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Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

ObjectivesTo compare the efficacy and safety of SB4 (an etanercept biosimilar) with reference product etanercept (ETN) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy.MethodsThis is a phase III, randomised, double-blind, parallel-group, multicentre study with a 24-week primary endpoint. Patients with moderate to severe RA despite MTX treatment were randomised to receive weekly dose of 50 mg of subcutaneous SB4 or ETN. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 24. Other efficacy endpoints as well as safety, immunogenicity and pharmacokinetic parameters were also measured.Results596 patients were randomised to either SB4 (N=299) or ETN (N=297). The ACR20 response rate at week 24 in the per-protocol set was 78.1% for SB4 and 80.3% for ETN. The 95% CI of the adjusted treatment difference was −9.41% to 4.98%, which is completely contained within the predefined equivalence margin of −15% to 15%, indicating therapeutic equivalence between SB4 and ETN. Other efficacy endpoints and pharmacokinetic endpoints were comparable. The incidence of treatment-emergent adverse events was comparable (55.2% vs 58.2%), and the incidence of antidrug antibody development up to week 24 was lower in SB4 compared with ETN (0.7% vs 13.1%).ConclusionsSB4 was shown to be equivalent with ETN in terms of efficacy at week 24. SB4 was well tolerated with a lower immunogenicity profile. The safety profile of SB4 was comparable with that of ETN.Trial registration numbersNCT01895309, EudraCT 2012-005026-30.

Idiopathic inflammatory myopathies (IIM), also known as myositis, are a heterogeneous group of autoimmune disorders with varying clinical manifestations, treatment responses and prognoses. Muscle weakness is usually the classical clinical manifestation but other organs can be affected, including the skin, joints, lungs, heart and gastrointestinal tract, and they can even result in the predominant manifestations, supporting that IIM are systemic inflammatory disorders. Different myositis-specific auto-antibodies have been identified and, on the basis of clinical, histopathological and serological features, IIM can be classified into several subgroups — dermatomyositis (including amyopathic dermatomyositis), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, polymyositis and overlap myositis. The prognoses, treatment responses and organ manifestations vary among these groups, implicating different pathophysiological mechanisms in each subtype. A deeper understanding of the molecular pathways underlying the pathogenesis and identifying the auto-antigens of the immune reactions in these subgroups is crucial to improving outcomes. New, more homogeneous subgroups defined by auto-antibodies may help define disease mechanisms and will also be important in future clinical trials for the development of targeted therapies and in identifying biomarkers to guide treatment decisions for the individual patient. Idiopathic inflammatory myopathies, also known as myositis, are a heterogeneous group of autoimmune disorders usually characterized by chronic inflammation of the muscle. This Primer reviews the epidemiology, pathophysiology, diagnosis, treatment, patient quality of life and future research needs of this group of diseases.

S100A11 (calgizzarin), a member of S100 family, is associated with several autoimmune diseases, including rheumatoid arthritis (RA). Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of RA and in the externalization of some S100 family members. Therefore, we aimed to determine the association between S100A11 and NETs in RA. For this purpose, the levels of S100A11 and NETosis markers were detected in the RA synovial fluid by immunoassays. The expression of S100A11 by neutrophils in the RA synovial tissue was assessed. Neutrophils isolated from peripheral blood were exposed to S100A11 or stimulated to release NETs. The levels of NETosis- and inflammation-associated proteins were analysed by immunoassays. NETs were visualized by immunofluorescence. We showed that S100A11 was expressed by the neutrophils in the RA synovial tissue. Moreover, S100A11 in the RA synovial fluid correlated with several NETosis markers. In vitro, S100A11 was abundantly released by neutrophils undergoing NETosis compared to untreated cells (p < 0.001). Extracellular S100A11 increased the secretion of IL-6 (p < 0.05) and TNF (p < 0.05) by neutrophils but did not induce NETosis. This study demonstrates, for the first time, that the release of S100A11 is dependent on NETosis and that extracellular S100A11 augments the inflammatory response by inducing pro-inflammatory cytokines in neutrophils.

ObjectiveTo compare the effectiveness, safety and costs of standard versus individually tailored reduced doses of anti-tumour necrosis factor (TNF) drugs in patients with ankylosing spondylitis (AS) after achieving low-disease activity.MethodsThis was a single-centre prospective observational study performed within the ATTRA registry. The anti-TNF dose tapering strategy was chosen by treating physicians, without prespecified protocol. We used propensity score (PS) methodology to identify two cohorts of patients matched for relevant baseline characteristics who were treated with either reduced (n=53) or standard (n=83) doses of TNF inhibitors. One-year outcomes and costs of anti-TNF drugs were compared between both PS-matched cohorts.ResultsIn the reduced dosing group, the median dose of TNF inhibitor corresponded to 0.67 and 0.5 of the standard dose initially and at 12 months respectively, and 21% of patients required return to standard dosing regimen. The mean change per year in Bath Ankylosing Spondylitis Activity Index, C-reactive protein , Health Assessment Questionnaire Disability Index and Bath AS functional index, as well as quality-adjusted life-year area under the curve were no different between both groups. The HR (95% CI) of reduced versus standard dosing group for relapse and any adverse event was 1.46 (0.66 to 3.19) and 0.56 (0.22 to 1.44), respectively. Mean difference (95% CI) in cost of anti-TNF drugs was €−4214 (−4707 to −3701) per year of treatment in favour of reduced dosing strategy.ConclusionsIn patients with AS after reaching low-disease activity, a tailored approach to reduce doses of anti-TNF drugs produced similar clinical outcomes at 1 year, but was substantially less costly.

BackgroundDuring the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.MethodsThe taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.ResultsThe comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.ConclusionsA set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.

Background Namilumab (AMG203), an immunoglobulin G1 monoclonal antibody that binds with high affinity to granulocyte-macrophage colony-stimulating factor (GM-CSF), was evaluated in a phase II randomized, double-blind, placebo-controlled study to investigate the efficacy and safety in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR) or anti-tumour necrosis factor therapy (TNF-IR). Methods Subcutaneous namilumab (20, 80, or 150 mg) or placebo was administered at baseline and weeks 2, 6, and 10 in patients on stable background methotrexate therapy who were with MTX-IR or TNF-IR. Primary endpoint was mean change from baseline in the 28-joint Disease Activity Score, C-reactive protein version (DAS28-CRP) at week 12 comparing each of the three doses of namilumab to placebo. Safety and tolerability were assessed by adverse events (AEs) and pulmonary parameters. Results were analysed using the per-protocol population. Results One hundred eight patients from Europe and Japan (48.4 ± 12.02 years old; 77.8% female; mean DAS28-CRP 5.60–5.79; rheumatoid factor/anti-citrullinated protein antibodies + 75%) were randomized to placebo or namilumab 20, 80, or 150 mg ( n  = 27, 28, 25, and 28, respectively). Ninety-two were MTX-IR; 16 were TNF-IR. At week 12, a statistically significant difference in DAS28-CRP ( p  = 0.005) was seen for namilumab 150 mg versus placebo and separation was seen as early as week 2 for namilumab 150 mg ( p  < 0.05), with higher ACR50 and response rates versus placebo at week 12. A dose-response effect was observed across the DAS28-CRP endpoint with separation versus placebo evident from week 2. The most common treatment-emergent AEs were nasopharyngitis (18.5%, 17.9%, 4.0%, 14.3%), dyspnoea (0.0%, 3.6%, 8.0%, 10.7%), bronchitis (7.4%, 3.6%, 4.0%, 3.6%), and headache (3.7%, 3.6%, 12.0%, 0.0%) for placebo and 20, 80, or 150 mg of namilumab, respectively. No serious infections were observed. One serious AE (myocardial infarction) was observed with 150 mg of namilumab. There was no apparent dose relationship for AEs. A biomarker-based disease activity score showed a dose-dependent decrease at week 12. Conclusions This phase II study demonstrates the benefit of inhibiting macrophage activity targeting the GM-CSF for RA. The study met its primary endpoint with a clear dose-response effect. An acceptable tolerability profile was demonstrated over the 12-week study. Trial registration ClinicalTrials.gov, NEXUS; NCT02379091 , submitted November 28, 2014

Background Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study. Methods ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0–16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16–40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented. Results The 95 patients enrolled were randomised to receive IVIg ( N  = 47) or placebo ( N  = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4–15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred. Conclusions Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors. Trial registration ProDERM study (NCT02728752).

Background Calgizzarin (S100A11) is a member of the S100 protein family that acts in different tumors by regulating a number of biologic functions. Recent data suggest its association with low-grade inflammation in osteoarthritis (OA). The aim of our study is to compare S100A11 expression in the synovial tissues, synovial fluid and serum of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to characterize the potential association between S100A11 and disease activity. Methods S100A11 protein expression was detected in synovial tissue from patients with RA ( n  = 6) and patients with OA ( n  = 6) by immunohistochemistry and immunofluorescence. Serum and synovial fluid S100A11 levels were measured by ELISA in patients with RA ( n  = 40) and patients with OA ( n  = 34). Disease activity scores in 28 joints based on C-reactive protein (DAS28-CRP) were used to assess disease activity. Cytokine content in peripheral blood mononuclear cells (PBMCs), synovial fibroblasts (SFs) and synovial fluid was analysed by ELISA, western blotting or cytometric bead array. Results S100A11 expression was significantly up-regulated in the synovial lining and sublining layers ( p  < 0.01) and vessels ( p  < 0.05) of patients with RA compared to patients with OA, and was associated with fibroblasts and T cells. S100A11 was significantly increased in synovial fluid ( p  < 0.0001) but not in serum ( p  = 0.158) from patients with RA compared to patients with OA when adjusted for age and sex. Synovial fluid S100A11 correlated with DAS28 ( r  = 0.350, p  = 0.027), serum CRP ( r  = 0.463, p  = 0.003), synovial fluid leukocyte count ( r  = 0.677, p  < 0.001), anti-cyclic citrullinated peptide antibodies (anti-CCP) ( r  = 0.424, p  = 0.006) and IL-6 ( r  = 0.578, p  = 0.002) and IL-8 ( r  = 0.740, p  < 0.001) in synovial fluid from patients with RA. PBMCs and SFs isolated from patients with RA synthesized and spontaneously secreted higher levels of S100A11 in comparison with PBMCs and SFs from patients with OA ( p  = 0.011 and 0.03, respectively). S100A11 stimulated the production of the pro-inflammatory cytokine IL-6 by PBMCs ( p  < 0.05) and SFs ( p  < 0.01). Conclusions Our data provide the first evidence of S100A11 up-regulation and its association with inflammation and disease activity in patients with RA.

To identify clinical features that predict the risk of meeting difficult-to-treat (D2T) rheumatoid arthritis (RA) definition in advance. This retrospective analysis included RA patients from the ATTRA registry who initiated biologic (b-) or targeted synthetic (ts-) disease-modifying anti-rheumatic drugs (DMARDs) between 2002 and 2023. Patients with D2T RA met the EULAR criteria, while controls achieved sustained remission, defined as a Simple Disease Activity Index (SDAI) < 3.3 and a Swollen Joint Count (SJC) ≤ 1, maintained across two consecutive visits 12 weeks apart. Patients were assessed at baseline and at one and two years before fulfilling the D2T RA definition. Predictive models were developed using machine learning techniques (lasso and ridge logistic regression, support vector machines, random forests, and XGBoost). Shapley additive explanation (SHAP) values were used to assess the contribution of individual variables to model predictions. Among 8,543 RA patients, 641 met the criteria for D2T RA, while 1,825 achieved remission. The machine learning models demonstrated an accuracy range of 0.606–0.747, with an area under the receiver operating characteristic curve (AUC) of 0.656–0.832 for predicting D2T RA. SHAP analysis highlighted key predictive variables, including disease activity measures (DAS28-ESR, CDAI, CRP), patient-reported outcomes (HAQ), and the duration of b/tsDMARD treatment. We identified clinical features predictive of D2T RA at baseline and up to one year before meeting the formal criteria. These findings provide valuable insights into early indicators of D2T RA progression and support the importance of earlier recognition and timely therapeutic intervention to improve long-term patient outcomes.