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Objectives: This study aimed to identify plasma proteomic signatures that differentiate active and inactive giant cell arteritis (GCA) from non-disease controls. By comprehensively profiling the plasma proteome of both patients with GCA and controls, we aimed to identify plasma proteins that (1) distinguish patients from controls and (2) associate with disease activity in GCA., Methods: Plasma samples were obtained from 30 patients with GCA in a multi-institutional, prospective longitudinal study: one captured during active disease and another while in clinical remission. Samples from 30 age-matched/sex-matched/race-matched non-disease controls were also collected. A high-throughput, aptamer-based proteomics assay, which examines over 7000 protein features, was used to generate plasma proteome profiles from study participants., Results: After adjusting for potential confounders, we identified 537 proteins differentially abundant between active GCA and controls, and 781 between inactive GCA and controls. These proteins suggest distinct immune responses, metabolic pathways and potentially novel physiological processes involved in each disease state. Additionally, we found 16 proteins associated with disease activity in patients with active GCA. Random forest models trained on the plasma proteome profiles accurately differentiated active and inactive GCA groups from controls (95.0% and 98.3% in 10-fold cross-validation, respectively). However, plasma proteins alone provided limited ability to distinguish between active and inactive disease states within the same patients., Conclusions: This comprehensive analysis of the plasma proteome in GCA suggests that blood protein signatures integrated with machine learning hold promise for discovering multiplex biomarkers for GCA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

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., Competing Interests: Competing interests: RMS reports research grant for the trial from Roche during the conduct of the study. RBJ reports contract with Roche for provision of rituximab for another trial. US reports grants from Genentech, during the conduct of the study. AB has received consulting fees from AstraZeneca, Bayer, ChemoCentryx, Fresenius, and Vifor and honoraria for lectures from AstraZeneca, Bayer, ChemoCentryx, Fresenius, and Vifor. AB sits on the Advisory Board for AstraZeneca and Bayer and is Chair of the Immunonephrology working group of ERA. BC has received honoraria from Astra Zeneca and NAPP Pharmaceuticals. SC is on an advisory board for Sanofi. CKC reports participation in an advisory board for CSL Vifor. VD reports grants from NIDDK/NIH, NIAID/NIH and NHLBI/NIH; royalties from UptoDate; consulting fees from Novartis and Forma Therapeutics; participation on advisory boards for Merck, Forma Therapeutics and Bayer. LF reports grants from Bristol Meyer Squibb and Novartis and consulting fees from Chemocentryx. S Fujimoto reports grants and honoraria from Chugai Pharmaceutical Co., Ltd. S Furuta reports honoraria from Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo, Kissei Pharma, Asahi Kasei Pharma and Eisai. NK reports grants from BMS, Abbvie and Sanofi; consulting fees from Roche and honoraria from AstraZeneca, Kataka Medical, Otsuka, GlaxoSmithKline and Mallinckrodt. CK reports honoraria from Chemocentryx. CL reports grants from Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca and National Institutes of Health and honoraria from Ohio Association of Rheumatology, McGraw Hill, California Rheumatology Alliance and American Academy of Allergy, Asthma and Immunology. PL reports a research grant from Vifor pharma and consulting fees from Pfizer and is Co-chair, Rare Autoimmune Rheumatic Disease Alliance (RAIRDA), and Rare Diseases Clinical Lead, National Disease Registration Service, NHS Digital. PN has received consulting fees from Chemocentryx and Q32. C Pagnoux has received research grants from Teva, Amgen, Pfizer and Otsuka, consulting fees from Roche, Otsuka and GlaxoSmithKline and honoraria from Roche, GlaxoSmithKline, AstraZeneca and Otsuka and participated on an advisory board for AstraZeneca. C Pusey has received research grants from Kidney Research UK, Wellcome Trust, Medical Research Council, Vasculitis UK and Imperial Health Charity; consulting fees from Vifor and Alentis; honoraria from MedUpdate and Amgen; participation in advisory boards for COMBIVAS and OBIVAS trials. RS has received research grants from Roche-Genentech, AstraZeneca, GlaxoSmithKline, Kadmon, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Novartis, Inflarx and Principia; consulting fees from GlaxoSmithKline, Boehringer Ingelheim, Regeneron, Abbvie, Sanofi, Chemocentryx, Novartis, Galderma, Vera, Chemomab and BMS; honoraria from GlaxoSmithKline, Abbvie, Sanofi, Chemocentryx, Novartis, Galderma and BMS. AS is an employee of Bristol-Myers Squibb. DJ has received grants from AstraZeneca, GlaxoSmithKline and Roche; consulting fees from Astra-Zeneca, Chemocentryx, GSK, Novartis, Otsuka, Takeda, Roche, Vifor; honoraria from GlaxoSmithKline and Vifor; participation on advisory boards for Chinook, GlaxoSmithKline and Takeda and stock options from Aurinia. PM reports research grants from AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, GlaxoSmithKline, Immagene, InfalRx, Jannsen, Jubilant, Kyverna, Magenta, MicroBio, Neutrolis, Novartis, NS Pharma, Otsuka, Q32, Regeneron, Sparrow, Takeda; royalties from UpToDate; Consulting fees from AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, GlaxoSmithKline, immagene, InfalRx, Jannsen, Jubilant, Kyverna, Magenta, MicroBio, Neutrolis, Novartis, NS Pharma, Otsuka, Q32, Regeneron, Sparrow, Takeda; meeting fees from ChemoCentryx and stock options from Kyverna., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial., Methods: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m 2 ) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse., Results: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections., Conclusions: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies., Competing Interests: Competing interests: RMS reports grants from Roche during the conduct of the study. RBJ reports grants from GlaxoSmithKline, personal fees from ChemoCentryx outside the submitted work. US reports grants from Genentech, during the conduct of the study, grants from ChemoCentryx, grants from BMS, grants from GSK, personal fees from Astra Zeneca, outside the submitted work. AB reports grants and personal fees from Astra Zeneca, personal fees from ChemoCentryx, personal fees from Merck/MSD, personal fees from Abbvie outside the submitted work. CKC reports grants from GlaxoSmithKline, grants and consultancy fees from Retrophin outside the submitted work. CL reports grants from Genentech during the conduct of the study. NK reports personal fees and non-financial support from Roche, non-financial support from Bristol Meyers Squibb outside the submitted work. CK reports other from Genentech, other from Roche outside the submitted work. RAL reports grants from Arthritis Research UK, grants from GlaxoSmithKline, grants from MRC, grants from University of Oxford Innovation Fund, grants from Canadian Institutes of Health Research, grants from The Vasculitis Foundation, grants from Celgene, grants from Vifor, personal fees from Grunenthal, personal fees from GSK, personal fees from InflaRx, personal fees from Medpace, personal fees from MedImmune, personal fees from Roche, outside the submitted work. HM reports personal fees from AbbVie, personal fees from Boehringer-Ingelheim, personal fees from Teijin, outside the submitted work. PM reports personal fees from Kiniksa, personal fees from ChemoCentryx, personal fees from Celgene, personal fees from Insmed, outside the submitted work. PN reports other from Chemocentryx, other from InflaRx, other from Omeros, other from Aurinia outside the submitted work. CP reports grants and personal fees from Roche, personal fees from ChemoCentryx, grants and personal fees from GlaxoSmithKline, personal fees from Sanofi, personal fees from InflaRx outside the submitted work. FP reports grants from Vifor pharma outside the submitted work. RS reports grants from GlaxoSmithKline, grants from chemocentryx, grants from Roche/Genentech, grants from BIPI, personal fees from GlaxoSmithKline, personal fees from chemocentryx. RS reports personal fees from Bristol-Myers Squibb, other from Alexion outside the submitted work. VT reports other from Abbvie, other from Amgen, other from Boehringer-Ingelheim, other from Calliditas, other from Chemocentryx, other from FMC, other from Retrophin outside the submitted work. PM reports personal fees from AbbVie, grants and personal fees from AstraZeneca, personal fees from Biogen, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Boeringher-Ingelheim, grants and personal fees from Celgene, grants and personal fees from ChemoCentryx, CSL Behring, grants and personal fees from Genentech/Roche, grants and personal fees from Genzyme/Sanofi, grants and personal fees from GlaxoSmithKline, grants and personal fees from InflaRx, personal fees from Insmed, personal fees from Jannsen, personal fees from Kiniksa, grants from Kypha, personal fees from Sparrow, grants from TerumoBCT outside the submitted work. DJ reports grants from Roche/Genentech, during the conduct of the study; grants from Sanofi-Genzyme, grants and personal fees from Chemocentryx, grants and personal fees from GSK, grants from Roche/Genentech, personal fees from Takeda, personal fees from Insmed, personal fees from Astra-Zeneca, personal fees from Infla-RX, personal fees from Chugai, personal fees from Boehringer-Ingelheim outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Prior studies have suggested a potential link between nasal microbes and granulomatosis with polyangiitis (GPA; Wegener's), but these studies relied on culture-dependent methods. This study comprehensively examined the entire community of nasal microbiota (bacteria and fungi) in participants with GPA compared with healthy controls using deep sequencing methods., Methods: 16S rRNA and internal transcribed spacer gene sequencing were performed on nasal microbial DNA isolated from nasal swabs of 60 participants with GPA and 41 healthy controls. Alpha and beta diversity were assessed as well as the relative abundance of the most abundant bacterial and fungal taxa. The effects of covariates including disease activity and immunosuppressive therapies on microbial composition were evaluated., Results: Compared with controls, participants with GPA had a significantly different microbial composition (weighted UniFrac p=0.04) and lower relative abundance of Propionibacterium acnes and Staphylococcus epidermidis (for both, false discovery rate-corrected p=0.02). Disease activity in GPA was associated with a lower abundance of fungal order Malasseziales compared with participants with GPA in remission (p=0.04) and controls (p=0.01). Use of non-glucocorticoid immunosuppressive therapy was associated with 'healthy' nasal microbiota while participants with GPA who were off immunosuppressive therapy had more dysbiosis (weighted UniFrac p=0.01). No difference in the relative abundance of Staphylococcus aureus was observed between GPA and controls., Conclusions: GPA is associated with an altered nasal microbial composition, at both the bacterial and fungal levels. Use of immunosuppressive therapies and disease remission are associated with healthy microbial communities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Alterations in the immune system and infections are suspected to increase susceptibility to giant cell arteritis (GCA). Recently herpes zoster has been directly implicated in the pathogenesis of GCA. We examined the association between prior infections, in particular herpes zoster, and incident GCA in a population-based cohort., Methods: A nested case-control study was performed using an electronic database from the UK. Cases with newly diagnosed GCA were identified using a validated algorithm and compared with age-matched, sex-matched and practice-matched controls. Conditional logistic regression was used to examine the relationship between any infection or herpes zoster infection on the development of GCA after adjusting for potential confounders; results were expressed as incidence rate ratios (IRRs)., Results: There were 4559 cases of GCA and 22 795 controls. Any prior infection and herpes zoster were associated with incident GCA (IRR 1.26 (95% CI 1.16 to 1.36), p<0.01; and 1.17 (95% CI 1.04 to 1.32), p<0.01, respectively). A greater number of infections was associated with a higher risk of developing GCA (IRR for 1, 2-4 and ≥5 infections was 1.28, 1.60 and 2.18, respectively)., Conclusions: Antecedent infections and, to a lesser extent, herpes zoster infections are modestly associated with incident GCA. These data provide population-level support for the hypothesis that long-standing alterations of the immune system are associated with susceptibility to GCA and suggest that herpes zoster is unlikely to play a major causal role in the pathogenesis of GCA., Competing Interests: Competing interests: Intercontinental Marketing Services (IMS) Health Real World Evidence Solutions is an UK-based expert in anonymous patient data for the healthcare industry. IMS Health is a commercial organisation that supplies data and trains and supports researchers in the use of primary care patient data. Data are available for us in medical research in the academic setting as well as in industry for a fee which varies depending on the type of data requested. Aside from undergoing ethical review by The Health Improvement Network (THIN) Scientific Review Committee, independent academic groups who voluntarily act as an ethical review body, this protocol was not in any way discussed with IMS Health nor were any changes made by the company. We did not receive financial support or other forms of computational or analytical support from IMS/THIN. The data were collected by IMS and the general practitioners without knowledge of the study objectives and hypotheses., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity as a surrogate marker for haemodynamics and predictor of outcome in isolated pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). We designed this work to address this issue., Methods: Treatment-naïve patients with SSc-PAH were prospectively included from two sources: the French PAH Network (a prospective epidemiological cohort) (n=83) and randomised clinical trials submitted for drug approval (Food and Drug Administration) (n=332). Correlations between absolute values of the 6MWD and haemodynamics at baseline, as well as between variations of 6MWD and haemodynamics during follow-up, were studied in both populations., Results: In the French cohort, baseline cardiac output (CO) (R(2)=0.19, p=0.001) and New York Heart Association class (R(2)=0.10, p<0.001) were significantly and independently correlated with baseline 6MWD in multivariate analysis. A significant, independent, but weaker, correlation with CO was also found in the Food and Drug Administration sample (R(2)=0.04, p<0.001). During follow-up, there was no association between the changes in 6MWD and haemodynamic parameters in patients under PAH-specific treatments., Conclusions: In SSc-PAH, CO independently correlates with 6MWD at baseline, but accounts for a small amount of the variance of 6MWD in both study samples. This suggests that other non-haemodynamic factors could have an impact on the walk distance. Moreover, variations of 6MWD do not reflect changes in haemodynamics among treated patients. Our results suggest that 6MWD is not an accurate surrogate marker for haemodynamic severity, nor an appropriate outcome measure to assess changes in haemodynamics during follow-up in treated SSc-PAH., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)