Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS).

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.

Web-Based Mindfulness-Based Interventions for Well-being: Randomized Comparative Effectiveness Trial.

BACKGROUND: Mindfulness can improve overall well-being by training individuals to focus on the present moment without judging their thoughts. However, it is unknown how much mindfulness practice and training are necessary to improve well-being. OBJECTIVE: The primary aim of this study was to determine whether a standard 8-session web-based mindfulness-based cognitive therapy (MBCT) program, compared with a brief 3-session mindfulness intervention, improved overall participant well-being. In addition, we sought to explore whether the treatment effects differed based on the baseline characteristics of the participants (ie, moderators). METHODS: Participants were recruited from 17 patient-powered research networks, web-based communities of stakeholders interested in a common research area. Participants were randomized to either a standard 8-session MBCT or a brief 3-session mindfulness training intervention accessed on the web. The participants were followed for 12 weeks. The primary outcome of the study was well-being, as measured by the World Health Organization-Five Well-Being Index. We hypothesized that MBCT would be superior to a brief mindfulness training. RESULTS: We randomized 4411 participants, 3873 (87.80%) of whom were White and 3547 (80.41%) of female sex assigned at birth. The mean baseline World Health Organization-Five Well-Being Index score was 50.3 (SD 20.7). The average self-reported well-being in each group increased over the intervention period (baseline to 8 weeks; model-based slope for the MBCT group: 0.78, 95% CI 0.63-0.93, and brief mindfulness group: 0.76, 95% CI 0.60-0.91) as well as the full study period (ie, intervention plus follow-up; baseline to 20 weeks; model-based slope for MBCT group: 0.41, 95% CI 0.34-0.48; and brief mindfulness group: 0.33, 95% CI 0.26-0.40). Changes in self-reported well-being were not significantly different between MBCT and brief mindfulness during the intervention period (model-based difference in slopes: -0.02, 95% CI -0.24 to 0.19; P=.80) or during the intervention period plus 12-week follow-up (-0.08, 95% CI -0.18 to 0.02; P=.10). During the intervention period, younger participants (P=.05) and participants who completed a higher percentage of intervention sessions (P=.005) experienced greater improvements in well-being across both interventions, with effects that were stronger for participants in the MBCT condition. Attrition was high (ie, 2142/4411, 48.56%), which is an important limitation of this study. CONCLUSIONS: Standard MBCT improved well-being but was not superior to a brief mindfulness intervention. This finding suggests that shorter mindfulness programs could yield important benefits across the general population of individuals with various medical conditions. Younger people and participants who completed more intervention sessions reported greater improvements in well-being, an effect that was more pronounced for participants in the MBCT condition. This finding suggests that standard MBCT may be a better choice for younger people as well as treatment-adherent individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03844321; https://clinicaltrials.gov/ct2/show/NCT03844321.

Harnessing health plan enrollee data to boost membership in patient-powered research networks.

BACKGROUND: Patient-powered research networks (PPRNs) have been employing and exploring different methods to engage patients in research activities specific to their conditions. One way to intensify patient engagement is to partner with payer stakeholders. The objective of this study was to evaluate the effectiveness of two common payer-initiated outreach methods (postal mail versus email) for inviting prospective candidates to participate in their initiatives. METHODS: This descriptive study linked members of a nationally-representative private insurance network to four disease-specific PPRN registries. Eligible members meeting diagnostic criteria who were not registered in any of the four PPRNs by 02/28/2018 were identified, and randomly assigned to either the mail or email group. They were contacted in two outreach efforts: first on 04/23/2018, and one follow-up on 05/23/2018. New registration rates by outreach method as of 8/31/2018 were determined by relinking. We compared registrants and non-registrants using bivariate analysis. RESULTS: A total of 14,571 patients were assigned to the mail group, and 14,574 to the email group. Invitations were successfully delivered to 13,834 (94.9%) mail group and 10,205 (70.0%) email group members. A small but significantly larger proportion of mail group members, (n = 78; 0.54, 95% Confidence Interval [CI] {0.42-0.67%}) registered in PPRNs relative to the email group (n = 24; 0.16, 95% CI {0.11-0.25%}), p < 0.001. Members who registered had more comorbidities, were more likely to be female, and had marginally greater medical utilization, especially emergency room visits, relative to non-registrants (52.0% vs. 42.5%, p = 0.05). CONCLUSION: A health plan outreach to invite members to participate in PPRNs was modestly effective. Regular mail outperformed less costly email. Providing more value-add to participants may be a possible way to increase recruitment success.

Racial and Ethnic Distribution of Rheumatic Diseases in Health Systems of the National Patient-Centered Clinical Research Network.

OBJECTIVE: To evaluate the relative prevalence of 8 rheumatic and musculoskeletal diseases (RMDs) across racial and ethnic groups within the National Patient-Centered Clinical Research Network (PCORnet). METHODS: Electronic health records from participating PCORnet institutions and systems from January 1, 2013, to December 31, 2018, were used to identify adult patients with ≥ 2 diagnosis codes for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), osteoporosis (OP), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis (GCA), and Takayasu arteritis (TAK). Among those with race and ethnicity data available, we compared prevalence of RMDs by race and ethnicity. RESULTS: Data from 28,059,546 patients were available for analysis. RA was more common in patients who were American Indian or Alaska Native vs White, with a prevalence of 11.57 vs 10.11/1000 (odds ratio [OR] 1.15, 95% CI 1.09-1.22). SLE was more common in patients who were Black or African American (6.73/1000), American Indian or Alaska Native (3.82/1000), and Asian (3.39/1000) vs White (2.80/1000; OR 2.43, 95% CI 2.39-2.46; OR 1.39, 95% CI 1.25-1.53; OR 1.26, 95% CI 1.21-1.31, respectively). SLE was more common in patients who were Hispanic vs non-Hispanic (prevalence 3.93 vs 3.45/1000, OR 1.14, 95% CI 1.12-1.16). TAK was more common in patients who were Asian vs White (prevalence 0.05 vs 0.04/1000, OR 1.43, 95% CI 1.00-2.03). OP, RA, and the vasculitides were all more common in patients who were White vs Black or African American. CONCLUSION: These data provide important information on the prevalence of RMDs by race and ethnicity in the United States. PCORnet can be used as a reliable data source to study RMDs within a large representative population.

Serum biomarkers of glucocorticoid response and safety in anti-neutrophil cytoplasmic antibody-associated vasculitis and juvenile dermatomyositis.

Glucocorticoids are standard of care for many chronic inflammatory conditions, including juvenile dermatomyositis (JDM) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We sought to define pharmacodynamic biomarkers of therapeutic efficacy and safety concerns of glucocorticoid treatment for these two disorders. Previous proteomic profiling of patients with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease (IBD) treated with glucocorticoids identified candidate biomarkers for efficacy and safety concerns of glucocorticoids. Serial serum samples from patients with AAV (n = 30) and JDM (n = 12) were obtained during active disease, and after treatment with glucocorticoids. For AAV, 8 of 11 biomarkers of the anti-inflammatory response to glucocorticoids were validated (P-value ≤0.05; CD23, macrophage-derived cytokine, interleukin-22 binding protein, matrix metalloproteinase-12, T lymphocyte surface antigen Ly9, fibrinogen gamma chain, angiopoietin-2 [all decreased], and protein C [increased]), as were 5 of 7 safety biomarkers (P-value ≤0.05; afamin, matrix metalloproteinase-3, insulin growth factor binding protein-5, angiotensinogen, leptin [all increased]). For JDM, 10 of 11 efficacy biomarkers were validated (P-value ≤0.05; all proteins except fibrinogen gamma chain) and 6 of 7 safety biomarkers (P-value ≤0.05; AAV proteins plus growth hormone binding protein). The identified efficacy biomarkers may be useful as objective outcome measures for early phase proof-of-concept studies when assessing novel anti-inflammatory drugs in JDM and AAV, and likely in other inflammatory disorders. Similarly, safety biomarkers may also be helpful assessing toxicity of alternatives to glucocorticoids.

Effect of Disease Activity, Glucocorticoid Exposure, and Rituximab on Body Composition During Induction Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: We investigated the relationships between glucocorticoid use, disease activity, and changes in body mass index (BMI) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We analyzed AAV patients enrolled in the Rituximab in AAV trial. Glucocorticoid use, BMI, and disease activity were measured regularly during the trial period. We performed mixed-effects regressions to examine the associations of time-dependent cumulative average glucocorticoid use and disease activity with changes in BMI over time, while adjusting for potential confounders. RESULTS: The mean ± SD baseline BMI of the 197 patients enrolled was 28.8 ± 6.3 kg/m2 . Patients with newly diagnosed AAV tended to have a lower mean ± SD BMI than those with relapsing disease (28.0 ± 5.7 kg/m2 versus 29.6 ± 6.8 kg/m2 ) and higher disease activity (mean ± SD Birmingham Vasculitis Activity Score for Wegener's Granulomatosis 8.7 ± 3.3 versus 7.4 ± 2.7). The most significant change in BMI occurred during the first 6 months of the trial (mean ± SD increase of 1.1 ± 2.2 kg/m2 ; P < 0.0001). Disease activity improvement, glucocorticoid exposure, and randomization to rituximab were each independently associated with an increase in BMI (P < 0.001 for all analyses). CONCLUSION: Our findings suggest that changes in BMI, as well as glucocorticoid exposure, are independently associated with improvements in disease activity in AAV. Rituximab may also have effects on BMI independent of its impact on disease activity.

Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: A meta-analysis.

OBJECTIVE: Disease relapses are common for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The role of low-dose glucocorticoids (GC) in relapse prevention is controversial. We undertook a systematic review and meta-analysis to determine if GC target doses influence relapses of AAV. METHODS: Medline, EMBase, and Cochrane databases were searched for observational studies and randomized controlled trials of treatment of AAV that included a predefined GC treatment plan. The association of GC target dose with the proportion of relapses in studies was assessed using meta-regression and multilevel generalized linear modeling. RESULTS: Thirteen studies (983 patients) were identified for inclusion. There were no studies directly comparing GC regimens. We classified 288 patients as having a nonzero GC target dose by study end and 695 patients as having a zero GC target dose by study end. The pooled proportion of patients with a relapse was 36% (95% confidence interval [95% CI] 25-47%). GC regimen was the most significant variable explaining the variability between the proportions of patients with relapses. The proportion of patients with a relapse was 14% (95% CI 10-19%) in nonzero GC target dose studies and 43% (95% CI 33-52%) in zero GC target dose studies. Differences other than GC regimens exist between studies that complicate the comparability of trials and isolation of the variability in relapses due to GC target alone. CONCLUSION: Studies with longer courses of GC in AAV are associated with fewer relapses. These results have implications for study design and outcome assessment in clinical trials of AAV.