Psoriasis

BERLIN – Medical therapy might prove to be the preferred approach for treating patients with early-stage Dupuytren’s contracture, suggest the findings of a small retrospective study.

Injection of collagenase Clostridium histolyticum in patients with early-stage Dupuytren’s contracture resulted in significantly better clinical outcomes than those that were seen in patients with advanced disease. Collagenase C. histolyticum (Xiaflex) injections are generally given only after patients with Dupuytren’s contracture develop fixed-flexion contracture angles of 30 degrees or more.

The retrospective study suggests a new treatment paradigm: The early injection of palpable cords with lesser fixed-flexion contracture angles results in near normal correction, bringing improvement that’s significantly greater than that achieved with delayed therapy, according to Dr. Clayton A. Peimer, an orthopedic surgeon at Michigan State University, East Lansing.

This is off-label therapy. At present, Xiaflex is approved in the United States and Europe under more restrictive conditions (injection of only a single palpable cord at a time, with a 4-week hiatus before either a repeat injection or an injection of another affected cord).

The finding warrants confirmation in prospective longitudinal studies aimed at determining whether collagenase injections into early-stage joints slows progression of Dupuytren’s contracture and improves upon the high contracture recurrence rate that follows surgical release, he added.

In a separate Australian study presented at the annual European Congress of Rheumatology, Dr. David Gilpin of the Brisbane (Queensland) Hand and Upper Limb Clinic reported that concurrent injections of collagenase C. histolyticum into two affected palpable cords in the same hand proved safe, effective, and well tolerated.

The advantages of being able to safely treat multiple contractures at the same time include shortened recovery times, fewer office visits for patients, and more efficient use of physicians’ time, noted Dr. Gilpin.

His study included 12 patients with three or more fixed-flexion contractures of 20% or greater in the proximal interphalangeal (PIP) and/or metacarpophalangeal (MP) joints on the same hand. The participants initially received a single collagenase injection in one palpable cord, followed roughly 24 hours later by the standard finger extension procedure that breaks the now-weakened cord. After 30 days, the patients received two injections into two different palpable cords on the same hand, followed by finger extension procedures the next day.

The first injection resulted in a mean 81% reduction in the degree of fixed-flexion contracture in treated MP joints, and a 66% decrease in PIP joints. The subsequent two concurrent injections of other affected cords showed near identical effectiveness (mean reduction in fixed-flexion contractures, 80% in MP and 63% in PIP joints).

Blood samples that were obtained 24 hours after the dual injections showed no detectable systemic levels of the biologic agent.

Not surprisingly, several treatment-related adverse events were more common when patients received two injections rather than one. These included injection site pain or discomfort, skin discoloration, itching, and blood blisters.

Dr. Peimer reviewed the charts of 302 patients with Dupuytren’s contracture who were treated with collagenase injections at 10 U.S. community and academic practices. Of affected joints, 20% were treated at an early stage (defined as a fixed-flexion contracture angle of 30 degrees or less). Their mean initial fixed-flexion contracture angle was 25 degrees, improving to 3.8 degrees after treatment. In contrast, the mean baseline fixed-flexion contracture angle in patients with advanced disease was 58 degrees, with an improvement to 14 degrees following collagenase treatment. No serious treatment-related adverse events occurred.

Dupuytren’s contracture is the result of a usually painless progressive thickening and shortening of the palmar fascia. This leads to curling of the fingers and impaired hand function. The most common surgical treatment, limited fasciectomy, can result in complications including digital nerve injury, hematoma, and complex regional pain syndrome. Xiaflex was approved in the United States in 2010 as the first nonsurgical treatment for Dupuytren’s contracture. European approval followed the next year.

The studies were sponsored by Auxillium Pharmaceuticals, which markets Xiaflex. Dr. Peimer and Dr. Gilpin were paid by the company for their research, and Dr. Gilpin owns stock in Auxillium.

BERLIN – Medical therapy might prove to be the preferred approach for treating patients with early-stage Dupuytren’s contracture, suggest the findings of a small retrospective study.

Injection of collagenase Clostridium histolyticum in patients with early-stage Dupuytren’s contracture resulted in significantly better clinical outcomes than those that were seen in patients with advanced disease. Collagenase C. histolyticum (Xiaflex) injections are generally given only after patients with Dupuytren’s contracture develop fixed-flexion contracture angles of 30 degrees or more.

The retrospective study suggests a new treatment paradigm: The early injection of palpable cords with lesser fixed-flexion contracture angles results in near normal correction, bringing improvement that’s significantly greater than that achieved with delayed therapy, according to Dr. Clayton A. Peimer, an orthopedic surgeon at Michigan State University, East Lansing.

This is off-label therapy. At present, Xiaflex is approved in the United States and Europe under more restrictive conditions (injection of only a single palpable cord at a time, with a 4-week hiatus before either a repeat injection or an injection of another affected cord).

The finding warrants confirmation in prospective longitudinal studies aimed at determining whether collagenase injections into early-stage joints slows progression of Dupuytren’s contracture and improves upon the high contracture recurrence rate that follows surgical release, he added.

In a separate Australian study presented at the annual European Congress of Rheumatology, Dr. David Gilpin of the Brisbane (Queensland) Hand and Upper Limb Clinic reported that concurrent injections of collagenase C. histolyticum into two affected palpable cords in the same hand proved safe, effective, and well tolerated.

The advantages of being able to safely treat multiple contractures at the same time include shortened recovery times, fewer office visits for patients, and more efficient use of physicians’ time, noted Dr. Gilpin.

His study included 12 patients with three or more fixed-flexion contractures of 20% or greater in the proximal interphalangeal (PIP) and/or metacarpophalangeal (MP) joints on the same hand. The participants initially received a single collagenase injection in one palpable cord, followed roughly 24 hours later by the standard finger extension procedure that breaks the now-weakened cord. After 30 days, the patients received two injections into two different palpable cords on the same hand, followed by finger extension procedures the next day.

The first injection resulted in a mean 81% reduction in the degree of fixed-flexion contracture in treated MP joints, and a 66% decrease in PIP joints. The subsequent two concurrent injections of other affected cords showed near identical effectiveness (mean reduction in fixed-flexion contractures, 80% in MP and 63% in PIP joints).

Blood samples that were obtained 24 hours after the dual injections showed no detectable systemic levels of the biologic agent.

Not surprisingly, several treatment-related adverse events were more common when patients received two injections rather than one. These included injection site pain or discomfort, skin discoloration, itching, and blood blisters.

Dr. Peimer reviewed the charts of 302 patients with Dupuytren’s contracture who were treated with collagenase injections at 10 U.S. community and academic practices. Of affected joints, 20% were treated at an early stage (defined as a fixed-flexion contracture angle of 30 degrees or less). Their mean initial fixed-flexion contracture angle was 25 degrees, improving to 3.8 degrees after treatment. In contrast, the mean baseline fixed-flexion contracture angle in patients with advanced disease was 58 degrees, with an improvement to 14 degrees following collagenase treatment. No serious treatment-related adverse events occurred.

Dupuytren’s contracture is the result of a usually painless progressive thickening and shortening of the palmar fascia. This leads to curling of the fingers and impaired hand function. The most common surgical treatment, limited fasciectomy, can result in complications including digital nerve injury, hematoma, and complex regional pain syndrome. Xiaflex was approved in the United States in 2010 as the first nonsurgical treatment for Dupuytren’s contracture. European approval followed the next year.

The studies were sponsored by Auxillium Pharmaceuticals, which markets Xiaflex. Dr. Peimer and Dr. Gilpin were paid by the company for their research, and Dr. Gilpin owns stock in Auxillium.

BERLIN – Medical therapy might prove to be the preferred approach for treating patients with early-stage Dupuytren’s contracture, suggest the findings of a small retrospective study.

Injection of collagenase Clostridium histolyticum in patients with early-stage Dupuytren’s contracture resulted in significantly better clinical outcomes than those that were seen in patients with advanced disease. Collagenase C. histolyticum (Xiaflex) injections are generally given only after patients with Dupuytren’s contracture develop fixed-flexion contracture angles of 30 degrees or more.

The retrospective study suggests a new treatment paradigm: The early injection of palpable cords with lesser fixed-flexion contracture angles results in near normal correction, bringing improvement that’s significantly greater than that achieved with delayed therapy, according to Dr. Clayton A. Peimer, an orthopedic surgeon at Michigan State University, East Lansing.

This is off-label therapy. At present, Xiaflex is approved in the United States and Europe under more restrictive conditions (injection of only a single palpable cord at a time, with a 4-week hiatus before either a repeat injection or an injection of another affected cord).

The finding warrants confirmation in prospective longitudinal studies aimed at determining whether collagenase injections into early-stage joints slows progression of Dupuytren’s contracture and improves upon the high contracture recurrence rate that follows surgical release, he added.

In a separate Australian study presented at the annual European Congress of Rheumatology, Dr. David Gilpin of the Brisbane (Queensland) Hand and Upper Limb Clinic reported that concurrent injections of collagenase C. histolyticum into two affected palpable cords in the same hand proved safe, effective, and well tolerated.

The advantages of being able to safely treat multiple contractures at the same time include shortened recovery times, fewer office visits for patients, and more efficient use of physicians’ time, noted Dr. Gilpin.

His study included 12 patients with three or more fixed-flexion contractures of 20% or greater in the proximal interphalangeal (PIP) and/or metacarpophalangeal (MP) joints on the same hand. The participants initially received a single collagenase injection in one palpable cord, followed roughly 24 hours later by the standard finger extension procedure that breaks the now-weakened cord. After 30 days, the patients received two injections into two different palpable cords on the same hand, followed by finger extension procedures the next day.

The first injection resulted in a mean 81% reduction in the degree of fixed-flexion contracture in treated MP joints, and a 66% decrease in PIP joints. The subsequent two concurrent injections of other affected cords showed near identical effectiveness (mean reduction in fixed-flexion contractures, 80% in MP and 63% in PIP joints).

Blood samples that were obtained 24 hours after the dual injections showed no detectable systemic levels of the biologic agent.

Not surprisingly, several treatment-related adverse events were more common when patients received two injections rather than one. These included injection site pain or discomfort, skin discoloration, itching, and blood blisters.

Dr. Peimer reviewed the charts of 302 patients with Dupuytren’s contracture who were treated with collagenase injections at 10 U.S. community and academic practices. Of affected joints, 20% were treated at an early stage (defined as a fixed-flexion contracture angle of 30 degrees or less). Their mean initial fixed-flexion contracture angle was 25 degrees, improving to 3.8 degrees after treatment. In contrast, the mean baseline fixed-flexion contracture angle in patients with advanced disease was 58 degrees, with an improvement to 14 degrees following collagenase treatment. No serious treatment-related adverse events occurred.

Dupuytren’s contracture is the result of a usually painless progressive thickening and shortening of the palmar fascia. This leads to curling of the fingers and impaired hand function. The most common surgical treatment, limited fasciectomy, can result in complications including digital nerve injury, hematoma, and complex regional pain syndrome. Xiaflex was approved in the United States in 2010 as the first nonsurgical treatment for Dupuytren’s contracture. European approval followed the next year.

The studies were sponsored by Auxillium Pharmaceuticals, which markets Xiaflex. Dr. Peimer and Dr. Gilpin were paid by the company for their research, and Dr. Gilpin owns stock in Auxillium.

VICTORIA, B.C. – Subclinical enthesitis occurs more commonly in patients with psoriatic arthritis than in those with psoriasis, possibly as a result of age and obesity rather than disease severity, to judge from the findings of a cross-sectional study conducted by investigators at Toronto Western Hospital.

The investigators used ultrasound as well as clinical examination to assess the extent, if any, of enthesitis in study participants, who were 59 patients with psoriatic arthritis and 79 patients with psoriasis. Study participants were recruited from longitudinal cohorts. The control group was made up of 60 healthy volunteers who did not have any personal or family history of spondyloarthropathy. They were evaluated for enthesitis at sites in the calcaneus, knee, and olecranon.

Findings on ultrasound – any enthesophytes, bony erosions, tendon thickness, and bursitis, within tendons – were scored using GUESS (Glasgow Ultrasound Enthesitis Scoring System), which reflects the overall burden bilaterally of enthesitis from abnormalities in five lower limb sites, and the MASEI (Madrid Sonography Enthesitis Index), which additionally includes calcifications and Doppler signals as elemental lesions as well as abnormalities of the olecranon tuberosity enthesis.

The average ages were 52, 53, and 42 years in the psoriasis, psoriatic arthritis, and healthy volunteer groups, respectively, and men accounted for 64%, 57%, and 32% of participants. Corresponding mean body mass indices were 27, 30, and 26 kg/m², respectively.

In all, 12 anatomical sites were assessed. The mean number showing ultrasonographic enthesitis differed significantly across groups, reported study coauthor Jai P. Jayakar at the annual meeting of the Canadian Rheumatology Association. The number of anatomical sites that showed enthesitis was highest in the psoriatic arthritis group (7.1), intermediate in the psoriasis group (5), and lowest in healthy volunteers (4).

There was also a significant, graded difference across groups in GUESS scores (8.9, 5.6, and 4.4 out of a possible 36, respectively, for psoriatic arthritis, psoriasis, and healthy controls) and in MASEI scores (18.5, 9.9, and 7.7 respectively for psoriatic arthritis, psoriasis, and healthy controls out of a possible 136). However, in multivariate analyses, disease status was not associated with these scores; only increasing age and BMI showed significant associations.

"Our study is one of the first comparative assessments of subclinical enthesitis in psoriasis vs. psoriatic arthritis," noted Mr. Jayakar. "Our results reveal that the prevalence of ultrasonographic entheseal abnormalities and indices of entheseal burden ... are greater in psoriatic arthritis than in psoriasis; however, this relationship may be modulated in a multifactorial manner by factors other than disease status, such as age and body mass index.

"Now, it is possible that enthesitis could be of predictive value in specific patient subgroups – for example, age- or obesity-stratified subgroups," he added. "However, larger studies are needed to confirm the utility of subclinical enthesitis as a predictive factor for the development of psoriatic arthritis in patients with psoriasis."

How could the investigators be certain, a session attendee asked, that they were detecting disease-related enthesitis and not simply mechanical tendonitis?

That is a valid concern, given the lack of consensus among rheumatologists as to which ultrasonographic abnormalities result from degeneration, inflammation, mechanical stress, or other etiologies, acknowledged Mr. Jayakar, a medical student at the University of Western Ontario, London. Large cohorts with well-defined disease status would be required to investigate this further, he said.

"One direction in which we could move forward is if we can find specific elemental lesions – or aggregates of elemental lesions – that are of predictive value, then perhaps those could be used pragmatically to help us in our clinical management," he noted. "But as of now, the pathophysiological underpinnings of these abnormalities are not very well described."

Mr. Jayakar disclosed no relevant conflicts of interest.

VICTORIA, B.C. – Subclinical enthesitis occurs more commonly in patients with psoriatic arthritis than in those with psoriasis, possibly as a result of age and obesity rather than disease severity, to judge from the findings of a cross-sectional study conducted by investigators at Toronto Western Hospital.

The investigators used ultrasound as well as clinical examination to assess the extent, if any, of enthesitis in study participants, who were 59 patients with psoriatic arthritis and 79 patients with psoriasis. Study participants were recruited from longitudinal cohorts. The control group was made up of 60 healthy volunteers who did not have any personal or family history of spondyloarthropathy. They were evaluated for enthesitis at sites in the calcaneus, knee, and olecranon.

Findings on ultrasound – any enthesophytes, bony erosions, tendon thickness, and bursitis, within tendons – were scored using GUESS (Glasgow Ultrasound Enthesitis Scoring System), which reflects the overall burden bilaterally of enthesitis from abnormalities in five lower limb sites, and the MASEI (Madrid Sonography Enthesitis Index), which additionally includes calcifications and Doppler signals as elemental lesions as well as abnormalities of the olecranon tuberosity enthesis.

The average ages were 52, 53, and 42 years in the psoriasis, psoriatic arthritis, and healthy volunteer groups, respectively, and men accounted for 64%, 57%, and 32% of participants. Corresponding mean body mass indices were 27, 30, and 26 kg/m², respectively.

In all, 12 anatomical sites were assessed. The mean number showing ultrasonographic enthesitis differed significantly across groups, reported study coauthor Jai P. Jayakar at the annual meeting of the Canadian Rheumatology Association. The number of anatomical sites that showed enthesitis was highest in the psoriatic arthritis group (7.1), intermediate in the psoriasis group (5), and lowest in healthy volunteers (4).

There was also a significant, graded difference across groups in GUESS scores (8.9, 5.6, and 4.4 out of a possible 36, respectively, for psoriatic arthritis, psoriasis, and healthy controls) and in MASEI scores (18.5, 9.9, and 7.7 respectively for psoriatic arthritis, psoriasis, and healthy controls out of a possible 136). However, in multivariate analyses, disease status was not associated with these scores; only increasing age and BMI showed significant associations.

"Our study is one of the first comparative assessments of subclinical enthesitis in psoriasis vs. psoriatic arthritis," noted Mr. Jayakar. "Our results reveal that the prevalence of ultrasonographic entheseal abnormalities and indices of entheseal burden ... are greater in psoriatic arthritis than in psoriasis; however, this relationship may be modulated in a multifactorial manner by factors other than disease status, such as age and body mass index.

"Now, it is possible that enthesitis could be of predictive value in specific patient subgroups – for example, age- or obesity-stratified subgroups," he added. "However, larger studies are needed to confirm the utility of subclinical enthesitis as a predictive factor for the development of psoriatic arthritis in patients with psoriasis."

How could the investigators be certain, a session attendee asked, that they were detecting disease-related enthesitis and not simply mechanical tendonitis?

That is a valid concern, given the lack of consensus among rheumatologists as to which ultrasonographic abnormalities result from degeneration, inflammation, mechanical stress, or other etiologies, acknowledged Mr. Jayakar, a medical student at the University of Western Ontario, London. Large cohorts with well-defined disease status would be required to investigate this further, he said.

"One direction in which we could move forward is if we can find specific elemental lesions – or aggregates of elemental lesions – that are of predictive value, then perhaps those could be used pragmatically to help us in our clinical management," he noted. "But as of now, the pathophysiological underpinnings of these abnormalities are not very well described."

Mr. Jayakar disclosed no relevant conflicts of interest.

VICTORIA, B.C. – Subclinical enthesitis occurs more commonly in patients with psoriatic arthritis than in those with psoriasis, possibly as a result of age and obesity rather than disease severity, to judge from the findings of a cross-sectional study conducted by investigators at Toronto Western Hospital.

The investigators used ultrasound as well as clinical examination to assess the extent, if any, of enthesitis in study participants, who were 59 patients with psoriatic arthritis and 79 patients with psoriasis. Study participants were recruited from longitudinal cohorts. The control group was made up of 60 healthy volunteers who did not have any personal or family history of spondyloarthropathy. They were evaluated for enthesitis at sites in the calcaneus, knee, and olecranon.

Findings on ultrasound – any enthesophytes, bony erosions, tendon thickness, and bursitis, within tendons – were scored using GUESS (Glasgow Ultrasound Enthesitis Scoring System), which reflects the overall burden bilaterally of enthesitis from abnormalities in five lower limb sites, and the MASEI (Madrid Sonography Enthesitis Index), which additionally includes calcifications and Doppler signals as elemental lesions as well as abnormalities of the olecranon tuberosity enthesis.

The average ages were 52, 53, and 42 years in the psoriasis, psoriatic arthritis, and healthy volunteer groups, respectively, and men accounted for 64%, 57%, and 32% of participants. Corresponding mean body mass indices were 27, 30, and 26 kg/m², respectively.

In all, 12 anatomical sites were assessed. The mean number showing ultrasonographic enthesitis differed significantly across groups, reported study coauthor Jai P. Jayakar at the annual meeting of the Canadian Rheumatology Association. The number of anatomical sites that showed enthesitis was highest in the psoriatic arthritis group (7.1), intermediate in the psoriasis group (5), and lowest in healthy volunteers (4).

There was also a significant, graded difference across groups in GUESS scores (8.9, 5.6, and 4.4 out of a possible 36, respectively, for psoriatic arthritis, psoriasis, and healthy controls) and in MASEI scores (18.5, 9.9, and 7.7 respectively for psoriatic arthritis, psoriasis, and healthy controls out of a possible 136). However, in multivariate analyses, disease status was not associated with these scores; only increasing age and BMI showed significant associations.

"Our study is one of the first comparative assessments of subclinical enthesitis in psoriasis vs. psoriatic arthritis," noted Mr. Jayakar. "Our results reveal that the prevalence of ultrasonographic entheseal abnormalities and indices of entheseal burden ... are greater in psoriatic arthritis than in psoriasis; however, this relationship may be modulated in a multifactorial manner by factors other than disease status, such as age and body mass index.

"Now, it is possible that enthesitis could be of predictive value in specific patient subgroups – for example, age- or obesity-stratified subgroups," he added. "However, larger studies are needed to confirm the utility of subclinical enthesitis as a predictive factor for the development of psoriatic arthritis in patients with psoriasis."

How could the investigators be certain, a session attendee asked, that they were detecting disease-related enthesitis and not simply mechanical tendonitis?

That is a valid concern, given the lack of consensus among rheumatologists as to which ultrasonographic abnormalities result from degeneration, inflammation, mechanical stress, or other etiologies, acknowledged Mr. Jayakar, a medical student at the University of Western Ontario, London. Large cohorts with well-defined disease status would be required to investigate this further, he said.

"One direction in which we could move forward is if we can find specific elemental lesions – or aggregates of elemental lesions – that are of predictive value, then perhaps those could be used pragmatically to help us in our clinical management," he noted. "But as of now, the pathophysiological underpinnings of these abnormalities are not very well described."

Mr. Jayakar disclosed no relevant conflicts of interest.

Genes play a key role in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis, and genetic distinctions exist between two of the condition’s main clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis, judging from data from a genomewide association study.

The findings also support the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. If true, those findings could have both immunopathogenic and therapeutic implications, according to Paul A. Lyons, Ph.D., of the Cambridge (England) Institute for Medical Research, and his colleagues in their online report in the July 19 issue of the New England Journal of Medicine.

"There is debate as to whether the clinical syndromes of granulomatosis with polyangiitis and microscopic polyangiitis represent distinct diseases or are part of a single disease spectrum," the investigators wrote. The concept of a single disease spectrum has resulted in similar treatment strategies being used in trials regardless of which of these two clinical syndromes are present, and also in the suggestion that genetic studies should consider the two syndromes together, they explained.

"Clear evidence that these clinical syndromes are etiologically distinct might provide a rationale for devising syndrome-specific therapeutic strategies," the investigators noted (N. Engl. J. Med. 2012 July 19 [doi: 10.1056/NEJMoa1108735]).

To identify genetic risk factors and evaluate whether a common or distinct genetic background exists for granulomatosis with polyangiitis and microscopic polyangiitis, they performed genotyping in a discovery cohort of 1,233 patients with ANCA-associated vasculitis from the United Kingdom and 5,884 controls, as well as in a replication cohort of 1,454 Northern European case patients and 1,666 controls.

Combined analysis of the discovery and replication cohorts demonstrated that four single nucleotide polymorphisms (SNPs) exceeded the significance threshold for genomewide association, including three from the major histocompatibility complex (MHC). The most significant of these three was within the gene encoding HLA-DPB1. The fourth was in the SERPINA1 locus at 14q32.

Another SNP in PRTN3, which was added to the replication analysis on the bases of a priori hypotheses, was also found to be significantly associated with disease.

"Together, these data provide evidence of a genetic base of ANCA-associated vasculitis that extends beyond the MHC," the investigators said.

Additional analysis of the discovery cohort after subdivision on the basis of whether patients were diagnosed with granulomatosis with polyangiitis or with microscopic polyangiitis showed that all three MHC-associated SNPs differed between the two groups, with "essentially all of the association" found in those with granulomatosis with polyangiitis.

"This was also true of SERPINA1 – while it did not show a significant difference when granulomatosis with polyangiitis and microscopic polyangiitis were compared directly, perhaps owing to small numbers of patients and thus reduced power, it was associated with granulomatosis with polyangiitis, but not microscopic polyangiitis, when each subtype was compared with controls," they added.

There also was a suggestion of an association between PRTN3 and granulomatosis with polyangiitis rather than with microscopic polyangiitis, and also between some less significant SNPs and granulomatosis with polyangiitis, they said.

"Overall, there was evidence that granulomatosis with polyangiitis had genetic associations distinct from microscopic polyangiitis at both the MHC and SERPIN loci," they said.

Additional subgroup analysis based on proteinase 3 and myeloperoxidase ANCA specificity showed significant differences at the MHC, SERPINA1, and PRTN3 loci, all of which included a genetic association with proteinase 3 ANCA but not with myeloperoxidase ANCA. Further analysis demonstrated associations of HLA-DP and the related SNPs SERPINA1 and PRTN3 in patients with proteinase 3 ANCA associated with granulomatosis with polyangiitis but not myeloperoxidase ANCA. The findings were the same in the microscopic polyangiitis group, showing an association of proteinase 3 ANCA and the HLA-DP SNP and SERPINA1. The converse was true for the HLA-DQ SNP, which was associated with myeloperoxidase ANCA rather than proteinase 3 ANCA in patients with microscopic polyangiitis.

The clear association of genetic background with autoantibody specificity suggests that it might contribute to the clinical classifications of granulomatosis with polyangiitis and microscopic polyangiitis, the investigators said.

"The genetic difference between proteinase 3 ANCA and myeloperoxidase ANCA polyangiitis could have immunopathogenic and therapeutic implications, ... and will require future genetic studies powered to detect associations with these conditions rather than with ANCA-associated vasculitis as a whole," they said.

The investigators concluded that this study "provides clear evidence of a genetic contribution to disease susceptibility, which differs between granulomatosis with polyangiitis and microscopic polyangiitis."

Further, "associations with HLA, SERPINA1, and PRTN3 are primarily aligned with ANCA specificity rather than with the clinically defined syndromes granulomatosis with polyangiitis and microscopic polyangiitis, making it logical to consider including ANCA specificity in the diagnostic criteria for ANCA-associated vasculitis," they argued.

Dr. Lyons and his associates disclosed that they had no relevant financial disclosures relevant to this research other than its funding. This study was supported by the British Heart Foundation; the Wellcome Trust; the National Institute of Health Research Biomedical Research Centres of Cambridge, Imperial College, and Manchester; the Medical Research Council and Kidney Research UK; the West Anglia Comprehensive Local Research Network; the Norfolk and Suffolk Comprehensive Local Research network; the German Research Foundation; and the European Union FP7 Infectious Triggers of Chronic Autoimmunity Consortium. Author disclosure forms for both the study authors and editorial author are available with the full text of the article at NEMJ.org.

Genes play a key role in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis, and genetic distinctions exist between two of the condition’s main clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis, judging from data from a genomewide association study.

The findings also support the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. If true, those findings could have both immunopathogenic and therapeutic implications, according to Paul A. Lyons, Ph.D., of the Cambridge (England) Institute for Medical Research, and his colleagues in their online report in the July 19 issue of the New England Journal of Medicine.

"There is debate as to whether the clinical syndromes of granulomatosis with polyangiitis and microscopic polyangiitis represent distinct diseases or are part of a single disease spectrum," the investigators wrote. The concept of a single disease spectrum has resulted in similar treatment strategies being used in trials regardless of which of these two clinical syndromes are present, and also in the suggestion that genetic studies should consider the two syndromes together, they explained.

"Clear evidence that these clinical syndromes are etiologically distinct might provide a rationale for devising syndrome-specific therapeutic strategies," the investigators noted (N. Engl. J. Med. 2012 July 19 [doi: 10.1056/NEJMoa1108735]).

To identify genetic risk factors and evaluate whether a common or distinct genetic background exists for granulomatosis with polyangiitis and microscopic polyangiitis, they performed genotyping in a discovery cohort of 1,233 patients with ANCA-associated vasculitis from the United Kingdom and 5,884 controls, as well as in a replication cohort of 1,454 Northern European case patients and 1,666 controls.

Combined analysis of the discovery and replication cohorts demonstrated that four single nucleotide polymorphisms (SNPs) exceeded the significance threshold for genomewide association, including three from the major histocompatibility complex (MHC). The most significant of these three was within the gene encoding HLA-DPB1. The fourth was in the SERPINA1 locus at 14q32.

Another SNP in PRTN3, which was added to the replication analysis on the bases of a priori hypotheses, was also found to be significantly associated with disease.

"Together, these data provide evidence of a genetic base of ANCA-associated vasculitis that extends beyond the MHC," the investigators said.

Additional analysis of the discovery cohort after subdivision on the basis of whether patients were diagnosed with granulomatosis with polyangiitis or with microscopic polyangiitis showed that all three MHC-associated SNPs differed between the two groups, with "essentially all of the association" found in those with granulomatosis with polyangiitis.

"This was also true of SERPINA1 – while it did not show a significant difference when granulomatosis with polyangiitis and microscopic polyangiitis were compared directly, perhaps owing to small numbers of patients and thus reduced power, it was associated with granulomatosis with polyangiitis, but not microscopic polyangiitis, when each subtype was compared with controls," they added.

There also was a suggestion of an association between PRTN3 and granulomatosis with polyangiitis rather than with microscopic polyangiitis, and also between some less significant SNPs and granulomatosis with polyangiitis, they said.

"Overall, there was evidence that granulomatosis with polyangiitis had genetic associations distinct from microscopic polyangiitis at both the MHC and SERPIN loci," they said.

Additional subgroup analysis based on proteinase 3 and myeloperoxidase ANCA specificity showed significant differences at the MHC, SERPINA1, and PRTN3 loci, all of which included a genetic association with proteinase 3 ANCA but not with myeloperoxidase ANCA. Further analysis demonstrated associations of HLA-DP and the related SNPs SERPINA1 and PRTN3 in patients with proteinase 3 ANCA associated with granulomatosis with polyangiitis but not myeloperoxidase ANCA. The findings were the same in the microscopic polyangiitis group, showing an association of proteinase 3 ANCA and the HLA-DP SNP and SERPINA1. The converse was true for the HLA-DQ SNP, which was associated with myeloperoxidase ANCA rather than proteinase 3 ANCA in patients with microscopic polyangiitis.

The clear association of genetic background with autoantibody specificity suggests that it might contribute to the clinical classifications of granulomatosis with polyangiitis and microscopic polyangiitis, the investigators said.

"The genetic difference between proteinase 3 ANCA and myeloperoxidase ANCA polyangiitis could have immunopathogenic and therapeutic implications, ... and will require future genetic studies powered to detect associations with these conditions rather than with ANCA-associated vasculitis as a whole," they said.

The investigators concluded that this study "provides clear evidence of a genetic contribution to disease susceptibility, which differs between granulomatosis with polyangiitis and microscopic polyangiitis."

Further, "associations with HLA, SERPINA1, and PRTN3 are primarily aligned with ANCA specificity rather than with the clinically defined syndromes granulomatosis with polyangiitis and microscopic polyangiitis, making it logical to consider including ANCA specificity in the diagnostic criteria for ANCA-associated vasculitis," they argued.

Dr. Lyons and his associates disclosed that they had no relevant financial disclosures relevant to this research other than its funding. This study was supported by the British Heart Foundation; the Wellcome Trust; the National Institute of Health Research Biomedical Research Centres of Cambridge, Imperial College, and Manchester; the Medical Research Council and Kidney Research UK; the West Anglia Comprehensive Local Research Network; the Norfolk and Suffolk Comprehensive Local Research network; the German Research Foundation; and the European Union FP7 Infectious Triggers of Chronic Autoimmunity Consortium. Author disclosure forms for both the study authors and editorial author are available with the full text of the article at NEMJ.org.

Genes play a key role in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis, and genetic distinctions exist between two of the condition’s main clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis, judging from data from a genomewide association study.

The findings also support the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. If true, those findings could have both immunopathogenic and therapeutic implications, according to Paul A. Lyons, Ph.D., of the Cambridge (England) Institute for Medical Research, and his colleagues in their online report in the July 19 issue of the New England Journal of Medicine.

"There is debate as to whether the clinical syndromes of granulomatosis with polyangiitis and microscopic polyangiitis represent distinct diseases or are part of a single disease spectrum," the investigators wrote. The concept of a single disease spectrum has resulted in similar treatment strategies being used in trials regardless of which of these two clinical syndromes are present, and also in the suggestion that genetic studies should consider the two syndromes together, they explained.

"Clear evidence that these clinical syndromes are etiologically distinct might provide a rationale for devising syndrome-specific therapeutic strategies," the investigators noted (N. Engl. J. Med. 2012 July 19 [doi: 10.1056/NEJMoa1108735]).

To identify genetic risk factors and evaluate whether a common or distinct genetic background exists for granulomatosis with polyangiitis and microscopic polyangiitis, they performed genotyping in a discovery cohort of 1,233 patients with ANCA-associated vasculitis from the United Kingdom and 5,884 controls, as well as in a replication cohort of 1,454 Northern European case patients and 1,666 controls.

Combined analysis of the discovery and replication cohorts demonstrated that four single nucleotide polymorphisms (SNPs) exceeded the significance threshold for genomewide association, including three from the major histocompatibility complex (MHC). The most significant of these three was within the gene encoding HLA-DPB1. The fourth was in the SERPINA1 locus at 14q32.

Another SNP in PRTN3, which was added to the replication analysis on the bases of a priori hypotheses, was also found to be significantly associated with disease.

"Together, these data provide evidence of a genetic base of ANCA-associated vasculitis that extends beyond the MHC," the investigators said.

Additional analysis of the discovery cohort after subdivision on the basis of whether patients were diagnosed with granulomatosis with polyangiitis or with microscopic polyangiitis showed that all three MHC-associated SNPs differed between the two groups, with "essentially all of the association" found in those with granulomatosis with polyangiitis.

"This was also true of SERPINA1 – while it did not show a significant difference when granulomatosis with polyangiitis and microscopic polyangiitis were compared directly, perhaps owing to small numbers of patients and thus reduced power, it was associated with granulomatosis with polyangiitis, but not microscopic polyangiitis, when each subtype was compared with controls," they added.

There also was a suggestion of an association between PRTN3 and granulomatosis with polyangiitis rather than with microscopic polyangiitis, and also between some less significant SNPs and granulomatosis with polyangiitis, they said.

"Overall, there was evidence that granulomatosis with polyangiitis had genetic associations distinct from microscopic polyangiitis at both the MHC and SERPIN loci," they said.

Additional subgroup analysis based on proteinase 3 and myeloperoxidase ANCA specificity showed significant differences at the MHC, SERPINA1, and PRTN3 loci, all of which included a genetic association with proteinase 3 ANCA but not with myeloperoxidase ANCA. Further analysis demonstrated associations of HLA-DP and the related SNPs SERPINA1 and PRTN3 in patients with proteinase 3 ANCA associated with granulomatosis with polyangiitis but not myeloperoxidase ANCA. The findings were the same in the microscopic polyangiitis group, showing an association of proteinase 3 ANCA and the HLA-DP SNP and SERPINA1. The converse was true for the HLA-DQ SNP, which was associated with myeloperoxidase ANCA rather than proteinase 3 ANCA in patients with microscopic polyangiitis.

The clear association of genetic background with autoantibody specificity suggests that it might contribute to the clinical classifications of granulomatosis with polyangiitis and microscopic polyangiitis, the investigators said.

"The genetic difference between proteinase 3 ANCA and myeloperoxidase ANCA polyangiitis could have immunopathogenic and therapeutic implications, ... and will require future genetic studies powered to detect associations with these conditions rather than with ANCA-associated vasculitis as a whole," they said.

The investigators concluded that this study "provides clear evidence of a genetic contribution to disease susceptibility, which differs between granulomatosis with polyangiitis and microscopic polyangiitis."

Further, "associations with HLA, SERPINA1, and PRTN3 are primarily aligned with ANCA specificity rather than with the clinically defined syndromes granulomatosis with polyangiitis and microscopic polyangiitis, making it logical to consider including ANCA specificity in the diagnostic criteria for ANCA-associated vasculitis," they argued.

Dr. Lyons and his associates disclosed that they had no relevant financial disclosures relevant to this research other than its funding. This study was supported by the British Heart Foundation; the Wellcome Trust; the National Institute of Health Research Biomedical Research Centres of Cambridge, Imperial College, and Manchester; the Medical Research Council and Kidney Research UK; the West Anglia Comprehensive Local Research Network; the Norfolk and Suffolk Comprehensive Local Research network; the German Research Foundation; and the European Union FP7 Infectious Triggers of Chronic Autoimmunity Consortium. Author disclosure forms for both the study authors and editorial author are available with the full text of the article at NEMJ.org.

BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.

The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.

The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.

Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.

"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.

The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.

At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.

All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.

Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.

After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.

Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.

CV Risk Higher Than Expected

Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.

In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.

The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.

Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.

Marker for Disease Severity

"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.

If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."

Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.

BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.

The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.

The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.

Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.

"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.

The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.

At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.

All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.

Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.

After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.

Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.

CV Risk Higher Than Expected

Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.

In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.

The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.

Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.

Marker for Disease Severity

"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.

If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."

Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.

BERLIN – The risk of cardiovascular events in patients with systemic lupus erythematosus is sevenfold higher than the risk predicted by the Framingham equation, a study shows.

The role of risk factors varies widely, with the presence of high triglyceride levels upping the risk nearly fourfold while use of cyclophosphamide, which may be a proxy for disease severity, raises the risk almost 17-fold, Dr. Sarah Skeoch, a clinical research fellow at the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, said at the annual European Congress of Rheumatology.

The research also showed that triglyceride level was the only independent traditional risk factor, with a 3.6-fold increased risk association. Damage related to lupus, according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index, increased risk 10-fold. Cyclophosphamide therapy was associated with a 16.7-fold increase in risk.

Although the patients have more of the classical risk factors, this does not seem to account for all the increased risk. Disease characteristics such as chronic inflammation or treatments may contribute, she suggested.

"We wanted to look at the association between risk and disease, for example, how active their lupus is, damage accrued over time, whether they have renal disease, and also whether their treatments are associated with CV events like heart disease and stroke," Dr. Skeoch added.

The study looked at these factors in 200 patients who were diagnosed between 2000 and 2003.

At baseline, 12 patients of the eventual 124 who were followed up had experienced a prior CV event. Also at baseline, the SLE disease activity index (SLEDAI) score was 1, indicating low disease activity, and the SLICC damage index was low.

All patients included in the study were over 18 years of age, female, and white. Their lupus was stable with therapy for at least 2 months prior to inclusion in the study. "They were a relatively well population of patients," said Dr. Skeoch.

Blood tests and clinical assessments were carried out to determine levels of traditional risk factors, lupus disease activity, and lupus-related damage, as well as measurements related to disease therapies.

After a 5-year interval, patients were invited back for assessments and the incidence of CV events, including coronary events, cerebral events, and peripheral vascular disease over the elapsed time period, was recorded.

Next, a comparison was made between the predicted CV risk at baseline according to the Framingham equation and the observed results in 112 patients with no prior CV disease.

CV Risk Higher Than Expected

Upon follow-up, patients were, on average, 56 years old and had had disease for approximately 16 years. Out of the 124 patients followed up over approximately 5 years, 12 (9.7%) had a CV event. Coronary events accounted for seven of these, cerebrovascular events were recorded in five patients, and peripheral vascular disease occurred in one patient. "One patient had both a coronary event and a cerebral event within the follow up," Dr. Skeoch said.

In those who had no prior CV event at baseline, predicted risk of a CV event according to the Framingham equation suggested that 1% of patients should have an event in the next 5 years. "In fact, we found 7% had an event – so seven times higher than predicted. This excess risk is most likely attributed to uncaptured traditional risk factors or alternatively, the disease itself, which is more likely," she commented.

The investigators looked at independent risk factors for a CV event regardless of which other risk factors a patient had and found that triglyceride levels were the only traditional risk factor, with an odds ratio (OR) of 3.61 (95% confidence interval, 1.23-10.56). Triglyceride levels often were not the primary target of lipid-lowering therapy, which was usually aimed at reducing total cholesterol or cholesterol ratio, she noted.

Other multivariable analyses of baseline characteristics associated with CV events suggested that the risk was elevated by two factors: the SLICC damage score (OR, 9.62; CI, 1.46-63.5) and cyclophosphamide therapy (OR, 16.7; CI, 1.46-123). "Factors associated with the patients’ lupus disease included having had a venous thromboembolism, damage related to SLE in the past, cyclophosphamide exposure, and a higher steroid dose at baseline which predisposed the patient to having an event," Dr. Skeoch said.

Marker for Disease Severity

"This is the first time cyclophosphamide [therapy] has been marked as an example of an independent predictor of CV risk. We don’t think it is the cyclophosphamide itself because it has been used in a number of diseases and there’s no known evidence to suggest it causes heart disease, but we think it is a measure of people with severe disease. Also, patients exposed to cyclophosphamide tend to have had more steroids," she explained.

If patients with lupus had severe disease, then they might be more likely to be at risk of CV events in the future, she concluded. "We have found that patients with SLE are at higher risk than expected of CV disease and that those with severe disease may be most at risk. We should endeavor to monitor and treat traditional risk factors and aim for good control of SLE disease activity in order to minimize this risk."

Dr. Skeoch has no relevant conflicts of interest. She is funded by the UK Medical Research Council.

RALEIGH, N.C. – Absolute differences in response rates for treatments of moderate to severe plaque psoriasis as commonly used in everyday clinical practice "are small and may not be clinically significant," Dr. Joy Wan said at the annual meeting of the Society for Investigative Dermatology.

The results of a multicenter, comparative effectiveness study provide a picture of how psoriasis treatments are performing in real-world practice as opposed to the setting of clinical trials, which typically feature a nonrepresentative patient population and physician investigators having expertise in the treatment under study, according to Dr. Wan.

The results suggest that the go-to treatments for moderate to severe plaque psoriasis aren’t as effective in routine practice as they were in randomized trials (Arch. Dermatol. 2012;148:487-94). For example, only 48% of patients on adalimumab (Humira) were clear or almost clear based on Physician Global Assessment (PGA) ratings, compared with a 73% rate in an earlier clinical trial, noted Dr. Wan of the University of Pennsylvania, Philadelphia.

The comparative effectiveness study was cross sectional, and involved 713 consecutive patients with moderate to severe plaque psoriasis seen for routine follow-up care in 10 practices participating in the Dermatology Clinical Effectiveness Research Network (DCERN), a nationwide network of private and academic dermatology practices established in 2010.

The study participants (mean age, 49 years; 50% men) had a median 19-year duration of psoriasis; 23% also had psoriatic arthritis. All patients in the study were on monotherapy with methotrexate, etanercept, adalimumab, ustekinumab, or narrow-band UVB phototherapy (NBUVB). In all, 27% of the patients were on etanercept, 24% on methotrexate, 21% on adalimumab, 17% on NBUVB, and the rest on ustekinumab. Patients had been on methotrexate, adalimumab, or etanercept for a median of 12 months; ustekinumab for 4 months; and NBUVB for 2 months. On average, participants had been on only one systemic therapy or phototherapy prior to their current treatment. Patients were evaluated using PGA ratings and the Dermatology Life Quality Index.

One striking finding, noted Dr. Wan, was that recommended dosing often was not optimal. Notably, 36% of patients on etanercept were on 50 mg twice weekly and 12% on adalimumab were on 40 mg once weekly; those are double the recommended maintenance doses based on clinical trial data. And only 11% of patients on NBUVB received the optimal dosing frequency of at least 12 sessions within the previous 4 weeks.

The primary study end point was the proportion of patients rated clear or almost clear on PGA. The rates were 24% with methotrexate, 48% with adalimumab, 34% with etanercept, 36% for ustekinumab, and 28% with NBUVB.

Using methotrexate as the reference standard in analyses adjusted for more than 20 factors, including patient age, gender, and treatment duration, patients on adalimumab were 2.15-fold more likely to have clear or almost clear skin. Patients on ustekinumab were 1.57-fold more likely and those on etanercept 1.45-fold more likely to have clear or almost clear skin than those on methotrexate. The response rate to NBUVB wasn’t significantly different from that for methotrexate.

The results suggest that the biologic agents are outperforming methotrexate. That being said, the median PGA scores for all of the therapies hovered in the range of 1.3-1.7 on a scale of 0 to 5. This indicates that the absolute differences in treatment effectiveness are "quite small," Dr. Wan said. Moreover, there were no significant differences between treatments in terms of quality of life.

"The proportion of patients who said psoriasis had no or only a small effect on their quality of life was generally high across the board, ranging from 68% with narrow-band UVB to 78% with adalimumab," she said.

The number of patients who would need to be treated with a given agent in order to achieve one additional "clear" or "almost clear" response beyond what would be expected if patients were treated with methotrexate – was 4 for adalimumab, 8 for ustekinumab, 10 for etanercept, and 12 for NBUVB.

This cross-sectional study provides a useful snapshot of how psoriasis therapies are performing in current practice. The next step will be to perform a longitudinal comparative effectiveness study, according to Dr. Wan.

The DCERN network was formed in response to the fact that comparative effectiveness research was becoming a hot research trend, she said. The Institute of Medicine has identified comparative effectiveness research as a top priority, with psoriasis and acne as the main diseases of interest within dermatology.

"Congress has spent billions of dollars to jump-start comparative effectiveness research efforts," Dr. Wan noted.

Dr. Alexa B. Kimball rose from the audience to comment on the interpretation of the study data.

"There’s a relatively consistent pattern in clinical practice: Many patients are started on methotrexate; then if need be they are moved to etanercept or adalimumab, then to ustekinumab. So in a sense, since you’re finding that the clinical improvement is not so different across these therapies, doesn’t that suggest that patients get to a certain level of improvement and then are no longer switched? In fact, it may be that what you’re really showing is the level of improvement patients tend to be satisfied at," said Dr. Kimball of Harvard Medical School, Boston.

The study was sponsored by the National Institutes of Health. Dr. Wan reported having no financial conflicts. Dr. Kimball is a clinical trial investigator of biologic agents.

RALEIGH, N.C. – Absolute differences in response rates for treatments of moderate to severe plaque psoriasis as commonly used in everyday clinical practice "are small and may not be clinically significant," Dr. Joy Wan said at the annual meeting of the Society for Investigative Dermatology.

The results of a multicenter, comparative effectiveness study provide a picture of how psoriasis treatments are performing in real-world practice as opposed to the setting of clinical trials, which typically feature a nonrepresentative patient population and physician investigators having expertise in the treatment under study, according to Dr. Wan.

The results suggest that the go-to treatments for moderate to severe plaque psoriasis aren’t as effective in routine practice as they were in randomized trials (Arch. Dermatol. 2012;148:487-94). For example, only 48% of patients on adalimumab (Humira) were clear or almost clear based on Physician Global Assessment (PGA) ratings, compared with a 73% rate in an earlier clinical trial, noted Dr. Wan of the University of Pennsylvania, Philadelphia.

The comparative effectiveness study was cross sectional, and involved 713 consecutive patients with moderate to severe plaque psoriasis seen for routine follow-up care in 10 practices participating in the Dermatology Clinical Effectiveness Research Network (DCERN), a nationwide network of private and academic dermatology practices established in 2010.

The study participants (mean age, 49 years; 50% men) had a median 19-year duration of psoriasis; 23% also had psoriatic arthritis. All patients in the study were on monotherapy with methotrexate, etanercept, adalimumab, ustekinumab, or narrow-band UVB phototherapy (NBUVB). In all, 27% of the patients were on etanercept, 24% on methotrexate, 21% on adalimumab, 17% on NBUVB, and the rest on ustekinumab. Patients had been on methotrexate, adalimumab, or etanercept for a median of 12 months; ustekinumab for 4 months; and NBUVB for 2 months. On average, participants had been on only one systemic therapy or phototherapy prior to their current treatment. Patients were evaluated using PGA ratings and the Dermatology Life Quality Index.

One striking finding, noted Dr. Wan, was that recommended dosing often was not optimal. Notably, 36% of patients on etanercept were on 50 mg twice weekly and 12% on adalimumab were on 40 mg once weekly; those are double the recommended maintenance doses based on clinical trial data. And only 11% of patients on NBUVB received the optimal dosing frequency of at least 12 sessions within the previous 4 weeks.

The primary study end point was the proportion of patients rated clear or almost clear on PGA. The rates were 24% with methotrexate, 48% with adalimumab, 34% with etanercept, 36% for ustekinumab, and 28% with NBUVB.

Using methotrexate as the reference standard in analyses adjusted for more than 20 factors, including patient age, gender, and treatment duration, patients on adalimumab were 2.15-fold more likely to have clear or almost clear skin. Patients on ustekinumab were 1.57-fold more likely and those on etanercept 1.45-fold more likely to have clear or almost clear skin than those on methotrexate. The response rate to NBUVB wasn’t significantly different from that for methotrexate.

The results suggest that the biologic agents are outperforming methotrexate. That being said, the median PGA scores for all of the therapies hovered in the range of 1.3-1.7 on a scale of 0 to 5. This indicates that the absolute differences in treatment effectiveness are "quite small," Dr. Wan said. Moreover, there were no significant differences between treatments in terms of quality of life.

"The proportion of patients who said psoriasis had no or only a small effect on their quality of life was generally high across the board, ranging from 68% with narrow-band UVB to 78% with adalimumab," she said.

The number of patients who would need to be treated with a given agent in order to achieve one additional "clear" or "almost clear" response beyond what would be expected if patients were treated with methotrexate – was 4 for adalimumab, 8 for ustekinumab, 10 for etanercept, and 12 for NBUVB.

This cross-sectional study provides a useful snapshot of how psoriasis therapies are performing in current practice. The next step will be to perform a longitudinal comparative effectiveness study, according to Dr. Wan.

The DCERN network was formed in response to the fact that comparative effectiveness research was becoming a hot research trend, she said. The Institute of Medicine has identified comparative effectiveness research as a top priority, with psoriasis and acne as the main diseases of interest within dermatology.

"Congress has spent billions of dollars to jump-start comparative effectiveness research efforts," Dr. Wan noted.

Dr. Alexa B. Kimball rose from the audience to comment on the interpretation of the study data.

"There’s a relatively consistent pattern in clinical practice: Many patients are started on methotrexate; then if need be they are moved to etanercept or adalimumab, then to ustekinumab. So in a sense, since you’re finding that the clinical improvement is not so different across these therapies, doesn’t that suggest that patients get to a certain level of improvement and then are no longer switched? In fact, it may be that what you’re really showing is the level of improvement patients tend to be satisfied at," said Dr. Kimball of Harvard Medical School, Boston.

The study was sponsored by the National Institutes of Health. Dr. Wan reported having no financial conflicts. Dr. Kimball is a clinical trial investigator of biologic agents.

RALEIGH, N.C. – Absolute differences in response rates for treatments of moderate to severe plaque psoriasis as commonly used in everyday clinical practice "are small and may not be clinically significant," Dr. Joy Wan said at the annual meeting of the Society for Investigative Dermatology.

The results of a multicenter, comparative effectiveness study provide a picture of how psoriasis treatments are performing in real-world practice as opposed to the setting of clinical trials, which typically feature a nonrepresentative patient population and physician investigators having expertise in the treatment under study, according to Dr. Wan.

The results suggest that the go-to treatments for moderate to severe plaque psoriasis aren’t as effective in routine practice as they were in randomized trials (Arch. Dermatol. 2012;148:487-94). For example, only 48% of patients on adalimumab (Humira) were clear or almost clear based on Physician Global Assessment (PGA) ratings, compared with a 73% rate in an earlier clinical trial, noted Dr. Wan of the University of Pennsylvania, Philadelphia.

The comparative effectiveness study was cross sectional, and involved 713 consecutive patients with moderate to severe plaque psoriasis seen for routine follow-up care in 10 practices participating in the Dermatology Clinical Effectiveness Research Network (DCERN), a nationwide network of private and academic dermatology practices established in 2010.

The study participants (mean age, 49 years; 50% men) had a median 19-year duration of psoriasis; 23% also had psoriatic arthritis. All patients in the study were on monotherapy with methotrexate, etanercept, adalimumab, ustekinumab, or narrow-band UVB phototherapy (NBUVB). In all, 27% of the patients were on etanercept, 24% on methotrexate, 21% on adalimumab, 17% on NBUVB, and the rest on ustekinumab. Patients had been on methotrexate, adalimumab, or etanercept for a median of 12 months; ustekinumab for 4 months; and NBUVB for 2 months. On average, participants had been on only one systemic therapy or phototherapy prior to their current treatment. Patients were evaluated using PGA ratings and the Dermatology Life Quality Index.

One striking finding, noted Dr. Wan, was that recommended dosing often was not optimal. Notably, 36% of patients on etanercept were on 50 mg twice weekly and 12% on adalimumab were on 40 mg once weekly; those are double the recommended maintenance doses based on clinical trial data. And only 11% of patients on NBUVB received the optimal dosing frequency of at least 12 sessions within the previous 4 weeks.

The primary study end point was the proportion of patients rated clear or almost clear on PGA. The rates were 24% with methotrexate, 48% with adalimumab, 34% with etanercept, 36% for ustekinumab, and 28% with NBUVB.

Using methotrexate as the reference standard in analyses adjusted for more than 20 factors, including patient age, gender, and treatment duration, patients on adalimumab were 2.15-fold more likely to have clear or almost clear skin. Patients on ustekinumab were 1.57-fold more likely and those on etanercept 1.45-fold more likely to have clear or almost clear skin than those on methotrexate. The response rate to NBUVB wasn’t significantly different from that for methotrexate.

The results suggest that the biologic agents are outperforming methotrexate. That being said, the median PGA scores for all of the therapies hovered in the range of 1.3-1.7 on a scale of 0 to 5. This indicates that the absolute differences in treatment effectiveness are "quite small," Dr. Wan said. Moreover, there were no significant differences between treatments in terms of quality of life.

"The proportion of patients who said psoriasis had no or only a small effect on their quality of life was generally high across the board, ranging from 68% with narrow-band UVB to 78% with adalimumab," she said.

The number of patients who would need to be treated with a given agent in order to achieve one additional "clear" or "almost clear" response beyond what would be expected if patients were treated with methotrexate – was 4 for adalimumab, 8 for ustekinumab, 10 for etanercept, and 12 for NBUVB.

This cross-sectional study provides a useful snapshot of how psoriasis therapies are performing in current practice. The next step will be to perform a longitudinal comparative effectiveness study, according to Dr. Wan.

The DCERN network was formed in response to the fact that comparative effectiveness research was becoming a hot research trend, she said. The Institute of Medicine has identified comparative effectiveness research as a top priority, with psoriasis and acne as the main diseases of interest within dermatology.

"Congress has spent billions of dollars to jump-start comparative effectiveness research efforts," Dr. Wan noted.

Dr. Alexa B. Kimball rose from the audience to comment on the interpretation of the study data.

"There’s a relatively consistent pattern in clinical practice: Many patients are started on methotrexate; then if need be they are moved to etanercept or adalimumab, then to ustekinumab. So in a sense, since you’re finding that the clinical improvement is not so different across these therapies, doesn’t that suggest that patients get to a certain level of improvement and then are no longer switched? In fact, it may be that what you’re really showing is the level of improvement patients tend to be satisfied at," said Dr. Kimball of Harvard Medical School, Boston.

The study was sponsored by the National Institutes of Health. Dr. Wan reported having no financial conflicts. Dr. Kimball is a clinical trial investigator of biologic agents.

BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.

Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.

The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.

National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.

Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.

The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.

Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.

In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."

In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).

"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.

In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."

Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.

BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.

Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.

The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.

National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.

Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.

The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.

Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.

In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."

In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).

"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.

In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."

Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.

BERLIN – Patients who have inflammatory rheumatic diseases and are on anti–tumor necrosis factor therapy have nearly double the risk of herpes zoster when they are compared with patients on disease-modifying antirheumatic drugs, according to the first meta-analysis in these patient populations.

Although the risk of bacterial infection is known to be increased among patients on anti-TNF therapy, less well known is whether the use of anti-TNF agents increases the risk for viral infections, especially herpes zoster, said Dr. Cedric Lukas of the department of rheumatology at Lapeyronie Hospital in Montpellier, France.

The meta-analysis of literature that was published between 2002 and 2010 involved a review of 655 articles and 134 congress abstracts, of which 22 articles and 28 abstracts eventually were included in the study. The anti-TNF therapies that were investigated included etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade), which were the agents available at the time.

National registries from the United States, United Kingdom, and other European countries were included in the meta-analysis, including BSRBR (British Society for Rheumatology Biologics Register), BIOBADASER (Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases), CORRONA (Consortium of Rheumatology Researchers of North America), the McDonald cohort of U.S. veterans (Clin. Infect. Dis. 2009;48:1364-71), and RABBIT (the German Rheumatoid Arthritis Observation of Biologic Therapy) were selected for inclusion. After selection for appropriate treatment regimens and diseases, 124, 966 patient years were included.

Upon meta-analysis, Dr. Lukas showed that there was a similar trend across the different registries, and no significant heterogeneity among data sources.

The meta-analysis showed an overall increased risk of herpes zoster infection up to 75% in patients whose inflammatory rheumatic diseases were treated with anti-TNF inhibitors. Overall, the pooled odds ratio for herpes zoster infection with anti-TNF therapy was 1.75 (95% confidence interval, 1.50-2.04). This was almost a twofold risk of developing disease with these drugs compared with DMARDs, Dr. Lukas said at the annual European Congress of Rheumatology.

Odds ratios by national registries were BIOBADASER, 2.45; BSRBR, 1.45; CORRONA, 2.34; McDonald, 1.33; and RABBIT, 1.82.

In addition to the meta-analysis, investigators used data from three registries specifically to determine whether the use of any particular anti-TNF drug was associated with a higher risk. "We found that one registry showed [that] infliximab had a somewhat higher risk, but this was only one out of three studies. The other two studies showed a similar risk across all anti-TNF agents."

In the McDonald registry, the risk was found to e higher with infliximab (OR, 1.32; 95% CI, 0.85-2.03) compared with etanercept (OR, 0.62; 95% CI, 0.40-0.95) and adalimumab (OR 0.53; 95% CI, 0.31-0.91).

"We already knew that these patients were prone to herpes zoster; we see the lesions in clinics." But there are preventive measures available that one can take, he said.

In the United States, there are vaccines to prevent herpes zoster, which are available to people who are older than age 60 years, or are at high specific risk of developing herpes zoster infection. "In these patients, we could think about vaccines before treatment is started," pointed out Dr. Lukas. "It is a live vaccine so it should be given a month before start of anti-TNF therapy. In Europe, where the vaccine is unavailable, we need to give patients prophylaxis."

Dr. Lukas reported no relevant conflicts of interest. The study was supported by an unrestricted educational grant from Abbott France.

BERLIN – Methotrexate cut the immune response to adalimumab in a dose-dependent way, in a series of 272 consecutive rheumatoid arthritis patients at one Dutch medical center.

A high methotrexate dosage (at least 22.5 mg/week) sliced the rate of antibody production against adalimumab by a statistically significant 86% compared with patients who got no methotrexate, and by a significant 61% compared with patients on low-dose methotrexate (10 mg/week or less), Dr. Charlotte Krieckaert reported at the annual European Congress of Rheumatology.

Mitchel L. Zoler/IMNG Medical Media

The message from this finding is that RA patients on adalimumab or other biologic drugs that could trigger antibody production should get "as much methotrexate as they can tolerate," ideally about 25 mg/week, according to Dr. Krieckaert, a rheumatology researcher at the Reade Centre for Rehabilitation and Rheumatology in Amsterdam. "The chances of a good response and a maintained response [to a biologic drug] are higher when you also give methotrexate," she said in an interview. "We saw incremental value from methotrexate, and it was most valuable during the first 6 months" on adalimumab. "Maybe we can taper off the methotrexate" after 6 months, but so far this has not been studied.

A prior report by Dr. Krieckaert and her associates documented that patients who produce antibodies against adalimumab have blunted beneficial effects from the treatment and have a lower remission rate (JAMA 2011;305:1460-8).

The problem of an immune response by some RA patients to biologics first appeared with infliximab, an effect that methotrexate also helped reduce. Antibody reactions against adalimumab were identified more recently, commented Dr. Jane Gibson, chief of the Fife (Scotland) Rheumatic Diseases Unit. "I think in 2 or 3 more years, once antibody responses to biologics are routinely measured in practice, you’ll find physicians tailoring the methotrexate dose," finding the minimum weekly dosage of methotrexate that an RA patient needs to prevent an immune response to whatever biologic the patient also takes, Dr. Gibson said in an interview.

The consecutive series that Dr. Krieckaert and her associates review included 272 patients who were begun on adalimumab in an observational cohort. In all, 70 (26%) received no methotrexate, 40 (15%) received a low dose, 54 (20%) got an intermediate dose (12.5-20 mg/week), and 108 (40%) got a high dose. (Percentages do not equal 100% because of rounding.)

During 3 years of follow-up, 76 patients (28%) developed a significant immune response to the adalimumab, accounting for half of those getting no methotrexate, 35% of patients on a low methotrexate dose, 22% on an intermediate dose, and 14% on a high dose.

An odds ratio analysis showed that low-dose methotrexate cut the frequency of immune responses by 64%, an intermediate dose cut the incidence of antibody production by 78%, and high dose cut the rate by 86% compared with no methotrexate, all statistically significant differences. Only high doses of methotrexate significantly cut the rate of antibody production compared with low doses.

Dr. Krieckaert said that she had no disclosures. Dr. Gibson said she had no disclosures.

BERLIN – Methotrexate cut the immune response to adalimumab in a dose-dependent way, in a series of 272 consecutive rheumatoid arthritis patients at one Dutch medical center.

A high methotrexate dosage (at least 22.5 mg/week) sliced the rate of antibody production against adalimumab by a statistically significant 86% compared with patients who got no methotrexate, and by a significant 61% compared with patients on low-dose methotrexate (10 mg/week or less), Dr. Charlotte Krieckaert reported at the annual European Congress of Rheumatology.

Mitchel L. Zoler/IMNG Medical Media

The message from this finding is that RA patients on adalimumab or other biologic drugs that could trigger antibody production should get "as much methotrexate as they can tolerate," ideally about 25 mg/week, according to Dr. Krieckaert, a rheumatology researcher at the Reade Centre for Rehabilitation and Rheumatology in Amsterdam. "The chances of a good response and a maintained response [to a biologic drug] are higher when you also give methotrexate," she said in an interview. "We saw incremental value from methotrexate, and it was most valuable during the first 6 months" on adalimumab. "Maybe we can taper off the methotrexate" after 6 months, but so far this has not been studied.

A prior report by Dr. Krieckaert and her associates documented that patients who produce antibodies against adalimumab have blunted beneficial effects from the treatment and have a lower remission rate (JAMA 2011;305:1460-8).

The problem of an immune response by some RA patients to biologics first appeared with infliximab, an effect that methotrexate also helped reduce. Antibody reactions against adalimumab were identified more recently, commented Dr. Jane Gibson, chief of the Fife (Scotland) Rheumatic Diseases Unit. "I think in 2 or 3 more years, once antibody responses to biologics are routinely measured in practice, you’ll find physicians tailoring the methotrexate dose," finding the minimum weekly dosage of methotrexate that an RA patient needs to prevent an immune response to whatever biologic the patient also takes, Dr. Gibson said in an interview.

The consecutive series that Dr. Krieckaert and her associates review included 272 patients who were begun on adalimumab in an observational cohort. In all, 70 (26%) received no methotrexate, 40 (15%) received a low dose, 54 (20%) got an intermediate dose (12.5-20 mg/week), and 108 (40%) got a high dose. (Percentages do not equal 100% because of rounding.)

During 3 years of follow-up, 76 patients (28%) developed a significant immune response to the adalimumab, accounting for half of those getting no methotrexate, 35% of patients on a low methotrexate dose, 22% on an intermediate dose, and 14% on a high dose.

An odds ratio analysis showed that low-dose methotrexate cut the frequency of immune responses by 64%, an intermediate dose cut the incidence of antibody production by 78%, and high dose cut the rate by 86% compared with no methotrexate, all statistically significant differences. Only high doses of methotrexate significantly cut the rate of antibody production compared with low doses.

Dr. Krieckaert said that she had no disclosures. Dr. Gibson said she had no disclosures.

BERLIN – Methotrexate cut the immune response to adalimumab in a dose-dependent way, in a series of 272 consecutive rheumatoid arthritis patients at one Dutch medical center.

A high methotrexate dosage (at least 22.5 mg/week) sliced the rate of antibody production against adalimumab by a statistically significant 86% compared with patients who got no methotrexate, and by a significant 61% compared with patients on low-dose methotrexate (10 mg/week or less), Dr. Charlotte Krieckaert reported at the annual European Congress of Rheumatology.

Mitchel L. Zoler/IMNG Medical Media

The message from this finding is that RA patients on adalimumab or other biologic drugs that could trigger antibody production should get "as much methotrexate as they can tolerate," ideally about 25 mg/week, according to Dr. Krieckaert, a rheumatology researcher at the Reade Centre for Rehabilitation and Rheumatology in Amsterdam. "The chances of a good response and a maintained response [to a biologic drug] are higher when you also give methotrexate," she said in an interview. "We saw incremental value from methotrexate, and it was most valuable during the first 6 months" on adalimumab. "Maybe we can taper off the methotrexate" after 6 months, but so far this has not been studied.

A prior report by Dr. Krieckaert and her associates documented that patients who produce antibodies against adalimumab have blunted beneficial effects from the treatment and have a lower remission rate (JAMA 2011;305:1460-8).

The problem of an immune response by some RA patients to biologics first appeared with infliximab, an effect that methotrexate also helped reduce. Antibody reactions against adalimumab were identified more recently, commented Dr. Jane Gibson, chief of the Fife (Scotland) Rheumatic Diseases Unit. "I think in 2 or 3 more years, once antibody responses to biologics are routinely measured in practice, you’ll find physicians tailoring the methotrexate dose," finding the minimum weekly dosage of methotrexate that an RA patient needs to prevent an immune response to whatever biologic the patient also takes, Dr. Gibson said in an interview.

The consecutive series that Dr. Krieckaert and her associates review included 272 patients who were begun on adalimumab in an observational cohort. In all, 70 (26%) received no methotrexate, 40 (15%) received a low dose, 54 (20%) got an intermediate dose (12.5-20 mg/week), and 108 (40%) got a high dose. (Percentages do not equal 100% because of rounding.)

During 3 years of follow-up, 76 patients (28%) developed a significant immune response to the adalimumab, accounting for half of those getting no methotrexate, 35% of patients on a low methotrexate dose, 22% on an intermediate dose, and 14% on a high dose.

An odds ratio analysis showed that low-dose methotrexate cut the frequency of immune responses by 64%, an intermediate dose cut the incidence of antibody production by 78%, and high dose cut the rate by 86% compared with no methotrexate, all statistically significant differences. Only high doses of methotrexate significantly cut the rate of antibody production compared with low doses.

Dr. Krieckaert said that she had no disclosures. Dr. Gibson said she had no disclosures.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.

BERLIN – A single intravitreal injection of infliximab is an effective treatment option in patients with Behçet’s disease who experience a sight-threatening acute uveitis attack but aren’t candidates for intravenous infliximab, Dr. Petros P. Sfikakis said at the annual European Congress of Rheumatology.

He presented the results of an uncontrolled pilot study involving 15 patients with Behçet’s disease who received a single intravitreal injection of infliximab (Remicade) at a dose of 1 mg in 0.05 mL on the day they experienced the onset of acute unilateral posterior uveitis.

In an earlier study, Dr. Sfikakis and his coworkers demonstrated that a single intravenous infusion of infliximab at a dose of 5 mg/kg was significantly more effective for rapid suppression of inflammation in the posterior eye segment than either high-dose intravenous methylprednisolone or intravitreal triamcinolone acetonide in Behçet’s disease patients experiencing sight-threatening attacks of acute uveitis (Rheumatology 2011;50:593-7). However, none of the participants in the new pilot study was eligible for systemic infliximab because of a history of cancer, heart failure, or latent tuberculosis.

In preclinical studies in rabbits, the investigators determined that a single intravitreal injection of 1 mg of infliximab resulted in therapeutic intraocular concentrations with essentially no systemic absorption, and that a 2-mg injection resulted in unacceptable complications.

Eleven of the 15 patients who received intravitreal infliximab were on systemic immunosuppressive therapy with various combinations of azathioprine, cyclosporine, and/or corticosteroids at the time. These background medications remained unchanged during 30 days of follow-up after intravitreal infliximab, noted Dr. Sfikakis, professor of internal medicine at Athens University and head of the rheumatology unit at the First Department of Propedeutic and Internal Medicine, Laikon University Hospital, also in Athens.

Best corrected visual acuity showed significant improvement by posttreatment day 7, and it continued to improve through day 30. Total ocular inflammation scores decreased from a baseline mean of 6.27 to 4.13 on day 7, 2.87 on day 14, and 1.13 on day 30. Indeed, by day 30 total inflammation scores of 0 had been achieved in 6 of 15 treated eyes.

In addition, profound reductions in anterior chamber cells and vitreous cells were documented. Central macular thickness decreased significantly by day 7 and continued to decrease through day 30. However, cystoid macular edema persisted through day 30 in 9 of 11 affected eyes. Retinal vasculitis was present at baseline in 10 of 15 eyes, but between days 14 and 30 it resolved in 9 of 10 cases.

Intravitreal infliximab was well tolerated by all patients, with no clinical ocular or extraocular side effects noted.

The intravitreal injection is a straightforward matter for ophthalmologists. However, Dr. Sfikakis stressed that in patients without a contraindication to systemic infliximab, the single 5-mg/kg intravenous infusion appears to be advantageous. It yielded significantly faster effects in the earlier published study than seen with intravitreal injection – and the more quickly suppression of inflammation in the posterior eye segment is achieved, the less likely are retinal scarring and damage to the optic disc.

For example, significant improvement in best corrected visual acuity was noted with intravenous infliximab on day 1 in 79% of eyes, compared with 20% with intravitreal injection. By day 7, 93% of patients treated with intravenous infliximab had achieved significant gains in best corrected visual acuity, compared with just one-third of participants in the intravitreal infliximab study. More importantly, cystoid macular edema had resolved by day 30 in all recipients of intravenous infliximab, but in only 2 of 11 affected patients who got an intravitreal injection.

Dr. Sfikakis reported having no relevant financial disclosures.