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 Wegener’s 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.)

Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01791153 .).

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.)

Objective. To reevaluate the efficacy and safety of adjunctive low-dose methotrexate (MTX) in giant cell arteritis (GCA).Methods. An individual patient data metaanalysis of 3 randomized placebo-controlled trials in patients with newly diagnosed GCA was performed. Treatment consisted of initial high-dose corticosteroids and randomly assigned oral MTX therapy (7.5-15 mg/ week) or placebo. Time-to-event outcomes were compared between groups using Cox proportional hazards models stratified by trial, and continuous outcomes were compared by calculating weighted mean differences.Results. The combined data set comprised 161 patients, of whom 84 received MTX and 77 received placebo. The mean duration of followup was 54.7 weeks (SD 39.2 weeks). Hazard ratios (HRs) for a first and second relapse of GCA were 0.65 (P ‫؍‬ 0.04) and 0.49 (P ‫؍‬ 0.02), respectively, in patients receiving MTX as compared with patients receiving placebo. Accordingly, a predicted 3.6 individuals (95% confidence interval [95% CI] 2.2-56.8) and 4.7 individuals (95% CI 3.3-21.9) need to be treated with MTX to prevent the occurrence of one first or one second relapse, respectively, up to 48 weeks. Use of MTX resulted in a reduction in the corticosteroid cumulative dose by 842 mg within 48 weeks (P < 0.001). Moreover, MTX treatment was associated with a higher probability of achieving sustained discontinuation of corticosteroids for >24 weeks (HR 2.84, P ‫؍‬ 0.001). Dropout rates and occurrence of adverse events did not differ between treatment groups.Conclusion. In GCA, adjunctive treatment with MTX lowers the risk of relapse and reduces exposure to corticosteroids. These findings indicate that MTX could be considered as a therapeutic option in addition to standard-of-care treatment with corticosteroids for patients with GCA.

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Objective. To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's 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 physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's 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 (withincase) 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, diseasespecific 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 interand intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.The investigation of new therapies for the treatment of systemic vasculitis and the organization of

Systemic sclerosis (SSc) is a multisystem life-threatening fibrosing disorder that lacks effective treatment. The link between the inflammation observed in organs such as the skin and profibrotic mechanisms is not well understood. The plasmacytoid dendritic cell (pDC) is a key cell type mediating Toll-like receptor (TLR)-induced inflammation in autoimmune disease patients, including lupus and skin diseases with interface dermatitis. However, the role of pDCs in fibrosis is less clear. We show that pDCs infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-α (IFN-α) and CXCL4, which are both hallmarks of the disease. We demonstrate that the secretion of CXCL4 is under the control of phosphatidylinositol 3-kinase δ and is due to the aberrant presence of TLR8 on pDCs of SSc patients, which is not seen in healthy donors or in lupus pDCs, and that CXCL4 primarily acts by potentiating TLR8- but also TLR9-induced IFN production by pDCs. Depleting pDCs prevented disease in a mouse model of scleroderma and could revert fibrosis in mice with established disease. In contrast, the disease was exacerbated in mice transgenic for TLR8 with recruitment of pDCs to the fibrotic skin, whereas TLR7 only partially contributed to the inflammatory response, indicating that TLR8 is the key RNA-sensing TLR involved in the establishment of fibrosis. We conclude that the pDC is an essential cell type involved in the pathogenesis of SSc and its removal using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc patients.

Objective To compare the efficacy of abatacept to placebo for giant cell arteritis (GCA). Methods In this multicenter trial, patients with newly-diagnosed or relapsing GCA were treated with abatacept 10 mg/kg IV on days 1, 15, 29, week 8, together with prednisone. At week 12, patients in remission underwent a double-blinded randomization to continue monthly abatacept or switch to placebo. Patients in both study arms received a standardized prednisone taper with discontinuation of prednisone at week 28. Patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary endpoint was duration of remission (relapse-free survival). Results Forty-nine eligible patients with GCA were enrolled and treated with prednisone and abatacept; forty-one reached the week 12 randomization and underwent a blinded randomization to abatacept or placebo. Prednisone was tapered using a standardized schedule reaching 20 mg daily at week 12 with discontinuation in all patients at week 28. The relapse-free survival at 12 months was 48% for those receiving abatacept and 31% for those receiving placebo (p=0.049). A longer median duration of remission was seen with abatacept (9.9 months) compared to placebo (3.9 months, p=0.023). There was no difference in the frequency or severity of adverse events between treatment arms, including infection. Conclusions In patients with GCA the addition of abatacept to a treatment regimen with prednisone reduced the risk of relapse and was not associated with a higher rate of toxicity compared to prednisone alone.