Objective To quantify muscle outcomes, independent of fat mass, in rheumatoid arthritis (RA) patients compared to healthy controls. Methods Quantitative computed tomography scans measured calf muscle and fat cross-sectional area (CSA) and muscle density (an index of intramuscular adipose tissue), and isometric dynamometry was used to measure ankle muscle strength in 50 participants with RA ages 18–70 years and 500 healthy controls. Multivariable linear regression models assessed muscle deficits in RA after adjusting for group differences in adiposity and assessing for an altered muscle–fat association. Associations between RA disease characteristics and fat-adjusted muscle outcomes were also assessed. Results Compared to controls, RA subjects had significantly greater body mass index (BMI) and fat area, and lower muscle area, muscle density, and muscle strength (P < 0.001 for all). Strength deficits were eliminated with adjustment for the smaller muscle area. The magnitude of muscle deficits, relative to controls, was significantly greater (P < 0.03 for interaction) in participants with lower fat area and BMI. Among those in the lower tertiles of adiposity, RA subjects demonstrated more significant deficits compared to controls with similar adiposity. In contrast, among those in the highest tertile for adiposity, RA was not associated with muscle deficits. Among RA, greater Sharp/van der Heijde scores were associated with lower muscle CSA and muscle density. Greater disease activity and disability were associated with low muscle density. Conclusion Deficits in muscle area and muscle density are present in RA patients compared to controls and are most pronounced in subjects with low fat mass. Greater joint destruction is associated with greater muscle deficits.

In this trial, treatment with baminercept failed to significantly improve glandular and extraglandular disease in patients with primary SS, despite evidence from mechanistic studies showing that it blocks LTβR signaling.

Objective To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes. Methods pSS patients met American–European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200. Results Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell–attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters. Conclusion Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

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BackgroundSjögren’s is a systemic autoimmune disease associated with marked morbidity and poor health-related quality of life, generally driven by the cardinal symptoms of the disease: dryness, pain, and fatigue (assessed via EULAR Sjögren’s Syndrome Patient Reported Index [ESSPRI]). The population of Sjögren’s patients with unacceptable symptomatic burden independent of systemic involvement represents a substantial proportion of Sjögren’s patients who have largely been excluded from recent trials despite significant disease burden and overall unacceptable health status.ObjectivesThe objective of this study (NCT04129164) was to evaluate the efficacy and safety of dazodalibep (DAZ), a non-antibody biologic antagonist of CD40L, in adult Sjögren’s subjects with an unacceptable symptom burden but limited systemic organ involvement.MethodsThis was a randomized, double-blind, placebo-controlled, crossover study of DAZ in adult Sjögren’s subjects with an unacceptable symptom burden but limited systemic organ involvement, as defined by having an ESSPRI score ≥ 5 and EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score <5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo (PBO) Q2W x 3 doses, then Q4W x 4 additional doses. Starting on Day 169, subjects initially randomized to DAZ received PBO Q4W x 5 doses and subjects randomized to PBO received DAZ Q4W x 5 doses and were then followed for 12 weeks. The primary endpoint was the change from baseline in ESSPRI at Day 169. Safety was also evaluated.ResultsA total of 109 subjects were randomized and received ≥1 dose of study medication (DAZ, N=54; PBO, N=55). The mean (standard deviation) age of subjects was 49.9 (12.1) years and most were female (94.5%). The change from baseline to Day 169 in ESSPRI (LS mean ± SE) was −1.80 ± 0.23 in the DAZ group compared to −0.53 ± 0.23 in the PBO group, a difference of −1.27 ± 0.33 (p = 0.0002). The change from baseline to Day 169 in each of the three domains of ESSPRI was significantly greater in the DAZ group compared to PBO (dryness: p = 0.0066; fatigue: p = 0.0022; pain: p = 0.0010). At Day 169, a significantly larger proportion of DAZ-treated subjects achieved a ≥1 point or ≥15% reduction in ESSPRI relative to PBO (66.7% vs 32.7%; p =0.008). The improvement from baseline to day 169 in the Functional Assessment of Chronic Illness Therapy-Fatigue score (LS mean ± SE) was significantly greater in the DAZ group (8.1 ± 1.4) relative to PBO (2.8 ± 1.4; p = 0.0095). Greater numerical improvement in DAZ-treated subjects was observed for the Ocular Surface Disease Index (−14.0 ± 3.0 vs −8.5 ± 2.9; p = 0.1936) and Patient’s Global Impression of Severity (−0.6 ± 0.1 vs −0.4 ± 0.1; p = 0.1781) at Day 169 relative to PBO.Through Day 169, a total of 75 subjects reported an adverse event (AE; DAZ: 37 [68.5%]; PBO: 38 [69.1%]) and the majority were mild/moderate in severity. The most frequently reported AEs occurring in ≥5% of DAZ-treated subjects were COVID-19, nasopharyngitis, anemia, and diarrhea. There were three serious AEs in the DAZ group (pneumonia influenza, post-acute COVID-19 syndrome, and gammopathy) and one in the PBO group (neutropenia). All serious AEs were deemed by investigators to be unrelated to study medication. One subject in the DAZ group discontinued the study due to an AE compared to two subjects in the PBO group.ConclusionIn this study of Sjögren’s subjects with an unacceptable symptom burden but limited systemic organ involvement, the primary endpoint was achieved. DAZ-treated subjects experienced a statistically significant and clinically meaningful improvement in the key subjective symptoms of Sjögren’s relative to PBO as measured by the improvement in ESSPRI and associated responder analysis. DAZ therapy was generally safe and well tolerated. Larger trials of DAZ therapy for Sjögren’s are warranted to further explore its safety profile and confirm its clinical efficacy.Figure 1.Adjusted Mean Change from Baseline in ESSPRI Score.Dashed line represents the MCID. Data analyzed using MMRM. ESSPRI, EULAR Sjögren’s Syndrome Patient Reported Index; LS, least squares; MCID, minimal clinically important difference; SE, standard error.REFERENCESNIL.AcknowledgmentsMedical writing support provided by Brendan Lujan, PhD, of Horizon Therapeutics.Disclosure of InterestsE. William St. Clair Consultant of: Horizon Therapeutics, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics and receives royalties from UpToDate, Ilias Alevizos Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, William Rees Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Liangwei Wang Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Alan Baer Consultant of: Bristol-Myers Squibb, Wan Fai Ng Consultant of: Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen, Resolve Therapeutics and UCB, Ghaith Noaiseh Consultant of: Novartis, Chiara Baldini Consultant of: GSK, and Sanofi.

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The use of biologics in the field of rheumatology has dramatically changed the way we treat rheumatic diseases. As the patent-expiration dates for many tumor necrosis-factor inhibitors and other biological agents are approaching, many large pharmaceutical companies are developing and testing their own versions of these agents; this is due to the biologics' huge revenue potential. The potential cost saving is a major incentive for their development. Producing a biosimilar is not an easy task, as minor changes in the production process can have profound immunological and clinical consequences. The European Medicines Agency (EMA) has led the efforts in issuing guidelines to streamline the approval process for applicants interested in developing biosimilars. The US Food and Drug Administration (FDA) has followed the EMA track and has guidelines in place, but the process varies in different countries. The approval process is far more complex than the one used for the approval of small-molecule generic products. Biosimilars should be developed according to the strict rules set forth by the EMA and FDA; other intended copies are available for clinical use in different parts of the world, but should not be considered biosimilars, as they do not fulfill the stringent definition criteria. Biosimilars will soon be in the market, and their use in rheumatic diseases will likely change our treatment approach. Rheumatologists and other health-care professionals will soon be faced with many questions and will have to be familiarized with the concept and the points of debate.