alone’
Sometimes it’s helpful to assure patients with AD that they’re not alone, and that many researchers and clinicians are working on effective treatment strategies. “We’re all familiar with atopic dermatitis because there’s so much of it. The numbers are surprisingly high,” Dr. Friedman said. Compared with the estimated 2.2 million Americans with psoriasis, AD eclipses their numbers substantially, affecting about 17 million people.
Dr. Friedman disclosed that he is a speaker for Amgen, Janssen, and Promius; receives research grants from Valeant; and is a consultant and/or advisory board member for Amgen, Aveeno, Biogen, Encore, Exeltis, Ferndale, Galderma, G&W Laboratories, Intraderm, La Roche-Posay, Loreal, Microcures, Nano Bio-Med, Novartis, Oakstone Institute, Occulus, Onset, Pfizer, Promius, Sanova Works, and Valeant. Dr. Friedman is also an editorial advisory board member for Dermatology News.
MIAMI – Tactics for managing patients with atopic dermatitis can go a long way to educate patients, set realistic expectations, and devise strategies for existing therapies, even as clinicians await some promising agents expected on the market soon.
“The good news is this is the Age of Eczema. In the last couple of years we’ve seen an explosion in the literature,” Adam Friedman, MD, of the department of dermatology, George Washington University, Washington, D.C., said at the Orlando Dermatology Aesthetic and Clinical Conference. Some of this research is spurring new therapeutics. a phosphodiesterase 4 inhibitor.
Crisaborole ointment, 2% (Eucrisa), a phosphodiesterase 4 inhibitor, was approved by the Food and Drug Administration in December 2016 for treating patients aged 2 years and older with mild to moderate AD, for example. It is a novel, nonsteroidal anti-inflammatory and the first prescription agent approved in the United States for atopic dermatitis in more than 10 years.
Dr. Friedman has no personal experience with crisaborole, which just became available. “But the data look encouraging. From what I’ve seen this may be a nonburning alternative to calcineurin inhibitors. It will be interesting to see how this will fit in our practices.”
Systemic management of pruritus
There’s also promise for patients troubled by one of the top manifestations of AD – the itch. “We have new targeted therapies coming down the pike, some hopefully [gaining approval] in the next few months. We have biologics going after the cytokines of itch. It’s a very, very exciting time right now,” Dr. Friedman said.
Current clinical trials are not only focusing on AD but also specifically on pruritus, he added.
In the meantime, itch can be managed with prescription and over-the-counter topical agents, as well as systemic therapies such as gabapentin, some antidepressants, and the antiemetic aprepitant. Aprepitant is a substance P antagonist (through blocking neurokinin 1 receptor) and can be effective for some patients when taken three times a week, but it is not indicated for itch, Dr. Friedman said. Because of its off label indication “it’s a little tricky getting [insurance] coverage.”
Back to basics
“Even with all the excitement, even with the new therapeutics, you have to stick with the basics,” he said. “Put the lotion on, put the cream on. You have to put moisturizer on wet skin and be cautious with soaps.” He added, “don’t be afraid to ask for help. The National Eczema Association has a wonderful website with research, education, tools – you name it.”
Keeping it real
For regional eczemas like hand dermatitis, what are the options? “Tell patients they can glove up, there are various latex alternatives … but it probably won’t fly in the real world,” Dr. Friedman said. Zinc oxide “works like armor, and patients will probably do well,” but the aesthetics are unacceptable for most, he added. “Newer alternatives, such as those with aluminum magnesium hydroxide stearate, have similar protecting power, but are not opaque and rub on easier.”
A goal of topical therapy is to get rid of the inflammation, and steroids have a long history of evidence supporting their use, but “topical steroid phobia in parents” is a problem, he said. To counter the reluctance or refusal to use topical steroids, he suggested exploring reasons for noncompliance, dispelling any myths, and working with parent to make it easier to apply the steroids to their child.
Interestingly, there is some evidence that a simpler regimen may work well for some patients. “We always say ‘apply twice a day.’ Why? Because all the clinical trials had participants apply steroids twice a day. But there is no evidence to show twice a day is better than once a day, and in fact, a meta-analysis suggests once a day works just as well” (Br J Dermatol. 2005 Jan;152[1]:130-41).
Topical calcineurin inhibitors are another option. In general, Dr. Friedman prescribes these agents for delicate areas, for patients with thin skin, or for patients who use a topical steroid “on and on and on and can’t seem to get off it.” Calcineurin inhibitors can also be used on in-between days during steroid maintenance therapy, he added. When prescribing, warn patients about the initial burn (due to substance P release) that commonly occurs so that they have realistic expectations.
Education remains essential
“I encourage you to educate your patients and empathize with them,” he said. “Show them how to apply a moisturizer. Also, use your nurses and assistants to help with education – really empower them to be part of the process.”
“Explain, explain, explain, so they have realistic expectations,” and know that there is no cure, so that when they experience a flare, they understand that “it’s not that the steroid didn’t work – this is a chronic disease,” added Dr. Friedman, who recommends providing patients with handouts that answer many of their questions.
Maximize moisturizing
When it comes to moisturizing, more is usually better. Effective products contain all the key ingredients: emollients to soften the skin, an occlusive to keep the water there, and a humectant to bond the water. “Just one or two is not going to cut it,” he said.
“Something we now know is that starting early is key,” he pointed out, referring to recent studies that have shown that in babies at high risk for AD, starting moisturizers early can decrease their risk for developing AD later (J Allergy Clin Immunol. 2014 Oct; 134[4]: 818-23).
“Another study that received a ton of press was in JAMA Pediatrics recently,” Dr. Friedman said. The study concluded that the use of different moisturizers to prevent AD in high risk babies was likely to be cost-effective (JAMA Pediatr. 2017 Feb 6;171[2]:e163909. doi: 10.1001/jamapediatrics.2016.3909). Although some news reports claimed starting babies with Vaseline as a moisturizer will prevent AD, “that’s actually not what the study showed. All the over-the-counter moisturizers they used worked, but Vaseline was the least expensive,” Dr. Friedman noted
Help patients select the right soap
Educate patients to avoid “true soaps” such as Dial, Ivory, Irish Spring, or Lever 2000. “Soaps can be a real enemy here. You want lower pH types of soaps. Depending on skin type, our skin is somewhere between 5.5 and 6.5 pH,” Dr. Friedman explained. “The paradigm shift for your patients is to hydrate, not to clean. Showers are okay if they’re not blaring hot. Baths are okay ... but you should not be sitting in a sudsy bath.”
Also, instruct patients to avoid irritating fabrics, dryer sheets, or harsh laundry detergents that could exacerbate AD.
‘You’re not alone’
Sometimes it’s helpful to assure patients with AD that they’re not alone, and that many researchers and clinicians are working on effective treatment strategies. “We’re all familiar with atopic dermatitis because there’s so much of it. The numbers are surprisingly high,” Dr. Friedman said. Compared with the estimated 2.2 million Americans with psoriasis, AD eclipses their numbers substantially, affecting about 17 million people.
Dr. Friedman disclosed that he is a speaker for Amgen, Janssen, and Promius; receives research grants from Valeant; and is a consultant and/or advisory board member for Amgen, Aveeno, Biogen, Encore, Exeltis, Ferndale, Galderma, G&W Laboratories, Intraderm, La Roche-Posay, Loreal, Microcures, Nano Bio-Med, Novartis, Oakstone Institute, Occulus, Onset, Pfizer, Promius, Sanova Works, and Valeant. Dr. Friedman is also an editorial advisory board member for Dermatology News.
AT ODAC 2017
Rituximab is dramatically effective in IgG4-related disease
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
IgG4-related disease can strike any organ system
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Using Patch Testing to Identify Culprit Agents in Suspected Drug Eruptions
VIDEO: Coffee break at the Hawaii Dermatology Seminar
WAILEA, HAWAII – A few attendees at the Hawaii Dermatology Seminar discussed some of the highlights of the presentations during a coffee break at the meeting.
New treatment protocols for psoriasis, details about skin disease in children, managing medication side effects, and promising data about biologics are discussed in this video, as are updates on the latest tips for treating atopic dermatitis.
The interviewees had no conflicts to disclose.
The meeting is provided by Global Academy for Medical Education/Skin Disease Education Foundation. SDEF and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WAILEA, HAWAII – A few attendees at the Hawaii Dermatology Seminar discussed some of the highlights of the presentations during a coffee break at the meeting.
New treatment protocols for psoriasis, details about skin disease in children, managing medication side effects, and promising data about biologics are discussed in this video, as are updates on the latest tips for treating atopic dermatitis.
The interviewees had no conflicts to disclose.
The meeting is provided by Global Academy for Medical Education/Skin Disease Education Foundation. SDEF and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WAILEA, HAWAII – A few attendees at the Hawaii Dermatology Seminar discussed some of the highlights of the presentations during a coffee break at the meeting.
New treatment protocols for psoriasis, details about skin disease in children, managing medication side effects, and promising data about biologics are discussed in this video, as are updates on the latest tips for treating atopic dermatitis.
The interviewees had no conflicts to disclose.
The meeting is provided by Global Academy for Medical Education/Skin Disease Education Foundation. SDEF and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT SDEF HAWAII DERMATOLOGY SEMINAR
VIDEO: Nonsteroidal topical expands options for pediatric AD
WAILEA, HAWAII – In an interview, pediatric dermatologist Lawrence F. Eichenfield, MD, discusses a recently approved topical therapy for atopic dermatitis, which provides a nonsteroidal option for treating the disease in young patients.
“We’re really excited to have a new topical agent” for AD, Dr. Eichenfield said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The product, crisaborole (Eucrisa), is a phosphodiesterase 4 (PDE-4) inhibitor, a new type of chemical entity “based on a different pathway of decreasing inflammation,” said Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego. Crisaborole, the first new chemical entity to become available for treating AD since 2001, blocks PDE-4 and decreases cytokines, thereby reducing the inflammation in AD, he explained.
In the United States, the product is approved for the topical treatment of mild to moderate AD for patients aged 2 years and older. No serious adverse events attributed to crisaborole have been reported so far, in phase II and III studies and in a 1-year study, he said.
Dr. Eichenfield disclosed relationships with companies including Anacor/Pfizer, Genentech, Lilly, Regeneron/Sanofi, Medimetriks, and Otsuka. Crisaborole is manufactured by Anacor. SDEF and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WAILEA, HAWAII – In an interview, pediatric dermatologist Lawrence F. Eichenfield, MD, discusses a recently approved topical therapy for atopic dermatitis, which provides a nonsteroidal option for treating the disease in young patients.
“We’re really excited to have a new topical agent” for AD, Dr. Eichenfield said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The product, crisaborole (Eucrisa), is a phosphodiesterase 4 (PDE-4) inhibitor, a new type of chemical entity “based on a different pathway of decreasing inflammation,” said Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego. Crisaborole, the first new chemical entity to become available for treating AD since 2001, blocks PDE-4 and decreases cytokines, thereby reducing the inflammation in AD, he explained.
In the United States, the product is approved for the topical treatment of mild to moderate AD for patients aged 2 years and older. No serious adverse events attributed to crisaborole have been reported so far, in phase II and III studies and in a 1-year study, he said.
Dr. Eichenfield disclosed relationships with companies including Anacor/Pfizer, Genentech, Lilly, Regeneron/Sanofi, Medimetriks, and Otsuka. Crisaborole is manufactured by Anacor. SDEF and this news organization are owned by the same parent company.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WAILEA, HAWAII – In an interview, pediatric dermatologist Lawrence F. Eichenfield, MD, discusses a recently approved topical therapy for atopic dermatitis, which provides a nonsteroidal option for treating the disease in young patients.
“We’re really excited to have a new topical agent” for AD, Dr. Eichenfield said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The product, crisaborole (Eucrisa), is a phosphodiesterase 4 (PDE-4) inhibitor, a new type of chemical entity “based on a different pathway of decreasing inflammation,” said Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego. Crisaborole, the first new chemical entity to become available for treating AD since 2001, blocks PDE-4 and decreases cytokines, thereby reducing the inflammation in AD, he explained.
In the United States, the product is approved for the topical treatment of mild to moderate AD for patients aged 2 years and older. No serious adverse events attributed to crisaborole have been reported so far, in phase II and III studies and in a 1-year study, he said.
Dr. Eichenfield disclosed relationships with companies including Anacor/Pfizer, Genentech, Lilly, Regeneron/Sanofi, Medimetriks, and Otsuka. Crisaborole is manufactured by Anacor. SDEF and this news organization are owned by the same parent company.
