Risk of severe infection associated with immunoglobulin deficiency under rituximab therapy in immune-mediated inflammatory disease.

OBJECTIVES: We evaluated the risk of severe infection in patients with immune-mediated inflammatory disease (IMID) treated with RTX and with Ig deficiency. METHODS: This was an observational, retrospective single-centre study of patients undergoing treatment with at least one rituximab (RTX) infusion for an IMID until 31 May 2020. Patients were followed up for at least 12 months after the last infusion or until severe infection or death. Ig deficiency was classified as prevalent (before RTX) or acquired (normal Ig assay results before RTX but Ig deficiency during a follow-up). RESULTS: Of 311 patients, 10.6% had prevalent and 19.6% acquired Ig deficiency. Prevalent Ig deficiency was related to concomitant treatment with glucocorticoids (GCs), in particular with a high daily dose at baseline; and acquired Ig deficiency to cumulative dose of RTX, mean Disease Activity Score in 28 joints (DAS28), immunosuppressor or GCs therapy at baseline, diabetes mellitus and obesity. Overall, 14.5% of patients had a severe infection during follow-up, which was numerically but not statistically more frequent in patients with prevalent Ig deficiency than normal Ig level. On multivariate analysis, risk of severe infection was associated with chronic pulmonary disease, GCs dose and mean DAS28-C reactive protein. In a time-dependent analysis, risk of severe infection was not associated with Ig deficiency, either acquired or prevalent (adjusted HR 1.04 (95% CI 0.5 to 2.3), p=0.92). CONCLUSION: Risk of severe infection was not associated with RTX-induced Ig deficiency in patients with an IMID. RTX management should be discussed according to an individual assessment of the infectious risk, especially in patients with GC therapy or chronic lung disease.

Diagnosis challenges in inception cohorts in axial spondyloarthritis: the case of the French national DESIR cohort.

BACKGROUND: Inception cohorts aim to describe chronic diseases from diagnosis and over years of follow-up. Axial spondyloarthritis (axSpA) diagnosis might be challenging during the first years of the disease. Thus, identifying the features that will be associated with a confirmed diagnosis over time is key. OBJECTIVES: To assess the frequency and the predisposing factors for a change of an initial diagnosis in an inception axSpA cohort. METHODS: DESIR is an ongoing national multicentre inception axSpA cohort with currently 12.5 years of follow-up. At the entry visit and confirmed at each visit, the diagnosis of axSpA was based on the opinion of the treating rheumatologist. Follow-up was interrupted in case of a change in this initial diagnosis. Multiple imputation was used to estimate the probability of a change in the initial diagnosis of axSpA for each patient lost to follow-up. Factors predisposing to an unchanged diagnosis of axSpA were then assessed using a multivariate logistic regression model on the imputed data sets. RESULTS: Of the 708 patients included, over 10 years of follow-up, 45 (6.4%) were excluded due to a diagnosis change and 300 (42.4%) patients were lost to follow-up. Based on the imputation of these 300 patients, a change in their initial axSpA diagnosis was estimated in 42 (14.0%). Factors predisposing to an unchanged initial axSpA diagnosis during follow-up were (ORs (95% CIs)): radiographic sacroiliitis: 17.0 (4.1 to 71.0); psoriasis: 5.3 (2.0 to 14.3); CRP≥6 mg/L: 2.7 (1.3 to 5.3); good NSAID response: 2.5 (1.5 to 4.2); HLA B27+: 2.0 (1.3 to 3.3); anterior chest wall pain: 2.0 (1.2 to 3.3) and female sex: 1.9 (1.2 to 3.0). CONCLUSION: These data suggest that a change in diagnosis in recent onset axSpA exists, but is not frequent, and is less likely to occur in the presence of objective features at baseline.

Efficacy and safety of upadacitinib in patients with rheumatoid arthritis and inadequate response or intolerance to biological treatments: results through 5 years from the SELECT-BEYOND study.

OBJECTIVE: To evaluate the efficacy and safety of upadacitinib over 5 years among patients with rheumatoid arthritis (RA) in a long-term extension (LTE) of the SELECT-BEYOND phase 3 trial. METHODS: Patients refractory to ≥1 biological disease-modifying antirheumatic drug (DMARD) received upadacitinib 15 mg or 30 mg once daily or placebo, in combination with background conventional synthetic DMARD(s). At week 12, patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg. All patients who completed the week 24 visit could enter the LTE for up to 5 years. Efficacy was analysed as observed and by non-responder imputation through week 260. Treatment-emergent adverse events per 100 patient-years were summarised over 5 years. RESULTS: Of the 498 patients randomised, 418 (84%) completed week 24 and entered the LTE. Of those who remained in the trial (n=80, upadacitinib 15 mg; n=81, upadacitinib 30 mg), 36%/36% and 81%/77% randomised to upadacitinib 15/30 mg were in Clinical Disease Activity Index (CDAI) remission or low disease activity at week 260, respectively (as observed). Approximately 47% of all patients who began in high disease activity demonstrated a CDAI improvement >12 at week 260 with upadacitinib 15/30 mg. Functional and pain-related outcomes also showed comparable improvements with both doses. Numerically higher rates of anaemia, herpes zoster and creatine phosphokinase elevation were observed with upadacitinib 30 mg vs 15 mg. No new safety issues were identified. CONCLUSIONS: Upadacitinib 15/30 mg continued to be effective in treating clinical and functional outcomes in patients with RA. The safety profile observed over 5 years was consistent with earlier study-specific and integrated assessments of upadacitinib treatment.

Repurposing the Fibrosis-4 Score in Rheumatoid Arthritis: Data from the ESPOIR Cohort.

Background: We aimed to evaluate the value of the Fibrosis-4 (FIB-4) score as a prognostic factor in RA in the prospective ESPOIR cohort. Methods: We included patients from the ESPOIR cohort with a diagnosis of RA according to ACR/EULAR criteria. The formula for the FIB-4 score is as follows: [age (years) × aspartate transaminase level (U/L)]/[platelet count (109/L) × alanine aminotransferase level (U/L)1/2]. We used a linear mixed-effects model with a random effect of patient to account for repeated measures over time. Results: Overall, 647 of the 813 patients included met the ACR/EULAR criteria for RA, with no differential diagnosis during the first 10 years of follow-up. Of these patients, at baseline, 633 had a calculable FIB-4 score. Median FIB-4 score was 0.75 (interquartile range 0.53-0.99). On multivariate analysis, FIB-4 score was not independently associated with progression of Disease Activity Score in 28 joints over 10 years of follow-up, unlike baseline C-reactive protein level and SJC. Baseline FIB-4 score was not associated with the modified Sharp score at 5-year follow-up, unlike age and ACPAs. FIB-4 score was not associated with mortality (hazard ratio 1.1 [95% CI 0.46; 2.8], p = 0.77) or major adverse cardiovascular events (0.46 [0.13; 1.6], p = 0.22) over the 10-year follow-up. No significant change in FIB-4 score over time was related to treatments. Conclusions: The present prospective cohort study did not find a prognostic role of FIB-4 score in RA. Reassuringly, FIB-4 score was not increased with DMARD treatment after 10 years of follow-up.

Ten-year clinical outcome of recent-onset axial spondyloarthritis: Results from the DESIR inception Cohort.

OBJECTIVES: This study aimed to evaluate the 10-year clinical outcome of patients with recent-onset axial spondyloarthritis (axSpA). METHODS STUDY DESIGN: The DESIR cohort is an inception cohort of axSpA patients. METHODS DIAGNOSIS AND MANAGEMENT: The diagnosis and management of patients were based on the decision of the treating rheumatologist. METHODS STATISTICAL ANALYSIS: Both complete cases and imputed data analyses were conducted. RESULTS: Of the 708 enrolled patients, 45 were excluded due to a change in the baseline diagnosis, 3 patients died, and 300 were lost to follow-up over the 10years. In the completer population, one patient required bilateral total hip replacement, and 56 patients received a pension due to invalidity. The prevalence of main extra-musculoskeletal features increased from baseline to year 10: psoriasis from 18% to 30%, acute anterior uveitis from 10% to 18%, and inflammatory bowel disease from 5% to 10%. The most frequent comorbidity was hypertension, with an increase from 5% to 15% from baseline to year 10. In the imputed data analysis the estimated proportions of patients with an acceptable status at year 10 were 70% [95% CI: 63; 77] for acceptable PASS, 43% [95% CI: 37; 49] for BASDAI<3, and 48% [95% CI: 41; 56] for ASDAS<2.1. CONCLUSION: These findings suggest that despite a quite favorable 10-year outcome exists for severe outcomes, a large proportion of patients present with an important disease burden reflected by patient-reported outcomes. This information can be valuable for providing patients with information at the time of diagnosis.

Adding ultrasound to treat-to-target shows no benefit in achieving clinical remission nor in slowing radiographic progression in rheumatoid arthritis: results from a multicenter prospective cohort.

OBJECTIVE: To assess whether using ultrasound (US) in addition to clinical information versus only clinical information in a treat-to-target (T2T) strategy leads to more clinical remission and to less radiographic progression in RA. METHODS: Patients with RA from the 2-year prospective BIODAM cohort were included. Clinical and US data (US7-score) were collected every 3 months and hands and feet radiographs every 6 months. At each visit, it was decided whether patients were treated according to the clinical definition of T2T with DAS44 remission as benchmark (T2T-DAS44). T2T-DAS44 was correctly applied if: (i) DAS44 remission had been achieved or (ii) if not, treatment was intensified. A T2T strategy also considering US data (T2T-DAS44-US) was correctly applied if: (i) both DAS44 and US remission (synovitis-score < 2, Doppler-score = 0) were present; or (ii) if not, treatment was intensified. The effect of T2T-DAS44-US on attaining clinical remission and on change in Sharp-van der Heijde score compared to T2T-DAS44 was analysed. RESULTS: A total of 1016 visits of 128 patients were included. T2T-DAS44 was correctly followed in 24% of visits and T2T-DAS44-US in 41%. DAS44 < 1.6 was achieved in 39% of visits. Compared to T2T-DAS44, using the T2T-DAS44-US strategy resulted in a 41% lower likelihood of DAS44 remission [OR (95% CI): 0.59 (0.40;0.87)] and had no effect on radiographic progression [ß(95% CI): 0.11 (- 0.16;0.39)] assessed at various intervals up to 12 months later. CONCLUSION: Our results do not suggest a benefit of using the US7-score in addition to clinical information as a T2T benchmark compared to clinical information alone. Key Points • Ultrasound has a valuable role in diagnostic evaluation of rheumatoid arthritis, but it is unclear whether adding ultrasound to the clinical assessment in a treat-to-target (T2T) strategy leads to more patients achieving remission and reduction in radiographic progression. • Our data from a real-world study demonstrated that adding information from ultrasound to the clinical assessment in a T2T strategy led to a lower rather than a higher likelihood of obtaining clinical remission as compared to using only clinical assessment. • Our data demonstrated that adding ultrasound data to a T2T strategy based only on clinical assessment did not offer additional protection against radiographic progression in patients with RA. • Adding US to a T2T strategy based on clinical assessment led to far more treatment intensifications (with consequences for costs and exposure to adverse events) without yielding a meaningful clinical benefit.

Referring early arthritis patients within 6 weeks versus 12 weeks after symptom onset: an observational cohort study.

BACKGROUND: The first recommendation of the European League Against Rheumatism for the management of early arthritis states that patients should be referred to, and seen by, a rheumatologist within 6 weeks after symptom onset. However, implementation of this recommendation is a challenge, and evidence supporting this timeframe compared with longer timeframes is absent. Therefore, we aimed to investigate whether visiting a rheumatologist within 6 weeks of symptom onset relates to improved long-term outcomes compared with visiting a rheumatologist between 7 and 12 weeks after symptom onset. METHODS: In this observation cohort study, consecutive patients with rheumatoid arthritis from the Leiden Early Arthritis Clinic (EAC) and the French Etude et Suivi des Polyarthrites Indifferenciées Recentes (ESPOIR) were included. In this analysis, we included patients who were diagnosed with rheumatoid arthritis and classified according to 1987 American College of Rheumatology criteria, and with symptom onset and remission data available. Patients were categorised into groups based on time between symptom onset and first encounter with a rheumatologist: within 6 weeks, between 7 weeks and 12 weeks, and after 12 weeks. The main outcomes were sustained disease-modifying antirheumatic drug (DMARD)-free remission and radiographic progression. Multivariable Cox regression, linear mixed models, and meta-analyses were used. FINDINGS: 1025 patients with rheumatoid arthritis included in the EAC between Jan 1, 1996, and Dec 31, 2017, and 514 patients with rheumatoid arthritis included in ESPOIR between Nov 1, 2002, and April 30, 2005, were included in this analysis. Median follow-up was 7·1 years (IQR 3·9-12·2) in the EAC and 10·0 years (9·0-10·0) in ESPOIR. After 7 years of follow-up in the EAC, 30 (24%) of 127 patients with a time to encounter of 6 weeks or less, 45 (20%) of 223 patients with a time of 7-12 weeks, and 100 (15%) of 675 patients with a time of more than 12 weeks achieved sustained DMARD-free remission. After 10 years of follow-up in ESPOIR, three (27%) of 11 patients with a time to encounter of 6 weeks or less, 11 (11%) of 100 patients with a time of 7-12 weeks, and 41 (10%) of 403 patients with a time of more than 12 weeks had sustained DMARD-free remission. In the EAC multivariable analysis, patients who encountered a rheumatologist within 6 weeks obtained sustained DMARD-free remission more often than those seen between 7 and 12 weeks (hazard ratio [HR] 1·59 [95% CI 1·02-2·49], p=0·042), and after 12 weeks (1·54 [1·04-2·29], p=0·032). In the ESPOIR multivariable analysis, similar but non-significant effects were observed (HR 2·81 [95% CI 0·75-10·53], p=0·12, for within 6 weeks vs 7-12 weeks and 3·05 [0·89-10·49], p=0·077, for within 6 weeks vs more than 12 weeks). The meta-analysis of both cohorts showed that the time to encounter of 6 weeks or less was associated with a higher chance of achieving sustained DMARD-free remission than a time of 7-12 weeks (HR 1·69 [95% CI 1·10-2·57], p=0·016) and a time of more than 12 weeks (1·67 [1·08-2·58], p=0·020). The multivariable analysis showed that patients who encountered a rheumatologist within 6 weeks had similar radiographic progression to those seen between 7 and 12 weeks in both cohorts (ß=1·00 [95% CI 0·95-1·05], p=0·96, in the EAC and 0·93 [0·80-1·07], p=0·30, in ESPOIR) and to those seen after 12 weeks (ß=0·96 [95% CI 0·92-1·00], p=0·064, in the EAC and 0·89 [0·77-1·02], p=0·10, in ESPOIR). In the meta-analysis, a time to encounter of 6 weeks or less was not associated with less radiographic progression than a time of 7-12 weeks (ß=0·99 [95% CI 0·95-1·04], p=0·75) but was associated with less radiographic progression than a time of more than 12 weeks (0·95 [0·91-0·99], p=0·028). INTERPRETATION: Visiting a rheumatologist within 6 weeks of symptom onset had benefits for achieving sustained DMARD-free remission, but not for radiographic progression. FUNDING: European Research Council, Dutch Arthritis Society, Merck Sharp & Dohme, INSERM, The French Society of Rheumatology, Pfizer, AbbVie, Lilly, and Sanofi.