Large-vessel involvement in ANCA-associated vasculitis: A multicenter case-control study.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) primarily affects small vessels. Large-vessel involvement (LVI) is rare. We aimed to describe the characteristics of LVI, to identify associated risk factors, and to describe its therapeutic management. METHODS: This multicenter case-control (1:2) study included patients with AAV according to the ACR/EULAR classification and LVI as defined by the Chapel Hill nomenclature, together with controls matched for age, sex, and AAV type. RESULTS: We included 26 patients, 15 (58 %) of whom were men, with a mean age of 56.0 ± 17.1 years. The patients had granulomatosis with polyangiitis (n = 20), or microscopic polyangiitis (n = 6). The affected vessels included the aorta (n = 18; 69 %) supra-aortic trunks (n = 9; 35 %), lower-limb arteries (n = 5; 19 %), mesenteric arteries (n = 5; 19 %), renal arteries (n = 4; 15 %), and upper-limb arteries (n = 2; 8 %). Imaging showed wall thickening (n = 10; 38 %), perivascular inflammation (n = 8; 31 %), aneurysms (n = 5; 19 %), and stenosis (n = 4; 15 %). Comparisons with the control group revealed that LVI was significantly associated with neurological manifestations (OR=3.23 [95 % CI: 1.11-10.01, p = 0.03]), but not with cardiovascular risk factors (OR=0.70 [95 % CI: 0.23-2.21, p = 0.60]), or AAV relapse (OR=2.01 [95 % CI: 0.70-5.88, p = 0.16]). All patients received corticosteroids, in combination with an immunosuppressant in 24 (92 %), mostly cyclophosphamide (n = 10, 38 %) or rituximab (n = 9, 35 %). CONCLUSION: Regardless of distinctions based on vessel size, clinicians should consider LVI as a potential manifestation of AAV, with the aorta commonly affected. The risk of developing LVI appears to be greater for clinical phenotypes of AAV with neurological involvement. Standard AAV treatment can be used to manage LVI.

Therapeutic management of fibrosis in systemic sclerosis patients - an analysis from the Swiss EUSTAR cohort.

OBJECTIVES: Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. METHODS: Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. RESULTS: A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. CONCLUSION: Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.

[Challenges and perspectives for the treatment of giant cell arteritis]. / Défis et perspectives pour le traitement de l'artérite à cellules géantes.

Early diagnosis and prompt initiation of treatment are crucial to avoid severe complications in giant cell arteritis (GCA). The European Alliance of Associations for Rheumatology (EULAR) recommendations for the use of imaging in large vessel vasculitis have helped better define the role of different techniques for diagnosing and monitoring the disease. Regarding the treatment, corticosteroids remain the standard, and tocilizumab is the preferred corticosteroid-sparing treatment. New corticosteroid-sparing treatments and "ultra-light" corticosteroid usage regimens are also under study and could represent valid therapeutic alternatives in the future.

L'artérite à cellules géantes est une vascularite pouvant avoir de graves conséquences, telles que la cécité. Le diagnostic et l'introduction d'un traitement dans les meilleurs délais sont cruciaux pour éviter ces complications. Les recommandations de l'Alliance des associations européennes pour la rhumatologie (EULAR) sur l'utilisation de l'imagerie dans les vascularites des gros vaisseaux ont permis de mieux définir le rôle des différentes techniques pour le diagnostic et le suivi de la maladie. Concernant le traitement, les corticostéroïdes restent la référence et le tocilizumab le traitement d'épargne cortisonique de choix. De nouveaux traitements d'épargne cortisonique et des schémas d'utilisation des glucocorticoïdes à doses « ultra-faibles ¼ sont aussi en phase d'étude et pourraient représenter de futures alternatives thérapeutiques.

[Rheumatology: what's new in 2023]. / Rhumatologie: ce qui a changé en 2023.

In rheumatology, this year has been characterized by a broader knowledge of the pathogenesis of rheumatoid arthritis and mechanisms involved in the onset and persistence of low back pain. Studies relevant to the management of of gout, axial spondyloarthritis, autoinflammatory diseases and systemic vasculitides were published. New data on the safety of JAK inhibitors have been published. The ASAS-EULAR recommendations for the treatment of axial spondyloarthritis were updated, and the 2023 EULAR/PReS guidelines for the diagnosis and treatment of systemic juvenile idiopathic arthritis and adult-onset Still's disease are now available. New molecules and different glucocorticoid sparing strategies were introduced for giant cell arteritis.

En 2023, en rhumatologie, une avancée des connaissances sur la pathogenèse de la polyarthrite rhumatoïde et des mécanismes impliqués dans l'apparition et la persistance des lombalgies a été notée. Des études relevantes pour le traitement de la goutte, de la spondylarthrite axiale, des maladies auto-inflammatoires et des vascularites systémiques ont été publiées. De nouvelles données concernant la sécurité des inhibiteurs de Janus kinase sont disponibles. Les directives ASAS-EULAR pour le traitement de la spondylarthrite axiale ont été actualisées et les recommandations EULAR/PReS 2023 pour le diagnostic et le traitement de l'arthrite juvénile idiopathique systémique et de la maladie de Still de l'adulte sont désormais disponibles. De nouvelles molécules et différentes stratégies d'épargne des glucocorticoïdes ont été proposées pour l'artérite à cellules géantes.

Can efficacy and safety data from clinical trials of rituximab in RA be extrapolated? Insights from 1984 patients from the AIR-PR Registry.

OBJECTIVES: To investigate whether the efficacy and safety data from drug-registration trials can be extrapolated to real-life RA patients receiving RTX. METHODS: The AIR-PR registry is a French multicentre, prospective cohort of RA patients treated with RTX in a real-life setting. We compared treatment responses at 12 months and serious AEs between eligible and non-eligible patients, by retrieving the eligibility criteria of the three rituximab-registration trials. We determined critical eligibility criteria and modelled the benefit-risk ratio according to the number of fulfilled critical eligibility criteria. RESULTS: Among 1984 RA patients, only 9-12% fulfilled all eligibility criteria. Non-eligible patients had less EULAR response at 12 months (40.3% vs 46.9%, p= 0.044). Critical inclusion criteria included SJC ≥ 4, TJC ≥ 4, CRP ≥ 15 mg/l, and RF positivity. Critical exclusion criteria were age >80 years, RA-associated systemic diseases, ACR functional class IV, other DMARD than methotrexate, and prednisone > 10 mg/day. Only 20.8% fulfilled those critical eligibility criteria. During the first year, serious AEs occurred for 182 (9.2%) patients, (70.3% serious infections) and patients with ≥1 critical exclusion criterion were at higher risk (HR 3.03; 95%CI 2.25-4.06; for ≥ 3 criteria vs 0). The incremental risk-benefit ratio decreased with the number of unmet critical inclusion criteria and of fulfilled exclusion criteria. CONCLUSION: Few real-life RA patients were eligible for the drug-registration trials. Non-eligible patients had lower chance of response, and higher risk of serious AEs. Efficacy and safety data obtained from those trials may not be generalizable to RA patients receiving RTX in real-world clinical practice.

Time to Publication and Time-Lag Publication Bias for Randomized Trials on Connective Tissue Diseases.

OBJECTIVE: To assess the time from completion to publication of randomized controlled trials (RCTs) on connective tissue diseases (CTDs), investigate the factors associated with, and explore the influence of significance of study results on time to publication (time-lag publication bias). METHODS: We included interventional, phase 2/3, 3, or 4 RCTs on CTDs registered in Clinicaltrials.gov from 2000 to 2016, whose results had been published in a peer-review journal less than 5 years after their completion. Main trial features, including the significance of primary outcome results, were collected. Time to publication was the time from study completion to the earliest publication date. Multivariable linear regression was used to identify factors associated with time to publication. RESULTS: We included 62 studies, mostly phase 3 (61%) trials on pharmacologic treatments (94%); we recruited patients with systemic lupus (55%) or systemic sclerosis (23%) and planned to enroll a median of 131 (IQR [interquartile range]: 61-288) patients. Twenty-two (35%) reported at least a statistically significant primary outcome. Median time to publication was 28 months (IQR: 17-36). In a multivariable analysis, time to publication progressively improved over time (faster publication in recent years, with the average time to publication decreasing by 1.3 [95% CI: 0.3-2.3] months per year) and was not influenced by the significance of primary outcome results, funder, impact factor of the journal, number of recruiting countries, and comparator. CONCLUSION: A high proportion of CTDs-RCTs is published beyond 2 years from completion. We did not find evidence of time-lag publication bias, and time to publication improved over time.

Management of giant-cell arteritis in Switzerland: an online national survey.

AIMS OF THE STUDY: To assess current practices in diagnosing, treating, and following-up giant-cell arteritis by specialists in Switzerland and to identify the main barriers to using diagnostic tools. METHODS: We performed a national survey of specialists potentially caring for patients with giant-cell arteritis. The survey was sent by email to all members of the Swiss Societies of Rheumatology and for Allergy and Immunology. A reminder was sent to nonresponders after 4 and 12 weeks. Its questions covered the following dimensions: respondents' main characteristics, diagnosis, treatment, and imaging's role during follow-up. The main study results were summarized using descriptive statistics. RESULTS: Ninety-one specialists, primarily aged 46-65 years (n = 53/89; 59%), working in academic or nonacademic hospitals or private practice, and treating a median of 7.5 (interquartile range [IQR]: 3-12) patients with giant-cell arteritis per year participated in this survey. Ultrasound of temporal arteries/large vessels (n = 75/90; 83%) and positron-emission-tomography-computed tomography (n = 52/91; 57%) or magnetic resonance imaging (n = 46/90; 51%) of the aorta/extracranial arteries were the most common techniques used to diagnose giant-cell arteritis with cranial or large vessel involvement, respectively. Most participants reported a short time to obtain imaging tests or arterial biopsy. The glucocorticoid tapering scheme, glucocorticoid-sparing agent, and glucocorticoid-sparing treatment duration varied among the participants. Most physicians did not follow a predefined repeat imaging scheme for follow-up and mainly relied on structural changes (vascular thickening, stenosis, or dilatation) to drive treatment choice. CONCLUSIONS: This survey indicates that imaging and temporal biopsy are rapidly accessible for diagnosing giant-cell arteritis in Switzerland but highlights heterogeneous practice in many disease management areas.

[What's new in the management of systemic sclerosis]. / Nouveautés dans la prise en charge de la sclérodermie systémique.

This review of the literature highlights the results of the recent randomized controlled trials about the management of systemic sclerosis (SSc) and its complications. The latest randomized studies have failed to demonstrate the utility against placebo of the injections of botulinum toxin A to achieve a better control of Raynaud's phenomenon and the efficacy of the adipose-derived cell transplantation for the treatment of hand dysfunction. Rituximab allows a significant improvement of cutaneous induration. The injections of mesenchymal stromal cells are well tolerated and should encourage future randomized trials to evaluate their efficacy. Finally, nintedanib and tocilizumab allow a reduction in the rate of decline of lung function, as well as a possible stabilization with tocilizumab.

Cet article expose les résultats des essais randomisés et contrôlés récents concernant la prise en charge de la sclérodermie systémique (SSc) et ses complications. Les études discutent l'utilité des injections de la toxine botulinique pour le contrôle du phénomène de Raynaud, et des injections de cellules dérivées du tissu adipeux pour améliorer la fonctionnalité de la main. Le rituximab permet une amélioration significative de l'induration cutanée, et les injections de cellules stromales mésenchymateuses, en plus d'être bien tolérées, ouvrent la voie à d'éventuels essais randomisés en vue d'évaluer leur efficacité. Finalement, le nintédanib et le tocilizumab permettent une réduction du taux de déclin de la fonction pulmonaire, jusqu'à une éventuelle stabilisation de cette dernière observée avec le tocilizumab.

Induction failure in granulomatosis with polyangiitis: a nationwide case-control study of risk factors and outcomes.

OBJECTIVE: To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy. METHODS: We conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment. RESULTS: We included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P = 0.02), relapsing disease (41% vs 7%, P < 0.001) and orbital mass (15% vs 0%, P < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P = 0.02) with renal failure (serum creatinine >100 µmol/l in 42% vs 8%, P = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone. CONCLUSION: In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality.

[Rheumatology : what's new in 2022]. / Rhumatologie : ce qui a changé en 2022.

In rheumatology, this year has seen an expansion of knowledge about the treatment of rheumatoid arthritis, with the availability of results from randomized trials evaluating a new molecule targeting IL-6, and regarding the safety profile of tofacitinib compared to TNF-alpha inhibitors. Interesting data on the outcome of pregnancy in patients with spondylarthritis have also been published. New molecules and different treatment strategies have shown promising results in psoriatic arthritis and systemic lupus erythematosus. The utility of botulinum toxin A injections for Raynaud's phenomenon and the efficacy of transplantation of autologous adipose-derived regenerative cells for the treatment of hand dysfunctions have been questioned by 2 randomized controlled trials of patients with systemic sclerosis.

Cette année a vu un approfondissement des connaissances sur le traitement de la polyarthrite rhumatoïde, avec la publication de résultats d'essais randomisés évaluant une nouvelle molécule ciblant l'IL-6 et le profil de sécurité du tofacitinib par rapport aux inhibiteurs du TNF-alpha. Des données intéressantes sur l'issue de la grossesse chez les patientes atteintes de spondylarthrite ont également été publiées. De nouvelles stratégies de traitement ont donné des résultats prometteurs dans le rhumatisme psoriasique et le lupus érythémateux systémique. L'utilité des injections de toxine botulique A pour le phénomène de Raynaud et l'efficacité de la transplantation de cellules régénératrices adipeuses autologues pour le traitement de dysfonctions de la main ont été remises en question par deux études dans la sclérose systémique.

Hydroxychloroquine daily dose, hydroxychloroquine blood levels and the risk of flares in patients with systemic lupus erythematosus.

BACKGROUND: Recent guidelines for SLE recommend using a hydroxychloroquine (HCQ) dose less than 5.0 mg/kg/day to reduce the risk of retinopathy. To determine if this dose reduction would have an impact on the clinical course of SLE, we compared flare incidence in a cohort of patients with SLE treated with two different oral HCQ dosages (≤5 mg/kg/day or >5 mg/kg/day). As a secondary analysis, we compared HCQ blood levels between the two different oral dosages, and evaluated the frequency of non-adherence in patients with SLE treated with HCQ. METHODS: We identified a cohort of patients with SLE taking HCQ for at least 6 months and followed for 24 months. At study entry and 6 months later, a blood venous sample was taken to measure HCQ blood levels by liquid chromatography. Incidence of new SLE flares after recruitment was put in relation to daily HCQ dose and mean HCQ blood levels. Cox regression analysis served to identify factors associated with SLE flares. RESULTS: 83 patients were enrolled. We observed 11 (16%) flares that developed in mean 14.8 months of follow-up. The difference in terms of flare rate and mean HCQ blood levels between the two oral dosages was not statistically significant. There was a trend (p=0.08) for high HCQ dose being associated with a lower flare rate. At Cox analysis, higher HCQ blood levels and older age at baseline were protective against flare occurrence, while concomitant immunosuppressant therapy showed significant positive association. HCQ blood levels did not correlate with prescribed HCQ dose. CONCLUSION: Patients with low oral HCQ dosage tend to have more flares, although the difference was not statistically significant. Higher HCQ blood levels were protective against flare occurrence. The risks and benefits must be balanced in choosing HCQ dose.

Extent of and Reasons for Discontinuation and Nonpublication of Interventional Trials on Connective Tissue Diseases: An Observational Study.

OBJECTIVE: To assess the proportion, the reasons, and the factors associated with the discontinuation or nonpublication of randomized controlled trials (RCTs) on connective tissue diseases (CTDs). METHODS: We searched all interventional RCTs on CTDs registered in ClinicalTrials.gov since 2000. Two reviewers selected studies according to prespecified eligibility criteria. Completion status, publication status, and reported reasons for discontinuation or nonpublication were retrieved on ClinicalTrials.gov, through literature search, and by contacting investigators. Multivariable logistic regression was used to identify factors associated with study noncompletion and nonpublication. RESULTS: We included 175 studies, mostly phase III, placebo-controlled trials on pharmacologic treatments recruiting patients with systemic lupus erythematosus (51%), systemic sclerosis (20%), Sjögren's syndrome (12%), or other CTDs. Fifty-eight (33%) had been discontinued, mainly for insufficient patient accrual, with no differences in discontinuation rates across the CTDs (P > 0.5). Forty-six (35%) of 130 studies having included at least 1 patient were unpublished, and 86 (65%) were published in a peer-reviewed journal after a median of 24 months (interquartile range 15-41) from completion, with a significantly higher publication rate in completed versus discontinued studies (81% versus 22%; P < 0.001). We were able to obtain reasons for nonpublication in one-third of cases. Small sample size (<100 participants) was the only factor associated with study noncompletion and nonpublication. CONCLUSION: One of 3 registered RCTs on CTDs fails to be completed or published. This represents a waste of resources and raises ethical concerns regarding hidden clinical data and unfruitful participation by patients.

Glucocorticoids prescribing practices in systemic sclerosis: an analysis of the EUSTAR database.

OBJECTIVES: To estimate the prevalence of long-term exposure to glucocorticoids (GCs) and to identify factors associated with, and variations in prescribing practices over time and across recruiting countries. METHODS: We included patients with SSc having a visit recorded in the EUSTAR database from January 2013 onward. We analysed the prevalence and the main features of GCs users, their exposure to GCs over time, and their GCs dosages. Multivariable linear regression was used to analyse the factors identified as associated with GCs intake duration. Time trends, and variations in GCs utilization across recruiting countries were explored. Missing data were imputed using multiple imputation with chained equations. RESULTS: The 9819 patients included were mostly females (85%), the majority had lcSSc (73%), and the median age was 58 years. At baseline, 34% of patients (n = 2769/8109) (48% dcSSc vs 29% lcSSc) were on GCs, and the median dose was 7.5 mg/day. GCs users were more frequently males and anti-Scl70 positive, and more commonly had dcSSc and more severe disease. On average, GCs users spent 25% of their follow-up time (median 33.2 months) on GCs, with no significant between-subsets difference. Notably, 33% (n = 971/2959) and 22% (n = 647/2959) of patients followed up for >1 year had received GCs for >6 and >12 months, respectively. Multivariable analysis showed that patient and disease characteristics poorly explained the variability in GCs exposure (adjusted-R2 = 0.06, P < 0.001). GCs utilization varied within and across countries, and gradually decreased over time (36% in 2013 vs 23% in 2018). CONCLUSIONS: GCs are widely and long-term prescribed in SSc, with significant between-countries and within-country differences. A gradual decrease in their utilization has been observed.

Reporting and Representativeness of Race, Ethnicity, and Socioeconomic Status in Systemic Sclerosis Randomized Trials: An Observational Study.

OBJECTIVE: To assess how and to what extent socioeconomic status and ethnicity/race of participants are reported in randomized controlled trials (RCTs) on systemic sclerosis (SSc), and to estimate the representativeness of different ethnic/racial groups in SSc RCTs. METHODS: We searched all published RCTs on SSc indexed in PubMed. We retrieved information on main features of RCTs published from 2000 onward and recorded for each study whether race/ethnicity was reported; how ethnicity/race was defined and assigned; and the number of patients included for each racial/ethnic group. Multivariable logistic regression was used to identify factors associated with race/ethnicity reporting. Proportion of races/ethnicities included in US-based RCTs on SSc was examined and compared with US demographic data. RESULTS: We included 106 studies, mostly conducted in Europe (42%) or North America (25%), published after 2010 (74%), and enrolling a total of 6,693 patients. About one-third of studies provided information about race/ethnicity, with no improved reporting over time. Only 2 papers reported patient's socioeconomic status. Study location (US or intercontinental) was the only significant factor associated with a better reporting of race/ethnicity in multivariable analysis. In studies where race/ethnicity was reported, White patients were mostly represented (79%), followed by Asian (7%), and African American (6%). In the sensitivity analysis limited to studies from the US, underrepresentation of African American patients was observed in the 2000-2010 time period, but not later. CONCLUSION: Documentation of race/ethnicity and socioeconomic status is poor in RCTs on SSc. More effort should be made to document race/ethnicity and socioeconomic status and to promote diversity in SSc RCTs.

Rituximab vs Cyclophosphamide Induction Therapy for Patients With Granulomatosis With Polyangiitis.

Importance: Results of randomized clinical trials have demonstrated rituximab's noninferiority to cyclophosphamide as induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), with neither treatment having a specific advantage for granulomatosis with polyangiitis (GPA). However, post hoc analysis results have suggested that rituximab might be more effective than cyclophosphamide in inducing remission in patients with proteinase 3-positive AAV. Objective: To compare the effectiveness of rituximab and cyclophosphamide in inducing GPA remission in a large population of unselected patients. Design, Setting, and Participants: This comparative effectiveness study used multicenter target trial emulation observational data from 32 French hospitals in the French Vasculitis Study Group Registry. Groups were determined according to treatments received, without any intervention from the investigators. Inverse probability of treatment weighting was used to correct for baseline imbalance between groups. Participants included patients with newly diagnosed or relapsing GPA who satisfied American College of Rheumatology classification criteria and/or Chapel Hill Consensus Conference nomenclature. Data were analyzed from October 1, 2021, to May 31, 2022. Exposures: At least 1 infusion of rituximab or cyclophosphamide for induction therapy between April 1, 2008, and April 1, 2018. Main Outcomes and Measures: The primary outcome was remission rate at month 6 (±2 months), with remission defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and prednisone dose of 10 mg/d or less. The BVAS is a validated tool for small-vessel vasculitis and used to assess the level of disease activity, with a numerical weight attached to each involved organ system. The BVAS has a range of 0 to 63 points; a score of 0 indicates no disease activity. Subgroup analyses included the primary outcome for patients with a new diagnosis, for most recently treated patients, and for patients with myeloperoxidase-ANCA positivity. Results: Among 194 patients with GPA included in the analysis (mean [SD] age, 54 [15] years; 110 men [56.7%]), 165 (85.1%) had a new diagnosis, and 147 of 182 with data available (80.8%) had proteinase 3-ANCA positivity. Sixty-one patients received rituximab and 133 received cyclophosphamide for induction therapy. In the weighted analysis, the primary outcome was reached for 73.1% of patients receiving rituximab vs 40.1% receiving cyclophosphamide (relative risk [RR], 1.82 [95% CI, 1.22-2.73]; risk difference, 33.0% [95% CI, 12.2%-53.8%]; E value for RR, 3.05). Similar results were observed in the subgroup of patients with newly diagnosed GPA and those with a more recent treatment. In the subset of 27 patients with myeloperoxidase-ANCA-positive GPA, 8 of 10 rituximab recipients and 8 of 17 cyclophosphamide recipients met the primary end point (unweighted RR, 1.73 [95% CI, 0.96-3.11]). Conclusions and Relevance: In this comparativeness effectiveness study using clinical data, rituximab induction therapy for GPA was more frequently associated with remission than cyclophosphamide. These results inform clinical decision-making concerning the choice of remission induction therapy for this subset of patients with AAV.

Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the 'JAK-pot' collaboration.

BACKGROUND: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. METHODS: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. RESULTS: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA. CONCLUSION: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

Influence of hydroxychloroquine blood levels on adhesion molecules associated with endothelial dysfunction in patients with systemic lupus erythematosus.

BACKGROUND: Patients with SLE have an endothelial dysfunction (ED), which is considered the earliest marker of cardiovascular (CV) disease. Endothelial cell activation induced by proinflammatory cytokines is defined by the endothelial expression of cell-surface adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. The aim of this study was to investigate whether serum endothelial adhesion molecule levels are influenced by blood hydroxychloroquine (HCQ) levels in SLE. METHODS: Consecutive patients with SLE taking a stable dose of HCQ were investigated. At study entry and 6 months later HCQ blood levels were quantified by tandem mass spectrometry. Serum levels of P-selectin, E-selectin, ICAM-1 and VCAM-1 were also measured using a Luminex 200 instrument. Comparison of endothelial soluble adhesion molecules in groups with different HCQ blood levels was performed by t-test. RESULTS: 83 patients with SLE were enrolled. Correlation were demonstrated between mean blood HCQ concentrations and endothelial soluble adhesion molecules (E-selectin, ICAM-1 and VCAM-1). Moreover, serum levels of ICAM-1 and VCAM-1 were significantly lower in the patients with SLE with HCQ blood levels >500 ng/mL (83.67±52.8 ng/mL vs 158.81±125.1 ng/mL and 8.9±2.2 ng/mL vs 10.4±2.3 ng/mL). Serum levels of E-selectin were nearly significantly lower in the patients with SLE with HCQ blood levels >500 ng/mL (64.7±30.2 ng/mL vs 71.6±42.2 ng/mL, p=0.06). No significant difference in concentration of P-selectin was detected. CONCLUSIONS: In the present study, there was a trend towards higher adhesion molecules levels with lower HCQ blood levels in patients with SLE. Further longitudinal studies will determine whether changes in endothelial biomarkers reflect decreased clinical CV events.