Psoriasis

The Food and Drug Administration expects to issue its guidance on biosimilars by the end of 2011, more than a year after legislation designed to make cheaper generic versions of therapeutic biologics available was incorporated into the Patient Protection and Affordable Care Act of 2010.

A year earlier, the Biologics Price Competition and Innovation Act of 2009 (BPCI) established an abbreviated approval pathway for biological products that are shown to be "highly similar" or "biosimilar" to, or "interchangeable" with, an FDA-approved biological product, according to the FDA's summary of the legislation.

The complex issues related to its implementation are still being worked out by a special committee at the agency, which met in November 2010 to discuss the issues and challenges of implementing the BPCI Act. Manufacturers of biologic therapeutics, generic pharmaceutical companies, patient groups, and other interested parties provided their input at that meeting.

An FDA spokesperson said that the agency "continues to carefully review and consider all comments from the November 2010 hearing and from the docket as we move forward in our implementation" of the statute. Biosimilars are also referred to as "follow-on biologics."

Of the major biologics, etanercept (Enbrel) will be the first to lose its patent, in 2012. 

Dr. Steven Kozlowski, director of the FDA's Office of Biotechnology Products, and other FDA officials noted that access to expensive biologic therapies "may be limited, not infrequently because of their cost" and emphasized the challenges the agency faced in implementing the act in a "Perspective" article published online on Aug. 4 in the New England Journal of Medicine (2011;365:385-8).

The coauthors of the article, "Developing the Nation's Biosimilar Program," were Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research; Dr. Karen Midthun, director of the Center for Biologics Evaluation and Research; and Dr. Rachel Behrman Sherman, director of the Office of Medical Policy.

"Reconciling the science of biosimilar development with the new regulatory framework required by the BPCI Act presents the FDA with numerous challenges," primarily, establishing scientific criteria "that address the key question: how similar is similar enough when it comes to the substitution of complex biologic drug products in clinical practice?" They cited immunogenicity as "a critical factor" when evaluating biosimilars, and noted that product-specific safety monitoring should be included in the process.

For now, it remains difficult to predict when these more affordable generic formulations of the expensive biologic treatments for inflammatory diseases will become available.

A spokesperson for the Generic Pharmaceutical Association (GPhA) said that the legislation left a lot to the FDA's discretion. FDA's regulations must not be burdensome and should not create barriers to making these products available, he said. "Ultimately, we want patients to have access to these drugs at affordable prices." A representative of the GPhA made a presentation at the November 2010 meeting and submitted formal comments to the docket in December.

In the dermatology arena, biosimilars would be welcomed primarily because of cost savings for patients and increased access to these effective treatments, said Dr. Mark G. Lebwohl, professor and chairman of the department of dermatology at Mount Sinai School of Medicine, N.Y.

Biosimilars will not be identical to the drugs they replace, "and when tested, they will have to come into a certain narrow window of similarity in terms of both safety and side effects," he said in an interview. The dilemma with the side effect profile is that it may not be fully characterized for years and, in terms of effectiveness, "the dilemma is that they have to be approximately equal to the drug that it is replacing."

For example, a biosimilar for etanercept that is 10% less effective than the original product could make a difference clinically. A biosimilar could conceivably work better than the biologic drug it is replacing, but "if it is too much more effective, it’s not a biosimilar and will have to through a new drug application." Moreover, if it is more effective, it might be more immunosuppressive, raising concerns about more side effects, Dr. Lebwohl pointed out.

Dr. Lebwohl disclosed that he has been an investigator for and the department of dermatology at Mount Sinai has received funds from most of the manufacturers of biologics for psoriasis.

More on the BPCI Act is available on the FDA website.

The Food and Drug Administration expects to issue its guidance on biosimilars by the end of 2011, more than a year after legislation designed to make cheaper generic versions of therapeutic biologics available was incorporated into the Patient Protection and Affordable Care Act of 2010.

A year earlier, the Biologics Price Competition and Innovation Act of 2009 (BPCI) established an abbreviated approval pathway for biological products that are shown to be "highly similar" or "biosimilar" to, or "interchangeable" with, an FDA-approved biological product, according to the FDA's summary of the legislation.

The complex issues related to its implementation are still being worked out by a special committee at the agency, which met in November 2010 to discuss the issues and challenges of implementing the BPCI Act. Manufacturers of biologic therapeutics, generic pharmaceutical companies, patient groups, and other interested parties provided their input at that meeting.

An FDA spokesperson said that the agency "continues to carefully review and consider all comments from the November 2010 hearing and from the docket as we move forward in our implementation" of the statute. Biosimilars are also referred to as "follow-on biologics."

Of the major biologics, etanercept (Enbrel) will be the first to lose its patent, in 2012. 

Dr. Steven Kozlowski, director of the FDA's Office of Biotechnology Products, and other FDA officials noted that access to expensive biologic therapies "may be limited, not infrequently because of their cost" and emphasized the challenges the agency faced in implementing the act in a "Perspective" article published online on Aug. 4 in the New England Journal of Medicine (2011;365:385-8).

The coauthors of the article, "Developing the Nation's Biosimilar Program," were Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research; Dr. Karen Midthun, director of the Center for Biologics Evaluation and Research; and Dr. Rachel Behrman Sherman, director of the Office of Medical Policy.

"Reconciling the science of biosimilar development with the new regulatory framework required by the BPCI Act presents the FDA with numerous challenges," primarily, establishing scientific criteria "that address the key question: how similar is similar enough when it comes to the substitution of complex biologic drug products in clinical practice?" They cited immunogenicity as "a critical factor" when evaluating biosimilars, and noted that product-specific safety monitoring should be included in the process.

For now, it remains difficult to predict when these more affordable generic formulations of the expensive biologic treatments for inflammatory diseases will become available.

A spokesperson for the Generic Pharmaceutical Association (GPhA) said that the legislation left a lot to the FDA's discretion. FDA's regulations must not be burdensome and should not create barriers to making these products available, he said. "Ultimately, we want patients to have access to these drugs at affordable prices." A representative of the GPhA made a presentation at the November 2010 meeting and submitted formal comments to the docket in December.

In the dermatology arena, biosimilars would be welcomed primarily because of cost savings for patients and increased access to these effective treatments, said Dr. Mark G. Lebwohl, professor and chairman of the department of dermatology at Mount Sinai School of Medicine, N.Y.

Biosimilars will not be identical to the drugs they replace, "and when tested, they will have to come into a certain narrow window of similarity in terms of both safety and side effects," he said in an interview. The dilemma with the side effect profile is that it may not be fully characterized for years and, in terms of effectiveness, "the dilemma is that they have to be approximately equal to the drug that it is replacing."

For example, a biosimilar for etanercept that is 10% less effective than the original product could make a difference clinically. A biosimilar could conceivably work better than the biologic drug it is replacing, but "if it is too much more effective, it’s not a biosimilar and will have to through a new drug application." Moreover, if it is more effective, it might be more immunosuppressive, raising concerns about more side effects, Dr. Lebwohl pointed out.

Dr. Lebwohl disclosed that he has been an investigator for and the department of dermatology at Mount Sinai has received funds from most of the manufacturers of biologics for psoriasis.

More on the BPCI Act is available on the FDA website.

The Food and Drug Administration expects to issue its guidance on biosimilars by the end of 2011, more than a year after legislation designed to make cheaper generic versions of therapeutic biologics available was incorporated into the Patient Protection and Affordable Care Act of 2010.

A year earlier, the Biologics Price Competition and Innovation Act of 2009 (BPCI) established an abbreviated approval pathway for biological products that are shown to be "highly similar" or "biosimilar" to, or "interchangeable" with, an FDA-approved biological product, according to the FDA's summary of the legislation.

The complex issues related to its implementation are still being worked out by a special committee at the agency, which met in November 2010 to discuss the issues and challenges of implementing the BPCI Act. Manufacturers of biologic therapeutics, generic pharmaceutical companies, patient groups, and other interested parties provided their input at that meeting.

An FDA spokesperson said that the agency "continues to carefully review and consider all comments from the November 2010 hearing and from the docket as we move forward in our implementation" of the statute. Biosimilars are also referred to as "follow-on biologics."

Of the major biologics, etanercept (Enbrel) will be the first to lose its patent, in 2012. 

Dr. Steven Kozlowski, director of the FDA's Office of Biotechnology Products, and other FDA officials noted that access to expensive biologic therapies "may be limited, not infrequently because of their cost" and emphasized the challenges the agency faced in implementing the act in a "Perspective" article published online on Aug. 4 in the New England Journal of Medicine (2011;365:385-8).

The coauthors of the article, "Developing the Nation's Biosimilar Program," were Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research; Dr. Karen Midthun, director of the Center for Biologics Evaluation and Research; and Dr. Rachel Behrman Sherman, director of the Office of Medical Policy.

"Reconciling the science of biosimilar development with the new regulatory framework required by the BPCI Act presents the FDA with numerous challenges," primarily, establishing scientific criteria "that address the key question: how similar is similar enough when it comes to the substitution of complex biologic drug products in clinical practice?" They cited immunogenicity as "a critical factor" when evaluating biosimilars, and noted that product-specific safety monitoring should be included in the process.

For now, it remains difficult to predict when these more affordable generic formulations of the expensive biologic treatments for inflammatory diseases will become available.

A spokesperson for the Generic Pharmaceutical Association (GPhA) said that the legislation left a lot to the FDA's discretion. FDA's regulations must not be burdensome and should not create barriers to making these products available, he said. "Ultimately, we want patients to have access to these drugs at affordable prices." A representative of the GPhA made a presentation at the November 2010 meeting and submitted formal comments to the docket in December.

In the dermatology arena, biosimilars would be welcomed primarily because of cost savings for patients and increased access to these effective treatments, said Dr. Mark G. Lebwohl, professor and chairman of the department of dermatology at Mount Sinai School of Medicine, N.Y.

Biosimilars will not be identical to the drugs they replace, "and when tested, they will have to come into a certain narrow window of similarity in terms of both safety and side effects," he said in an interview. The dilemma with the side effect profile is that it may not be fully characterized for years and, in terms of effectiveness, "the dilemma is that they have to be approximately equal to the drug that it is replacing."

For example, a biosimilar for etanercept that is 10% less effective than the original product could make a difference clinically. A biosimilar could conceivably work better than the biologic drug it is replacing, but "if it is too much more effective, it’s not a biosimilar and will have to through a new drug application." Moreover, if it is more effective, it might be more immunosuppressive, raising concerns about more side effects, Dr. Lebwohl pointed out.

Dr. Lebwohl disclosed that he has been an investigator for and the department of dermatology at Mount Sinai has received funds from most of the manufacturers of biologics for psoriasis.

More on the BPCI Act is available on the FDA website.

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

The use of biologic agents for chronic plaque psoriasis was not associated with a significant increase in the risk of major adverse cardiovascular events in a meta-analysis of 22 randomized clinical trials reported in the Aug. 24/31 issue of JAMA.

However, the study had several limitations that prevented the investigators from definitively establishing whether anti-interleukin-12 and anti-interleukin 23 (anti-IL12/23) agents such as usetekinumab and briakinumab or anti-TNFa agents such as adalimumab, etanercept, and infliximab expose psoriasis patients to excess cardiovascular risk.

"Access to patient-level data for these studies was not granted by any of the study sponsors, which precluded the use of a more statistically robust time-to-event analysis. [In addition,] the small number of major adverse CV events in placebo-controlled phases of these studies and the limited duration of the placebo-controlled phases reduce the power of this meta-analysis to detect a change in risk," said Caitriona Ryan, MB, BAO, BCh, of the department of dermatology, Baylor Research Institute, Dallas, and her associates.

"Until more definitive data become available, we believe that dermatologists should exercise heightened vigilance for CV risk factors when initiating anti-Il12/23 agents in psoriasis patients," they noted.

Initially, it was thought that these biologic agents, which help control inflammation in RA and psoriasis patients, might also exert a cardioprotective effect. So there was surprise and concern when preliminary reports showed a numerical excess of major adverse CV events (MACE) in industry-sponsored trials of ustekinumab (Centocor Ortho) and briakinumab (Abbott). "A total of 53 MACEs have occurred to date across all phases of these studies; 26 MACES, including 1 CV death, in studies of ustekinumab and 27 MACEs, including 4 CV deaths, in studies of briakinumab," the investigators said.

To clarify a possible link, they performed a meta-analysis of all randomized clinical trials (RCTs) in which these two agents as well as anti-TNFa agents were compared with placebo in subjects who had chronic plaque psoriasis but no psoriatic arthritis. A total of 10,183 patients comprised the study population. "The primary outcome measure was the number of MACEs during the placebo-controlled phase of treatment," the researchers said.

Although they found no significant rise in risk of MACEs, the investigators said they were limited in their ability to do so by small numbers of subjects, small numbers of MACEs, short duration of drug exposure, and flaws in the RCTs. For example, two myocardial infarctions were not reported in the "adverse event" sections of one prominent industry-sponsored study.

Even though meta-analysis is intended to increase the power to detect rare events by pooling data from several studies, it "cannot correct for limitations in quality of the original clinical trials, most notably the absence of a systematic strategy to screen for, capture, and adjudicate CV events," they noted (JAMA 2011;306:864-71).

"We remain concerned about the MACE rate of 1.33 per 100 patient-years in the placebo-controlled phase of the phase III briakinumab study, with an overall rate of 0.60 events per 100 patient-years across all treatment periods. Indeed, after identification of these cases," patients with two or more CV risk factors were withdrawn from the study. "Subsequently, in July 2011, all clinical trials of briakinumab were discontinued by Abbott, pending further investigations particularly relating to possible mechanistic links to MACEs," the investigators said.

"With numerous therapeutics agents inhibiting IL-17 and IL-23 currently in development, it is essential that the effect of these cytokines on vascular inflammation be fully explored," they stressed.

Their results highlight "the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events given their current design." RCTs often are underpowered and too brief to detect rare or long-term adverse events, the researchers added.

The investigators reported receiving no external funding for this study. Dr. Ryan reported ties to Janssen-Cilag, Pfizer (a maker of etanercept), Galderma, and Abbott (maker of briakinumab and adalimumab), and his associates reported ties to numerous pharmaceutical companies including the above and Centocor (maker of ustekinumab and infliximab), Amgen (comaker of etanercept), and Schering-Plough (a maker of infliximab).

NEW YORK – Raynaud’s phenomenon can cause nipple pain in breastfeeding mothers – but a small case series found that it is almost always misdiagnosed.

Of 86 women in the series – the largest ever accrued – 24 patients had Raynaud’s, all of whom were misdiagnosed as having fungal mastitis, Dr. Honor Fullerton Stone and her colleagues reported in a poster presented at the American Academy of Dermatology’s Summer Academy Meeting.

Although the physical exam can be complicated by other factors – a flare of atopic dermatitis or a fungal or bacterial superinfection – Raynaud’s should always be considered in the differential diagnosis of lactating women with nipple pain, according to Dr. Fullerton Stone of Stanford (Calif.) University.

She presented a chart review of 86 lactating women complaining of nipple pain; the cases were accrued from 2004 to 2010 in a single medical center. Of these, 24 (28%) were diagnosed with Raynaud’s, based on the presence of at least two of the following diagnostic characteristics:

– Color changes of the nipple (blue, white, or red), especially with exposure to cold.

– Cold sensitivity or color changes of acral surfaces with cold exposure.

– Chronic deep breast pain for 4 weeks or longer and failed therapy with oral antifungals and/or antibiotics.

All 24 women with Raynaud’s presented with enlarged breasts, mild to moderate erythema of the areola, and desquamation of one or both nipples. Two also had plugged milk ducts.

All were initially diagnosed as having a candida breast infection. Ten of them reported that their babies had experienced an episode of oral thrush. And 20 of the 24 (83%) had been unsuccessfully treated with topical or oral antifungals, including at least one course of fluconazole (18; 75%).

Two also had a skin superinfection, growing Staphylococcus aureus on a bacterial culture; these women also received a course of oral antibiotics.

After being diagnosed with Raynaud’s, about 16 (67%) received a course of nifedipine; 3 discontinued the drug because of headache, dizziness, or nausea. Of the 13 who continued the drug, 10 (77%) reported a decrease or elimination of their nipple pain.

Other Raynaud’s-specific treatment included advice to wear warm clothing, to take hot showers before nursing, and to avoid caffeine and other vasoconstrictive drugs that could precipitate symptoms.

In addition to the Raynaud’s-specific treatment, all of the women were treated for accompanying issues, including breast dermatitis and antifungal therapy.

All received a prescription for a low- or moderate-strength hydrocortisone butyrate cream or alclometasone dipropionate to be applied twice a day for 2 weeks. They were also told to apply Aquaphor two or three times daily, over the steroid cream. Most (23) also had an additional standard course of oral fluconazole (400 mg on day 1 followed by 200 mg daily for the next 8-10 days).

Twenty women participated in a follow-up survey. Most (15, 75%) also reported that they had cold sensitivity or color changes in their hands and feet. Two reported having been diagnosed with an autoimmune disease – either lupus or Sjögren’s syndrome, and two reported having had a breast cyst removed.

They also described the pain they experienced during a Raynaud’s episode of the nipple. All said the pain continued throughout breastfeeding; 25% said that the pain increased during the beginning of lactation. Most, however, (75%) said the pain occurred before, during, and after breastfeeding.

Since the physical exam may be inconclusive, the quality of the pain can be a diagnostic clue to Raynaud’s in the nursing mother, Dr. Fullerton Stone noted. Letdown pain is more common in the weeks after birth, and usually improves. It is typically experienced as a mild pain during the first minutes of breast feeding, which may continue for 12-15 minutes afterward.

Candida infections are described as causing moderate, burning pain that is worse when the baby latches on for a nursing session. The pain can radiate from the nipple throughout the breast; it typically improves dramatically within the first few days of oral antifungal treatment.

Raynaud’s is usually described as moderate sharp, shocking-type, or throbbing pain before, during, and after nursing. As is typically observed with Raynaud’s of the hands and feet, there is a color change that signifies the vasoconstriction characteristic of the disorder.

Dr. Fullerton Stone said she had no financial declarations with regard to her work.

NEW YORK – Raynaud’s phenomenon can cause nipple pain in breastfeeding mothers – but a small case series found that it is almost always misdiagnosed.

Of 86 women in the series – the largest ever accrued – 24 patients had Raynaud’s, all of whom were misdiagnosed as having fungal mastitis, Dr. Honor Fullerton Stone and her colleagues reported in a poster presented at the American Academy of Dermatology’s Summer Academy Meeting.

Although the physical exam can be complicated by other factors – a flare of atopic dermatitis or a fungal or bacterial superinfection – Raynaud’s should always be considered in the differential diagnosis of lactating women with nipple pain, according to Dr. Fullerton Stone of Stanford (Calif.) University.

She presented a chart review of 86 lactating women complaining of nipple pain; the cases were accrued from 2004 to 2010 in a single medical center. Of these, 24 (28%) were diagnosed with Raynaud’s, based on the presence of at least two of the following diagnostic characteristics:

– Color changes of the nipple (blue, white, or red), especially with exposure to cold.

– Cold sensitivity or color changes of acral surfaces with cold exposure.

– Chronic deep breast pain for 4 weeks or longer and failed therapy with oral antifungals and/or antibiotics.

All 24 women with Raynaud’s presented with enlarged breasts, mild to moderate erythema of the areola, and desquamation of one or both nipples. Two also had plugged milk ducts.

All were initially diagnosed as having a candida breast infection. Ten of them reported that their babies had experienced an episode of oral thrush. And 20 of the 24 (83%) had been unsuccessfully treated with topical or oral antifungals, including at least one course of fluconazole (18; 75%).

Two also had a skin superinfection, growing Staphylococcus aureus on a bacterial culture; these women also received a course of oral antibiotics.

After being diagnosed with Raynaud’s, about 16 (67%) received a course of nifedipine; 3 discontinued the drug because of headache, dizziness, or nausea. Of the 13 who continued the drug, 10 (77%) reported a decrease or elimination of their nipple pain.

Other Raynaud’s-specific treatment included advice to wear warm clothing, to take hot showers before nursing, and to avoid caffeine and other vasoconstrictive drugs that could precipitate symptoms.

In addition to the Raynaud’s-specific treatment, all of the women were treated for accompanying issues, including breast dermatitis and antifungal therapy.

All received a prescription for a low- or moderate-strength hydrocortisone butyrate cream or alclometasone dipropionate to be applied twice a day for 2 weeks. They were also told to apply Aquaphor two or three times daily, over the steroid cream. Most (23) also had an additional standard course of oral fluconazole (400 mg on day 1 followed by 200 mg daily for the next 8-10 days).

Twenty women participated in a follow-up survey. Most (15, 75%) also reported that they had cold sensitivity or color changes in their hands and feet. Two reported having been diagnosed with an autoimmune disease – either lupus or Sjögren’s syndrome, and two reported having had a breast cyst removed.

They also described the pain they experienced during a Raynaud’s episode of the nipple. All said the pain continued throughout breastfeeding; 25% said that the pain increased during the beginning of lactation. Most, however, (75%) said the pain occurred before, during, and after breastfeeding.

Since the physical exam may be inconclusive, the quality of the pain can be a diagnostic clue to Raynaud’s in the nursing mother, Dr. Fullerton Stone noted. Letdown pain is more common in the weeks after birth, and usually improves. It is typically experienced as a mild pain during the first minutes of breast feeding, which may continue for 12-15 minutes afterward.

Candida infections are described as causing moderate, burning pain that is worse when the baby latches on for a nursing session. The pain can radiate from the nipple throughout the breast; it typically improves dramatically within the first few days of oral antifungal treatment.

Raynaud’s is usually described as moderate sharp, shocking-type, or throbbing pain before, during, and after nursing. As is typically observed with Raynaud’s of the hands and feet, there is a color change that signifies the vasoconstriction characteristic of the disorder.

Dr. Fullerton Stone said she had no financial declarations with regard to her work.

NEW YORK – Raynaud’s phenomenon can cause nipple pain in breastfeeding mothers – but a small case series found that it is almost always misdiagnosed.

Of 86 women in the series – the largest ever accrued – 24 patients had Raynaud’s, all of whom were misdiagnosed as having fungal mastitis, Dr. Honor Fullerton Stone and her colleagues reported in a poster presented at the American Academy of Dermatology’s Summer Academy Meeting.

Although the physical exam can be complicated by other factors – a flare of atopic dermatitis or a fungal or bacterial superinfection – Raynaud’s should always be considered in the differential diagnosis of lactating women with nipple pain, according to Dr. Fullerton Stone of Stanford (Calif.) University.

She presented a chart review of 86 lactating women complaining of nipple pain; the cases were accrued from 2004 to 2010 in a single medical center. Of these, 24 (28%) were diagnosed with Raynaud’s, based on the presence of at least two of the following diagnostic characteristics:

– Color changes of the nipple (blue, white, or red), especially with exposure to cold.

– Cold sensitivity or color changes of acral surfaces with cold exposure.

– Chronic deep breast pain for 4 weeks or longer and failed therapy with oral antifungals and/or antibiotics.

All 24 women with Raynaud’s presented with enlarged breasts, mild to moderate erythema of the areola, and desquamation of one or both nipples. Two also had plugged milk ducts.

All were initially diagnosed as having a candida breast infection. Ten of them reported that their babies had experienced an episode of oral thrush. And 20 of the 24 (83%) had been unsuccessfully treated with topical or oral antifungals, including at least one course of fluconazole (18; 75%).

Two also had a skin superinfection, growing Staphylococcus aureus on a bacterial culture; these women also received a course of oral antibiotics.

After being diagnosed with Raynaud’s, about 16 (67%) received a course of nifedipine; 3 discontinued the drug because of headache, dizziness, or nausea. Of the 13 who continued the drug, 10 (77%) reported a decrease or elimination of their nipple pain.

Other Raynaud’s-specific treatment included advice to wear warm clothing, to take hot showers before nursing, and to avoid caffeine and other vasoconstrictive drugs that could precipitate symptoms.

In addition to the Raynaud’s-specific treatment, all of the women were treated for accompanying issues, including breast dermatitis and antifungal therapy.

All received a prescription for a low- or moderate-strength hydrocortisone butyrate cream or alclometasone dipropionate to be applied twice a day for 2 weeks. They were also told to apply Aquaphor two or three times daily, over the steroid cream. Most (23) also had an additional standard course of oral fluconazole (400 mg on day 1 followed by 200 mg daily for the next 8-10 days).

Twenty women participated in a follow-up survey. Most (15, 75%) also reported that they had cold sensitivity or color changes in their hands and feet. Two reported having been diagnosed with an autoimmune disease – either lupus or Sjögren’s syndrome, and two reported having had a breast cyst removed.

They also described the pain they experienced during a Raynaud’s episode of the nipple. All said the pain continued throughout breastfeeding; 25% said that the pain increased during the beginning of lactation. Most, however, (75%) said the pain occurred before, during, and after breastfeeding.

Since the physical exam may be inconclusive, the quality of the pain can be a diagnostic clue to Raynaud’s in the nursing mother, Dr. Fullerton Stone noted. Letdown pain is more common in the weeks after birth, and usually improves. It is typically experienced as a mild pain during the first minutes of breast feeding, which may continue for 12-15 minutes afterward.

Candida infections are described as causing moderate, burning pain that is worse when the baby latches on for a nursing session. The pain can radiate from the nipple throughout the breast; it typically improves dramatically within the first few days of oral antifungal treatment.

Raynaud’s is usually described as moderate sharp, shocking-type, or throbbing pain before, during, and after nursing. As is typically observed with Raynaud’s of the hands and feet, there is a color change that signifies the vasoconstriction characteristic of the disorder.

Dr. Fullerton Stone said she had no financial declarations with regard to her work.

The decision to use vaccines in children with rheumatic diseases must be guided by what ongoing therapy they are on, with an eye to timing the vaccination before initiation of particularly immunosuppressive treatments when possible. Follow-up titers should be assessed in some cases to document that the child has mounted a protective response, according to guidelines issued by a task force convened by the European League Against Rheumatism.

These are among the recommendations on use of vaccines in children with rheumatic diseases that the panel made after a systematic literature review of MEDLINE in December 2009, MEDLINE and EMBASE in November 2010, and abstracts from EULAR and American College of Rheumatology meetings in 2008 and 2009 (Ann. Rheum. Dis. 2011 Aug. 3 [doi:10.1136/ard.2011.150193]).

Lead by Dr. M.W. Heijstek of Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the task force reviewed 67 papers, combining the search terms "vaccinations" with "immunosuppressive drugs" and 147 papers using "vaccinations" and "pediatric autoinflammatory or rheumatic disease."

Their first set of guidelines address vaccination in children on immunosuppressive medications:

• Pediatric patients who use glucocorticosteroids, disease-modifying antirheumatic drugs (DMARDs), and/or anti–tumor necrosis factor-alpha (anti-TNF-alpha) therapy can receive nonlive vaccines, when indicated according to national guidelines.

• Clinicians should determine pathogen-specific antibody concentrations after vaccination in patients who are taking either high-dose glucocorticosteroids (daily dose of 2 mg/kg higher or a total dose of at least 20 mg/day for 2 weeks or more) or rituximab and possibly in patients using an anti–TNF-alpha agent.

• The pneumococcal or influenza vaccine should be given before patients initiate treatment with rituximab.

• Tetanus immunoglobulin is indicated when patients who have been taking rituximab within the past 6 months develop a contaminated wound.

• Physicians should determine pneumococcal serotype–specific antibody concentrations after pneumococcal polysaccharide vaccine 23 vaccination in patients on methotrexate at the time of vaccination.

The panel also developed recommendations for use of live attenuated and nonlive composite vaccines in pediatric patients with rheumatic disease. For live attenuated vaccines, the panel recommends that clinicians:

• Withhold them in patients using high-doses of DMARDs or glucocorticosteroids or biological agents.

• Adhere to national vaccination guidelines for live-attenuated vaccines in patients unless they are are on high-dose DMARD, high-dose glucocorticosteroids or biological agents.

• Consider booster vaccinations against varicella zoster virus (VZV); measles, mumps and rubella (MMR); and yellow fever in patients using less than 15mg/m2 methotrexate per week or low-dose glucocorticosteroids.

• Withhold bacillus Calmette-Guerin (BCG) vaccination during active Kawasaki disease.

• Assess VZV infection and vaccination history, especially in those patients likely to use high-dose immunosuppressive therapy or biological agents. In history is negative for VZV infection or vaccination, consider using the vaccine before initiating immunosuppressive therapy.

In the case of non-live composite vaccines, the guidelines recommend that clinicians:

• Administer the tetanus toxoid (TT) vaccine to patients with juvenile systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) according to national vaccination guidelines.

• Adhere to national vaccination guidelines for vaccination against the following: hepatitis A and B viruses, tetanus, diphtheria, pertussis, Haemophilus influenzae type B (Hib), pneumococci and meningococci, cholera, Japanese and tickborne encephalitis, poliovirus, rabies, encephalitis, typhoid fever, and human papillomavirus (HPV).

• If vaccinations against Hib, pneumococci, and meningococci are not included in the national vaccination programs, these vaccinations are recommended for children with rheumatic diseases who have low complement levels or functional asplenia. These vaccinations can be considered in patients on high-dose immunosuppressive drugs or biologic agents before therapy.

• Vaccinate female patients with SLE against HPV during adolescence, as they are at higher risk for HPV, but remain vigilant for potential thromboembolic events.

• Consider annual influenza vaccination in all pediatric patients with rheumatic disease.

The recommendations often refer to national vaccination guidelines, which consider local epidemiology, programmatic issues, resources, and policies, the authors say.

"Generally, the immunogenicity of vaccines is good in [children with rheumatic diseases]," they added. "There are some exceptions, depending on the type of dose of immunosuppressive treatment and type of vaccine."

The researchers also studied disease activity and adverse events. Most studies were underpowered to assess safety, they say, meaning that additional safety studies are warranted.

Finally, the authors recommend that these guidelines be updated regularly as new evidence on vaccinating pediatric patients on immunomodulating drugs becomes available.

The authors have no conflicts to disclose. The study was funded by EULAR.

The decision to use vaccines in children with rheumatic diseases must be guided by what ongoing therapy they are on, with an eye to timing the vaccination before initiation of particularly immunosuppressive treatments when possible. Follow-up titers should be assessed in some cases to document that the child has mounted a protective response, according to guidelines issued by a task force convened by the European League Against Rheumatism.

These are among the recommendations on use of vaccines in children with rheumatic diseases that the panel made after a systematic literature review of MEDLINE in December 2009, MEDLINE and EMBASE in November 2010, and abstracts from EULAR and American College of Rheumatology meetings in 2008 and 2009 (Ann. Rheum. Dis. 2011 Aug. 3 [doi:10.1136/ard.2011.150193]).

Lead by Dr. M.W. Heijstek of Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the task force reviewed 67 papers, combining the search terms "vaccinations" with "immunosuppressive drugs" and 147 papers using "vaccinations" and "pediatric autoinflammatory or rheumatic disease."

Their first set of guidelines address vaccination in children on immunosuppressive medications:

• Pediatric patients who use glucocorticosteroids, disease-modifying antirheumatic drugs (DMARDs), and/or anti–tumor necrosis factor-alpha (anti-TNF-alpha) therapy can receive nonlive vaccines, when indicated according to national guidelines.

• Clinicians should determine pathogen-specific antibody concentrations after vaccination in patients who are taking either high-dose glucocorticosteroids (daily dose of 2 mg/kg higher or a total dose of at least 20 mg/day for 2 weeks or more) or rituximab and possibly in patients using an anti–TNF-alpha agent.

• The pneumococcal or influenza vaccine should be given before patients initiate treatment with rituximab.

• Tetanus immunoglobulin is indicated when patients who have been taking rituximab within the past 6 months develop a contaminated wound.

• Physicians should determine pneumococcal serotype–specific antibody concentrations after pneumococcal polysaccharide vaccine 23 vaccination in patients on methotrexate at the time of vaccination.

The panel also developed recommendations for use of live attenuated and nonlive composite vaccines in pediatric patients with rheumatic disease. For live attenuated vaccines, the panel recommends that clinicians:

• Withhold them in patients using high-doses of DMARDs or glucocorticosteroids or biological agents.

• Adhere to national vaccination guidelines for live-attenuated vaccines in patients unless they are are on high-dose DMARD, high-dose glucocorticosteroids or biological agents.

• Consider booster vaccinations against varicella zoster virus (VZV); measles, mumps and rubella (MMR); and yellow fever in patients using less than 15mg/m2 methotrexate per week or low-dose glucocorticosteroids.

• Withhold bacillus Calmette-Guerin (BCG) vaccination during active Kawasaki disease.

• Assess VZV infection and vaccination history, especially in those patients likely to use high-dose immunosuppressive therapy or biological agents. In history is negative for VZV infection or vaccination, consider using the vaccine before initiating immunosuppressive therapy.

In the case of non-live composite vaccines, the guidelines recommend that clinicians:

• Administer the tetanus toxoid (TT) vaccine to patients with juvenile systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) according to national vaccination guidelines.

• Adhere to national vaccination guidelines for vaccination against the following: hepatitis A and B viruses, tetanus, diphtheria, pertussis, Haemophilus influenzae type B (Hib), pneumococci and meningococci, cholera, Japanese and tickborne encephalitis, poliovirus, rabies, encephalitis, typhoid fever, and human papillomavirus (HPV).

• If vaccinations against Hib, pneumococci, and meningococci are not included in the national vaccination programs, these vaccinations are recommended for children with rheumatic diseases who have low complement levels or functional asplenia. These vaccinations can be considered in patients on high-dose immunosuppressive drugs or biologic agents before therapy.

• Vaccinate female patients with SLE against HPV during adolescence, as they are at higher risk for HPV, but remain vigilant for potential thromboembolic events.

• Consider annual influenza vaccination in all pediatric patients with rheumatic disease.

The recommendations often refer to national vaccination guidelines, which consider local epidemiology, programmatic issues, resources, and policies, the authors say.

"Generally, the immunogenicity of vaccines is good in [children with rheumatic diseases]," they added. "There are some exceptions, depending on the type of dose of immunosuppressive treatment and type of vaccine."

The researchers also studied disease activity and adverse events. Most studies were underpowered to assess safety, they say, meaning that additional safety studies are warranted.

Finally, the authors recommend that these guidelines be updated regularly as new evidence on vaccinating pediatric patients on immunomodulating drugs becomes available.

The authors have no conflicts to disclose. The study was funded by EULAR.

The decision to use vaccines in children with rheumatic diseases must be guided by what ongoing therapy they are on, with an eye to timing the vaccination before initiation of particularly immunosuppressive treatments when possible. Follow-up titers should be assessed in some cases to document that the child has mounted a protective response, according to guidelines issued by a task force convened by the European League Against Rheumatism.

These are among the recommendations on use of vaccines in children with rheumatic diseases that the panel made after a systematic literature review of MEDLINE in December 2009, MEDLINE and EMBASE in November 2010, and abstracts from EULAR and American College of Rheumatology meetings in 2008 and 2009 (Ann. Rheum. Dis. 2011 Aug. 3 [doi:10.1136/ard.2011.150193]).

Lead by Dr. M.W. Heijstek of Wilhelmina Children’s Hospital, University Medical Center, Utrecht, the task force reviewed 67 papers, combining the search terms "vaccinations" with "immunosuppressive drugs" and 147 papers using "vaccinations" and "pediatric autoinflammatory or rheumatic disease."

Their first set of guidelines address vaccination in children on immunosuppressive medications:

• Pediatric patients who use glucocorticosteroids, disease-modifying antirheumatic drugs (DMARDs), and/or anti–tumor necrosis factor-alpha (anti-TNF-alpha) therapy can receive nonlive vaccines, when indicated according to national guidelines.

• Clinicians should determine pathogen-specific antibody concentrations after vaccination in patients who are taking either high-dose glucocorticosteroids (daily dose of 2 mg/kg higher or a total dose of at least 20 mg/day for 2 weeks or more) or rituximab and possibly in patients using an anti–TNF-alpha agent.

• The pneumococcal or influenza vaccine should be given before patients initiate treatment with rituximab.

• Tetanus immunoglobulin is indicated when patients who have been taking rituximab within the past 6 months develop a contaminated wound.

• Physicians should determine pneumococcal serotype–specific antibody concentrations after pneumococcal polysaccharide vaccine 23 vaccination in patients on methotrexate at the time of vaccination.

The panel also developed recommendations for use of live attenuated and nonlive composite vaccines in pediatric patients with rheumatic disease. For live attenuated vaccines, the panel recommends that clinicians:

• Withhold them in patients using high-doses of DMARDs or glucocorticosteroids or biological agents.

• Adhere to national vaccination guidelines for live-attenuated vaccines in patients unless they are are on high-dose DMARD, high-dose glucocorticosteroids or biological agents.

• Consider booster vaccinations against varicella zoster virus (VZV); measles, mumps and rubella (MMR); and yellow fever in patients using less than 15mg/m2 methotrexate per week or low-dose glucocorticosteroids.

• Withhold bacillus Calmette-Guerin (BCG) vaccination during active Kawasaki disease.

• Assess VZV infection and vaccination history, especially in those patients likely to use high-dose immunosuppressive therapy or biological agents. In history is negative for VZV infection or vaccination, consider using the vaccine before initiating immunosuppressive therapy.

In the case of non-live composite vaccines, the guidelines recommend that clinicians:

• Administer the tetanus toxoid (TT) vaccine to patients with juvenile systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA) according to national vaccination guidelines.

• Adhere to national vaccination guidelines for vaccination against the following: hepatitis A and B viruses, tetanus, diphtheria, pertussis, Haemophilus influenzae type B (Hib), pneumococci and meningococci, cholera, Japanese and tickborne encephalitis, poliovirus, rabies, encephalitis, typhoid fever, and human papillomavirus (HPV).

• If vaccinations against Hib, pneumococci, and meningococci are not included in the national vaccination programs, these vaccinations are recommended for children with rheumatic diseases who have low complement levels or functional asplenia. These vaccinations can be considered in patients on high-dose immunosuppressive drugs or biologic agents before therapy.

• Vaccinate female patients with SLE against HPV during adolescence, as they are at higher risk for HPV, but remain vigilant for potential thromboembolic events.

• Consider annual influenza vaccination in all pediatric patients with rheumatic disease.

The recommendations often refer to national vaccination guidelines, which consider local epidemiology, programmatic issues, resources, and policies, the authors say.

"Generally, the immunogenicity of vaccines is good in [children with rheumatic diseases]," they added. "There are some exceptions, depending on the type of dose of immunosuppressive treatment and type of vaccine."

The researchers also studied disease activity and adverse events. Most studies were underpowered to assess safety, they say, meaning that additional safety studies are warranted.

Finally, the authors recommend that these guidelines be updated regularly as new evidence on vaccinating pediatric patients on immunomodulating drugs becomes available.

The authors have no conflicts to disclose. The study was funded by EULAR.

Catastrophic antiphospholipid syndrome is a potentially fatal thrombotic disease that develops in a subset of patients with antiphospholipid syndrome. Survival of patients with the rare condition, which is characterized by the development of multiple organ thromboses over a short period of time, depends on the vigilance of the treating clinicians, early diagnosis, and aggressive therapy, all of which can be compromised by multiple factors including the overlap of clinical and laboratory features with other autoimmune and infectious conditions, according to rheumatologist Dr. Doruk Erkan.

Dr. Erkan (along with Dr. Gerard Espinosa and Dr. Ricard Cervera of the Hospital Clinic Barcelona) recently published a summary of the diagnostic challenges associated with catastrophic antiphospholipid syndrome (APS) and proposed updated diagnostic algorithms to streamline its management (Autoimmun. Rev. 2010;10:74-9). In this column, Dr. Erkan discusses the critical diagnostic and management considerations necessary to improve the outcomes of catastrophic APS patients.

SKIN & ALLERGY NEWS: What are the characteristic signs and symptoms of catastrophic APS?

DR. ERKAN: Multiple organ dysfunction, driven mainly by thrombotic microangiopathy, is responsible for the majority of the clinical events in catastrophic APS, although large venous or arterial thrombosis can also occur. The three most commonly involved organs are kidneys (renal thrombotic microangiopathy, and renal artery/vein thrombosis), lungs (pulmonary infarction and/or hemorrhage, and acute respiratory distress syndrome), and brain (stroke, seizure, and encephalopathy). However, thromboses in atypical locations are common in catastrophic APS patients. Any organ system can be involved, including the myocardial, skin, hepatic, and adrenal systems. Intestinal infarctions and peripheral gangrene can also develop, and hematologic manifestations such as thrombocytopenia and schistocytic hemolytic anemia commonly occur, creating a diagnostic challenge for physicians.

SAN: What risk factors, if any, have been identified for catastrophic APS?

DR. ERKAN: The presence of multiple thrombosis risk factors is associated with a higher risk of thrombosis in individuals with antiphospholipid antibodies (aPL) and even in aPL-negative populations. A "trigger event" such as surgery, pregnancy, infection, or oral contraceptive use is commonly identified in aPL-positive patients when they develop thrombosis. Similarly, about 50%-60% of patients with catastrophic APS have an identifiable "trigger event." However, it is not well understood why some aPL-positive patients develop only single-vessel thrombosis and others go on to develop the rapidly progressive microthrombosis and organ failure that are seen in catastrophic APS. Potential genetic risk factors that may predispose aPL-positive patients to catastrophic APS are under investigation (Am. J. Med. 2011;124:290-6).

SAN: What are the key elements for establishing a timely, accurate diagnosis of catastrophic APS?

DR. ERKAN: The first step in diagnosis is to obtain an accurate history. Previous APS diagnosis and/or persistent clinically significant aPL positivity (as determined by a positive lupus anticoagulant [LA] test and/or moderate- to high-titer aPL on ELISA) is of great importance for diagnosis. However, almost half of the patients who develop catastrophic APS do not have any previous history of a thrombosis or aPL positivity. In this group of patients, the diagnosis is a particular challenge as multiple factors can impede the timely diagnosis, as in the following examples:

• A positive aPL test can be associated with infections (usually low-titer aPL ELISA) or anticoagulation (positive LA test); thus, at times it can be difficult to exclude the possibility that positive aPL tests are occurring as bystanders, not necessarily as contributors for thrombosis.

• False-negative aPL results may occur during acute catastrophic APS events.

• A continuum of thrombotic microangiopathic conditions exists, accounting for patients with thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and catastrophic APS.

• Both sepsis and heparin-induced thrombocytopenia share similarities with catastrophic APS, and these three conditions may overlap.

For these reasons, the timely diagnosis of catastrophic APS can be challenging. At times, the differential diagnosis cannot be narrowed to a single disease during the acute period, and thus continuous assessment of patients is warranted. The most recent updated algorithms provide a "step-by-step" approach for clinicians in the assessment of patients with multiorgan thrombosis. Important steps of the diagnostic algorithms include the assessment of a history of APS or persistent aPL positivity; three or more new organ new thromboses developing in less than a week; biopsy diagnosis of microthrombosis; and other explanations for multiple organ thromboses and/or microthrombosis.

SAN: Once a diagnosis has been established, what are the most important management considerations?

DR. ERKAN: If catastrophic APS is suspected, aggressive multimodal treatment is required without any delay. The most important treatment consideration is the timely administration of the right combination of medications in addition to the elimination of the potential triggers. Although there are no controlled studies, based on the analysis of the International CAPS (catastrophic APS) Registry, patients who receive the combination of anticoagulation plus corticosteroids plus plasma exchange or intravenous immunoglobulins have the highest survival rate. In the case of a deteriorating clinical situation, an additional agent, such as cyclophosphamide (especially in lupus patients) or rituximab (especially in patients with severe thrombocytopenia or hemolytic anemia) can be considered. Despite optimal therapy, the mortality rate is estimated to be approximately 30%, and may be higher if publication bias is considered.

The most pressing treatment challenges in catastrophic APS include delay in diagnosis for the reasons discussed above, ongoing thrombosis despite anticoagulation, high risk of simultaneous thrombosis and bleeding, and high prevalence of accompanying comorbidities (such as sepsis) that directly affect the mortality.

SAN: How has the availability of the International CAPS Registry changed the understanding and management of catastrophic APS?

DR. ERKAN: Our current knowledge of catastrophic APS is mostly based on the international Web-based registry, coordinated by Dr. Cervera. Patients with a catastrophic APS diagnosis have been included in this registry since 2000 through published or voluntary physician reports. The registry, which can be acc essed freely contains clinical, laboratory, and therapeutic data on all reported cases of catastrophic APS, with approximately 300 patients as of May 2011; the most recent descriptive analysis of the registry reported by Dr. Cervera on behalf of the CAPS Registry group was published in April 2010 (Lupus 2010;19:412-8).

Because of the rarity of catastrophic APS, it is very difficult to study this life-threatening disease. The CAPS Registry is currently the only source that allows researchers to systematically analyze the demographic and clinical characteristics of these patients. Furthermore, there are no randomized, controlled trials evaluating the efficacy of various therapies, and the treatment outcome data are also based on the analysis of the registry. Thus, the registry has been crucial in our understanding as well as the management of catastrophic APS.

Dr. Erkan is an associate physician-scientist at the Barbara Volcker Center for Women and Rheumatic Diseases; assistant attending rheumatologist and clinical researcher at Hospital for Special Surgery; and assistant professor of medicine at Weill Cornell Medical College in New York. Dr. Erkan disclosed having a research grant from Genentech.

--Reported and written by Diana Mahoney

Catastrophic antiphospholipid syndrome is a potentially fatal thrombotic disease that develops in a subset of patients with antiphospholipid syndrome. Survival of patients with the rare condition, which is characterized by the development of multiple organ thromboses over a short period of time, depends on the vigilance of the treating clinicians, early diagnosis, and aggressive therapy, all of which can be compromised by multiple factors including the overlap of clinical and laboratory features with other autoimmune and infectious conditions, according to rheumatologist Dr. Doruk Erkan.

Dr. Erkan (along with Dr. Gerard Espinosa and Dr. Ricard Cervera of the Hospital Clinic Barcelona) recently published a summary of the diagnostic challenges associated with catastrophic antiphospholipid syndrome (APS) and proposed updated diagnostic algorithms to streamline its management (Autoimmun. Rev. 2010;10:74-9). In this column, Dr. Erkan discusses the critical diagnostic and management considerations necessary to improve the outcomes of catastrophic APS patients.

SKIN & ALLERGY NEWS: What are the characteristic signs and symptoms of catastrophic APS?

DR. ERKAN: Multiple organ dysfunction, driven mainly by thrombotic microangiopathy, is responsible for the majority of the clinical events in catastrophic APS, although large venous or arterial thrombosis can also occur. The three most commonly involved organs are kidneys (renal thrombotic microangiopathy, and renal artery/vein thrombosis), lungs (pulmonary infarction and/or hemorrhage, and acute respiratory distress syndrome), and brain (stroke, seizure, and encephalopathy). However, thromboses in atypical locations are common in catastrophic APS patients. Any organ system can be involved, including the myocardial, skin, hepatic, and adrenal systems. Intestinal infarctions and peripheral gangrene can also develop, and hematologic manifestations such as thrombocytopenia and schistocytic hemolytic anemia commonly occur, creating a diagnostic challenge for physicians.

SAN: What risk factors, if any, have been identified for catastrophic APS?

DR. ERKAN: The presence of multiple thrombosis risk factors is associated with a higher risk of thrombosis in individuals with antiphospholipid antibodies (aPL) and even in aPL-negative populations. A "trigger event" such as surgery, pregnancy, infection, or oral contraceptive use is commonly identified in aPL-positive patients when they develop thrombosis. Similarly, about 50%-60% of patients with catastrophic APS have an identifiable "trigger event." However, it is not well understood why some aPL-positive patients develop only single-vessel thrombosis and others go on to develop the rapidly progressive microthrombosis and organ failure that are seen in catastrophic APS. Potential genetic risk factors that may predispose aPL-positive patients to catastrophic APS are under investigation (Am. J. Med. 2011;124:290-6).

SAN: What are the key elements for establishing a timely, accurate diagnosis of catastrophic APS?

DR. ERKAN: The first step in diagnosis is to obtain an accurate history. Previous APS diagnosis and/or persistent clinically significant aPL positivity (as determined by a positive lupus anticoagulant [LA] test and/or moderate- to high-titer aPL on ELISA) is of great importance for diagnosis. However, almost half of the patients who develop catastrophic APS do not have any previous history of a thrombosis or aPL positivity. In this group of patients, the diagnosis is a particular challenge as multiple factors can impede the timely diagnosis, as in the following examples:

• A positive aPL test can be associated with infections (usually low-titer aPL ELISA) or anticoagulation (positive LA test); thus, at times it can be difficult to exclude the possibility that positive aPL tests are occurring as bystanders, not necessarily as contributors for thrombosis.

• False-negative aPL results may occur during acute catastrophic APS events.

• A continuum of thrombotic microangiopathic conditions exists, accounting for patients with thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and catastrophic APS.

• Both sepsis and heparin-induced thrombocytopenia share similarities with catastrophic APS, and these three conditions may overlap.

For these reasons, the timely diagnosis of catastrophic APS can be challenging. At times, the differential diagnosis cannot be narrowed to a single disease during the acute period, and thus continuous assessment of patients is warranted. The most recent updated algorithms provide a "step-by-step" approach for clinicians in the assessment of patients with multiorgan thrombosis. Important steps of the diagnostic algorithms include the assessment of a history of APS or persistent aPL positivity; three or more new organ new thromboses developing in less than a week; biopsy diagnosis of microthrombosis; and other explanations for multiple organ thromboses and/or microthrombosis.

SAN: Once a diagnosis has been established, what are the most important management considerations?

DR. ERKAN: If catastrophic APS is suspected, aggressive multimodal treatment is required without any delay. The most important treatment consideration is the timely administration of the right combination of medications in addition to the elimination of the potential triggers. Although there are no controlled studies, based on the analysis of the International CAPS (catastrophic APS) Registry, patients who receive the combination of anticoagulation plus corticosteroids plus plasma exchange or intravenous immunoglobulins have the highest survival rate. In the case of a deteriorating clinical situation, an additional agent, such as cyclophosphamide (especially in lupus patients) or rituximab (especially in patients with severe thrombocytopenia or hemolytic anemia) can be considered. Despite optimal therapy, the mortality rate is estimated to be approximately 30%, and may be higher if publication bias is considered.

The most pressing treatment challenges in catastrophic APS include delay in diagnosis for the reasons discussed above, ongoing thrombosis despite anticoagulation, high risk of simultaneous thrombosis and bleeding, and high prevalence of accompanying comorbidities (such as sepsis) that directly affect the mortality.

SAN: How has the availability of the International CAPS Registry changed the understanding and management of catastrophic APS?

DR. ERKAN: Our current knowledge of catastrophic APS is mostly based on the international Web-based registry, coordinated by Dr. Cervera. Patients with a catastrophic APS diagnosis have been included in this registry since 2000 through published or voluntary physician reports. The registry, which can be acc essed freely contains clinical, laboratory, and therapeutic data on all reported cases of catastrophic APS, with approximately 300 patients as of May 2011; the most recent descriptive analysis of the registry reported by Dr. Cervera on behalf of the CAPS Registry group was published in April 2010 (Lupus 2010;19:412-8).

Because of the rarity of catastrophic APS, it is very difficult to study this life-threatening disease. The CAPS Registry is currently the only source that allows researchers to systematically analyze the demographic and clinical characteristics of these patients. Furthermore, there are no randomized, controlled trials evaluating the efficacy of various therapies, and the treatment outcome data are also based on the analysis of the registry. Thus, the registry has been crucial in our understanding as well as the management of catastrophic APS.

Dr. Erkan is an associate physician-scientist at the Barbara Volcker Center for Women and Rheumatic Diseases; assistant attending rheumatologist and clinical researcher at Hospital for Special Surgery; and assistant professor of medicine at Weill Cornell Medical College in New York. Dr. Erkan disclosed having a research grant from Genentech.

--Reported and written by Diana Mahoney

Catastrophic antiphospholipid syndrome is a potentially fatal thrombotic disease that develops in a subset of patients with antiphospholipid syndrome. Survival of patients with the rare condition, which is characterized by the development of multiple organ thromboses over a short period of time, depends on the vigilance of the treating clinicians, early diagnosis, and aggressive therapy, all of which can be compromised by multiple factors including the overlap of clinical and laboratory features with other autoimmune and infectious conditions, according to rheumatologist Dr. Doruk Erkan.

Dr. Erkan (along with Dr. Gerard Espinosa and Dr. Ricard Cervera of the Hospital Clinic Barcelona) recently published a summary of the diagnostic challenges associated with catastrophic antiphospholipid syndrome (APS) and proposed updated diagnostic algorithms to streamline its management (Autoimmun. Rev. 2010;10:74-9). In this column, Dr. Erkan discusses the critical diagnostic and management considerations necessary to improve the outcomes of catastrophic APS patients.

SKIN & ALLERGY NEWS: What are the characteristic signs and symptoms of catastrophic APS?

DR. ERKAN: Multiple organ dysfunction, driven mainly by thrombotic microangiopathy, is responsible for the majority of the clinical events in catastrophic APS, although large venous or arterial thrombosis can also occur. The three most commonly involved organs are kidneys (renal thrombotic microangiopathy, and renal artery/vein thrombosis), lungs (pulmonary infarction and/or hemorrhage, and acute respiratory distress syndrome), and brain (stroke, seizure, and encephalopathy). However, thromboses in atypical locations are common in catastrophic APS patients. Any organ system can be involved, including the myocardial, skin, hepatic, and adrenal systems. Intestinal infarctions and peripheral gangrene can also develop, and hematologic manifestations such as thrombocytopenia and schistocytic hemolytic anemia commonly occur, creating a diagnostic challenge for physicians.

SAN: What risk factors, if any, have been identified for catastrophic APS?

DR. ERKAN: The presence of multiple thrombosis risk factors is associated with a higher risk of thrombosis in individuals with antiphospholipid antibodies (aPL) and even in aPL-negative populations. A "trigger event" such as surgery, pregnancy, infection, or oral contraceptive use is commonly identified in aPL-positive patients when they develop thrombosis. Similarly, about 50%-60% of patients with catastrophic APS have an identifiable "trigger event." However, it is not well understood why some aPL-positive patients develop only single-vessel thrombosis and others go on to develop the rapidly progressive microthrombosis and organ failure that are seen in catastrophic APS. Potential genetic risk factors that may predispose aPL-positive patients to catastrophic APS are under investigation (Am. J. Med. 2011;124:290-6).

SAN: What are the key elements for establishing a timely, accurate diagnosis of catastrophic APS?

DR. ERKAN: The first step in diagnosis is to obtain an accurate history. Previous APS diagnosis and/or persistent clinically significant aPL positivity (as determined by a positive lupus anticoagulant [LA] test and/or moderate- to high-titer aPL on ELISA) is of great importance for diagnosis. However, almost half of the patients who develop catastrophic APS do not have any previous history of a thrombosis or aPL positivity. In this group of patients, the diagnosis is a particular challenge as multiple factors can impede the timely diagnosis, as in the following examples:

• A positive aPL test can be associated with infections (usually low-titer aPL ELISA) or anticoagulation (positive LA test); thus, at times it can be difficult to exclude the possibility that positive aPL tests are occurring as bystanders, not necessarily as contributors for thrombosis.

• False-negative aPL results may occur during acute catastrophic APS events.

• A continuum of thrombotic microangiopathic conditions exists, accounting for patients with thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and catastrophic APS.

• Both sepsis and heparin-induced thrombocytopenia share similarities with catastrophic APS, and these three conditions may overlap.

For these reasons, the timely diagnosis of catastrophic APS can be challenging. At times, the differential diagnosis cannot be narrowed to a single disease during the acute period, and thus continuous assessment of patients is warranted. The most recent updated algorithms provide a "step-by-step" approach for clinicians in the assessment of patients with multiorgan thrombosis. Important steps of the diagnostic algorithms include the assessment of a history of APS or persistent aPL positivity; three or more new organ new thromboses developing in less than a week; biopsy diagnosis of microthrombosis; and other explanations for multiple organ thromboses and/or microthrombosis.

SAN: Once a diagnosis has been established, what are the most important management considerations?

DR. ERKAN: If catastrophic APS is suspected, aggressive multimodal treatment is required without any delay. The most important treatment consideration is the timely administration of the right combination of medications in addition to the elimination of the potential triggers. Although there are no controlled studies, based on the analysis of the International CAPS (catastrophic APS) Registry, patients who receive the combination of anticoagulation plus corticosteroids plus plasma exchange or intravenous immunoglobulins have the highest survival rate. In the case of a deteriorating clinical situation, an additional agent, such as cyclophosphamide (especially in lupus patients) or rituximab (especially in patients with severe thrombocytopenia or hemolytic anemia) can be considered. Despite optimal therapy, the mortality rate is estimated to be approximately 30%, and may be higher if publication bias is considered.

The most pressing treatment challenges in catastrophic APS include delay in diagnosis for the reasons discussed above, ongoing thrombosis despite anticoagulation, high risk of simultaneous thrombosis and bleeding, and high prevalence of accompanying comorbidities (such as sepsis) that directly affect the mortality.

SAN: How has the availability of the International CAPS Registry changed the understanding and management of catastrophic APS?

DR. ERKAN: Our current knowledge of catastrophic APS is mostly based on the international Web-based registry, coordinated by Dr. Cervera. Patients with a catastrophic APS diagnosis have been included in this registry since 2000 through published or voluntary physician reports. The registry, which can be acc essed freely contains clinical, laboratory, and therapeutic data on all reported cases of catastrophic APS, with approximately 300 patients as of May 2011; the most recent descriptive analysis of the registry reported by Dr. Cervera on behalf of the CAPS Registry group was published in April 2010 (Lupus 2010;19:412-8).

Because of the rarity of catastrophic APS, it is very difficult to study this life-threatening disease. The CAPS Registry is currently the only source that allows researchers to systematically analyze the demographic and clinical characteristics of these patients. Furthermore, there are no randomized, controlled trials evaluating the efficacy of various therapies, and the treatment outcome data are also based on the analysis of the registry. Thus, the registry has been crucial in our understanding as well as the management of catastrophic APS.

Dr. Erkan is an associate physician-scientist at the Barbara Volcker Center for Women and Rheumatic Diseases; assistant attending rheumatologist and clinical researcher at Hospital for Special Surgery; and assistant professor of medicine at Weill Cornell Medical College in New York. Dr. Erkan disclosed having a research grant from Genentech.

--Reported and written by Diana Mahoney

SEOUL, SOUTH KOREA – Onset of subacute cutaneous lupus erythematosus after the age of 50 years is a good clue it is more likely to be drug induced, findings from two recent studies indicate.

Prompt recognition of drug-induced subacute cutaneous lupus erythematosus (SCLE) by physicians prevents significant morbidity, both by quelling the number and activity of skin lesions and by sparing affected patients from exposure to the potent immunosuppressive agents that are often used in idiopathic SCLE.

In drug-induced SCLE, the treatment of choice is withdrawal of the offending medication and nothing more, Dr. Christopher B. Hansen said at the World Congress of Dermatology.

"The important thing is stopping the medication. Most patients don't require additional therapy," emphasized Dr. Hansen of the University of Utah in Salt Lake City.

He and his coinvestigators recently combed the medical literature and published a systematic review of 117 cases of drug-induced SCLE, the largest series to date (Br. J. Dermatol. 2011;164:465-72). One of the standout findings was that the average age of onset was 58 years, compared with just 43 years in patients with idiopathic SCLE culled from the literature.

Strikingly, this 15-year age gap was identical to that reported in a recent study by investigators at the University of Milan, Dr. Hansen noted. In the Italian series, the average age of onset of drug-induced SCLE was 67 years, or 15 years more than the 52 years in 79 patients with idiopathic SCLE.

The Italian investigators described several key cutaneous features that helped differentiate drug-induced from idiopathic SCLE. Lesions were widespread in 82% of patients with drug-induced SCLE, compared with just 6% of those with the idiopathic form. Malar rash occurred in 45% of drug-induced SCLE patients versus 6% with idiopathic SCLE. Bullous and erythema multiforme-like lesions were present in 45% of the drug-induced SCLE cohort, compared with just 1% of those with idiopathic SCLE. Vasculitic lesions were noted in 45% of patients with drug-induced SCLE but only 3% of those with idiopathic SCLE (Br. J. Dermatol. 2011 May 12 [doi:10.1111/j.1365-2133.2011.10397.x]).

Internal organ involvement was notably absent in patients with drug-induced SCLE, both in Dr. Hansen’s study and in the Italian investigation. That's an important point of distinction between drug-induced SCLE and drug-induced systemic lupus erythematosus (SLE).

Also, the drugs implicated in causing SCLE are generally different from those that trigger drug-induced SLE, which is probably an indication of fundamentally different underlying mechanisms of disease, he continued.

The list of medications linked to drug-induced SCLE is lengthy. Topping the list are antihypertensive agents, responsible for 34% of cases in the study by Dr. Hansen and his colleagues, and antifungals, which triggered another 26%. Terbinafine, thiazide diuretics, and calcium channel blockers were particularly common offenders. Chemotherapeutic agents were a distant third category of triggering medications, responsible for 9% of cases, followed closely by antihistamines at 8% and immunomodulators at 7%.

A defining characteristic of drug-induced SCLE is the lengthy incubation and resolution times compared with most drug eruptions. After stopping the offending drug, it took a median of 4 weeks and a mean of 7.3 weeks for the skin lesions to go away, according to Dr. Hansen.

Anti-Ro/SSA autoantibodies were present in 81% of patients at diagnosis. Two-thirds of patients remained autoantibody-positive at testing conducted 6 weeks to 3 years after resolution of the rash.

Several theories have been put forth regarding the pathogenesis of drug-induced SCLE. One is that it is a photosensitivity reaction, given that many of the drugs linked to the condition are known to be photosensitizers.

Another theory is that the skin disease results from a drug-induced disruption of T-cell function and immune tolerance. Still another theory holds that the drug or its metabolite causes direct cytotoxicity.

Asked for tips on how to discover the offending medication in older patients on many drugs, he said the best approach is to start by trying to eliminate any medications that have been started within the past month or two. Secondly, he added, take a close look at any remaining medications the patient is on that have been reported as triggers most frequently in the literature.

Dr. Hansen declared having no financial conflicts of interest.

SEOUL, SOUTH KOREA – Onset of subacute cutaneous lupus erythematosus after the age of 50 years is a good clue it is more likely to be drug induced, findings from two recent studies indicate.

Prompt recognition of drug-induced subacute cutaneous lupus erythematosus (SCLE) by physicians prevents significant morbidity, both by quelling the number and activity of skin lesions and by sparing affected patients from exposure to the potent immunosuppressive agents that are often used in idiopathic SCLE.

In drug-induced SCLE, the treatment of choice is withdrawal of the offending medication and nothing more, Dr. Christopher B. Hansen said at the World Congress of Dermatology.

"The important thing is stopping the medication. Most patients don't require additional therapy," emphasized Dr. Hansen of the University of Utah in Salt Lake City.

He and his coinvestigators recently combed the medical literature and published a systematic review of 117 cases of drug-induced SCLE, the largest series to date (Br. J. Dermatol. 2011;164:465-72). One of the standout findings was that the average age of onset was 58 years, compared with just 43 years in patients with idiopathic SCLE culled from the literature.

Strikingly, this 15-year age gap was identical to that reported in a recent study by investigators at the University of Milan, Dr. Hansen noted. In the Italian series, the average age of onset of drug-induced SCLE was 67 years, or 15 years more than the 52 years in 79 patients with idiopathic SCLE.

The Italian investigators described several key cutaneous features that helped differentiate drug-induced from idiopathic SCLE. Lesions were widespread in 82% of patients with drug-induced SCLE, compared with just 6% of those with the idiopathic form. Malar rash occurred in 45% of drug-induced SCLE patients versus 6% with idiopathic SCLE. Bullous and erythema multiforme-like lesions were present in 45% of the drug-induced SCLE cohort, compared with just 1% of those with idiopathic SCLE. Vasculitic lesions were noted in 45% of patients with drug-induced SCLE but only 3% of those with idiopathic SCLE (Br. J. Dermatol. 2011 May 12 [doi:10.1111/j.1365-2133.2011.10397.x]).

Internal organ involvement was notably absent in patients with drug-induced SCLE, both in Dr. Hansen’s study and in the Italian investigation. That's an important point of distinction between drug-induced SCLE and drug-induced systemic lupus erythematosus (SLE).

Also, the drugs implicated in causing SCLE are generally different from those that trigger drug-induced SLE, which is probably an indication of fundamentally different underlying mechanisms of disease, he continued.

The list of medications linked to drug-induced SCLE is lengthy. Topping the list are antihypertensive agents, responsible for 34% of cases in the study by Dr. Hansen and his colleagues, and antifungals, which triggered another 26%. Terbinafine, thiazide diuretics, and calcium channel blockers were particularly common offenders. Chemotherapeutic agents were a distant third category of triggering medications, responsible for 9% of cases, followed closely by antihistamines at 8% and immunomodulators at 7%.

A defining characteristic of drug-induced SCLE is the lengthy incubation and resolution times compared with most drug eruptions. After stopping the offending drug, it took a median of 4 weeks and a mean of 7.3 weeks for the skin lesions to go away, according to Dr. Hansen.

Anti-Ro/SSA autoantibodies were present in 81% of patients at diagnosis. Two-thirds of patients remained autoantibody-positive at testing conducted 6 weeks to 3 years after resolution of the rash.

Several theories have been put forth regarding the pathogenesis of drug-induced SCLE. One is that it is a photosensitivity reaction, given that many of the drugs linked to the condition are known to be photosensitizers.

Another theory is that the skin disease results from a drug-induced disruption of T-cell function and immune tolerance. Still another theory holds that the drug or its metabolite causes direct cytotoxicity.

Asked for tips on how to discover the offending medication in older patients on many drugs, he said the best approach is to start by trying to eliminate any medications that have been started within the past month or two. Secondly, he added, take a close look at any remaining medications the patient is on that have been reported as triggers most frequently in the literature.

Dr. Hansen declared having no financial conflicts of interest.

SEOUL, SOUTH KOREA – Onset of subacute cutaneous lupus erythematosus after the age of 50 years is a good clue it is more likely to be drug induced, findings from two recent studies indicate.

Prompt recognition of drug-induced subacute cutaneous lupus erythematosus (SCLE) by physicians prevents significant morbidity, both by quelling the number and activity of skin lesions and by sparing affected patients from exposure to the potent immunosuppressive agents that are often used in idiopathic SCLE.

In drug-induced SCLE, the treatment of choice is withdrawal of the offending medication and nothing more, Dr. Christopher B. Hansen said at the World Congress of Dermatology.

"The important thing is stopping the medication. Most patients don't require additional therapy," emphasized Dr. Hansen of the University of Utah in Salt Lake City.

He and his coinvestigators recently combed the medical literature and published a systematic review of 117 cases of drug-induced SCLE, the largest series to date (Br. J. Dermatol. 2011;164:465-72). One of the standout findings was that the average age of onset was 58 years, compared with just 43 years in patients with idiopathic SCLE culled from the literature.

Strikingly, this 15-year age gap was identical to that reported in a recent study by investigators at the University of Milan, Dr. Hansen noted. In the Italian series, the average age of onset of drug-induced SCLE was 67 years, or 15 years more than the 52 years in 79 patients with idiopathic SCLE.

The Italian investigators described several key cutaneous features that helped differentiate drug-induced from idiopathic SCLE. Lesions were widespread in 82% of patients with drug-induced SCLE, compared with just 6% of those with the idiopathic form. Malar rash occurred in 45% of drug-induced SCLE patients versus 6% with idiopathic SCLE. Bullous and erythema multiforme-like lesions were present in 45% of the drug-induced SCLE cohort, compared with just 1% of those with idiopathic SCLE. Vasculitic lesions were noted in 45% of patients with drug-induced SCLE but only 3% of those with idiopathic SCLE (Br. J. Dermatol. 2011 May 12 [doi:10.1111/j.1365-2133.2011.10397.x]).

Internal organ involvement was notably absent in patients with drug-induced SCLE, both in Dr. Hansen’s study and in the Italian investigation. That's an important point of distinction between drug-induced SCLE and drug-induced systemic lupus erythematosus (SLE).

Also, the drugs implicated in causing SCLE are generally different from those that trigger drug-induced SLE, which is probably an indication of fundamentally different underlying mechanisms of disease, he continued.

The list of medications linked to drug-induced SCLE is lengthy. Topping the list are antihypertensive agents, responsible for 34% of cases in the study by Dr. Hansen and his colleagues, and antifungals, which triggered another 26%. Terbinafine, thiazide diuretics, and calcium channel blockers were particularly common offenders. Chemotherapeutic agents were a distant third category of triggering medications, responsible for 9% of cases, followed closely by antihistamines at 8% and immunomodulators at 7%.

A defining characteristic of drug-induced SCLE is the lengthy incubation and resolution times compared with most drug eruptions. After stopping the offending drug, it took a median of 4 weeks and a mean of 7.3 weeks for the skin lesions to go away, according to Dr. Hansen.

Anti-Ro/SSA autoantibodies were present in 81% of patients at diagnosis. Two-thirds of patients remained autoantibody-positive at testing conducted 6 weeks to 3 years after resolution of the rash.

Several theories have been put forth regarding the pathogenesis of drug-induced SCLE. One is that it is a photosensitivity reaction, given that many of the drugs linked to the condition are known to be photosensitizers.

Another theory is that the skin disease results from a drug-induced disruption of T-cell function and immune tolerance. Still another theory holds that the drug or its metabolite causes direct cytotoxicity.

Asked for tips on how to discover the offending medication in older patients on many drugs, he said the best approach is to start by trying to eliminate any medications that have been started within the past month or two. Secondly, he added, take a close look at any remaining medications the patient is on that have been reported as triggers most frequently in the literature.

Dr. Hansen declared having no financial conflicts of interest.

SEOUL, SOUTH KOREA – Infliximab appears to be an effective corticosteroid-sparing treatment for patients with refractory cutaneous sarcoidosis, albeit an off-label one.

"Infliximab seems to be a good candidate as third-line therapy for refractory cutaneous sarcoidosis. We recommend a continuous evaluation of clinical response and an increase in infliximab dosing up to 10 mg/kg every 4 weeks in cases of insufficient response [as well as] the use of concomitant low-dose methotrexate to increase infliximab efficacy and prevent the development of anti-infliximab antibodies," noted Dr. Fabien Guibal at the World Congress of Dermatology.

Skin involvement is common in sarcoidosis, affecting up to 30% of patients. It carries substantial morbidity, and treatment options are limited. Systemic corticosteroids are the mainstay, but the associated side effects are well known. Methotrexate is a good second-line therapy, although the response is highly variable. Azathioprine, antimalarials, and thalidomide are among the alternative options, noted Dr. Guibal of Hôpital Saint-Louis, Paris.

He presented a retrospective, single-center study involving nine patients placed on infliximab (Remicade) for refractory cutaneous sarcoidosis. Participants had failed to improve on a median of five prior immunosuppressive drugs.

The subjects (eight women and one man) were a median of 43 years old when diagnosed with sarcoidosis, and 51 years of age when they started on infliximab. The cutaneous lesions consisted of lupus pernio in eight patients, disseminated papules in seven, and a large facial plaque in one. All patients had extracutaneous disease, including pulmonary sarcoidosis in eight individuals and CNS involvement in one.

The impetus for turning to the tumor necrosis factor–alpha inhibitor in these nine patients was the fact that TNF-alpha is known to be a critical cytokine in the formation and maintenance of granulomas. Plus, there have been several reports of favorable treatment responses in patients with pulmonary sarcoidosis and other internal organ involvement.

Three of nine patients experienced resolution of cutaneous lesions on their first course of infliximab. Another four had near-resolution, and the remaining two patients showed partial improvement. The median lag time until maximal response was 12 weeks (range, 2-22 weeks).

When infliximab was eventually discontinued in six patients, five relapsed after a median 9 weeks off the drug. The sole patient who didn’t relapse had successfully replaced the biologic agent with methotrexate.

The five relapsers underwent a second course of infliximab. Four experienced near-resolution of their cutaneous disease, and the fifth showed lesion stabilization. Three of them eventually discontinued infliximab, one because of loss of efficacy, another who remained relapse free while replacing the biologic with methotrexate, and a third who was lost to follow-up.

After a median 34 months of follow-up, five of the nine patients remain on infliximab. Their average oral prednisone dose is half of the 12 mg/day it was before they started taking infliximab. No serious adverse effects have occurred.

Dr. Guibal declared having no relevant financial relationships.

SEOUL, SOUTH KOREA – Infliximab appears to be an effective corticosteroid-sparing treatment for patients with refractory cutaneous sarcoidosis, albeit an off-label one.

"Infliximab seems to be a good candidate as third-line therapy for refractory cutaneous sarcoidosis. We recommend a continuous evaluation of clinical response and an increase in infliximab dosing up to 10 mg/kg every 4 weeks in cases of insufficient response [as well as] the use of concomitant low-dose methotrexate to increase infliximab efficacy and prevent the development of anti-infliximab antibodies," noted Dr. Fabien Guibal at the World Congress of Dermatology.

Skin involvement is common in sarcoidosis, affecting up to 30% of patients. It carries substantial morbidity, and treatment options are limited. Systemic corticosteroids are the mainstay, but the associated side effects are well known. Methotrexate is a good second-line therapy, although the response is highly variable. Azathioprine, antimalarials, and thalidomide are among the alternative options, noted Dr. Guibal of Hôpital Saint-Louis, Paris.

He presented a retrospective, single-center study involving nine patients placed on infliximab (Remicade) for refractory cutaneous sarcoidosis. Participants had failed to improve on a median of five prior immunosuppressive drugs.

The subjects (eight women and one man) were a median of 43 years old when diagnosed with sarcoidosis, and 51 years of age when they started on infliximab. The cutaneous lesions consisted of lupus pernio in eight patients, disseminated papules in seven, and a large facial plaque in one. All patients had extracutaneous disease, including pulmonary sarcoidosis in eight individuals and CNS involvement in one.

The impetus for turning to the tumor necrosis factor–alpha inhibitor in these nine patients was the fact that TNF-alpha is known to be a critical cytokine in the formation and maintenance of granulomas. Plus, there have been several reports of favorable treatment responses in patients with pulmonary sarcoidosis and other internal organ involvement.

Three of nine patients experienced resolution of cutaneous lesions on their first course of infliximab. Another four had near-resolution, and the remaining two patients showed partial improvement. The median lag time until maximal response was 12 weeks (range, 2-22 weeks).

When infliximab was eventually discontinued in six patients, five relapsed after a median 9 weeks off the drug. The sole patient who didn’t relapse had successfully replaced the biologic agent with methotrexate.

The five relapsers underwent a second course of infliximab. Four experienced near-resolution of their cutaneous disease, and the fifth showed lesion stabilization. Three of them eventually discontinued infliximab, one because of loss of efficacy, another who remained relapse free while replacing the biologic with methotrexate, and a third who was lost to follow-up.

After a median 34 months of follow-up, five of the nine patients remain on infliximab. Their average oral prednisone dose is half of the 12 mg/day it was before they started taking infliximab. No serious adverse effects have occurred.

Dr. Guibal declared having no relevant financial relationships.

SEOUL, SOUTH KOREA – Infliximab appears to be an effective corticosteroid-sparing treatment for patients with refractory cutaneous sarcoidosis, albeit an off-label one.

"Infliximab seems to be a good candidate as third-line therapy for refractory cutaneous sarcoidosis. We recommend a continuous evaluation of clinical response and an increase in infliximab dosing up to 10 mg/kg every 4 weeks in cases of insufficient response [as well as] the use of concomitant low-dose methotrexate to increase infliximab efficacy and prevent the development of anti-infliximab antibodies," noted Dr. Fabien Guibal at the World Congress of Dermatology.

Skin involvement is common in sarcoidosis, affecting up to 30% of patients. It carries substantial morbidity, and treatment options are limited. Systemic corticosteroids are the mainstay, but the associated side effects are well known. Methotrexate is a good second-line therapy, although the response is highly variable. Azathioprine, antimalarials, and thalidomide are among the alternative options, noted Dr. Guibal of Hôpital Saint-Louis, Paris.

He presented a retrospective, single-center study involving nine patients placed on infliximab (Remicade) for refractory cutaneous sarcoidosis. Participants had failed to improve on a median of five prior immunosuppressive drugs.

The subjects (eight women and one man) were a median of 43 years old when diagnosed with sarcoidosis, and 51 years of age when they started on infliximab. The cutaneous lesions consisted of lupus pernio in eight patients, disseminated papules in seven, and a large facial plaque in one. All patients had extracutaneous disease, including pulmonary sarcoidosis in eight individuals and CNS involvement in one.

The impetus for turning to the tumor necrosis factor–alpha inhibitor in these nine patients was the fact that TNF-alpha is known to be a critical cytokine in the formation and maintenance of granulomas. Plus, there have been several reports of favorable treatment responses in patients with pulmonary sarcoidosis and other internal organ involvement.

Three of nine patients experienced resolution of cutaneous lesions on their first course of infliximab. Another four had near-resolution, and the remaining two patients showed partial improvement. The median lag time until maximal response was 12 weeks (range, 2-22 weeks).

When infliximab was eventually discontinued in six patients, five relapsed after a median 9 weeks off the drug. The sole patient who didn’t relapse had successfully replaced the biologic agent with methotrexate.

The five relapsers underwent a second course of infliximab. Four experienced near-resolution of their cutaneous disease, and the fifth showed lesion stabilization. Three of them eventually discontinued infliximab, one because of loss of efficacy, another who remained relapse free while replacing the biologic with methotrexate, and a third who was lost to follow-up.

After a median 34 months of follow-up, five of the nine patients remain on infliximab. Their average oral prednisone dose is half of the 12 mg/day it was before they started taking infliximab. No serious adverse effects have occurred.

Dr. Guibal declared having no relevant financial relationships.

LONDON – The quadrivalent human papillomavirus vaccine is safe for patients with systemic lupus erythematosus and should be considered for women with inactive disease who receive stable doses of standard immunomodulatory therapy, according to data presented by Dr. Chi Chiu Mok at the annual European Congress of Rheumatology.

Multiple studies have demonstrated higher rates of persistent HPV infections and precancerous lesions in women with SLE, compared with women in the general population, said Dr. Mok. Although the increased risk of HPV infection suggests that SLE patients would be good candidates for immunization against the virus, it has been hypothesized that immune dysfunction related to SLE or to treatment-induced immune suppression may prevent patients with the condition from being able to produce an effective immune response to the vaccine, and could possibly lead to disease flares or the production of new autoantibodies, he explained.

The recombinant quadrivalent HPV vaccine (Gardisil) provides protection against infection of the HPV serotypes 6, 11, 16, and 18, and it has been demonstrated to be safe and efficacious in female patients in the general population aged 9-26 years, according to Dr. Mok. Along with colleagues at Tuen Mun Hospital in Hong Kong, Dr. Mok sought to evaluate the safety and immunogenicity of the vaccine in a cohort of SLE patients.

Toward this end, the investigators recruited 50 female patients aged 18-35 years who fulfilled at least four American College of Rheumatology criteria for SLE, and who had received a stable dose of prednisolone or other immunosuppressive agent within the previous 3 months, to participate in the prospective investigation. The mean age of the study participants was 25.8 years, and their mean disease duration was 6.6 years, he reported.

All of the study subjects received intramuscular injections of the vaccine and were evaluated at baseline and at 2 and 6 months post vaccination via the SLEDAI (SLE Disease Activity Index), PGA (Physicians’ Global Assessment), and the SELENA (Safety of Estrogens in Lupus Erythematosus – National Assessment) disease flare index. Additionally, complement levels (C3 and C4) and anti-dsDNA (anti–double-stranded DNA) titers were assessed and patient-reported adverse events were recorded at the same time points, said Dr. Mok. With respect to baseline disease characteristics, the median SLEDAI score was 4; the mean anti-dsDNA titers, C3 levels, and C4 levels were 139 IU/mL, 0.81 g/dL, and 0.15 g/dL, respectively; and none of the patients had SELENA flares at baseline compared to preceding status, he said.

There were no significant changes in anti-dsDNA titers, C3 or C4 levels, or SLEDAI and PGA scores at any of the time points, Dr. Mok reported. "There were three mild to moderate mucocutaneous flares during the study period (one at month 2 and two at month 6), all of which were controlled with usual treatment," he said. "It’s unclear whether a causal relationship exists between the vaccination and the three lupus flares, but the rate of flares [0.08 per patient per year] was lower than the rate observed in our lupus cohort during the previous 5 years [0.10 per patient per year], and no other adverse events associated with the vaccination were reported."

The study findings indicate that the vaccine is safe in SLE patients, and the lack of significant alterations in the various SLE antibody measures suggests it does not induce an increased incidence of lupus flares, Dr. Mok stated. Considering the increased susceptibility to HPV infection in these patients and the link between HPV infection and cervical cancer, "vaccination is an important consideration in protecting them," he said.

Dr. Mok disclosed having no financial conflicts of interest.

LONDON – The quadrivalent human papillomavirus vaccine is safe for patients with systemic lupus erythematosus and should be considered for women with inactive disease who receive stable doses of standard immunomodulatory therapy, according to data presented by Dr. Chi Chiu Mok at the annual European Congress of Rheumatology.

Multiple studies have demonstrated higher rates of persistent HPV infections and precancerous lesions in women with SLE, compared with women in the general population, said Dr. Mok. Although the increased risk of HPV infection suggests that SLE patients would be good candidates for immunization against the virus, it has been hypothesized that immune dysfunction related to SLE or to treatment-induced immune suppression may prevent patients with the condition from being able to produce an effective immune response to the vaccine, and could possibly lead to disease flares or the production of new autoantibodies, he explained.

The recombinant quadrivalent HPV vaccine (Gardisil) provides protection against infection of the HPV serotypes 6, 11, 16, and 18, and it has been demonstrated to be safe and efficacious in female patients in the general population aged 9-26 years, according to Dr. Mok. Along with colleagues at Tuen Mun Hospital in Hong Kong, Dr. Mok sought to evaluate the safety and immunogenicity of the vaccine in a cohort of SLE patients.

Toward this end, the investigators recruited 50 female patients aged 18-35 years who fulfilled at least four American College of Rheumatology criteria for SLE, and who had received a stable dose of prednisolone or other immunosuppressive agent within the previous 3 months, to participate in the prospective investigation. The mean age of the study participants was 25.8 years, and their mean disease duration was 6.6 years, he reported.

All of the study subjects received intramuscular injections of the vaccine and were evaluated at baseline and at 2 and 6 months post vaccination via the SLEDAI (SLE Disease Activity Index), PGA (Physicians’ Global Assessment), and the SELENA (Safety of Estrogens in Lupus Erythematosus – National Assessment) disease flare index. Additionally, complement levels (C3 and C4) and anti-dsDNA (anti–double-stranded DNA) titers were assessed and patient-reported adverse events were recorded at the same time points, said Dr. Mok. With respect to baseline disease characteristics, the median SLEDAI score was 4; the mean anti-dsDNA titers, C3 levels, and C4 levels were 139 IU/mL, 0.81 g/dL, and 0.15 g/dL, respectively; and none of the patients had SELENA flares at baseline compared to preceding status, he said.

There were no significant changes in anti-dsDNA titers, C3 or C4 levels, or SLEDAI and PGA scores at any of the time points, Dr. Mok reported. "There were three mild to moderate mucocutaneous flares during the study period (one at month 2 and two at month 6), all of which were controlled with usual treatment," he said. "It’s unclear whether a causal relationship exists between the vaccination and the three lupus flares, but the rate of flares [0.08 per patient per year] was lower than the rate observed in our lupus cohort during the previous 5 years [0.10 per patient per year], and no other adverse events associated with the vaccination were reported."

The study findings indicate that the vaccine is safe in SLE patients, and the lack of significant alterations in the various SLE antibody measures suggests it does not induce an increased incidence of lupus flares, Dr. Mok stated. Considering the increased susceptibility to HPV infection in these patients and the link between HPV infection and cervical cancer, "vaccination is an important consideration in protecting them," he said.

Dr. Mok disclosed having no financial conflicts of interest.

LONDON – The quadrivalent human papillomavirus vaccine is safe for patients with systemic lupus erythematosus and should be considered for women with inactive disease who receive stable doses of standard immunomodulatory therapy, according to data presented by Dr. Chi Chiu Mok at the annual European Congress of Rheumatology.

Multiple studies have demonstrated higher rates of persistent HPV infections and precancerous lesions in women with SLE, compared with women in the general population, said Dr. Mok. Although the increased risk of HPV infection suggests that SLE patients would be good candidates for immunization against the virus, it has been hypothesized that immune dysfunction related to SLE or to treatment-induced immune suppression may prevent patients with the condition from being able to produce an effective immune response to the vaccine, and could possibly lead to disease flares or the production of new autoantibodies, he explained.

The recombinant quadrivalent HPV vaccine (Gardisil) provides protection against infection of the HPV serotypes 6, 11, 16, and 18, and it has been demonstrated to be safe and efficacious in female patients in the general population aged 9-26 years, according to Dr. Mok. Along with colleagues at Tuen Mun Hospital in Hong Kong, Dr. Mok sought to evaluate the safety and immunogenicity of the vaccine in a cohort of SLE patients.

Toward this end, the investigators recruited 50 female patients aged 18-35 years who fulfilled at least four American College of Rheumatology criteria for SLE, and who had received a stable dose of prednisolone or other immunosuppressive agent within the previous 3 months, to participate in the prospective investigation. The mean age of the study participants was 25.8 years, and their mean disease duration was 6.6 years, he reported.

All of the study subjects received intramuscular injections of the vaccine and were evaluated at baseline and at 2 and 6 months post vaccination via the SLEDAI (SLE Disease Activity Index), PGA (Physicians’ Global Assessment), and the SELENA (Safety of Estrogens in Lupus Erythematosus – National Assessment) disease flare index. Additionally, complement levels (C3 and C4) and anti-dsDNA (anti–double-stranded DNA) titers were assessed and patient-reported adverse events were recorded at the same time points, said Dr. Mok. With respect to baseline disease characteristics, the median SLEDAI score was 4; the mean anti-dsDNA titers, C3 levels, and C4 levels were 139 IU/mL, 0.81 g/dL, and 0.15 g/dL, respectively; and none of the patients had SELENA flares at baseline compared to preceding status, he said.

There were no significant changes in anti-dsDNA titers, C3 or C4 levels, or SLEDAI and PGA scores at any of the time points, Dr. Mok reported. "There were three mild to moderate mucocutaneous flares during the study period (one at month 2 and two at month 6), all of which were controlled with usual treatment," he said. "It’s unclear whether a causal relationship exists between the vaccination and the three lupus flares, but the rate of flares [0.08 per patient per year] was lower than the rate observed in our lupus cohort during the previous 5 years [0.10 per patient per year], and no other adverse events associated with the vaccination were reported."

The study findings indicate that the vaccine is safe in SLE patients, and the lack of significant alterations in the various SLE antibody measures suggests it does not induce an increased incidence of lupus flares, Dr. Mok stated. Considering the increased susceptibility to HPV infection in these patients and the link between HPV infection and cervical cancer, "vaccination is an important consideration in protecting them," he said.

Dr. Mok disclosed having no financial conflicts of interest.