Steven R. Ytterberg

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.)

Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis

Context Most patients with Wegener granulomatosis have antineutrophil cytoplasmic antibodies (ANCA). The role of ANCA testing in monitoring response to treatment is controversial. Contribution Using data from a large treatment trial, the authors found little association between disease activity and ANCA levels. Decreases in ANCA levels were not associated with remission, and increases were not associated with relapse. Caution Because follow-up duration differed by patient, standard measures of ANCA accuracy, such as sensitivity and specificity for detecting remission and relapse, could not be calculated. Implication Serial ANCA testing should not be used to monitor disease activity or to guide decisions about immunosuppressive treatment in patients with Wegener granulomatosis. The Editors Wegener granulomatosis is characterized by necrotizing granulomatous inflammation and vasculitis, most commonly affecting the respiratory tract and kidneys (1, 2). Remission can be induced in most patients by using glucocorticoids with cyclophosphamide or methotrexate (17), but most patients have relapse when immunosuppression is reduced or withdrawn (1, 2, 6, 8). Consequently, patients experience substantial illness and damage from both the disease and treatment toxicity (1, 9). Accurate assessment of disease activity and prediction of relapse remain the biggest challenges in management of Wegener granulomatosis (10). Most patients with Wegener granulomatosis have antineutrophil cytoplasmic antibodies (ANCA), which produce a cytoplasmic immunofluorescence pattern on ethanol-fixed neutrophils and react with the neutrophil serine protease proteinase 3 (PR3) (1115). Proteinase 3 is synthesized as a proenzyme (pro-PR3) containing an amino-terminal activation dipeptide that preserves PR3 in an inactive state (16). Subsequent cleavage of this dipeptide allows PR3 to assume its active enzyme conformation (mature-PR3) (16). The diagnostic value of ANCA is well established (17, 18); however, the role of serial ANCA measurements during follow-up and their utility in guiding treatment remain controversial (10, 19, 20). A recent study indicated that in individual patients with Wegener granulomatosis, ANCA against pro-PR3 had a stronger correlation with disease activity than did ANCA against mature-PR3 (21). Therefore, we sought to determine whether pro-PR3ANCA levels correlate more strongly with disease activity than do mature-PR3ANCA levels, whether a decrease in pro- or mature-PR3ANCA levels during remission-induction therapy is associated with a shorter time to sustained remission, and whether an increase in pro- or mature-PR3ANCA levels is associated with relapse. Methods This prospective study was done in the context of the WGET (Wegener Granulomatosis Etanercept Trial) (6, 22, 23), a randomized, placebo-controlled trial that evaluated etanercept for maintenance of remission in 180 patients with Wegener granulomatosis at 8 centers across the United States (Appendix 1). All patients met at least 2 of the 5 modified American College of Rheumatology criteria for classification of Wegener granulomatosis and had active disease within 28 days before enrollment and a Birmingham Vasculitis Activity Score for Wegener granulomatosis (BVAS/WG) of at least 3 (22, 24). Follow-up evaluations were done at baseline, after 6 and 12 weeks, and then every 3 months until the end of the trial. Two additional evaluations took place at 3 and 6 months after the end of the trial. During each visit, disease activity was measured by using the BVAS/WG, and serum samples were obtained, frozen, and stored at 80 C. Treatment Patients were treated in a protocol-defined manner with etanercept or placebo in addition to standard therapies. Patients with severe Wegener granulomatosis (life- or organ-threatening disease) received cyclophosphamide and glucocorticoids at enrollment (22, 24). Those with limited (that is, nonsevere) Wegener granulomatosis received methotrexate and glucocorticoids. Medication dosages were tapered according to protocol once disease activity was controlled (6, 22). Assessment of Disease Activity and Definitions of Sustained Remission and Relapse Disease activity was measured by using the BVAS/WG (24). This index considers all manifestations of active disease during the 28 days preceding the date of assessment. A BVAS/WG of 1 or greater is considered active disease, and a BVAS/WG of 0 indicates remission (24). Our analyses focused on first sustained remission and first relapse. Sustained remission was defined as a BVAS/WG of 0 for at least 6 months (6, 22). The PR3-ANCA level at the visit in the middle of this period was considered the PR3-ANCA level at sustained remission. Disease relapse was defined as an increase of at least 1 point in the BVAS/WG in patients who had sustained remission. ANCA Detection Methods A standard immunofluorescence assay and direct enzyme-linked immunosorbent assays (ELISAs) for PR3-ANCA and ANCA against myeloperoxidase were done as described elsewhere (25). Capture ELISA was used to measure PR3-ANCA (2527); levels are expressed as net absorbance, and a level of 0.10 or greater is considered positive (26, 27). The intra-assay and interassay coefficients of variation are 9% and 31%, respectively, for pro-PR3 capture ELISA, and 6% and 28%, respectively, for mature-PR3 capture ELISA. All baseline serum samples were screened at first thaw by using all methods. Patients whose baseline samples tested positive for perinuclear-staining ANCA or ANCA against myeloperoxidase (n= 24) were excluded from further analyses because of substantial differences in disease phenotype between patients positive for ANCA against myeloperoxidase and those positive for PR3-ANCA. In addition, the number of patients who were positive for ANCA against myeloperoxidase was too small for meaningful longitudinal analysis (5, 28, 29). Subsequently, all serum samples were tested for mature- and pro-PR3ANCA in parallel by using capture ELISA at first thaw (except for the baseline samples, which were retested at second thaw). To minimize variability, all serum samples from an individual patient were run at once in the same plate and the same lots of all reagents were used for all assays. Laboratory personnel were blinded to the clinical data. Increase and Decrease of PR3-ANCA Levels We defined an increase in PR3-ANCA levels a priori as an increase of at least 100% in the net absorbance over 6 months. An absolute increase of at least 0.4 was also required to ensure that small elevations were above the intra-assay coefficient of variation. We classified a negative-to-positive conversion of PR3-ANCA status as an increase only if the absolute increase was at least 0.4. Because 6 months corresponded to 3 clinical visits (except for the initial 6 months after enrollment, when it corresponded to 4 clinical visits), we compared the PR3-ANCA levels at each visit with those from the previous 2 to determine whether the criteria for increase were fulfilled. We first looked for an increase in PR3-ANCA 9 months after enrollment (the fourth visit), because that was the first time that a patient could meet the definition of sustained remission. Thus, the PR3-ANCA level at the fourth visit was compared with the levels at the third and second visits after enrollment. No increase in PR3-ANCA before the fourth visit after enrollment was analyzed (Appendix Figure 1). Appendix Figure 1. Diagram of the initial 4 clinical visits. The fourth clinical visit was the first point at which a patient could meet the study definition of sustained remission (SR) (a Birmingham Vasculitis Activity Score for Wegener granulomatosis [BVAS/WG] of 0 for 6 months) and was the first time we looked for an increase in proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) levels. We compared the net absorbance of PR3-ANCA at this visit with that of the previous 2 visits or the previous 6 months (curved lines). The same comparison was done at every subsequent visit. We defined a decrease in PR3-ANCA levels during the initial 6 months of follow-up as a decline of at least 50% in the net absorbance with an absolute decrease of at least 0.4; for values between 0.1 and 0.4, the capture ELISA needed to yield negative results. Statistical Analysis Descriptive data are summarized as mean (SD), median (interquartile range), or percentages. Groups were compared by using the t test (or the rank-sum test) or the chi-square test (or Fisher exact test), with 95% CIs calculated as appropriate. A P value less than 0.05 was considered statistically significant. We performed unadjusted and adjusted analyses. The adjusting variables were age, sex, disease severity (severe vs. limited Wegener granulomatosis), treatment group (etanercept vs. placebo), disease duration, baseline BVAS/WG, and clinical center (see Appendix 2 for additional details). PR3-ANCA Levels and Disease Activity The cross-sectional and longitudinal associations between the BVAS/WG and the levels of mature- and pro-PR3ANCA were estimated by using random-effect models. We constructed the models with BVAS/WG as the dependent variable and included a random effect for each patient (random intercept) and 2 terms for PR3-ANCA levelsone term for the value of PR3-ANCA level at baseline and the other for the change in PR3-ANCA level from baseline to time t. To assess the magnitude of the association between PR3-ANCA levels and the BVAS/WG, we estimated the relative reduction in the residual variance by comparing the residual variance of the model that included a random effect for each patient and 2 terms for PR3-ANCA levels with the residual variance of a model that only included the random effect for each patient. These analyses included only observations in which both BVAS/WG and PR3-ANCA level were available (9% of the observations had missing PR3-ANCA information). For patients who achieved sustained remission, the mature- and pro-PR3ANCA level

Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): Ten‐year experience at a single center

OBJECTIVE This study was conducted to evaluate the efficacy and safety of repeated and prolonged B cell depletion with rituximab (RTX) for the maintenance of long-term remission in patients with chronic relapsing granulomatosis with polyangiitis (Wegeners) (GPA). METHODS We conducted a single-center observational study of all patients with chronic relapsing GPA treated with at least 2 courses of RTX between January 1, 2000 and May 31, 2010. Participants in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were excluded from this analysis. Data were abstracted from electronic medical records. RESULTS Fifty-three patients with refractory GPA (median age 46 years [interquartile range (IQR) 30-61 years]; 53% women) received at least 2 courses of RTX to treat GPA relapses or to maintain remission. All but 1 patient had antineutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3). These patients received a median of 4 courses of RTX (IQR 3-5); all had depletion of B cells, and the median time to return of B cells was 8.5 months (IQR 6-11 months). All observed relapses occurred after reconstitution of B cells and were accompanied or preceded by an increase in ANCA levels, except for the 1 ANCA-negative patient. Infusion-related adverse events occurred in 16 patients. During the period of B cell depletion, 30 infections requiring antimicrobial therapy were recorded. CONCLUSION RTX appeared to be effective and safe for the induction and maintenance of remission in patients with chronic relapsing GPA. Repeated depletion of B lymphocytes seems to be associated with a low risk of infections. Preemptive re-treatment decisions can be individualized based on serial B lymphocyte and PR3 ANCA monitoring. The use of RTX for the maintenance of long-term remission merits further formal investigation.

Distribution of arterial lesions in Takayasu's arteritis and giant cell arteritis

Objectives To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasus arteritis (TAK) and giant cell arteritis (GCA). Methods Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification. Results Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA. Conclusions Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.

Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis

Objectives To evaluate incidence-trends and timing of large-vessel (LV) manifestations in patients with giant cell arteritis (GCA), and to examine the influence of LV manifestations on survival. Methods A population-based incident cohort of patients diagnosed with GCA between 1950 and 2004 was used. LV involvement was defined as large-artery stenosis or aortic aneurysm/dissection that developed in the 1 year before GCA diagnosis or at any time thereafter. Patients were followed up until death or 31 December 2009. Results The study included 204 patients, 80% women, mean age at diagnosis of GCA 76.0 years (±8.2 years). Median length of follow-up was 8.8 years. The cumulative incidence of any LV manifestation at 10 years was 24.9% for patients diagnosed with GCA between 1980 and 2004 compared with 8.3% for patients diagnosed with GCA between 1950 and 1979. The incidence of any LV event was high within the first year of GCA diagnosis. The incidence of aortic aneurysm/dissection increased 5 years after GCA diagnosis. Compared with the general population, survival was decreased in patients with an aortic aneurysm/dissection (standardized mortality ratio (SMR) 2.63; 95% CI 1.78 to 3.73) but not in patients with large-artery stenosis (SMR 1.44; 95% CI 0.87 to 2.25). Patients with GCA and aortic manifestations had a higher than expected number of deaths from cardiovascular and pulmonary causes than the general population. Among patients with GCA, aortic manifestations were associated with increased mortality (HR=3.4; 95% CI 2.2 to 5.4). Conclusions Vigilance and screening for aortic aneurysms should be considered in all patients 5 years after the incidence of GCA. Aortic aneurysm/dissection is associated with increased mortality in GCA.

Utility of Erythrocyte Sedimentation Rate and C-Reactive Protein for the Diagnosis of Giant Cell Arteritis

OBJECTIVES To evaluate the utility of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for the diagnosis of giant cell arteritis (GCA) and to determine the frequency of normal ESR and CRP at diagnosis of GCA. METHODS All patients undergoing temporal artery biopsy (TAB) between 2000 and 2008 were identified. Only subjects with both ESR and CRP at the time of TAB were included. The medical records of all patients were reviewed. RESULTS We included 764 patients (65% women), mean age 72.7 (±9.27) years, who underwent TAB. Biopsy was consistent with GCA in 177 patients (23%). Elevated CRP and elevated ESR provided a sensitivity of 86.9% and 84.1%, respectively, for a positive TAB. The odds ratio of a concordantly elevated ESR and CRP for positive TAB was 3.06 (95% CI 2.03, 4.62), whereas the odds ratio for concordantly normal ESR and CRP was 0.49 (95% CI 0.29, 0.83). Seven patients (4%) with a positive TAB for GCA had a normal ESR and CRP at diagnosis. Compared with GCA patients with elevated markers of inflammation, a greater proportion of these patients had polymyalgia rheumatica symptoms (P = 0.008), whereas constitutional symptoms, anemia and thrombocytosis, were observed less often (P < 0.05). CONCLUSIONS CRP is a more sensitive marker than ESR for a positive TAB that is diagnostic of GCA. There may be clinical utility in obtaining both tests in the evaluation of patients with suspected GCA. A small proportion of patients with GCA may have normal inflammatory markers at diagnosis.

Codeine and oxycodone use in patients with chronic rheumatic disease pain

OBJECTIVE Opioid treatment of chronic rheumatic disease pain is controversial because of concerns regarding efficacy, toxicity, tolerance, dependence, and abuse. This study examined opioid use in a cohort of patients with pain due to defined rheumatic diseases. METHODS Opioid use was studied retrospectively in a cohort of 644 rheumatology clinic patients. Computerized pharmacy records identified patients who had been prescribed opioids during the previous 3 years. Medical records were reviewed to determine reasons for opioid dosage escalations. Patients were interviewed to determine efficacy, frequency and types of side effects, and history of alcohol or street-drug abuse. RESULTS Opioid prescriptions were found in the 3-year pharmacy database for 290 of 644 clinic patients: 153 for <3 consecutive months and 137 for > or =3 months. All opioid-treated patients received codeine and/or oxycodone. In this cohort, 133 patients in each opioid-treated group and 76 of the 354 non-opioid-treated control patients were studied. Opioids significantly reduced rheumatic disease pain severity scores from 8.2 to 3.6 (on a 0-10 scale) (P < 0.001). Mild side effects were reported in 38%; nausea, dyspepsia, constipation, and sedation were the most common. The mean +/-SD initial dosage was 2.1+/-1.7 30-mg codeine equivalents/day, the mean peak was 3.4+/-3.3 per day, and the mean current dose was 2.7+/-2.0 per day. Dosage escalations occurred in 32 patients and were attributable to worsening of the underlying painful condition or a medical complication thereof in all but 4 patients, who also displayed other abuse behaviors. Abuse behaviors were not more frequent in those with or without a history of abuse/ addiction. CONCLUSION Prolonged treatment of rheumatic disease pain with codeine or oxycodone was effective in reducing pain severity and was associated with only mild toxicity. Doses were stable for prolonged periods of time, with escalations of the opioid dose almost always related to worsening of the painful condition or a complication thereof, rather than the development of tolerance to opioids. Doubts or concerns about opioid efficacy, toxicity, tolerance, and abuse or addiction should no longer be used to justify withholding opioids from patients with well-defined rheumatic disease pain.

Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study

Objectives To assess the accuracy of dual-energy CT (DECT) for diagnosing gout, and to explore whether it can have any impact on clinical decision making beyond the established diagnostic approach using polarising microscopy of synovial fluid (diagnostic yield). Methods Diagnostic single-centre study of 40 patients with active gout, and 41 individuals with other types of joint disease. Sensitivity and specificity of DECT for diagnosing gout was calculated against a combined reference standard (polarising and electron microscopy of synovial fluid). To explore the diagnostic yield of DECT scanning, a third cohort was assembled consisting of patients with inflammatory arthritis and risk factors for gout who had negative synovial fluid polarising microscopy results. Among these patients, the proportion of subjects with DECT findings indicating a diagnosis of gout was assessed. Results The sensitivity and specificity of DECT for diagnosing gout was 0.90 (95% CI 0.76 to 0.97) and 0.83 (95% CI 0.68 to 0.93), respectively. All false negative patients were observed among patients with acute, recent-onset gout. All false positive patients had advanced knee osteoarthritis. DECT in the diagnostic yield cohort revealed evidence of uric acid deposition in 14 out of 30 patients (46.7%). Conclusions DECT provides good diagnostic accuracy for detection of monosodium urate (MSU) deposits in patients with gout. However, sensitivity is lower in patients with recent-onset disease. DECT has a significant impact on clinical decision making when gout is suspected, but polarising microscopy of synovial fluid fails to demonstrate the presence of MSU crystals.

Identification of multiple genetic susceptibility loci in Takayasu arteritis

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).