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Objectives: To evaluate the survival of different biologic or targeted-synthetic disease-modifying antirheumatic drugs (b/tsDMARD) administered after fulfilling difficult-to-treat rheumatoid arthritis (D2TRA) criteria, and to assess factors related to treatment discontinuation., Methods: Retrospective study including D2TRA patients. Drug retention of the b/tsDMARD administered after fulfilling D2TRA was assessed by Kaplan-Meier plots and the log-rank test. Cox hazard models were used to identify factors affecting treatment discontinuation., Results: Of the 122 patients included, 75 maintained active treatment (61.5%) with a subsequent line after D2T compared to 47 (38.5%) who discontinued and required more successive lines of b/tsDMARDs. The median survival of the treatments was 78.3(7.6) months and the treatment after D2T with the better rate of survival was rituximab, followed by JAKi and IL6Ri, while worse survival rates were associated with abatacept and TNFi. Significant differences were noted among b/tsDMARDs (log-rank p < 0.01) and to evaluate these differences, a Cox regression was performed, taking each b/tsDMARD as a reference and comparing it with the others. DAS28 values 6-months after initiation of treatment were higher in those patients who discontinued treatment [4.4(1.2) vs 3.5(1.3), p = 0.01]. The multivariate cox regression model revealed that treatment choice after D2T [HR = 1.26(95%CI 1.06-1.05)] and lower DAS28 values at 6 months [HR = 1.49(95%CI 1.16-1.52)] were independent risk factors associated with treatment discontinuation., Conclusions: Once patients met the D2TRA criteria, the subsequent line of b/tsDMARDs with the best survival rates were rituximab, JAKi and IL6Ri. Moreover, DAS28 at 6-months of treatment after D2T was an independent risk factor for drug discontinuation. Key Points • Rituximab, IL6Ri and JAKi have better retention rates in patients after fulfilling D2TRA criteria • Clinical disease activity in the first six months after fulfillment of D2TRA criteria is an independent risk factor of subsequent treatment survival., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objectives: The aim of this study is to evaluate risk factors for severe coronavirus disease 2019 (COVID-19) in patients with immune-mediated rheumatic diseases, stratified by systemic autoimmune conditions and chronic inflammatory arthritis., Methods: An observational, cross-sectional multicentre study was performed. Patients from 10 rheumatology departments in Madrid who presented with severe acute respiratory syndrome coronavirus-2 infection between February 2020 and May 2021 were included. The main outcome was COVID-19 severity (hospital admission or mortality). Risk factors for severity were estimated, adjusting for covariates (socio-demographic, clinical, and treatments), using logistic regression analyses., Results: In total, 523 patients with COVID-19 were included, among whom 192 (35.6%) patients required hospital admission and 38 (7.3%) died. Male gender, older age, and comorbidities such as diabetes mellitus, hypertension, and obesity were associated with severe COVID-19. Corticosteroid doses >10 mg/day, rituximab, sulfasalazine, and mycophenolate use, were independently associated with worse outcomes. COVID-19 severity decreased over the different pandemic waves. Mortality was higher in the systemic autoimmune conditions (univariate analysis, P < .001), although there were no differences in the overall severity in the multivariate analysis., Conclusions: This study confirms and provides new insights regarding the harmful effects of corticosteroids, rituximab, and other therapies (mycophenolate and sulfasalazine) in COVID-19. Methotrexate and anti-tumour necrosis factor therapy were not associated with worse outcomes., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: To analyse the trajectories of Disease Activity Score 28 (DAS28), patient global assessment (PGA) and physician global assessment (PhGA) and to assess their predictive capabilities on difficult-to-treat rheumatoid arthritis (D2TRA) classification., Methods: Longitudinal study of patients with rheumatoid arthritis (RA) from 2020 to 2022. Based on the D2TRA EULAR (European Alliance of Associations for Rheumatology) definition, patients were classified as D2TRA according to biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) failure due to inefficacy (D2TRA-inefficacy) or other reasons (D2TRA-other). Patients who did not fulfil the D2TRA criteria were classified as NoD2TRA. DAS28, PGA and PhGA scores collected every 6 months during the first 24 months of b/tsDMARD treatment were used to identify different trajectories using latent class mixed models (LCMM)., Results: The study population comprised 255 patients with RA, of whom 167 were NoD2TRA, 58 D2TRA-inefficacy and 30 D2TRA-other. LCMM stratified patients into two different trajectories for DAS28 and PhGA and three for PGA according to the most stable model. The most notable variation occurred during the first 6 months of treatment, thereafter remaining stable during the follow-up period. Most D2TRA-inefficacy patients fitted the trajectory, showing higher values of the studied parameters. NoD2TRA followed the trajectory with lower values, and D2TRA-other were distributed more homogeneously across all trajectories., Conclusions: The assessment of disease activity, together with patients' and physicians' perceptions, form a key element in the correct discrimination of patients who are going to develop D2TRA-inefficacy. However, identifying those patients who will be D2TRA-other remains challenging, whether by subjective or objective parameters., Competing Interests: Competing interests: MNN reports grants from UCB, Lilly, Galapagos and Janssen outside the submitted work. AV reports grants from Janssen. IM reports grants from Roche, Novartis, UCB and Gedeon Richter outside the submitted work. CP-R reports grants from AbbVie, Pfizer, Novartis, Lilly and Roche outside the submitted work. AB reports grants from AbbVie, Amgen, Pfizer, Galapagos, Novartis, Gilead, BMS, Nordic, Sanofi, Sandoz, Lilly, UCB and Roche outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Biological therapies have improved the clinical course and quality of life of rheumatoid arthritis (RA) patients. Despite the availability and effectiveness of these treatments, some patients experience multiple failures to biologic disease-modifying antirheumatic drugs (bDMARDs), constituting a particular challenge to clinicians., Objectives: This study aims to determine the percentage of rheumatoid arthritis (RA) patients who fail to respond to subsequent bDMARDs, describe their characteristics, and identify specific baseline and early features during the first bDMARD as possible predictors of consecutive multiple bDMARD failure., Methods: This is a longitudinal study involving RA patients from the prospective biological cohort drawn from the La Paz University Hospital RA Registry (RA-Paz), starting a bDMARD during the years 2000 to 2019. Patients who presented insufficient response (due to primary or secondary inefficacy) to at least three bDMARDs or two bDMARDs with different mechanism of action were considered multi-refractory (MR-patients). Patients who achieved low disease activity or remission (by DAS-28) with the first bDMARD and maintained this over a follow-up period of at least 5 years were considered non-refractory (NR-patients)., Results: A total of 41 out of 402 (10%) patients were MR-patients and 71 (18%) NR-patients. In the multivariate analysis, the presence of erosions, younger age, higher baseline DAS-28 and mostly achieving delta-DAS < 1.2 after 6 months of the first bDMARD (OR 11.12; 95% CI 3.34-26.82) were independently associated with being MR-patients to bDMARDs., Conclusions: In our cohort, 10% of patients with RA were observed to have multi-refractoriness to bDMARDs. This study supports the contention that younger patients with erosive disease and especially the early absence of clinical response to the first bDMARDs are predictors of multi-refractoriness to consecutive biologics. Hence, patients with these characteristics should be monitored more closely and may benefit from personalized treatments.

Objective: The protagonism of regulatory B cells seems to vary along the course of the disease in murine models of inflammatory conditions. Decreased numbers of circulating regulatory CD19+CD24hiCD38hi transitional (cTr) B cells have been described in patients with long-standing RA, thus our objective was to examine the frequency and evolution of cTr B cells in the peripheral blood of early RA (ERA) patients., Methods: Freshly isolated peripheral blood mononuclear cells from 48 steroid- and DMARD-naïve ERA patients with a disease duration of <24 weeks and 48 healthy controls (HCs) were examined by flow cytometry. Co-cultures of isolated memory B cells were established with autologous T cells in the absence or presence of Tr B cells., Results: As compared with HCs, ERA patients demonstrated an increased frequency of cTr B cells. cTr B cells of ERA patients and HCs displayed an anti-inflammatory cytokine profile and were able to downregulate T cell IFN-γ and IL-21 production, together with ACPA secretion in autologous B/T cell co-cultures. Basal frequencies of cTr B cells above the median value observed in HCs were associated with a good EULAR response to MTX at 12 months [relative risk 2.91 (95% CI 1.37, 6.47)]. A significant reduction of cTr B cells was observed 12 months after initiating MTX, when the cTr B cell frequency was no longer elevated but decreased, and this was independent of the degree of clinical response or the intake of prednisone., Conclusion: An increased frequency of regulatory cTr B cells is apparent in untreated ERA and the baseline cTr B cell frequency is associated with the clinical response to MTX at 12 months., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To investigate the effect of concomitant conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with adalimumab or infliximab on maintaining serum drug and clinical outcomes after the first year of treatment in patients with rheumatoid arthritis (RA). Second, to assess the influence of methotrexate (MTX) dose on these outcomes. Ninety-two patients with RA starting infliximab (n = 67) or adalimumab (n = 25) tumor necrosis factor inhibitor (TNFi) with available drug levels and clinical improvement assessment (European League Against Rheumatism [EULAR] response) after 12 months were included. Patients were grouped according to concomitant csDMARD use: (i) TNFi monotherapy; (ii) TNFi+MTX; (iii) TNFi with csDMARDs other than MTX (TNFi+OD). Patients receiving MTX were also classified by dose as < 15 mg/week (TNFi+MTX<15) and ≥ 15 mg/week (TNFi+MTX≥15). Logistic regression analyses were employed. More TNFi+MTX patients had circulating serum TNFi at 12 months (71% TNFi+MTX vs. 20% TNFi+OD vs. 9% TNFi monotherapy). Of these, the probability of maintaining serum TNFi levels was twice (OR 2.3; p = 0.06) than that of patients without MTX. However, statistically significant results were observed only for the highest MTX dose (OR 4.9; p = 0.02). Most patients achieving good EULAR response were treated with TNFi+MTX (81%). The probability of achieving this response was three times higher in patients within the TNFi+MTX group (OR 3.4; p = 0.03); however, no differences were found with regard to MTX dose. The persistence of serum TNFi and the probability of achieving clinical response are influenced by MTX but not by OD in patients with RA treated with infliximab or adalimumab.

Objectives: The aim of this study is to compare clinical outcomes, incidence of flares and administered drug reduction between rheumatoid arthritis (RA) patients under TNF inhibitors (TNFi) tapering strategy and RA patients on standard regimen., Methods: Two groups of RA patients on TNFi with DAS28<3.2 were compared: the tapering group (TG: 67 pts from Spain) and the control group with standard therapy regimen (CG: 77 pts from the Netherlands). DAS28 was measured at different time points: visit 0 (prior starting TNFi), visit 1 (prior to start tapering in TG and with DAS28<3.2 in TG and CG), visit 2 (6 months after visit 1), visit 3 (1 year after visit 1), visit 4 (the last visit available after visit 1) and visit-flare (visit with the worst flare between visit 1 and visit 4)., Results: Despite the reduction of administered drug at visit 4 in the TG (interval elongation of 32.8% in infliximab, 52.9% in adalimumab and 52.6% in etanercept), the DAS28 remained similar between groups at the end of the study (DAS28: 2.7±0.9 in TG vs. 2.5±1 in CG, p=0.1). No differences were seen in the number of patients with flares [26/67 (38.9%) in the TG vs. 30/77 (39%) in the CG, p=0.324] and only nineteen out of 136 patients (14%) had anti-drug antibodies at the end of the study., Conclusions: The tapering strategy of TNFi in RA patients result in a reduction of the drug administered, while the disease control is not worse than patients on the standard regimen.

Objective: To compare clinical outcomes, incidence of flares, and administered drug reduction between patients with spondyloarthritis (SpA) under TNF inhibitor (TNFi) tapering strategy with patients receiving a standard regimen., Methods: In this retrospective study, 74 patients with SpA from Spain on tapering strategy (tapering group; TG) were compared with 43 patients from the Netherlands receiving a standard regimen (control group; CG). The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at visit 0 (prior to starting the TNFi), visit 1 (prior to starting tapering strategy in TG and at least 6 months with BASDAI < 4 after starting the TNFi in the TG and CG), visit 2 (6 mos after visit 1), visit 3 (1 year after visit 1), and visit 4 (the last visit available after visit 1)., Results: An overall reduction of the administered drug was seen at visit 4 in the TG [dose reduction of 22% for infliximab (IFX) and an interval elongation of 28.7% for IFX, 45.2% for adalimumab, and 51.5% for etanercept] without significant differences in the BASDAI between the groups at visit 4 (2.15 ± 1.55 in TG vs 2.11 ± 1.31 in CG, p = 0.883). The number of patients with flares was similar in both groups [22/74 (30%) in the TG vs 8/43 (19%) in the CG, p = 0.184]., Conclusion: The tapering strategy in SpA results in an important reduction of the drug administered, and the disease control remains similar to that of the patients with SpA receiving the standard regimen.

Introduction: Anti-TNF drugs have proven to be effective against spondyloarthritis (SpA), although 30% of patients fail to respond or experience adverse events leading to treatment discontinuation. In rheumatoid arthritis, the presence of anti-drug antibodies (ADA) against the first TNF inhibitor influences the outcome after switching. Our aim was to assess whether the response to a second anti-TNF drug is related to the previous development of ADA to the first anti-TNF drug SpA patients., Methods: Forty-two SpA patients began a second anti-TNF drug after failing to respond to the first anti-TNF therapy. Clinical activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline (at the beginning of the first and second anti-TNF therapy) and at 6 months after switching. The drug and ADA levels were measured by ELISA before each administration., Results: All patients were treated with anti-TNF drugs and mainly due to inefficacy were switched to a second anti-TNF drug. Eleven of 42 (26.2%) developed ADA during the first biologic treatment. At baseline, no differences in ASDAS were found in patients with or without ADA to the first anti-TNF drug (3.52 ± 1.03 without ADA vs. 3.14 ± 0.95 with ADA, p = 0.399) and to the second anti-TNF drug (3.36 ± 0.94 without ADA vs. 3.09 ± 0.91 with ADA, p = 0.466). At 6 months after switching, patients with previous ADA had lower disease activity (1.62 ± 0.93 with ADA vs. 2.79 ± 1.01 without ADA, p = 0.002) and most patients without ADA had high disease activity state by the ASDAS (25 out of 31 (80.6%) without ADA vs. 3 out of 11 (27.3%) with ADA, p = 0.002)., Conclusions: In SpA the failure to respond to the first anti-TNF drug due to the presence of ADA predicts a better clinical response to a second anti-TNF drug.

Background: Infliximab (IFX) is a monoclonal antibody against tumour necrosis factor α that is effective for treating spondyloarthritis (SpA). However, after initial success of the drug some patients lose responsiveness or develop infusion reactions, which may be related to the development of antibodies against the drug., Objective: To investigate the clinical relevance of antibodies to infliximab (ATI) formation in patients with SpA undergoing IFX treatment over a prolonged period., Methods: 94 patients with SpA treated with IFX from 1999 to 2010 were studied. Their clinical characteristics, serum trough IFX levels and ATI status were evaluated for a mean of 6.99 (95% CI:6.28 to 7.7) years. Clinical activity and improvement were measured using the Ankylosing Spondylitis Disease Activity Score (ASDAS): inactive <1.3, moderate ≥1.3 and <2.1, high ≥2.1-≤3.5, and very high >3.5 at three time points (6 months, 12 months and >4 years)., Results: ATI were detected in 24 (25.5%) patients. The patients with ATI had higher ASDAS scores than those without ATI (2.55±0.89 vs 1.79±1.04, p=0.038 at 6 months; 1.95±0.67 vs 1.67±0.71, p=0.042 at 1 year; 2.52±0.99 vs 1.53±0.81, p=0.024 at >4 years). Eleven patients (12%) developed infusion-related reactions, and of these, ATI were present in eight patients (73%). The patients with infusion-related reactions had higher ATI titres (median 12 931 AU/ml, IQR 853-82 437) vs median 2454 AU/ml, IQR 449-7718, p=0.028) and shorter survival (4.25 years vs 8.19 years, p<0.001). ATI development occurred more frequently in the patients not receiving methotrexate (20/58 (34.5%) vs 4/36 (11.1%), p=0.011)., Conclusion: In patients with SpA treated with IFX, ATI formation is associated with a poor clinical response, the appearance of infusion reactions and the discontinuation of treatment.

Objective: To analyse the clinical relevance of the production of anti-infliximab antibodies (anti-infliximab Abs) in patients with RA undergoing infliximab treatment over a prolonged period of time., Methods: Clinical characteristics, serum trough infliximab and antibody levels were evaluated in 85 RA patients treated with infliximab for a median of 4.42 (interval 0.4-10.2) years. DAS in 28 joints (DAS-28), EULAR response criteria and survival of treatment were assessed at 3 time points (6 months, 12 months and >4 years)., Results: Antibodies against infliximab were detected in 28 (32.9%) patients and were present in all EULAR non-responder patients. Antibody levels were higher in EULAR non-responders throughout the study period (P = 0.05 at 6 months, P = 0.02 at 1 year, P = 0.003 at >4 years) compared with EULAR (good and moderate) responders. Nine (10.5%) patients, all of them with high-serum anti-infliximab Ab levels, developed infusion-related reactions. Patients with anti-infliximab Abs more often required increased infliximab doses (51.7%) (P = 0.032) and median survival time on treatment was shorter (4.15 vs 8.89 years) (P = 0.0006). MTX co-therapy was not associated with lower proportion of anti-infliximab Ab-positive patients, but those receiving both infliximab and MTX had lower levels of anti-infliximab Abs (P = 0.073) and longer survival (P = 0.015) on treatment., Conclusion: The formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.