Peter A. Merkel

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Jennette;R. Falk;P. Bacon;N. Basu;M. Cid;F. Ferrario;L. Flores-Suarez;W. Gross;L. Guillevin;E. Hagen;G. Hoffman;D. Jayne;C. Kallenberg;P. Lamprecht;C. Langford;R. Luqmani;A. Mahr;E. Matteson;P. Merkel;S. Ozen;C. Pusey;N. Rasmussen;A. Rees;D. Scott;U. Specks;J. Stone;K. Takahashi;R. Watts; Arthritis & Rheumatism

Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis

BACKGROUND Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS Nine centers enrolled 197 ANCA-positive patients with either Wegeners granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

OBJECTIVE The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

EULAR recommendations for the management of primary small and medium vessel vasculitis

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis

Objectives: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis. Methods: An expert consensus group was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis. Results: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research. Conclusions: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.

Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell Arteritis: A Randomized Trial

Context Up to 80% of patients with giant cell arteritis (GCA) experience complications related to glucocorticoid therapy. Case reports suggest that patients with GCA who received infliximab achieved sustained disease remission and independence from glucocorticoids. Contribution Patients with glucocorticoid-induced GCA remission were randomly assigned to infusions of infliximab, 5 mg/kg, or placebo at 0, 2, and 6 weeks and every 8 weeks thereafter. The investigators found that infliximab did not reduce rates of relapse or any secondary end point. Caution The study was small and stopped early (after week 22 of the planned 54 weeks), so it could not definitively identify harms or small benefits. Implication Infliximab is unlikely to cause large reductions in rates of relapse of GCA. The Editors In northern Europe and North America, the estimated annual incidence of giant cell arteritis is 19 to 32 cases per 100000 persons older than 50 years of age. In Mediterranean countries, the annual incidence appears to be lower: 6 to 10 cases per 100000 persons (15). Treatment with glucocorticosteroids dramatically alters the symptoms and course of giant cell arteritis, reducing the likelihood that the patient will develop blindness (6, 7). However, relapses usually occur when glucocorticosteroid dosages are tapered, resulting in frequent re-treatment and glucocorticosteroid dependence and toxicity (810). Approximately 80% of patients with giant cell arteritis will eventually experience at least 1 adverse event attributable to glucocorticosteroids, and about 60% will have 2 or more adverse events. Compared with age- and sex-matched controls, patients with giant cell arteritis have an increased risk for fractures and corticosteroid-related cataracts (9). Adjunctive treatments are needed that would effectively reduce the dose and duration of glucocorticosteroid therapy and provide more durable remissions of giant cell arteritis. Other investigators have evaluated the utility of cytotoxic and anti-inflammatory agents in giant cell arteritis. However, the reports have been anecdotal, of uncontrolled studies, or of controlled studies with conflicting results in terms of efficacy (11, 12). Increased knowledge of cell types and mediators within vessels damaged by giant cell arteritis has led to speculation about the potential therapeutic role of several cytokine antagonists. Interleukin-1, interleukin-6, tumor necrosis factor (TNF), and interferon- have been implicated in contributing to vascular injury in patients with giant cell arteritis (1316). Published case studies reported that some patients with giant cell arteritis or polymyalgia rheumatica who received the antiTNF- agent infliximab had sustained remission and became glucocorticosteroid-independent (17, 18). However, the investigators cautioned that randomized, controlled studies were needed to validate these results. We report the results of the first randomized, placebo-controlled, double-blind, multicenter trial of standardized treatment with glucocorticosteroids and adjunctive treatment with placebo or infliximab in patients with newly diagnosed giant cell arteritis. Methods Design We designed a multicenter, randomized, double-blind, placebo-controlled study to determine whether infliximab added to a standardized program of glucocorticosteroid therapy (equivalent daily doses of prednisone or prednisolone) in patients with newly diagnosed giant cell arteritis would decrease the frequency of relapse, cumulative glucocorticosteroid requirement, and glucocorticosteroid-associated toxicity. The study protocol was approved by the institutional review boards or ethics committees of the individual study sites. The study was conducted according to the current regulations of the U.S. Food and Drug Administration, the International Conference on Harmonization guidelines, and the principles of the Declaration of Helsinki. All patients provided written informed consent before participating in any protocol-specific procedures. An independent safety monitoring committee reviewed safety information during the trial. The first patient was enrolled on 22 October 2003, and the last patient completed the study on 29 July 2005. The primary objective was to obtain preliminary evidence on the safety and efficacy of infliximab therapy in patients with glucocorticoid-induced remission of newly diagnosed giant cell arteritis, as measured by the proportion of patients who were relapse-free through week 22 and the incidence of adverse events. The secondary objective was to further evaluate the preliminary evidence of the efficacy of infliximab therapy, as measured by the proportion of patients who remained relapse-free through week 54, time to first relapse, levels of biochemical markers of inflammation and disease activity, and cumulative dose of glucocorticosteroids. Setting The study was conducted at 22 sites in the United States, United Kingdom, Belgium, Italy, and Spain. Participants To be eligible for the study, patients must have had a diagnosis of giant cell arteritis within 4 weeks of enrollment, satisfied the American College of Rheumatology criteria for giant cell arteritis (19), had an erythrocyte sedimentation rate 40 mm or greater in the first hour at the time of diagnosis, and achieved clinical remission before randomization. For at least 1 week before randomization, patients were required to be receiving prednisone or prednisolone at a stable dosage of 40 to 60 mg/d, have a normal erythrocyte sedimentation rate (<40 mm in the first hour, as determined by using the Westergren method), and have no symptoms or signs of active giant cell arteritis. Patients were excluded if they had received a diagnosis of giant cell arteritis or polymyalgia rheumatica more than 4 weeks before screening, did not respond to glucocorticosteroid therapy within 5 days of initiation of therapy, received intravenous glucocorticosteroid therapy with an equivalent dose of methylprednisolone (>1000 mg/d for >3 days), or received other forms of immunosuppressive therapy (such as methotrexate, azathioprine, or other cytotoxic agents) or any investigational or biological agents within the 3 months before screening. Patients with screening blood test results within the following ranges were also excluded: leukocyte count less than 3.5109 cells/L, neutrophil count less than 1.5109 cells/L, hemoglobin level less than 85 g/L, platelet count less than 100109 cells/L, or hepatic aminotransferase or alkaline phosphatase levels greater than 3 times the upper limit of normal. We excluded patients with serious or chronic infections in the previous 3 months; opportunistic infections within the 6 months before screening; cancer within the 5 years before screening (with the exception of treated and cured squamous or basal cell carcinoma of the skin); a history of severe congestive heart failure or demyelinating disease; current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease; a transplanted organ (with the exception of corneal transplantation done more than 3 months before screening); or evidence of active or previous tuberculosis. Randomization and Intervention Patients were randomly assigned in a 2:1 ratio to receive infliximab, 5 mg/kg, or placebo by using adaptive treatment allocation (20, 21) stratified by baseline glucocorticosteroid dosage (40 to 50 mg/d or 51 to 60 mg/d prednisone equivalent). Patients received infusions at weeks 0, 2, and 6 and every 8 weeks thereafter. Allocation to treatment group was performed by using a central randomization procedure through an interactive voice response system. Patients, investigators, and study personnel were blinded to treatment assignments during the study; the site pharmacists, who prepared study medication, were not blinded to this information. Infliximab and placebo were supplied as sterile, white, lyophilized powders that were reconstituted with sterile water for injection. The reconstituted placebo solution contained the same excipients as the infliximab solution but did not contain infliximab. Glucocorticosteroid dosages were tapered according to a predefined schedule (Table 1). Each week, the daily dose of prednisone or prednisolone was decreased by 10 mg until the dosage reached 20 mg/d. It was then tapered by 2.5 mg until it reached 10 mg/d and then by 1 mg until the dosage was 0 mg/d. In the absence of a relapse, this schedule results in a glucocorticosteroid dosage of 10 mg/d after 4 months and no glucocorticosteroid use after 6 months. If a relapse occurred, the patient was to resume treatment with the previous higher dose of prednisone or prednisolone that provided disease remission, plus 10 mg/d. If the relapse resolved within 72 hours, the patient was to continue receiving that dosage for 2 weeks and then resume tapering according to the protocol. If relapse did not resolve within 72 hours, the patient was to receive another increase of 10 mg and resume treatment according to the protocol. Table 1. Schedule of Dosage Tapering for Glucocorticosteroid Therapy* If relapse included visual symptoms, the patient was to receive at least 40 mg/d or the previous higher dosage of prednisone or prednisolone, plus 10 mg (whichever was higher). If the visual symptoms improved within 48 hours, the patient was to resume tapering according to the protocol above. If the visual symptoms did not resolve within 48 hours, the patients vision was threatened, or there was concern about any other catastrophic event, the investigator was to take any measures necessary according to clinical judgment to treat the patient, including but not limited to increasing the glucocorticosteroid dosage to more than 60 mg/d. If a patient received more than 60 mg of oral prednisone or prednisolone daily or more than 1000 mg of intravenous glucocorticosteroid daily for more than

EULAR Recommendations for the management of large vessel vasculitis

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. Methods: An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.

Efficacy of Remission-Induction Regimens for ANCA-Associated Vasculitis

BACKGROUND The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is unknown. METHODS In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. RESULTS A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P=0.01) and at 12 months (P=0.009) but not at 18 months (P=0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. CONCLUSIONS In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

A disease-specific activity index for Wegener's granulomatosis: Modification of the Birmingham Vasculitis Activity Score

OBJECTIVE To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegeners granulomatosis (WG). METHODS Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physicians global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearmans rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.