Eugene Y. Kissin

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.)

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.)

Diagnostic imaging in Takayasu arteritis.

Purpose of reviewNew imaging modalities may help accurately diagnose and monitor Takayasu arteritis (TAK). Examination of the published literature on arterial imaging studies other than conventional angiography will help guide appropriate use of these studies in TAK. MRI, magnetic resonance angiography (MRA), Doppler ultrasound, CT, and positron emission tomography (PET) are all potentially useful for evaluation of TAK. Recent findingsMRI/A avoids the risks of arterial puncture, iodinated contrast load, and radiation exposure, while providing information on arterial wall anatomy and obtaining a generalized arterial survey in TAK. Ultrasound can be helpful in detecting submillimeter changes in wall thickness of the carotid arteries and in differentiating TAK from atherosclerotic disease based on minimal plaque content, concentric and long segmental involvement, and location of lesion. Like MRI, CT angiography can be used to detect areas of aortic wall thickening and obtain a generalized survey of the aorta and its proximal branches for areas of stenosis and without the risks associated with arterial puncture. However, CT provides less detailed resolution than ultrasound and incurs the risks of contrast administration. Finally, PET scanning may provide valuable information about cellular activity within an inflamed arterial wall before morphologic changes on other imaging studies. SummaryAlthough it is still unclear how often early arterial wall changes lead to stenotic lesions, use of these modalities in combination, for both routine monitoring and evaluation of new symptoms, may facilitate the detection of TAK disease activity at a more treatable stage.

B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis

OBJECTIVE To determine the safety of rituximab, to provide preliminary data regarding the potential efficacy of rituximab, and to investigate the effects of rituximab on autoimmunity and fibrosis in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS Fifteen patients with dcSSc, all of whom experienced their first non-Raynauds disease-associated disease manifestation within 18 months of trial entry, were recruited to receive 2 intravenous doses of rituximab (1,000 mg), administered 2 weeks apart. Safety, clinical, and exploratory outcomes were evaluated at baseline and at 6 months. The primary outcome was the change in the modified Rodnan skin thickness score (MRSS) at 6 months compared with baseline. RESULTS Adverse events included frequent infusion reactions and rare infections (urinary tract infection and dental abscess occurred in 1 patient each). The mean change in the MRSS between baseline and 6 months was not significant. Results of pulmonary function tests and other measures of major organ involvement were stable. The modest B cell infiltrates that were present in most skin biopsy specimens at baseline were completely depleted at 6 months in most patients. Autoantibody titers showed only modest and variable changes after treatment. CONCLUSION In this pilot study, treatment with rituximab appeared to be safe and well tolerated among patients with dcSSc. Rituximab treatment resulted in both depletion of circulating B cells and depletion of dermal B cells but had little effect on the levels of SSc-associated autoantibodies. Rituximab treatment did not appear to result in a significant beneficial effect on skin disease. The potential efficacy of rituximab in other organs such as the lung could not be clearly evaluated in this small open-label trial.

Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis

BackgroundThere are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra-articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks.MethodsThis was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria.ResultsThe mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo.ConclusionsThere was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis.

Clinical Outcomes of Remission Induction Therapy for Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

OBJECTIVE To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegeners Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Fibrosis in scleroderma

The pathogenesis of fibrosis in scleroderma involves a complex set of interactions between the fibroblast and its surroundings. Multiple fibrotic pathways are activated for reasons that are not completely clear, but involve immune activation, microvascular damage, and fibroblast transformation into the myofibroblast. Differential proliferation and apoptosis preserve the myofibroblast phenotype rather that leading to a selective depletion of activated fibroblasts after an acute injury has healed. Disproportionate fibroblast activity could result from a combination of possible cellular and matrix defects that include fibrillin protein abnormalities, autoantibody formation, type II immune response, excessive endothelial reaction to injury, and excessive fibroblast response to TGF-beta. Development of therapies that are targeted to correcting these abnormalities will eventually lead to effective treatment for the fibrotic complications of scleroderma.

The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis.

In this study we sought to determine whether an intraarticular administration of a vanilloid agonist resiniferatoxin (RTX) produces an analgesic effect in experimental arthritis. Knee joint inflammation was induced in rats by intraarticular carrageenan (2%, 30 &mgr;L). Pain score and left/right hind leg weight distribution ratio were used to assess pain behavior. Changes in knee dimensions were evaluated by measuring external circumference and intraarticular area (ultrasound scanning). The intraarticular administration of RTX (0.0003% or 0.003%, 30 &mgr;L) provided a significant analgesic effect. Twenty-four hours after RTX administration, the pain score was reduced from 15.1 ± 4.7 to 6.9 ± 4.4 (P < 0.01) with 0.0003% and was abolished (P < 0.0001) with 0.003%. The improvement in weight distribution ratio lasted for several days after the RTX administration. Reduction in knee circumference demonstrated that intraarticular RTX suppressed the carrageenan-induced edema by at least one third. Ultrasound scanning revealed no RTX-induced decrease of the intraarticular area. The experiments demonstrated that intraarticular RTX inhibits pain behavior in knee-joint arthritis and that this effect is dose-dependent. These results suggest a new direction for peripheral analgesia.

Rituximab for the Treatment of Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Disease relapses are frequent in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re‐treated with rituximab (RTX) and prednisone for severe disease relapses.

Self-directed learning of basic musculoskeletal ultrasound among rheumatologists in the United States

Because musculoskeletal ultrasound (MSUS) is highly user dependent, we aimed to establish whether non‐mentored learning of MSUS is sufficient to achieve the same level of diagnostic accuracy and scanning reliability as has been achieved by rheumatologists recognized as international experts in MSUS.