Psoriasis

A new formula accurately calculates the risk of pulmonary hypertension by predicting the mean pulmonary artery pressure using data obtained from pulmonary function testing and pulse oximetry, according to a report by Dr. Benjamin E. Schreiber, of the Royal Free Hampstead National Health Service Trust, London, and his associates.

They developed the formula based on findings in 257 patients with systemic sclerosis; the investigators validated it with data from another 129 similar patients.

Patients with a predicted mean pulmonary artery pressure (mPAP) below 25 mm Hg had a low pulmonary hypertension (PH) prevalence (4.4%). Those with a predicted mPAP between 25-35 mm Hg had an average PH prevalence (11.3%). Finally, those with a predicted mPAP above 35 mm Hg had a high PH prevalence (62.9%), which justifies using right-sided heart catheterization (RHC) (Arthritis Rheum. 2011;63:3531-9).

The study started with 838 patients who have systemic sclerosis (SSc) who had undergone an RHC. Of those, 386 patients had undergone pulmonary function testing (PFT) within 6 months of the RHC. Data on oxygen saturation as measured by pulse oximetry (SpO2) at the time of the RHC were included in the study. Of the total number of patients, 452 were excluded because they had incomplete PFT data.

The investigators randomly split the remaining 386 into two groups: the derivation and validation cohorts. The derivation cohort had 257 patients and its data were used to create the formula. The validation cohort had 129 subjects and its data were used to validate the formula. An additional 155 patients with connective tissue diseases other than SSc were obtained from the Royal Free Pulmonary Hypertension Service in London, United Kingdom.

The formula was derived using multivariable linear regression in the derivation cohort. Dr. Schreiber and his team examined the relationship between the SpO₂, PFTs, clinical subtype, autoimmune serologic features, and the mPAP on RHC and developed the following formula: predicted mPAP = 136 – SpO₂ –0.25 x diffusing capacity for carbon monoxide (DLCO)% predicted.

Applying the formula to the validation cohort gave an area under the curve (AUC) of 0.75. The formula performed best in patients with anticentromere antibodies, with an AUC of 0.87. In patients with connective tissue diseases other than SSc, the formula gave an AUC of 0.64.

The researchers suggested the PFT-derived formula can complement data obtained through echocardiography, and that both tests are predictive. Echocardiography is a good tool for diagnosing PH, but it cannot evaluate lung disease and is not always feasible to conduct. Therefore, the formula can calculate which patients are most likely to have PH.

Some of the limitations of this retrospective study included missing data, especially from echocardiograms and PFTs, and lack of rigorous selection of patients for RHC. There were no echocardiographic data available for most patients, and there may have been selection bias in the patients who had a second echocardiography performed.

Dr. Schreiber and his team suggested that further research should combine PFT data with other noninvasive information, such as symptoms, 6-minute walking distance, and brain natriuretic peptide levels. They also said that they plan to continue to validate their formula in patients recruited into the DETECT (Detection of Pulmonary Artery Hypertension in Systemic Sclerosis) study.

No relevant financial disclosures were reported.

A new formula accurately calculates the risk of pulmonary hypertension by predicting the mean pulmonary artery pressure using data obtained from pulmonary function testing and pulse oximetry, according to a report by Dr. Benjamin E. Schreiber, of the Royal Free Hampstead National Health Service Trust, London, and his associates.

They developed the formula based on findings in 257 patients with systemic sclerosis; the investigators validated it with data from another 129 similar patients.

Patients with a predicted mean pulmonary artery pressure (mPAP) below 25 mm Hg had a low pulmonary hypertension (PH) prevalence (4.4%). Those with a predicted mPAP between 25-35 mm Hg had an average PH prevalence (11.3%). Finally, those with a predicted mPAP above 35 mm Hg had a high PH prevalence (62.9%), which justifies using right-sided heart catheterization (RHC) (Arthritis Rheum. 2011;63:3531-9).

The study started with 838 patients who have systemic sclerosis (SSc) who had undergone an RHC. Of those, 386 patients had undergone pulmonary function testing (PFT) within 6 months of the RHC. Data on oxygen saturation as measured by pulse oximetry (SpO2) at the time of the RHC were included in the study. Of the total number of patients, 452 were excluded because they had incomplete PFT data.

The investigators randomly split the remaining 386 into two groups: the derivation and validation cohorts. The derivation cohort had 257 patients and its data were used to create the formula. The validation cohort had 129 subjects and its data were used to validate the formula. An additional 155 patients with connective tissue diseases other than SSc were obtained from the Royal Free Pulmonary Hypertension Service in London, United Kingdom.

The formula was derived using multivariable linear regression in the derivation cohort. Dr. Schreiber and his team examined the relationship between the SpO₂, PFTs, clinical subtype, autoimmune serologic features, and the mPAP on RHC and developed the following formula: predicted mPAP = 136 – SpO₂ –0.25 x diffusing capacity for carbon monoxide (DLCO)% predicted.

Applying the formula to the validation cohort gave an area under the curve (AUC) of 0.75. The formula performed best in patients with anticentromere antibodies, with an AUC of 0.87. In patients with connective tissue diseases other than SSc, the formula gave an AUC of 0.64.

The researchers suggested the PFT-derived formula can complement data obtained through echocardiography, and that both tests are predictive. Echocardiography is a good tool for diagnosing PH, but it cannot evaluate lung disease and is not always feasible to conduct. Therefore, the formula can calculate which patients are most likely to have PH.

Some of the limitations of this retrospective study included missing data, especially from echocardiograms and PFTs, and lack of rigorous selection of patients for RHC. There were no echocardiographic data available for most patients, and there may have been selection bias in the patients who had a second echocardiography performed.

Dr. Schreiber and his team suggested that further research should combine PFT data with other noninvasive information, such as symptoms, 6-minute walking distance, and brain natriuretic peptide levels. They also said that they plan to continue to validate their formula in patients recruited into the DETECT (Detection of Pulmonary Artery Hypertension in Systemic Sclerosis) study.

No relevant financial disclosures were reported.

A new formula accurately calculates the risk of pulmonary hypertension by predicting the mean pulmonary artery pressure using data obtained from pulmonary function testing and pulse oximetry, according to a report by Dr. Benjamin E. Schreiber, of the Royal Free Hampstead National Health Service Trust, London, and his associates.

They developed the formula based on findings in 257 patients with systemic sclerosis; the investigators validated it with data from another 129 similar patients.

Patients with a predicted mean pulmonary artery pressure (mPAP) below 25 mm Hg had a low pulmonary hypertension (PH) prevalence (4.4%). Those with a predicted mPAP between 25-35 mm Hg had an average PH prevalence (11.3%). Finally, those with a predicted mPAP above 35 mm Hg had a high PH prevalence (62.9%), which justifies using right-sided heart catheterization (RHC) (Arthritis Rheum. 2011;63:3531-9).

The study started with 838 patients who have systemic sclerosis (SSc) who had undergone an RHC. Of those, 386 patients had undergone pulmonary function testing (PFT) within 6 months of the RHC. Data on oxygen saturation as measured by pulse oximetry (SpO2) at the time of the RHC were included in the study. Of the total number of patients, 452 were excluded because they had incomplete PFT data.

The investigators randomly split the remaining 386 into two groups: the derivation and validation cohorts. The derivation cohort had 257 patients and its data were used to create the formula. The validation cohort had 129 subjects and its data were used to validate the formula. An additional 155 patients with connective tissue diseases other than SSc were obtained from the Royal Free Pulmonary Hypertension Service in London, United Kingdom.

The formula was derived using multivariable linear regression in the derivation cohort. Dr. Schreiber and his team examined the relationship between the SpO₂, PFTs, clinical subtype, autoimmune serologic features, and the mPAP on RHC and developed the following formula: predicted mPAP = 136 – SpO₂ –0.25 x diffusing capacity for carbon monoxide (DLCO)% predicted.

Applying the formula to the validation cohort gave an area under the curve (AUC) of 0.75. The formula performed best in patients with anticentromere antibodies, with an AUC of 0.87. In patients with connective tissue diseases other than SSc, the formula gave an AUC of 0.64.

The researchers suggested the PFT-derived formula can complement data obtained through echocardiography, and that both tests are predictive. Echocardiography is a good tool for diagnosing PH, but it cannot evaluate lung disease and is not always feasible to conduct. Therefore, the formula can calculate which patients are most likely to have PH.

Some of the limitations of this retrospective study included missing data, especially from echocardiograms and PFTs, and lack of rigorous selection of patients for RHC. There were no echocardiographic data available for most patients, and there may have been selection bias in the patients who had a second echocardiography performed.

Dr. Schreiber and his team suggested that further research should combine PFT data with other noninvasive information, such as symptoms, 6-minute walking distance, and brain natriuretic peptide levels. They also said that they plan to continue to validate their formula in patients recruited into the DETECT (Detection of Pulmonary Artery Hypertension in Systemic Sclerosis) study.

No relevant financial disclosures were reported.

CHICAGO – Newly updated American College of Rheumatology guidelines for the screening and management of lupus nephritis in adults, which are expected to be published in early 2012, focus largely on induction therapy with mycophenolate mofetil or cyclophosphamide and on maintenance therapy with mycophenolate mofetil and azathioprine.

An algorithm for diffuse proliferative nephritis, for example, indicates that in patients with active class III and IV disease without cellular crescents, induction therapy should include mycophenolate mofetil (MMF) at 2-3 g/day for 6 months. Cyclophosphamide is an alternative option in these patients, according to the guidelines, which note that the literature suggests MMF is preferred for initial therapy in African Americans and Hispanics in North America and Latin America.

These recommendations are based on level A evidence from multiple randomized controlled trials or a meta-analysis, Dr. Bevra H. Hahn noted at the annual meeting of the American College of Rheumatology, where she presented the updated guidelines.

In patients who are given cyclophosphamide, the dose should be 500 mg intravenously every 2 weeks for 6 weeks, or 500-1,000 mg/m² of body surface area. This recommendation is based on level B evidence from a single randomized controlled trial or nonrandomized studies. The latter choice has been studied only in Caucasians of European descent, noted Dr. Hahn, a professor of medicine and chair of the rheumatology department at the University of California, Los Angeles, as well as a member of the core working group for the updated guidelines.

Also recommended for class III and IV patients without cellular crescents is a concomitant pulse of steroids for 3 days, then prednisone at a dose of 0.5-1.0 mg/kg to induce improvement, with tapering to the lowest effective dose after a few weeks. Data supporting a specific dose in this range are lacking, and this recommendation, which is based on level C evidence indicating the recommendation is derived from consensus, expert opinion, or a case series, also states that the prednisone should continue for 6 months.

The algorithm for patients with diffuse proliferative disease also addresses patients with cellular crescents. Such patients should receive the higher 1.0-mg/kg per day prednisone dose. Patients who do not respond to induction should be switched from their initial induction regimen, be it MMF or cyclophosphamide, to the other. Maintenance therapy for responders to either MMF or cyclophosphamide should include MMF at 1-2 g/day or azathioprine at 2 mg/kg per day plus low-dose daily glucocorticoids.

The updated guidelines also address renal biopsy, adjunctive treatments, patients with focal disease, patients with class V disease, lupus nephritis in pregnancy, and recommendations for monitoring.

Notably, the guidelines do not advocate use of belimumab, as it has not been studied in active lupus nephritis, Dr. Hahn said, noting that despite the expanded literature on lupus nephritis that led to development of these updated guidelines, there are a number of unmet needs.

Between 20% and 35% of patients do not respond at all to induction therapies, and in many the response is slow, taking up to 52 weeks to determine response. Furthermore, response rates remain low.

"So it takes a long time, and you certainly don’t get 100% response rates, she said.

The guidelines, developed by a core working group that conducted the literature reviews and wrote scenarios, and by a task force panel of international experts in rheumatology, nephrology, and pathology who voted on the scenarios, will be published in Arthritis Care & Research, most likely in the spring, Dr. Hahn said. Currently they are pending approval by the ACR Guidelines Subcommittee, Quality of Care Committee, and Board of Directors.

Dr. Hahn, however, is already looking forward to new advances in the treatment of lupus nephritis and to the next guidelines update.

"I can’t wait to have something that’s better, so in another decade when we write guidelines, we can talk to you about 80% to 100% response rates," she said.

The lupus nephritis guideline project was sponsored by the ACR via a competitive grant mechanism. Of the 39 working group and task force members, 16 declared potential conflicts of interest, including relationships with Aspreva, Bristol-Myers Squibb, Genentech, and Human Genome Sciences.

CHICAGO – Newly updated American College of Rheumatology guidelines for the screening and management of lupus nephritis in adults, which are expected to be published in early 2012, focus largely on induction therapy with mycophenolate mofetil or cyclophosphamide and on maintenance therapy with mycophenolate mofetil and azathioprine.

An algorithm for diffuse proliferative nephritis, for example, indicates that in patients with active class III and IV disease without cellular crescents, induction therapy should include mycophenolate mofetil (MMF) at 2-3 g/day for 6 months. Cyclophosphamide is an alternative option in these patients, according to the guidelines, which note that the literature suggests MMF is preferred for initial therapy in African Americans and Hispanics in North America and Latin America.

These recommendations are based on level A evidence from multiple randomized controlled trials or a meta-analysis, Dr. Bevra H. Hahn noted at the annual meeting of the American College of Rheumatology, where she presented the updated guidelines.

In patients who are given cyclophosphamide, the dose should be 500 mg intravenously every 2 weeks for 6 weeks, or 500-1,000 mg/m² of body surface area. This recommendation is based on level B evidence from a single randomized controlled trial or nonrandomized studies. The latter choice has been studied only in Caucasians of European descent, noted Dr. Hahn, a professor of medicine and chair of the rheumatology department at the University of California, Los Angeles, as well as a member of the core working group for the updated guidelines.

Also recommended for class III and IV patients without cellular crescents is a concomitant pulse of steroids for 3 days, then prednisone at a dose of 0.5-1.0 mg/kg to induce improvement, with tapering to the lowest effective dose after a few weeks. Data supporting a specific dose in this range are lacking, and this recommendation, which is based on level C evidence indicating the recommendation is derived from consensus, expert opinion, or a case series, also states that the prednisone should continue for 6 months.

The algorithm for patients with diffuse proliferative disease also addresses patients with cellular crescents. Such patients should receive the higher 1.0-mg/kg per day prednisone dose. Patients who do not respond to induction should be switched from their initial induction regimen, be it MMF or cyclophosphamide, to the other. Maintenance therapy for responders to either MMF or cyclophosphamide should include MMF at 1-2 g/day or azathioprine at 2 mg/kg per day plus low-dose daily glucocorticoids.

The updated guidelines also address renal biopsy, adjunctive treatments, patients with focal disease, patients with class V disease, lupus nephritis in pregnancy, and recommendations for monitoring.

Notably, the guidelines do not advocate use of belimumab, as it has not been studied in active lupus nephritis, Dr. Hahn said, noting that despite the expanded literature on lupus nephritis that led to development of these updated guidelines, there are a number of unmet needs.

Between 20% and 35% of patients do not respond at all to induction therapies, and in many the response is slow, taking up to 52 weeks to determine response. Furthermore, response rates remain low.

"So it takes a long time, and you certainly don’t get 100% response rates, she said.

The guidelines, developed by a core working group that conducted the literature reviews and wrote scenarios, and by a task force panel of international experts in rheumatology, nephrology, and pathology who voted on the scenarios, will be published in Arthritis Care & Research, most likely in the spring, Dr. Hahn said. Currently they are pending approval by the ACR Guidelines Subcommittee, Quality of Care Committee, and Board of Directors.

Dr. Hahn, however, is already looking forward to new advances in the treatment of lupus nephritis and to the next guidelines update.

"I can’t wait to have something that’s better, so in another decade when we write guidelines, we can talk to you about 80% to 100% response rates," she said.

The lupus nephritis guideline project was sponsored by the ACR via a competitive grant mechanism. Of the 39 working group and task force members, 16 declared potential conflicts of interest, including relationships with Aspreva, Bristol-Myers Squibb, Genentech, and Human Genome Sciences.

CHICAGO – Newly updated American College of Rheumatology guidelines for the screening and management of lupus nephritis in adults, which are expected to be published in early 2012, focus largely on induction therapy with mycophenolate mofetil or cyclophosphamide and on maintenance therapy with mycophenolate mofetil and azathioprine.

An algorithm for diffuse proliferative nephritis, for example, indicates that in patients with active class III and IV disease without cellular crescents, induction therapy should include mycophenolate mofetil (MMF) at 2-3 g/day for 6 months. Cyclophosphamide is an alternative option in these patients, according to the guidelines, which note that the literature suggests MMF is preferred for initial therapy in African Americans and Hispanics in North America and Latin America.

These recommendations are based on level A evidence from multiple randomized controlled trials or a meta-analysis, Dr. Bevra H. Hahn noted at the annual meeting of the American College of Rheumatology, where she presented the updated guidelines.

In patients who are given cyclophosphamide, the dose should be 500 mg intravenously every 2 weeks for 6 weeks, or 500-1,000 mg/m² of body surface area. This recommendation is based on level B evidence from a single randomized controlled trial or nonrandomized studies. The latter choice has been studied only in Caucasians of European descent, noted Dr. Hahn, a professor of medicine and chair of the rheumatology department at the University of California, Los Angeles, as well as a member of the core working group for the updated guidelines.

Also recommended for class III and IV patients without cellular crescents is a concomitant pulse of steroids for 3 days, then prednisone at a dose of 0.5-1.0 mg/kg to induce improvement, with tapering to the lowest effective dose after a few weeks. Data supporting a specific dose in this range are lacking, and this recommendation, which is based on level C evidence indicating the recommendation is derived from consensus, expert opinion, or a case series, also states that the prednisone should continue for 6 months.

The algorithm for patients with diffuse proliferative disease also addresses patients with cellular crescents. Such patients should receive the higher 1.0-mg/kg per day prednisone dose. Patients who do not respond to induction should be switched from their initial induction regimen, be it MMF or cyclophosphamide, to the other. Maintenance therapy for responders to either MMF or cyclophosphamide should include MMF at 1-2 g/day or azathioprine at 2 mg/kg per day plus low-dose daily glucocorticoids.

The updated guidelines also address renal biopsy, adjunctive treatments, patients with focal disease, patients with class V disease, lupus nephritis in pregnancy, and recommendations for monitoring.

Notably, the guidelines do not advocate use of belimumab, as it has not been studied in active lupus nephritis, Dr. Hahn said, noting that despite the expanded literature on lupus nephritis that led to development of these updated guidelines, there are a number of unmet needs.

Between 20% and 35% of patients do not respond at all to induction therapies, and in many the response is slow, taking up to 52 weeks to determine response. Furthermore, response rates remain low.

"So it takes a long time, and you certainly don’t get 100% response rates, she said.

The guidelines, developed by a core working group that conducted the literature reviews and wrote scenarios, and by a task force panel of international experts in rheumatology, nephrology, and pathology who voted on the scenarios, will be published in Arthritis Care & Research, most likely in the spring, Dr. Hahn said. Currently they are pending approval by the ACR Guidelines Subcommittee, Quality of Care Committee, and Board of Directors.

Dr. Hahn, however, is already looking forward to new advances in the treatment of lupus nephritis and to the next guidelines update.

"I can’t wait to have something that’s better, so in another decade when we write guidelines, we can talk to you about 80% to 100% response rates," she said.

The lupus nephritis guideline project was sponsored by the ACR via a competitive grant mechanism. Of the 39 working group and task force members, 16 declared potential conflicts of interest, including relationships with Aspreva, Bristol-Myers Squibb, Genentech, and Human Genome Sciences.

The Food and Drug Administration has asked manufacturers of tumor necrosis factor blockers to enhance their follow-up of pediatric and young adult patients who develop malignancies while on these treatments.

The agency also is advising health care professionals to “remain vigilant” for malignancies in these patients, according to a statement issued by the FDA Nov. 4.

Manufacturers of TNF blockers have been asked by the FDA to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them. They also are asked to provide the agency with annual summaries and assessments of malignancies and data on the use of TNF blockers in these age groups.

“This type of safety surveillance is important for our improved understanding of malignancies in pediatric and young adult patients treated with TNF blockers, because it will allow FDA to more completely capture and analyze all reported malignancies based on more complete and consistent reports,” the agency said in its statement.

The FDA statement updates the agency’s ongoing safety review of TNF blockers and malignancies in children, adolescents, and young adults, and does not include any new cases or previously unrecognized risks associated with TNF blockers in this patient population.

The agency has previously issued reports about the increased risk of lymphomas and other cancers associated with the use of TNF blockers and malignancies in children and young adults in June 2008, August 2009, and most recently, April 2011.

TNF blockers are used to treat Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis. TNF blockers used in the United States are infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi).

Health care professionals also should report these cases to the FDA’s Medwatch program.

The Food and Drug Administration has asked manufacturers of tumor necrosis factor blockers to enhance their follow-up of pediatric and young adult patients who develop malignancies while on these treatments.

The agency also is advising health care professionals to “remain vigilant” for malignancies in these patients, according to a statement issued by the FDA Nov. 4.

Manufacturers of TNF blockers have been asked by the FDA to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them. They also are asked to provide the agency with annual summaries and assessments of malignancies and data on the use of TNF blockers in these age groups.

“This type of safety surveillance is important for our improved understanding of malignancies in pediatric and young adult patients treated with TNF blockers, because it will allow FDA to more completely capture and analyze all reported malignancies based on more complete and consistent reports,” the agency said in its statement.

The FDA statement updates the agency’s ongoing safety review of TNF blockers and malignancies in children, adolescents, and young adults, and does not include any new cases or previously unrecognized risks associated with TNF blockers in this patient population.

The agency has previously issued reports about the increased risk of lymphomas and other cancers associated with the use of TNF blockers and malignancies in children and young adults in June 2008, August 2009, and most recently, April 2011.

TNF blockers are used to treat Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis. TNF blockers used in the United States are infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi).

Health care professionals also should report these cases to the FDA’s Medwatch program.

The Food and Drug Administration has asked manufacturers of tumor necrosis factor blockers to enhance their follow-up of pediatric and young adult patients who develop malignancies while on these treatments.

The agency also is advising health care professionals to “remain vigilant” for malignancies in these patients, according to a statement issued by the FDA Nov. 4.

Manufacturers of TNF blockers have been asked by the FDA to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them. They also are asked to provide the agency with annual summaries and assessments of malignancies and data on the use of TNF blockers in these age groups.

“This type of safety surveillance is important for our improved understanding of malignancies in pediatric and young adult patients treated with TNF blockers, because it will allow FDA to more completely capture and analyze all reported malignancies based on more complete and consistent reports,” the agency said in its statement.

The FDA statement updates the agency’s ongoing safety review of TNF blockers and malignancies in children, adolescents, and young adults, and does not include any new cases or previously unrecognized risks associated with TNF blockers in this patient population.

The agency has previously issued reports about the increased risk of lymphomas and other cancers associated with the use of TNF blockers and malignancies in children and young adults in June 2008, August 2009, and most recently, April 2011.

TNF blockers are used to treat Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis. TNF blockers used in the United States are infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi).

Health care professionals also should report these cases to the FDA’s Medwatch program.

LISBON – Adding methotrexate to etanercept in patients with moderate to severe plaque psoriasis brings a bump in efficacy with no increase in serious adverse events, according to a large, double-blind, randomized clinical trial.

The multicenter trial included 478 patients on etanercept (Enbrel) at 50 mg twice weekly for 12 weeks, followed by once-weekly treatment thereafter. Participants were randomized to methotrexate or placebo from the outset. Methotrexate was dosed at 7.5 mg/week for the first 2 weeks, 10 mg/week for the next 2 weeks, and 15 mg/week after that.

The primary study end point was the proportion of patients attaining a PASI 75 response – that is, at least a 75% improvement over baseline scores on the Psoriasis Area and Severity Index – at week 24. The PASI 75 rate was 77.3% with dual therapy, significantly better than the 60.3% rate with etanercept alone, Dr. Alice B. Gottlieb reported at the annual congress of the European Academy of Dermatology and Venereology.

These results with combination therapy are in line with the enhanced efficacy seen with ustekinumab (Stelara) and other biologics targeting interleukin-23/Th17. But the combination therapy relies upon familiar medications that have been around a long time and have well-understood safety profiles, she noted.

The 24-week PASI 90 rate was also markedly better with dual therapy: 53.8%, compared with 34.2%. Seventy-two percent of patients on methotrexate plus etanercept were rated clear or almost clear on Physician’s Global Assessment, as were 53% on etanercept alone, according to Dr. Gottlieb, professor and chair of dermatology at Tufts Medical Center, Boston.

Adding methotrexate accelerated the time course of improvement. By week 12, 70% of patients on methotrexate plus etanercept had achieved a PASI 75 response, compared with 54% of those on etanercept alone.

Three serious adverse events occurred in each study arm. In the dual-therapy arm, there was one case each of bacterial pneumonia, lumbar spinal stenosis, and synovial cyst. In the etanercept-only arm, there was a case of acute MI, cholecystitis, and asthma.

Dr. Gottlieb disclosed that she serves as a consultant to Amgen, which sponsored the trial. In addition, she is a consultant and/or advisory board member for numerous other pharmaceutical companies.

LISBON – Adding methotrexate to etanercept in patients with moderate to severe plaque psoriasis brings a bump in efficacy with no increase in serious adverse events, according to a large, double-blind, randomized clinical trial.

The multicenter trial included 478 patients on etanercept (Enbrel) at 50 mg twice weekly for 12 weeks, followed by once-weekly treatment thereafter. Participants were randomized to methotrexate or placebo from the outset. Methotrexate was dosed at 7.5 mg/week for the first 2 weeks, 10 mg/week for the next 2 weeks, and 15 mg/week after that.

The primary study end point was the proportion of patients attaining a PASI 75 response – that is, at least a 75% improvement over baseline scores on the Psoriasis Area and Severity Index – at week 24. The PASI 75 rate was 77.3% with dual therapy, significantly better than the 60.3% rate with etanercept alone, Dr. Alice B. Gottlieb reported at the annual congress of the European Academy of Dermatology and Venereology.

These results with combination therapy are in line with the enhanced efficacy seen with ustekinumab (Stelara) and other biologics targeting interleukin-23/Th17. But the combination therapy relies upon familiar medications that have been around a long time and have well-understood safety profiles, she noted.

The 24-week PASI 90 rate was also markedly better with dual therapy: 53.8%, compared with 34.2%. Seventy-two percent of patients on methotrexate plus etanercept were rated clear or almost clear on Physician’s Global Assessment, as were 53% on etanercept alone, according to Dr. Gottlieb, professor and chair of dermatology at Tufts Medical Center, Boston.

Adding methotrexate accelerated the time course of improvement. By week 12, 70% of patients on methotrexate plus etanercept had achieved a PASI 75 response, compared with 54% of those on etanercept alone.

Three serious adverse events occurred in each study arm. In the dual-therapy arm, there was one case each of bacterial pneumonia, lumbar spinal stenosis, and synovial cyst. In the etanercept-only arm, there was a case of acute MI, cholecystitis, and asthma.

Dr. Gottlieb disclosed that she serves as a consultant to Amgen, which sponsored the trial. In addition, she is a consultant and/or advisory board member for numerous other pharmaceutical companies.

LISBON – Adding methotrexate to etanercept in patients with moderate to severe plaque psoriasis brings a bump in efficacy with no increase in serious adverse events, according to a large, double-blind, randomized clinical trial.

The multicenter trial included 478 patients on etanercept (Enbrel) at 50 mg twice weekly for 12 weeks, followed by once-weekly treatment thereafter. Participants were randomized to methotrexate or placebo from the outset. Methotrexate was dosed at 7.5 mg/week for the first 2 weeks, 10 mg/week for the next 2 weeks, and 15 mg/week after that.

The primary study end point was the proportion of patients attaining a PASI 75 response – that is, at least a 75% improvement over baseline scores on the Psoriasis Area and Severity Index – at week 24. The PASI 75 rate was 77.3% with dual therapy, significantly better than the 60.3% rate with etanercept alone, Dr. Alice B. Gottlieb reported at the annual congress of the European Academy of Dermatology and Venereology.

These results with combination therapy are in line with the enhanced efficacy seen with ustekinumab (Stelara) and other biologics targeting interleukin-23/Th17. But the combination therapy relies upon familiar medications that have been around a long time and have well-understood safety profiles, she noted.

The 24-week PASI 90 rate was also markedly better with dual therapy: 53.8%, compared with 34.2%. Seventy-two percent of patients on methotrexate plus etanercept were rated clear or almost clear on Physician’s Global Assessment, as were 53% on etanercept alone, according to Dr. Gottlieb, professor and chair of dermatology at Tufts Medical Center, Boston.

Adding methotrexate accelerated the time course of improvement. By week 12, 70% of patients on methotrexate plus etanercept had achieved a PASI 75 response, compared with 54% of those on etanercept alone.

Three serious adverse events occurred in each study arm. In the dual-therapy arm, there was one case each of bacterial pneumonia, lumbar spinal stenosis, and synovial cyst. In the etanercept-only arm, there was a case of acute MI, cholecystitis, and asthma.

Dr. Gottlieb disclosed that she serves as a consultant to Amgen, which sponsored the trial. In addition, she is a consultant and/or advisory board member for numerous other pharmaceutical companies.

Treatment for systemic sclerosis–associated active interstitial lung disease with a relatively high dose of imatinib can be effective, but it carries many side effects, judging from findings of a 20-person study.

The study subjects met the American College of Rheumatology criteria for systemic sclerosis (SSc). The mean disease duration was less than 10 years, their mean forced vital capacity (FVC) was less than 85% of predicted, their dyspnea on exertion was at least grade 2 on the magnitude of task component of the Mahler Baseline Dyspnea Index, and high-resolution computed tomography showed the presence of ground-glass opacifications.

Patients with SSc received oral therapy with imatinib up to 600 mg/day for a period of 1 year. The researchers recorded adverse events and tested pulmonary function. In addition, the modified Rodnan skin thickness score (MRSS) was assessed every 3 months, according to Dr. Dinesh Khanna of the University of California at Los Angeles.

Imatinib treatment increased FVC by 1.74%, though this was not statistically significant. In addition, the MRSS increased by 3.9 units. The total lung capacity increased by 4.17% over predicted and the diffusing capacity for carbon monoxide increased improved by 1.46% versus predicted, according to the investigators (Arthritis Rheum. 2011;63:3540-6 [doi 10.1002/art.30548]).

Of the 20 who participated, 5 did not complete the study due to adverse events that were caused by the treatment itself. A further two dropped out due to adverse events caused by SSc, and one was lost due to follow-up. The rest completed the study.

Some of the common adverse events the participants experienced were fatigue, edema of the face and/or lower extremities, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria.

Because of its efficacy, the authors suggest further research with smaller doses of imatinib, so as to reduce AEs while maintaining the positive effects.

The researchers reported no relevant financial disclosures. Novartis Pharmaceuticals provided the study drug and partial support for the study.

Treatment for systemic sclerosis–associated active interstitial lung disease with a relatively high dose of imatinib can be effective, but it carries many side effects, judging from findings of a 20-person study.

The study subjects met the American College of Rheumatology criteria for systemic sclerosis (SSc). The mean disease duration was less than 10 years, their mean forced vital capacity (FVC) was less than 85% of predicted, their dyspnea on exertion was at least grade 2 on the magnitude of task component of the Mahler Baseline Dyspnea Index, and high-resolution computed tomography showed the presence of ground-glass opacifications.

Patients with SSc received oral therapy with imatinib up to 600 mg/day for a period of 1 year. The researchers recorded adverse events and tested pulmonary function. In addition, the modified Rodnan skin thickness score (MRSS) was assessed every 3 months, according to Dr. Dinesh Khanna of the University of California at Los Angeles.

Imatinib treatment increased FVC by 1.74%, though this was not statistically significant. In addition, the MRSS increased by 3.9 units. The total lung capacity increased by 4.17% over predicted and the diffusing capacity for carbon monoxide increased improved by 1.46% versus predicted, according to the investigators (Arthritis Rheum. 2011;63:3540-6 [doi 10.1002/art.30548]).

Of the 20 who participated, 5 did not complete the study due to adverse events that were caused by the treatment itself. A further two dropped out due to adverse events caused by SSc, and one was lost due to follow-up. The rest completed the study.

Some of the common adverse events the participants experienced were fatigue, edema of the face and/or lower extremities, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria.

Because of its efficacy, the authors suggest further research with smaller doses of imatinib, so as to reduce AEs while maintaining the positive effects.

The researchers reported no relevant financial disclosures. Novartis Pharmaceuticals provided the study drug and partial support for the study.

Treatment for systemic sclerosis–associated active interstitial lung disease with a relatively high dose of imatinib can be effective, but it carries many side effects, judging from findings of a 20-person study.

The study subjects met the American College of Rheumatology criteria for systemic sclerosis (SSc). The mean disease duration was less than 10 years, their mean forced vital capacity (FVC) was less than 85% of predicted, their dyspnea on exertion was at least grade 2 on the magnitude of task component of the Mahler Baseline Dyspnea Index, and high-resolution computed tomography showed the presence of ground-glass opacifications.

Patients with SSc received oral therapy with imatinib up to 600 mg/day for a period of 1 year. The researchers recorded adverse events and tested pulmonary function. In addition, the modified Rodnan skin thickness score (MRSS) was assessed every 3 months, according to Dr. Dinesh Khanna of the University of California at Los Angeles.

Imatinib treatment increased FVC by 1.74%, though this was not statistically significant. In addition, the MRSS increased by 3.9 units. The total lung capacity increased by 4.17% over predicted and the diffusing capacity for carbon monoxide increased improved by 1.46% versus predicted, according to the investigators (Arthritis Rheum. 2011;63:3540-6 [doi 10.1002/art.30548]).

Of the 20 who participated, 5 did not complete the study due to adverse events that were caused by the treatment itself. A further two dropped out due to adverse events caused by SSc, and one was lost due to follow-up. The rest completed the study.

Some of the common adverse events the participants experienced were fatigue, edema of the face and/or lower extremities, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria.

Because of its efficacy, the authors suggest further research with smaller doses of imatinib, so as to reduce AEs while maintaining the positive effects.

The researchers reported no relevant financial disclosures. Novartis Pharmaceuticals provided the study drug and partial support for the study.

LISBON – Validation of the interleukin-17 cytokine family in psoriasis pathophysiology has gotten a boost from positive, phase II clinical trials involving two novel biologic agents.

The double-blind, placebo-controlled, phase II studies documented rapid and marked improvement in patients who had moderate to severe plaque psoriasis and were treated with secukinumab or AMG 827.

Roughly 80% of patients who were randomized to the maximum dose of either biologic experienced at least a PASI 75 (that is, improvement of 75% as measured by the Psoriasis Area and Severity Index) at 12 weeks. Those are efficacy rates in excess of the improvement obtainable with the earlier-generation biologics that targeted tumor necrosis factor–alpha, according to Dr. Kim A. Papp, who presented the data on both drugs at the annual congress of the European Academy of Dermatology and Venereology.

"This is a very robust, profound response suggesting that we’re really getting to the fundamentals of what’s driving psoriasis," Dr. Papp said.

Secukinumab is the agent further along in the developmental pipeline. A phase III clinical trial is already underway on the strength of three phase II studies presented at the congress.

Secukinumab is a fully human monoclonal antibody targeting IL-17A, a key member of the IL-17 cytokine family. The sequence of pathophysiologic events in psoriasis, as understood today, is that IL-23 induces activated Th17 cells, which in lesional skin express IL-17, in turn eliciting the production of proinflammatory cytokines by keratinocytes and keratinocyte hyperproliferation. IL-17A is one of several types of IL-17 that bind to the IL-17 receptor.

In contrast, AMG 827 is a human monoclonal antibody that blocks the IL-17 receptor itself, explained Dr. Papp, director of research at Probity Medical Research Inc. in Waterloo, Ont.

Secukinumab: Study 1

Dr. Papp presented the results of two of the three phase II studies of secukinumab. One study randomized 125 patients to subcutaneous secukinumab of 150 mg, 75 mg, or 25 mg once monthly for 3 months; to a single 25-mg dose; or to placebo.

The primary end point (PASI 75 response rate at 12 weeks) was 81%, 57%, 19%, 3%, and 9%, respectively. PASI 90 (that is, an improvement of 90% on the PASI) response rates were 52%, 19%, 8%, 0%, and 5%, respectively. Investigator Global Assessment scores of clear or almost clear at 12 weeks were achieved in 48% of patients in the 150-mg group and in 33% of those who received 75 mg, which were significantly better ratings than the 0%-12% rates in the other study arms.

Secukinumab: Study 2

The second secukinumab phase II study that was presented by Dr. Papp examined possible intravenous induction doses. The 100 participants were randomized to 3 mg/kg given on day 1; to 10 mg/kg on day 1; to 10 mg/kg on days 1, 15, and 29; or to placebo. The PASI 75 rates at 12 weeks were 40%, 75%, 83%, and 10%, respectively. The PASI 90 response rates were 10%, 54%, 76%, and 0%.

Secukinumab: Study 3

Dr. Phoebe A. Rich presented the third secukinumab phase II trial, which aimed to find the best dosing regimen. The study included 404 patients at 63 centers in seven countries who were randomized 1:2:2:1 to subcutaneous placebo; to a single 150-mg dose at week 0; to 150 mg at weeks 0, 4, and 8; or to 150 mg at weeks 0, 1, 2, and 4.

The treatment arm with dosing at weeks 0, 1, 2 and 4 was the winner, with a PASI 75 response rate of 55% at week 12, compared with 42% with dosing at weeks 0, 4, and 8; 11% for a single dose; and 2% with placebo. The corresponding PASI 90 rates were 32%, 17%, 3%, and 2%, added Dr. Phoebe of the Oregon Dermatology and Research Center, Portland.

None of these relatively brief trials suggested any safety signals. The side effect pattern was basically the same as in the placebo arms, according to the investigators.

AMG 827

Dr. Papp also presented the first phase II, randomized, double-blind trial of AMG 827. It involved 198 patients who were randomized to subcutaneous AMG 827 at 280 mg monthly; to 70, 140, or 210 mg every 2 weeks; or to placebo. The primary end point was the PASI 75 response rate at week 12. It was highest (83%) in patients who received 210 mg every 2 weeks.

Interestingly, nearly all of the PASI 75 responders were also PASI 90 responders. The PASI 90 and PASI 100 response rates in the group taking 210 mg every 2 weeks were 75% and 63%, respectively. Again, as for secukinumab, the safety profile was unremarkable.

The response waned 4-10 weeks after the last dose of AMG 827. This took the form of a gradual, progressive relapse rather than an abrupt rebound, noted Dr. Papp.

Dr. Papp said that the large turnout to his presentation at the meeting, "shows the interest and excitement that surrounds what I think is a new adventure and really a new revolution in the understanding and treatment of psoriasis."

Dr. Papp is on the advisory boards of Novartis, which is developing secukinumab, and Amgen, manufacturer of AMG 827. He is also an advisor to many other pharmaceutical companies developing drugs for psoriasis. Dr. Rich is also on the advisory board of Novartis and other companies that are developing drugs for psoriasis.

LISBON – Validation of the interleukin-17 cytokine family in psoriasis pathophysiology has gotten a boost from positive, phase II clinical trials involving two novel biologic agents.

The double-blind, placebo-controlled, phase II studies documented rapid and marked improvement in patients who had moderate to severe plaque psoriasis and were treated with secukinumab or AMG 827.

Roughly 80% of patients who were randomized to the maximum dose of either biologic experienced at least a PASI 75 (that is, improvement of 75% as measured by the Psoriasis Area and Severity Index) at 12 weeks. Those are efficacy rates in excess of the improvement obtainable with the earlier-generation biologics that targeted tumor necrosis factor–alpha, according to Dr. Kim A. Papp, who presented the data on both drugs at the annual congress of the European Academy of Dermatology and Venereology.

"This is a very robust, profound response suggesting that we’re really getting to the fundamentals of what’s driving psoriasis," Dr. Papp said.

Secukinumab is the agent further along in the developmental pipeline. A phase III clinical trial is already underway on the strength of three phase II studies presented at the congress.

Secukinumab is a fully human monoclonal antibody targeting IL-17A, a key member of the IL-17 cytokine family. The sequence of pathophysiologic events in psoriasis, as understood today, is that IL-23 induces activated Th17 cells, which in lesional skin express IL-17, in turn eliciting the production of proinflammatory cytokines by keratinocytes and keratinocyte hyperproliferation. IL-17A is one of several types of IL-17 that bind to the IL-17 receptor.

In contrast, AMG 827 is a human monoclonal antibody that blocks the IL-17 receptor itself, explained Dr. Papp, director of research at Probity Medical Research Inc. in Waterloo, Ont.

Secukinumab: Study 1

Dr. Papp presented the results of two of the three phase II studies of secukinumab. One study randomized 125 patients to subcutaneous secukinumab of 150 mg, 75 mg, or 25 mg once monthly for 3 months; to a single 25-mg dose; or to placebo.

The primary end point (PASI 75 response rate at 12 weeks) was 81%, 57%, 19%, 3%, and 9%, respectively. PASI 90 (that is, an improvement of 90% on the PASI) response rates were 52%, 19%, 8%, 0%, and 5%, respectively. Investigator Global Assessment scores of clear or almost clear at 12 weeks were achieved in 48% of patients in the 150-mg group and in 33% of those who received 75 mg, which were significantly better ratings than the 0%-12% rates in the other study arms.

Secukinumab: Study 2

The second secukinumab phase II study that was presented by Dr. Papp examined possible intravenous induction doses. The 100 participants were randomized to 3 mg/kg given on day 1; to 10 mg/kg on day 1; to 10 mg/kg on days 1, 15, and 29; or to placebo. The PASI 75 rates at 12 weeks were 40%, 75%, 83%, and 10%, respectively. The PASI 90 response rates were 10%, 54%, 76%, and 0%.

Secukinumab: Study 3

Dr. Phoebe A. Rich presented the third secukinumab phase II trial, which aimed to find the best dosing regimen. The study included 404 patients at 63 centers in seven countries who were randomized 1:2:2:1 to subcutaneous placebo; to a single 150-mg dose at week 0; to 150 mg at weeks 0, 4, and 8; or to 150 mg at weeks 0, 1, 2, and 4.

The treatment arm with dosing at weeks 0, 1, 2 and 4 was the winner, with a PASI 75 response rate of 55% at week 12, compared with 42% with dosing at weeks 0, 4, and 8; 11% for a single dose; and 2% with placebo. The corresponding PASI 90 rates were 32%, 17%, 3%, and 2%, added Dr. Phoebe of the Oregon Dermatology and Research Center, Portland.

None of these relatively brief trials suggested any safety signals. The side effect pattern was basically the same as in the placebo arms, according to the investigators.

AMG 827

Dr. Papp also presented the first phase II, randomized, double-blind trial of AMG 827. It involved 198 patients who were randomized to subcutaneous AMG 827 at 280 mg monthly; to 70, 140, or 210 mg every 2 weeks; or to placebo. The primary end point was the PASI 75 response rate at week 12. It was highest (83%) in patients who received 210 mg every 2 weeks.

Interestingly, nearly all of the PASI 75 responders were also PASI 90 responders. The PASI 90 and PASI 100 response rates in the group taking 210 mg every 2 weeks were 75% and 63%, respectively. Again, as for secukinumab, the safety profile was unremarkable.

The response waned 4-10 weeks after the last dose of AMG 827. This took the form of a gradual, progressive relapse rather than an abrupt rebound, noted Dr. Papp.

Dr. Papp said that the large turnout to his presentation at the meeting, "shows the interest and excitement that surrounds what I think is a new adventure and really a new revolution in the understanding and treatment of psoriasis."

Dr. Papp is on the advisory boards of Novartis, which is developing secukinumab, and Amgen, manufacturer of AMG 827. He is also an advisor to many other pharmaceutical companies developing drugs for psoriasis. Dr. Rich is also on the advisory board of Novartis and other companies that are developing drugs for psoriasis.

LISBON – Validation of the interleukin-17 cytokine family in psoriasis pathophysiology has gotten a boost from positive, phase II clinical trials involving two novel biologic agents.

The double-blind, placebo-controlled, phase II studies documented rapid and marked improvement in patients who had moderate to severe plaque psoriasis and were treated with secukinumab or AMG 827.

Roughly 80% of patients who were randomized to the maximum dose of either biologic experienced at least a PASI 75 (that is, improvement of 75% as measured by the Psoriasis Area and Severity Index) at 12 weeks. Those are efficacy rates in excess of the improvement obtainable with the earlier-generation biologics that targeted tumor necrosis factor–alpha, according to Dr. Kim A. Papp, who presented the data on both drugs at the annual congress of the European Academy of Dermatology and Venereology.

"This is a very robust, profound response suggesting that we’re really getting to the fundamentals of what’s driving psoriasis," Dr. Papp said.

Secukinumab is the agent further along in the developmental pipeline. A phase III clinical trial is already underway on the strength of three phase II studies presented at the congress.

Secukinumab is a fully human monoclonal antibody targeting IL-17A, a key member of the IL-17 cytokine family. The sequence of pathophysiologic events in psoriasis, as understood today, is that IL-23 induces activated Th17 cells, which in lesional skin express IL-17, in turn eliciting the production of proinflammatory cytokines by keratinocytes and keratinocyte hyperproliferation. IL-17A is one of several types of IL-17 that bind to the IL-17 receptor.

In contrast, AMG 827 is a human monoclonal antibody that blocks the IL-17 receptor itself, explained Dr. Papp, director of research at Probity Medical Research Inc. in Waterloo, Ont.

Secukinumab: Study 1

Dr. Papp presented the results of two of the three phase II studies of secukinumab. One study randomized 125 patients to subcutaneous secukinumab of 150 mg, 75 mg, or 25 mg once monthly for 3 months; to a single 25-mg dose; or to placebo.

The primary end point (PASI 75 response rate at 12 weeks) was 81%, 57%, 19%, 3%, and 9%, respectively. PASI 90 (that is, an improvement of 90% on the PASI) response rates were 52%, 19%, 8%, 0%, and 5%, respectively. Investigator Global Assessment scores of clear or almost clear at 12 weeks were achieved in 48% of patients in the 150-mg group and in 33% of those who received 75 mg, which were significantly better ratings than the 0%-12% rates in the other study arms.

Secukinumab: Study 2

The second secukinumab phase II study that was presented by Dr. Papp examined possible intravenous induction doses. The 100 participants were randomized to 3 mg/kg given on day 1; to 10 mg/kg on day 1; to 10 mg/kg on days 1, 15, and 29; or to placebo. The PASI 75 rates at 12 weeks were 40%, 75%, 83%, and 10%, respectively. The PASI 90 response rates were 10%, 54%, 76%, and 0%.

Secukinumab: Study 3

Dr. Phoebe A. Rich presented the third secukinumab phase II trial, which aimed to find the best dosing regimen. The study included 404 patients at 63 centers in seven countries who were randomized 1:2:2:1 to subcutaneous placebo; to a single 150-mg dose at week 0; to 150 mg at weeks 0, 4, and 8; or to 150 mg at weeks 0, 1, 2, and 4.

The treatment arm with dosing at weeks 0, 1, 2 and 4 was the winner, with a PASI 75 response rate of 55% at week 12, compared with 42% with dosing at weeks 0, 4, and 8; 11% for a single dose; and 2% with placebo. The corresponding PASI 90 rates were 32%, 17%, 3%, and 2%, added Dr. Phoebe of the Oregon Dermatology and Research Center, Portland.

None of these relatively brief trials suggested any safety signals. The side effect pattern was basically the same as in the placebo arms, according to the investigators.

AMG 827

Dr. Papp also presented the first phase II, randomized, double-blind trial of AMG 827. It involved 198 patients who were randomized to subcutaneous AMG 827 at 280 mg monthly; to 70, 140, or 210 mg every 2 weeks; or to placebo. The primary end point was the PASI 75 response rate at week 12. It was highest (83%) in patients who received 210 mg every 2 weeks.

Interestingly, nearly all of the PASI 75 responders were also PASI 90 responders. The PASI 90 and PASI 100 response rates in the group taking 210 mg every 2 weeks were 75% and 63%, respectively. Again, as for secukinumab, the safety profile was unremarkable.

The response waned 4-10 weeks after the last dose of AMG 827. This took the form of a gradual, progressive relapse rather than an abrupt rebound, noted Dr. Papp.

Dr. Papp said that the large turnout to his presentation at the meeting, "shows the interest and excitement that surrounds what I think is a new adventure and really a new revolution in the understanding and treatment of psoriasis."

Dr. Papp is on the advisory boards of Novartis, which is developing secukinumab, and Amgen, manufacturer of AMG 827. He is also an advisor to many other pharmaceutical companies developing drugs for psoriasis. Dr. Rich is also on the advisory board of Novartis and other companies that are developing drugs for psoriasis.

Briakinumab was more effective than methotrexate at reducing the signs and symptoms of moderate to severe plaque psoriasis in a 52-week, phase-III study reported in the Oct. 27 issue of the New England Journal of Medicine.

However, serious adverse events, adverse events leading to withdrawal from the study, serious infections, and cancers occurred more often with briakinumab, a monoclonal antibody that targets the "p40 molecule shared by interleukin-12 and interleukin-23, which is overexpressed in psoriatic skin lesions," according to Dr. Kristian Reich, medical director of the Dermatologikum Hamburg, and his associates. However, "Too few patients were enrolled in the study to draw conclusions regarding these adverse events."

In the study, conducted at 43 sites in Europe and Canada and funded by Abbott Laboratories, 317 patients with stable plaque psoriasis were randomly assigned to receive subcutaneous briakinumab (154 subjects) or oral methotrexate plus oral folate (163 subjects) in a double-blind fashion. Efficacy was assessed at week 24 and week 52 (N. Engl. J. Med. 2011;365:1586-96).

Significantly more patients in the briakinumab group showed at least a 75% improvement in their score on the psoriasis area and severity index (PASI) at both week 24 (81.8%) and week 52 (66.2%), compared with patients on methotrexate (39.9% at week 24 and 23.9% at week 52). The median time to such improvement was 56 days with briakinumab, compared with 140 days with methotrexate.

In addition, "the percentage of patients who had at least 75% improvement in the PASI score was significantly greater in the briakinumab group than in the methotrexate group by week 4 and at all time points through week 52," Dr. Reich and his colleagues reported.

The difference between the two groups became significant at week 2, and the difference in the proportion of patients showing 90%-100% improvement became significant at week 8.

Also, significantly more patients who received briakinumab met the efficacy end point of a score of 0-1 on a 5-point measure of the physician’s global assessment at both week 24 (80.5% vs. 34.4%) and week 52 (63.0% vs. 20.2%). Significantly more patients receiving briakinumab (46.1%) than methotrexate (9.2%) had a score of 0, indicating complete clearing at week 24, with similar results at week 52 (45.5% vs. 9.8%, respectively).

The median time to achieving a score of 0-1 on the physician’s global assessment was 69 days with briakinumab, compared with 171 days with methotrexate. And significantly more patients in the briakinumab group had a score of 0-1 at every time point from week 4 through week 52.

On the Dermatology Quality of Life Index, which measures the impact of skin disease on quality of life, more patients taking briakinumab (70.8%) than methotrexate (34.4%) had a score of 0-1, indicating minimal impact at week 24, as well as at week 52 (61.7% vs 17.8%, respectively). And significantly more patients taking briakinumab had a clinically meaningful reduction in Dermatology Quality of Life Index score at all time points.

In all, 12 patients in the briakinumab group (7.8%) and 10 in the methotrexate group (6.1%) withdrew from the study because of adverse events. The incidence of serious infections was 4.1 per 100 patient-years with briakinumab and 2.7 per 100 patient-years with methotrexate.

The four serious infections with briakinumab included one case of legionella with candidemia and septic shock, one case of osteomyelitis, one case of herpes zoster, and one case of tonsillitis. In the methotrexate group, there were two cases of diverticulitis and one case of hepatitis.

Three patients in the briakinumab group were diagnosed with cancer. And one death was reported: a patient receiving methotrexate died from an esophageal rupture.

This study was supported by Abbott, maker of briakinumab. Dr. Reich and his associates reported ties to Amgen, Astellas Celgene, Centocor, Biogen-Idec, Galderma, Janssen-Cilag, Graceway, Johnson & Johnson, LEO-Pharma, Meda-Pharma, Merck, Novartis, Ortho Biotech, Pfizer, Schering-Plough, UCB, and Wyeth.

Briakinumab was more effective than methotrexate at reducing the signs and symptoms of moderate to severe plaque psoriasis in a 52-week, phase-III study reported in the Oct. 27 issue of the New England Journal of Medicine.

However, serious adverse events, adverse events leading to withdrawal from the study, serious infections, and cancers occurred more often with briakinumab, a monoclonal antibody that targets the "p40 molecule shared by interleukin-12 and interleukin-23, which is overexpressed in psoriatic skin lesions," according to Dr. Kristian Reich, medical director of the Dermatologikum Hamburg, and his associates. However, "Too few patients were enrolled in the study to draw conclusions regarding these adverse events."

In the study, conducted at 43 sites in Europe and Canada and funded by Abbott Laboratories, 317 patients with stable plaque psoriasis were randomly assigned to receive subcutaneous briakinumab (154 subjects) or oral methotrexate plus oral folate (163 subjects) in a double-blind fashion. Efficacy was assessed at week 24 and week 52 (N. Engl. J. Med. 2011;365:1586-96).

Significantly more patients in the briakinumab group showed at least a 75% improvement in their score on the psoriasis area and severity index (PASI) at both week 24 (81.8%) and week 52 (66.2%), compared with patients on methotrexate (39.9% at week 24 and 23.9% at week 52). The median time to such improvement was 56 days with briakinumab, compared with 140 days with methotrexate.

In addition, "the percentage of patients who had at least 75% improvement in the PASI score was significantly greater in the briakinumab group than in the methotrexate group by week 4 and at all time points through week 52," Dr. Reich and his colleagues reported.

The difference between the two groups became significant at week 2, and the difference in the proportion of patients showing 90%-100% improvement became significant at week 8.

Also, significantly more patients who received briakinumab met the efficacy end point of a score of 0-1 on a 5-point measure of the physician’s global assessment at both week 24 (80.5% vs. 34.4%) and week 52 (63.0% vs. 20.2%). Significantly more patients receiving briakinumab (46.1%) than methotrexate (9.2%) had a score of 0, indicating complete clearing at week 24, with similar results at week 52 (45.5% vs. 9.8%, respectively).

The median time to achieving a score of 0-1 on the physician’s global assessment was 69 days with briakinumab, compared with 171 days with methotrexate. And significantly more patients in the briakinumab group had a score of 0-1 at every time point from week 4 through week 52.

On the Dermatology Quality of Life Index, which measures the impact of skin disease on quality of life, more patients taking briakinumab (70.8%) than methotrexate (34.4%) had a score of 0-1, indicating minimal impact at week 24, as well as at week 52 (61.7% vs 17.8%, respectively). And significantly more patients taking briakinumab had a clinically meaningful reduction in Dermatology Quality of Life Index score at all time points.

In all, 12 patients in the briakinumab group (7.8%) and 10 in the methotrexate group (6.1%) withdrew from the study because of adverse events. The incidence of serious infections was 4.1 per 100 patient-years with briakinumab and 2.7 per 100 patient-years with methotrexate.

The four serious infections with briakinumab included one case of legionella with candidemia and septic shock, one case of osteomyelitis, one case of herpes zoster, and one case of tonsillitis. In the methotrexate group, there were two cases of diverticulitis and one case of hepatitis.

Three patients in the briakinumab group were diagnosed with cancer. And one death was reported: a patient receiving methotrexate died from an esophageal rupture.

This study was supported by Abbott, maker of briakinumab. Dr. Reich and his associates reported ties to Amgen, Astellas Celgene, Centocor, Biogen-Idec, Galderma, Janssen-Cilag, Graceway, Johnson & Johnson, LEO-Pharma, Meda-Pharma, Merck, Novartis, Ortho Biotech, Pfizer, Schering-Plough, UCB, and Wyeth.

Briakinumab was more effective than methotrexate at reducing the signs and symptoms of moderate to severe plaque psoriasis in a 52-week, phase-III study reported in the Oct. 27 issue of the New England Journal of Medicine.

However, serious adverse events, adverse events leading to withdrawal from the study, serious infections, and cancers occurred more often with briakinumab, a monoclonal antibody that targets the "p40 molecule shared by interleukin-12 and interleukin-23, which is overexpressed in psoriatic skin lesions," according to Dr. Kristian Reich, medical director of the Dermatologikum Hamburg, and his associates. However, "Too few patients were enrolled in the study to draw conclusions regarding these adverse events."

In the study, conducted at 43 sites in Europe and Canada and funded by Abbott Laboratories, 317 patients with stable plaque psoriasis were randomly assigned to receive subcutaneous briakinumab (154 subjects) or oral methotrexate plus oral folate (163 subjects) in a double-blind fashion. Efficacy was assessed at week 24 and week 52 (N. Engl. J. Med. 2011;365:1586-96).

Significantly more patients in the briakinumab group showed at least a 75% improvement in their score on the psoriasis area and severity index (PASI) at both week 24 (81.8%) and week 52 (66.2%), compared with patients on methotrexate (39.9% at week 24 and 23.9% at week 52). The median time to such improvement was 56 days with briakinumab, compared with 140 days with methotrexate.

In addition, "the percentage of patients who had at least 75% improvement in the PASI score was significantly greater in the briakinumab group than in the methotrexate group by week 4 and at all time points through week 52," Dr. Reich and his colleagues reported.

The difference between the two groups became significant at week 2, and the difference in the proportion of patients showing 90%-100% improvement became significant at week 8.

Also, significantly more patients who received briakinumab met the efficacy end point of a score of 0-1 on a 5-point measure of the physician’s global assessment at both week 24 (80.5% vs. 34.4%) and week 52 (63.0% vs. 20.2%). Significantly more patients receiving briakinumab (46.1%) than methotrexate (9.2%) had a score of 0, indicating complete clearing at week 24, with similar results at week 52 (45.5% vs. 9.8%, respectively).

The median time to achieving a score of 0-1 on the physician’s global assessment was 69 days with briakinumab, compared with 171 days with methotrexate. And significantly more patients in the briakinumab group had a score of 0-1 at every time point from week 4 through week 52.

On the Dermatology Quality of Life Index, which measures the impact of skin disease on quality of life, more patients taking briakinumab (70.8%) than methotrexate (34.4%) had a score of 0-1, indicating minimal impact at week 24, as well as at week 52 (61.7% vs 17.8%, respectively). And significantly more patients taking briakinumab had a clinically meaningful reduction in Dermatology Quality of Life Index score at all time points.

In all, 12 patients in the briakinumab group (7.8%) and 10 in the methotrexate group (6.1%) withdrew from the study because of adverse events. The incidence of serious infections was 4.1 per 100 patient-years with briakinumab and 2.7 per 100 patient-years with methotrexate.

The four serious infections with briakinumab included one case of legionella with candidemia and septic shock, one case of osteomyelitis, one case of herpes zoster, and one case of tonsillitis. In the methotrexate group, there were two cases of diverticulitis and one case of hepatitis.

Three patients in the briakinumab group were diagnosed with cancer. And one death was reported: a patient receiving methotrexate died from an esophageal rupture.

This study was supported by Abbott, maker of briakinumab. Dr. Reich and his associates reported ties to Amgen, Astellas Celgene, Centocor, Biogen-Idec, Galderma, Janssen-Cilag, Graceway, Johnson & Johnson, LEO-Pharma, Meda-Pharma, Merck, Novartis, Ortho Biotech, Pfizer, Schering-Plough, UCB, and Wyeth.

The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.

To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the NOD2 mutation.

Most clinicians "have never seen a case of Blau syndrome, or think they haven’t," said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation (J. Rheumatol. 2005;32:373-5).

Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.

Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because "chances are that wherever they live, no one in their local community has Blau." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.

But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del. updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters in September (Curr. Opin. Rheumatol. 2011;23:411-8).

The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; and severe hypertension.

Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, according to Dr. Rosé.

But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. The triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although "it is a triad over time," which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes.

Rather, "bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion," Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis (JIA) is usually accompanied by positive ANA.

An unexplained fever – one that is "not periodic or hectic, [like those] you see in the autoinflammatory diseases" – should also be considered in the context of possible Blau, according to Dr. Rosé.

Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said.

Thalidomide, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. "We’re a little nervous using thalidomide in children," he said.

Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.

Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.

Dr. Rosé said that he uses "a lot of oral prednisone" to combat uveitis in his Blau patients, and recommends that all Blau patients undergo a slit-lamp examination every 3 months. Although oral steroids are "not a solution," he said, "sometimes they are the only thing you can offer."

Dr. Martin has been studying an unusual family of uveitis patients and looking for clues to solve some of the many genetic mysteries Blau presents.

Asked to consult on a family with severe bilateral uveitis with onset in early adulthood instead of childhood and no arthritis or other symptoms of Blau, Dr. Martin subsequently found that the family has an NOD2 mutation that is slightly different from the mutation seen in most Blau cases.

Another family in the registry has incomplete penetrance; the father of an affected and mutation-positive child carried the same NOD2 mutation but never developed the disease (Arthritis Rheum. 2009:60:1804-6). "There’s some genetic or environmental modifier that’s quenching that NOD2 mutation," she said.

Finding it will entail deeper investigations into the NOD2 mutations, and other mutations that may produce Blau-like pathology. The 100-plus patients in the international registry who have Blau-like symptoms but lack NOD2 mutations may in fact have other, yet-undescribed syndromes that further genetic work may reveal.

"We’re finding so many new mutations," Dr. Martin said, as well as new sorts of disease within the registry. One small group in the registry presented atypical for Blau and had infantile panniculitis, along with fever, uveitis, and systemic granulomatous inflammation (J. Pediatr. 2007;151:707-9).

The finding suggests, Dr. Martin said, that the registry contains unknown diseases that are not truly Blau syndrome but that may be identified through genotyping, which "is starting to get cheap enough that we can do it for a reasonable amount of money."

The genetics, Dr. Martin said, are "helping us find that Blau," – whatever it is, and however it is ultimately defined – "may not be as rare as we thought."

At the same conference, Kevin Foley, Ph.D., a researcher at GlaxoSmithKline, presented new data on Blau biomarkers (Pediatric Rheumatology 2011, 9 [suppl. 1]:O25), which may prove helpful in developing agents targeting the NOD2 signaling pathway.

GlaxoSmithKline is investigating a medication – currently in preclinical testing – that inhibits RIP-2, one of the proteins involved in NOD2 signaling. The company is also funding a prospective cohort study, led by Dr. Rosé, that aims to describe the natural history of Blau from infancy and to isolate additional biomarkers of inflammation driven by hyperactive RIP-2.

John Bertin, Ph.D., head of GlaxoSmithKline’s pattern recognition receptor discovery unit, said in an interview that he hopes the Blau cohort "will provide information that will enable us to determine the feasibility of performing a clinical study in this patient population."

And because hyperactive RIP-2 signaling drives proinflammatory cytokine production in Crohn’s and ulcerative colitis, Dr. Bertin said, a RIP-2 inhibitor could offer promise treating those diseases as well.

Dr. Martin reported having no relevant financial disclosures. Dr. Rosé has an unrestricted grant to study Blau syndrome funded by GlaxoSmithKline and administered by the University of Leuven. Dr. Bertin and Dr. Foley are employees of GlaxoSmithKline.

The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.

To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the NOD2 mutation.

Most clinicians "have never seen a case of Blau syndrome, or think they haven’t," said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation (J. Rheumatol. 2005;32:373-5).

Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.

Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because "chances are that wherever they live, no one in their local community has Blau." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.

But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del. updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters in September (Curr. Opin. Rheumatol. 2011;23:411-8).

The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; and severe hypertension.

Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, according to Dr. Rosé.

But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. The triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although "it is a triad over time," which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes.

Rather, "bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion," Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis (JIA) is usually accompanied by positive ANA.

An unexplained fever – one that is "not periodic or hectic, [like those] you see in the autoinflammatory diseases" – should also be considered in the context of possible Blau, according to Dr. Rosé.

Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said.

Thalidomide, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. "We’re a little nervous using thalidomide in children," he said.

Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.

Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.

Dr. Rosé said that he uses "a lot of oral prednisone" to combat uveitis in his Blau patients, and recommends that all Blau patients undergo a slit-lamp examination every 3 months. Although oral steroids are "not a solution," he said, "sometimes they are the only thing you can offer."

Dr. Martin has been studying an unusual family of uveitis patients and looking for clues to solve some of the many genetic mysteries Blau presents.

Asked to consult on a family with severe bilateral uveitis with onset in early adulthood instead of childhood and no arthritis or other symptoms of Blau, Dr. Martin subsequently found that the family has an NOD2 mutation that is slightly different from the mutation seen in most Blau cases.

Another family in the registry has incomplete penetrance; the father of an affected and mutation-positive child carried the same NOD2 mutation but never developed the disease (Arthritis Rheum. 2009:60:1804-6). "There’s some genetic or environmental modifier that’s quenching that NOD2 mutation," she said.

Finding it will entail deeper investigations into the NOD2 mutations, and other mutations that may produce Blau-like pathology. The 100-plus patients in the international registry who have Blau-like symptoms but lack NOD2 mutations may in fact have other, yet-undescribed syndromes that further genetic work may reveal.

"We’re finding so many new mutations," Dr. Martin said, as well as new sorts of disease within the registry. One small group in the registry presented atypical for Blau and had infantile panniculitis, along with fever, uveitis, and systemic granulomatous inflammation (J. Pediatr. 2007;151:707-9).

The finding suggests, Dr. Martin said, that the registry contains unknown diseases that are not truly Blau syndrome but that may be identified through genotyping, which "is starting to get cheap enough that we can do it for a reasonable amount of money."

The genetics, Dr. Martin said, are "helping us find that Blau," – whatever it is, and however it is ultimately defined – "may not be as rare as we thought."

At the same conference, Kevin Foley, Ph.D., a researcher at GlaxoSmithKline, presented new data on Blau biomarkers (Pediatric Rheumatology 2011, 9 [suppl. 1]:O25), which may prove helpful in developing agents targeting the NOD2 signaling pathway.

GlaxoSmithKline is investigating a medication – currently in preclinical testing – that inhibits RIP-2, one of the proteins involved in NOD2 signaling. The company is also funding a prospective cohort study, led by Dr. Rosé, that aims to describe the natural history of Blau from infancy and to isolate additional biomarkers of inflammation driven by hyperactive RIP-2.

John Bertin, Ph.D., head of GlaxoSmithKline’s pattern recognition receptor discovery unit, said in an interview that he hopes the Blau cohort "will provide information that will enable us to determine the feasibility of performing a clinical study in this patient population."

And because hyperactive RIP-2 signaling drives proinflammatory cytokine production in Crohn’s and ulcerative colitis, Dr. Bertin said, a RIP-2 inhibitor could offer promise treating those diseases as well.

Dr. Martin reported having no relevant financial disclosures. Dr. Rosé has an unrestricted grant to study Blau syndrome funded by GlaxoSmithKline and administered by the University of Leuven. Dr. Bertin and Dr. Foley are employees of GlaxoSmithKline.

The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.

To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the NOD2 mutation.

Most clinicians "have never seen a case of Blau syndrome, or think they haven’t," said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation (J. Rheumatol. 2005;32:373-5).

Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.

Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because "chances are that wherever they live, no one in their local community has Blau." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.

But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del. updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters in September (Curr. Opin. Rheumatol. 2011;23:411-8).

The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; and severe hypertension.

Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, according to Dr. Rosé.

But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. The triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although "it is a triad over time," which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes.

Rather, "bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion," Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis (JIA) is usually accompanied by positive ANA.

An unexplained fever – one that is "not periodic or hectic, [like those] you see in the autoinflammatory diseases" – should also be considered in the context of possible Blau, according to Dr. Rosé.

Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said.

Thalidomide, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. "We’re a little nervous using thalidomide in children," he said.

Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.

Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.

Dr. Rosé said that he uses "a lot of oral prednisone" to combat uveitis in his Blau patients, and recommends that all Blau patients undergo a slit-lamp examination every 3 months. Although oral steroids are "not a solution," he said, "sometimes they are the only thing you can offer."

Dr. Martin has been studying an unusual family of uveitis patients and looking for clues to solve some of the many genetic mysteries Blau presents.

Asked to consult on a family with severe bilateral uveitis with onset in early adulthood instead of childhood and no arthritis or other symptoms of Blau, Dr. Martin subsequently found that the family has an NOD2 mutation that is slightly different from the mutation seen in most Blau cases.

Another family in the registry has incomplete penetrance; the father of an affected and mutation-positive child carried the same NOD2 mutation but never developed the disease (Arthritis Rheum. 2009:60:1804-6). "There’s some genetic or environmental modifier that’s quenching that NOD2 mutation," she said.

Finding it will entail deeper investigations into the NOD2 mutations, and other mutations that may produce Blau-like pathology. The 100-plus patients in the international registry who have Blau-like symptoms but lack NOD2 mutations may in fact have other, yet-undescribed syndromes that further genetic work may reveal.

"We’re finding so many new mutations," Dr. Martin said, as well as new sorts of disease within the registry. One small group in the registry presented atypical for Blau and had infantile panniculitis, along with fever, uveitis, and systemic granulomatous inflammation (J. Pediatr. 2007;151:707-9).

The finding suggests, Dr. Martin said, that the registry contains unknown diseases that are not truly Blau syndrome but that may be identified through genotyping, which "is starting to get cheap enough that we can do it for a reasonable amount of money."

The genetics, Dr. Martin said, are "helping us find that Blau," – whatever it is, and however it is ultimately defined – "may not be as rare as we thought."

At the same conference, Kevin Foley, Ph.D., a researcher at GlaxoSmithKline, presented new data on Blau biomarkers (Pediatric Rheumatology 2011, 9 [suppl. 1]:O25), which may prove helpful in developing agents targeting the NOD2 signaling pathway.

GlaxoSmithKline is investigating a medication – currently in preclinical testing – that inhibits RIP-2, one of the proteins involved in NOD2 signaling. The company is also funding a prospective cohort study, led by Dr. Rosé, that aims to describe the natural history of Blau from infancy and to isolate additional biomarkers of inflammation driven by hyperactive RIP-2.

John Bertin, Ph.D., head of GlaxoSmithKline’s pattern recognition receptor discovery unit, said in an interview that he hopes the Blau cohort "will provide information that will enable us to determine the feasibility of performing a clinical study in this patient population."

And because hyperactive RIP-2 signaling drives proinflammatory cytokine production in Crohn’s and ulcerative colitis, Dr. Bertin said, a RIP-2 inhibitor could offer promise treating those diseases as well.

Dr. Martin reported having no relevant financial disclosures. Dr. Rosé has an unrestricted grant to study Blau syndrome funded by GlaxoSmithKline and administered by the University of Leuven. Dr. Bertin and Dr. Foley are employees of GlaxoSmithKline.

SAN FRANCISCO – Methotrexate is not a disease-modifying antirheumatic drug in psoriatic arthritis, despite how well it works in psoriasis, according to Dr. Christopher T. Ritchlin.

Methotrexate is the most widely used drug in the world for psoriatic arthritis (PsA), based on almost no supporting evidence. There have been only two published double-blind, randomized, controlled trials of methotrexate in PsA done over the last 20 years, and both were underpowered and used a low dose of methotrexate (10 mg/week), said Dr. Ritchlin, professor of medicine and director of the clinical immunology research center at the University of Rochester (N.Y.).

A still-unpublished study that was presented at the annual meeting of the American College of Rheumatology in 2010 showed that methotrexate was not more effective than placebo in PsA (Arthritis Rheum. 2010:62 [suppl.]:S277, abstract 664). The study involved 221 patients who were given 15 mg/week of methotrexate or placebo for 6 months. About 65% of subjects in each group dropped out. The primary outcome measure was the psoriatic arthritis response criteria (PsARC), which most rheumatologists do not think is a good outcome measure, Dr. Ritchlin said at the Perspectives in Rheumatic Diseases 2011 meeting.

At the end of 3 and 6 months of the study, there were no differences between methotrexate and placebo on the PsARC, the ACR 20 (the American College of Rheumatology scale based on a 20% improvement in certain parameters), the DAS28 (Disease Activity Score based on a 28-joint count), a sensitive joint count, a tender joint count, and the C-reactive protein level/erythrocyte sedimentation rates. Only the patient and physician global scores and the skin score showed significant improvement in the methotrexate group.

Methotrexate is the most widely used drug in the world for psoriatic arthritis (PsA), based on almost no supporting evidence.

Another unpublished study, conducted in the former Soviet Union and presented at the ARC’s annual meeting in 2009, showed the opposite. The researchers compared infliximab vs. methotrexate in methotrexate-naive patients. The dosage used was 15-20 mg/week. They found that 66% of the patients achieved an ACR 20 improvement on methotrexate alone, as did 86% of those on methotrexate plus infliximab. Remissions according to the DAS28 were reported in 30% of those on methotrexate and in 69% of those on combination therapy.

Although it may be possible to find methotrexate-naive patients in the former Soviet Union, such patients are much less likely to walk into their rheumatologist’s office in the West.

Indirect data supporting the inefficacy of methotrexate come from NOR-DMARD. These data show that 6 months of treatment with a tumor necrosis factor inhibitor (146 patients) had significantly greater beneficial effects on patients with PsA than did methotrexate (356 patients) (Ann. Rheum. Dis. 2007;66:1038-42).

The propensity toward liver disease is another reason not to use methotrexate in patients with PsA, said Dr. Ritchlin at the meeting, which was sponsored by Skin Disease Education Foundation. Methotrexate is hepatotoxic. Data on the findings of 169 liver biopsies that were done on 71 patients with psoriasis showed that methotrexate significantly increased the risk for stage 3 or 4 fibrosis. The risk was highest in obese patients or those with diabetes (J. Hepatol. 2007;46:1111-8).

These findings serve to support "my own bias that this is due to their fatty livers," which have developed as a consequence of their obesity, a common comorbidity in PsA, he said. Another cause of fatty liver in this population may be the metabolic syndrome that often develops in patients with psoriasis.

Dr. Ritchlin reported financial relationships with Abbott, Amgen, Centocor, Genentech, Targacept, UCB, and Wyeth. SDEF and this news organization are owned by Elsevier.

SAN FRANCISCO – Methotrexate is not a disease-modifying antirheumatic drug in psoriatic arthritis, despite how well it works in psoriasis, according to Dr. Christopher T. Ritchlin.

Methotrexate is the most widely used drug in the world for psoriatic arthritis (PsA), based on almost no supporting evidence. There have been only two published double-blind, randomized, controlled trials of methotrexate in PsA done over the last 20 years, and both were underpowered and used a low dose of methotrexate (10 mg/week), said Dr. Ritchlin, professor of medicine and director of the clinical immunology research center at the University of Rochester (N.Y.).

A still-unpublished study that was presented at the annual meeting of the American College of Rheumatology in 2010 showed that methotrexate was not more effective than placebo in PsA (Arthritis Rheum. 2010:62 [suppl.]:S277, abstract 664). The study involved 221 patients who were given 15 mg/week of methotrexate or placebo for 6 months. About 65% of subjects in each group dropped out. The primary outcome measure was the psoriatic arthritis response criteria (PsARC), which most rheumatologists do not think is a good outcome measure, Dr. Ritchlin said at the Perspectives in Rheumatic Diseases 2011 meeting.

At the end of 3 and 6 months of the study, there were no differences between methotrexate and placebo on the PsARC, the ACR 20 (the American College of Rheumatology scale based on a 20% improvement in certain parameters), the DAS28 (Disease Activity Score based on a 28-joint count), a sensitive joint count, a tender joint count, and the C-reactive protein level/erythrocyte sedimentation rates. Only the patient and physician global scores and the skin score showed significant improvement in the methotrexate group.

Methotrexate is the most widely used drug in the world for psoriatic arthritis (PsA), based on almost no supporting evidence.

Another unpublished study, conducted in the former Soviet Union and presented at the ARC’s annual meeting in 2009, showed the opposite. The researchers compared infliximab vs. methotrexate in methotrexate-naive patients. The dosage used was 15-20 mg/week. They found that 66% of the patients achieved an ACR 20 improvement on methotrexate alone, as did 86% of those on methotrexate plus infliximab. Remissions according to the DAS28 were reported in 30% of those on methotrexate and in 69% of those on combination therapy.

Although it may be possible to find methotrexate-naive patients in the former Soviet Union, such patients are much less likely to walk into their rheumatologist’s office in the West.

Indirect data supporting the inefficacy of methotrexate come from NOR-DMARD. These data show that 6 months of treatment with a tumor necrosis factor inhibitor (146 patients) had significantly greater beneficial effects on patients with PsA than did methotrexate (356 patients) (Ann. Rheum. Dis. 2007;66:1038-42).

The propensity toward liver disease is another reason not to use methotrexate in patients with PsA, said Dr. Ritchlin at the meeting, which was sponsored by Skin Disease Education Foundation. Methotrexate is hepatotoxic. Data on the findings of 169 liver biopsies that were done on 71 patients with psoriasis showed that methotrexate significantly increased the risk for stage 3 or 4 fibrosis. The risk was highest in obese patients or those with diabetes (J. Hepatol. 2007;46:1111-8).

These findings serve to support "my own bias that this is due to their fatty livers," which have developed as a consequence of their obesity, a common comorbidity in PsA, he said. Another cause of fatty liver in this population may be the metabolic syndrome that often develops in patients with psoriasis.

Dr. Ritchlin reported financial relationships with Abbott, Amgen, Centocor, Genentech, Targacept, UCB, and Wyeth. SDEF and this news organization are owned by Elsevier.

SAN FRANCISCO – Methotrexate is not a disease-modifying antirheumatic drug in psoriatic arthritis, despite how well it works in psoriasis, according to Dr. Christopher T. Ritchlin.

Methotrexate is the most widely used drug in the world for psoriatic arthritis (PsA), based on almost no supporting evidence. There have been only two published double-blind, randomized, controlled trials of methotrexate in PsA done over the last 20 years, and both were underpowered and used a low dose of methotrexate (10 mg/week), said Dr. Ritchlin, professor of medicine and director of the clinical immunology research center at the University of Rochester (N.Y.).

A still-unpublished study that was presented at the annual meeting of the American College of Rheumatology in 2010 showed that methotrexate was not more effective than placebo in PsA (Arthritis Rheum. 2010:62 [suppl.]:S277, abstract 664). The study involved 221 patients who were given 15 mg/week of methotrexate or placebo for 6 months. About 65% of subjects in each group dropped out. The primary outcome measure was the psoriatic arthritis response criteria (PsARC), which most rheumatologists do not think is a good outcome measure, Dr. Ritchlin said at the Perspectives in Rheumatic Diseases 2011 meeting.

At the end of 3 and 6 months of the study, there were no differences between methotrexate and placebo on the PsARC, the ACR 20 (the American College of Rheumatology scale based on a 20% improvement in certain parameters), the DAS28 (Disease Activity Score based on a 28-joint count), a sensitive joint count, a tender joint count, and the C-reactive protein level/erythrocyte sedimentation rates. Only the patient and physician global scores and the skin score showed significant improvement in the methotrexate group.

Methotrexate is the most widely used drug in the world for psoriatic arthritis (PsA), based on almost no supporting evidence.

Another unpublished study, conducted in the former Soviet Union and presented at the ARC’s annual meeting in 2009, showed the opposite. The researchers compared infliximab vs. methotrexate in methotrexate-naive patients. The dosage used was 15-20 mg/week. They found that 66% of the patients achieved an ACR 20 improvement on methotrexate alone, as did 86% of those on methotrexate plus infliximab. Remissions according to the DAS28 were reported in 30% of those on methotrexate and in 69% of those on combination therapy.

Although it may be possible to find methotrexate-naive patients in the former Soviet Union, such patients are much less likely to walk into their rheumatologist’s office in the West.

Indirect data supporting the inefficacy of methotrexate come from NOR-DMARD. These data show that 6 months of treatment with a tumor necrosis factor inhibitor (146 patients) had significantly greater beneficial effects on patients with PsA than did methotrexate (356 patients) (Ann. Rheum. Dis. 2007;66:1038-42).

The propensity toward liver disease is another reason not to use methotrexate in patients with PsA, said Dr. Ritchlin at the meeting, which was sponsored by Skin Disease Education Foundation. Methotrexate is hepatotoxic. Data on the findings of 169 liver biopsies that were done on 71 patients with psoriasis showed that methotrexate significantly increased the risk for stage 3 or 4 fibrosis. The risk was highest in obese patients or those with diabetes (J. Hepatol. 2007;46:1111-8).

These findings serve to support "my own bias that this is due to their fatty livers," which have developed as a consequence of their obesity, a common comorbidity in PsA, he said. Another cause of fatty liver in this population may be the metabolic syndrome that often develops in patients with psoriasis.

Dr. Ritchlin reported financial relationships with Abbott, Amgen, Centocor, Genentech, Targacept, UCB, and Wyeth. SDEF and this news organization are owned by Elsevier.

Greater global cooperation and collaboration among scleroderma researchers and clinicians would be all that is required to fuel a drive toward important discoveries and optimize outcomes for patients with this chronic, progressive, and often debilitating autoimmune disease. And the organizations are in place to support such collaboration.

"Scleroderma is a multisystem disease, and we as a community, working together, can learn to understand it, treat it, and perhaps cure it," Dr. Daniel Furst said.

Currently, multiple research groups in multiple countries around the world strive in a largely independent way to combat scleroderma through experimental, translational, and clinical studies. These separate silos of researchers – and patients – could benefit from increased interaction and cooperation, Dr. Furst said in an interview.

"If the international community agrees to work together, we can move things forward much more quickly," said Dr. Furst, Carl M. Pearson chair of rheumatology and director of interventional therapeutics at University of California, Los Angeles Medical Center for Health Sciences.

"The scientific complexity and the clinical heterogeneity of scleroderma benefit from multiple collaborators each contributing a piece to the puzzle."

"The timing is right for this," said Dr. Furst, now that there is an organization, the World Scleroderma Foundation (WSF), to facilitate increased collaboration worldwide. He cofounded the foundation in 2009 and currently serves as treasurer.

"The main message is that we need to work together and share our experiences in order to better understand the disease, thus ameliorating our capacity to fight its evolution," said Dr. Marco Matucci-Cerinic, WSF chairman and professor of rheumatology at the University of Florence in Italy.

"Recently, we have worked all together to lift the cultural barrier differentiating the clinical behavior of the American and European physicians," Dr. Matucci-Cerinic said. "The challenge for the future is, therefore, to foster worldwide the awareness of the disease and teach the rheumatologist to have all the same approach to the disease in order to make an early diagnosis, obtain remission and [block] disease progression."

Increased collaboration also is a matter of economics, Dr. Furst said. "There isn’t enough money in any given place to do all the research that is needed."

The Switzerland-based WSF also aims to increase translational research worldwide or find ways to take scientific findings in scleroderma from the bench to the bedside. For this reason, the U.S.-based Scleroderma Research Foundation, with its focus on experimental rather than clinical research, could be an important ally in increasing the amount of translational research studies.

Promotion of greater patient awareness about scleroderma is a second major aim for the WSF. Greater education could foster earlier scleroderma diagnoses and greater participation in care, Dr. Furst said. Ten years ago, it took 1-2 years from the onset of symptoms until patients with scleroderma received the correct diagnosis. "Even today, in the United States, it’s still 6 to 9 months on average for time to diagnosis. So awareness is a major issue."

In terms of physician education, every American College of Rheumatology annual meeting includes a skin scoring session. The intention is for rheumatologists to learn how to recognize and score the skin changes in scleroderma. Dr. Furst said, "We are trying to teach rheumatologists how to recognize and score scleroderma, and we are trying to teach patients how to educate their rheumatologists."

"Not only rheumatologists, but internists as well, through listening to their patients and through accessing things like the WSF or the Scleroderma Foundation in the U.S., can make it easier for patients to understand their disease," Dr. Furst said.

Leading the charge in Europe is the EULAR Scleroderma Trials and Research (EUSTAR) group. This group "has significantly helped to raise the awareness of the disease among physicians and politicians and has pushed ahead the clinical and basic research on the disease," Dr. Matucci-Cerinic said.

"The main message is that we need to work together and share our experiences in order to better understand [scleroderma]."

Scleroderma affects people worldwide, even in regions without a strong research base. There are approximately 100,000 persons with scleroderma in the European Union and the United States, but as many as 2.5 million worldwide, said Dr. James R. Seibold, founder and principal member of Scleroderma Research Consultants in Avon, Conn. "The scientific complexity and the clinical heterogeneity of scleroderma benefit from multiple collaborators each contributing a piece to the puzzle."

There are smaller groups, including PANLAR in South America. There is also a scleroderma group in Australia, and there are national groups in Asia, "but they are not really well organized," Dr. Furst said.

"Large populations where scleroderma is both prevalent and high impact lack the infrastructure and financial resources," Dr. Seibold said. "I would include South Asia, China, and much of South America as currently underserved areas."

Even though findings will come from multiple research groups around the globe, Dr. Furst does not expect any significant hurdles in terms of protected data. "It just so happens that the scleroderma community is very collaborative. While there always will be some proprietary issues, partially because of governmental regulations, the overwhelming urge among scleroderma community researchers is to work together rather than to work apart."

The WSF is holding its second annual World Scleroderma Congress in Florence in February 2012. Dr. Furst said, "We already have over 500 registrants four or five months ahead. It really is very encouraging."

Dr. Furst disclosed that his scleroderma research is supported by the National Institutes of Health, Gilead, and Actelion. Dr. Matucci-Cerinic said the he had no relevant disclosures. Dr. Seibold said he has consultancy relationships with a number of companies considering drug development projects in scleroderma, including Actelion, Bristol Myers Squibb, Celgene, Genentech, Gilead, MedImmune, NexMed, Pfizer, Sanofi-Aventis, Sigma Tau, and United Therapeutics.

Greater global cooperation and collaboration among scleroderma researchers and clinicians would be all that is required to fuel a drive toward important discoveries and optimize outcomes for patients with this chronic, progressive, and often debilitating autoimmune disease. And the organizations are in place to support such collaboration.

"Scleroderma is a multisystem disease, and we as a community, working together, can learn to understand it, treat it, and perhaps cure it," Dr. Daniel Furst said.

Currently, multiple research groups in multiple countries around the world strive in a largely independent way to combat scleroderma through experimental, translational, and clinical studies. These separate silos of researchers – and patients – could benefit from increased interaction and cooperation, Dr. Furst said in an interview.

"If the international community agrees to work together, we can move things forward much more quickly," said Dr. Furst, Carl M. Pearson chair of rheumatology and director of interventional therapeutics at University of California, Los Angeles Medical Center for Health Sciences.

"The scientific complexity and the clinical heterogeneity of scleroderma benefit from multiple collaborators each contributing a piece to the puzzle."

"The timing is right for this," said Dr. Furst, now that there is an organization, the World Scleroderma Foundation (WSF), to facilitate increased collaboration worldwide. He cofounded the foundation in 2009 and currently serves as treasurer.

"The main message is that we need to work together and share our experiences in order to better understand the disease, thus ameliorating our capacity to fight its evolution," said Dr. Marco Matucci-Cerinic, WSF chairman and professor of rheumatology at the University of Florence in Italy.

"Recently, we have worked all together to lift the cultural barrier differentiating the clinical behavior of the American and European physicians," Dr. Matucci-Cerinic said. "The challenge for the future is, therefore, to foster worldwide the awareness of the disease and teach the rheumatologist to have all the same approach to the disease in order to make an early diagnosis, obtain remission and [block] disease progression."

Increased collaboration also is a matter of economics, Dr. Furst said. "There isn’t enough money in any given place to do all the research that is needed."

The Switzerland-based WSF also aims to increase translational research worldwide or find ways to take scientific findings in scleroderma from the bench to the bedside. For this reason, the U.S.-based Scleroderma Research Foundation, with its focus on experimental rather than clinical research, could be an important ally in increasing the amount of translational research studies.

Promotion of greater patient awareness about scleroderma is a second major aim for the WSF. Greater education could foster earlier scleroderma diagnoses and greater participation in care, Dr. Furst said. Ten years ago, it took 1-2 years from the onset of symptoms until patients with scleroderma received the correct diagnosis. "Even today, in the United States, it’s still 6 to 9 months on average for time to diagnosis. So awareness is a major issue."

In terms of physician education, every American College of Rheumatology annual meeting includes a skin scoring session. The intention is for rheumatologists to learn how to recognize and score the skin changes in scleroderma. Dr. Furst said, "We are trying to teach rheumatologists how to recognize and score scleroderma, and we are trying to teach patients how to educate their rheumatologists."

"Not only rheumatologists, but internists as well, through listening to their patients and through accessing things like the WSF or the Scleroderma Foundation in the U.S., can make it easier for patients to understand their disease," Dr. Furst said.

Leading the charge in Europe is the EULAR Scleroderma Trials and Research (EUSTAR) group. This group "has significantly helped to raise the awareness of the disease among physicians and politicians and has pushed ahead the clinical and basic research on the disease," Dr. Matucci-Cerinic said.

"The main message is that we need to work together and share our experiences in order to better understand [scleroderma]."

Scleroderma affects people worldwide, even in regions without a strong research base. There are approximately 100,000 persons with scleroderma in the European Union and the United States, but as many as 2.5 million worldwide, said Dr. James R. Seibold, founder and principal member of Scleroderma Research Consultants in Avon, Conn. "The scientific complexity and the clinical heterogeneity of scleroderma benefit from multiple collaborators each contributing a piece to the puzzle."

There are smaller groups, including PANLAR in South America. There is also a scleroderma group in Australia, and there are national groups in Asia, "but they are not really well organized," Dr. Furst said.

"Large populations where scleroderma is both prevalent and high impact lack the infrastructure and financial resources," Dr. Seibold said. "I would include South Asia, China, and much of South America as currently underserved areas."

Even though findings will come from multiple research groups around the globe, Dr. Furst does not expect any significant hurdles in terms of protected data. "It just so happens that the scleroderma community is very collaborative. While there always will be some proprietary issues, partially because of governmental regulations, the overwhelming urge among scleroderma community researchers is to work together rather than to work apart."

The WSF is holding its second annual World Scleroderma Congress in Florence in February 2012. Dr. Furst said, "We already have over 500 registrants four or five months ahead. It really is very encouraging."

Dr. Furst disclosed that his scleroderma research is supported by the National Institutes of Health, Gilead, and Actelion. Dr. Matucci-Cerinic said the he had no relevant disclosures. Dr. Seibold said he has consultancy relationships with a number of companies considering drug development projects in scleroderma, including Actelion, Bristol Myers Squibb, Celgene, Genentech, Gilead, MedImmune, NexMed, Pfizer, Sanofi-Aventis, Sigma Tau, and United Therapeutics.

Greater global cooperation and collaboration among scleroderma researchers and clinicians would be all that is required to fuel a drive toward important discoveries and optimize outcomes for patients with this chronic, progressive, and often debilitating autoimmune disease. And the organizations are in place to support such collaboration.

"Scleroderma is a multisystem disease, and we as a community, working together, can learn to understand it, treat it, and perhaps cure it," Dr. Daniel Furst said.

Currently, multiple research groups in multiple countries around the world strive in a largely independent way to combat scleroderma through experimental, translational, and clinical studies. These separate silos of researchers – and patients – could benefit from increased interaction and cooperation, Dr. Furst said in an interview.

"If the international community agrees to work together, we can move things forward much more quickly," said Dr. Furst, Carl M. Pearson chair of rheumatology and director of interventional therapeutics at University of California, Los Angeles Medical Center for Health Sciences.

"The scientific complexity and the clinical heterogeneity of scleroderma benefit from multiple collaborators each contributing a piece to the puzzle."

"The timing is right for this," said Dr. Furst, now that there is an organization, the World Scleroderma Foundation (WSF), to facilitate increased collaboration worldwide. He cofounded the foundation in 2009 and currently serves as treasurer.

"The main message is that we need to work together and share our experiences in order to better understand the disease, thus ameliorating our capacity to fight its evolution," said Dr. Marco Matucci-Cerinic, WSF chairman and professor of rheumatology at the University of Florence in Italy.

"Recently, we have worked all together to lift the cultural barrier differentiating the clinical behavior of the American and European physicians," Dr. Matucci-Cerinic said. "The challenge for the future is, therefore, to foster worldwide the awareness of the disease and teach the rheumatologist to have all the same approach to the disease in order to make an early diagnosis, obtain remission and [block] disease progression."

Increased collaboration also is a matter of economics, Dr. Furst said. "There isn’t enough money in any given place to do all the research that is needed."

The Switzerland-based WSF also aims to increase translational research worldwide or find ways to take scientific findings in scleroderma from the bench to the bedside. For this reason, the U.S.-based Scleroderma Research Foundation, with its focus on experimental rather than clinical research, could be an important ally in increasing the amount of translational research studies.

Promotion of greater patient awareness about scleroderma is a second major aim for the WSF. Greater education could foster earlier scleroderma diagnoses and greater participation in care, Dr. Furst said. Ten years ago, it took 1-2 years from the onset of symptoms until patients with scleroderma received the correct diagnosis. "Even today, in the United States, it’s still 6 to 9 months on average for time to diagnosis. So awareness is a major issue."

In terms of physician education, every American College of Rheumatology annual meeting includes a skin scoring session. The intention is for rheumatologists to learn how to recognize and score the skin changes in scleroderma. Dr. Furst said, "We are trying to teach rheumatologists how to recognize and score scleroderma, and we are trying to teach patients how to educate their rheumatologists."

"Not only rheumatologists, but internists as well, through listening to their patients and through accessing things like the WSF or the Scleroderma Foundation in the U.S., can make it easier for patients to understand their disease," Dr. Furst said.

Leading the charge in Europe is the EULAR Scleroderma Trials and Research (EUSTAR) group. This group "has significantly helped to raise the awareness of the disease among physicians and politicians and has pushed ahead the clinical and basic research on the disease," Dr. Matucci-Cerinic said.

"The main message is that we need to work together and share our experiences in order to better understand [scleroderma]."

Scleroderma affects people worldwide, even in regions without a strong research base. There are approximately 100,000 persons with scleroderma in the European Union and the United States, but as many as 2.5 million worldwide, said Dr. James R. Seibold, founder and principal member of Scleroderma Research Consultants in Avon, Conn. "The scientific complexity and the clinical heterogeneity of scleroderma benefit from multiple collaborators each contributing a piece to the puzzle."

There are smaller groups, including PANLAR in South America. There is also a scleroderma group in Australia, and there are national groups in Asia, "but they are not really well organized," Dr. Furst said.

"Large populations where scleroderma is both prevalent and high impact lack the infrastructure and financial resources," Dr. Seibold said. "I would include South Asia, China, and much of South America as currently underserved areas."

Even though findings will come from multiple research groups around the globe, Dr. Furst does not expect any significant hurdles in terms of protected data. "It just so happens that the scleroderma community is very collaborative. While there always will be some proprietary issues, partially because of governmental regulations, the overwhelming urge among scleroderma community researchers is to work together rather than to work apart."

The WSF is holding its second annual World Scleroderma Congress in Florence in February 2012. Dr. Furst said, "We already have over 500 registrants four or five months ahead. It really is very encouraging."

Dr. Furst disclosed that his scleroderma research is supported by the National Institutes of Health, Gilead, and Actelion. Dr. Matucci-Cerinic said the he had no relevant disclosures. Dr. Seibold said he has consultancy relationships with a number of companies considering drug development projects in scleroderma, including Actelion, Bristol Myers Squibb, Celgene, Genentech, Gilead, MedImmune, NexMed, Pfizer, Sanofi-Aventis, Sigma Tau, and United Therapeutics.