Frank Buttgereit

The synovial membrane is a key regulator of joint homeostasis, inflammation, and tissue remodeling, yet human in vitro models that reproduce its spatial organization while enabling controlled investigation of macrophage–fibroblast-like stromal cell (FLS) interactions remain limited. Here, we developed a xeno-free, spatially organized 3D synovial membrane model that reconstructs the structural relationship between the macrophage lining and fibroblast-rich sublining compartment. The model was generated by establishing an apically organized macrophage-containing lining-like compartment on a transwell membrane, followed by stepwise assembly of FLS laden hydrogel constructs. Hydrogel screening identified a 1:3 VitroGel® RGD formulation as the most suitable condition to support FLS viability, homogeneous cell distribution, and stable tissue organization. Experimentally induced M1-like and M2-like macrophages were incorporated, and the model was stimulated with TNF- α , TGF- β , or Osteoarthritis (OA) synovial fluid (SF). Cytotoxicity, proliferation, metabolic activity, gene expression, and cytokine secretion were analyzed. Pharmacological responsiveness was evaluated using adalimumab and 4-octyl itaconate (4-OI). The spatially organized construct enabled compartment-specific analysis of macrophage–FLS communication. M1-like macrophages induced inflammatory FLS responses characterized by elevated IL1B, IL6, TNFA , and MMP1 expression, whereas M2-like macrophages promoted matrix-remodeling and myofibroblast-related programs, including increased TGFB and ACTA2 expression. Exposure to OA-SF and cytokine stimulation induced FLS hyperproliferation, metabolic adaptation, and distinct transcriptional responses. Treatment with adalimumab suppressed TNF-driven inflammatory responses, whereas 4-OI reduced selected inflammatory markers and altered remodeling-associated responses. Together, these findings establish a spatially organized, xeno-free 3D synovial membrane model as a defined and experimentally tractable platform for studying macrophage–FLS communication and synovial activation. By combining physiologically inspired tissue organization with compartment-specific analysis, the model provides a human in vitro platform for investigating OA-associated inflammatory and remodeling processes and evaluating pharmacological modulation under defined experimental conditions.

Objectives: To study the implementation of the 2015 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) management recommendations for polymyalgia rheumatica (PMR) among rheumatologists and general practitioners (GPs). Methods: An online survey (Survey Monkey) comprising 28 questions was distributed among members of the EULAR Study Group on PMR and giant cell arteritis (n=375). Each member was asked to invite at least one GP (snowball principle) with experience in PMR to participate. Statistical analysis included descriptive statistics; differences were tested using Fisher’s exact test. Results: There were 308 respondents from 37 countries including data from 211 rheumatologists and 73 GPs. Adherence to the 2015 EULAR/ACR recommendations was higher among rheumatologists (83%) than GPs (35%). Rheumatologists (96%) prescribed glucocorticoids more frequently at dosages within the recommended range than GPs (84%). Concerning tapering, a similar proportion of rheumatologists (83%) and GPs (72%) reached the suggested 10 mg prednisone equivalent after 4–8 weeks. Almost all rheumatologists used methotrexate as a glucocorticoid-sparing agent (95%) as compared with only 26% of GPs. Similarly, 70% of rheumatologists, but only 2% of GPs, had experience with interleukin-6 receptor inhibitors for PMR. For follow-up, more rheumatologists preferred scheduled (as opposed to on demand) visits than GPs (99% vs 82%), while more GPs than rheumatologists (47% vs 31%) planned a short follow-up interval (4–8 weeks) in the first year of disease. Conclusion: Implementation of the EULAR/ACR recommendation for the management of PMR remains incomplete, particularly among GPs. Future updates should incorporate projects to foster diffusion and implementation of the recommendations among all professionals managing this disease.

A fundamental challenge in drug development is the frequent failure of early laboratory research to translate into clinical benefit. One promising solution is to confirm findings from exploratory single-laboratory studies across multiple laboratories before clinical testing. We investigated this approach following the conduct of preclinical multi-laboratory studies across different fields of medicine. For this, we evaluated effect sizes, experimental rigor, and a set of criteria to identify determinants of confirmation success. When tested under increased rigor, only a fraction of multi-laboratory studies confirmed the initial results. The underlying effect size reduction was associated with outcome-relevant experimental differences between exploratory and confirmatory stages. In summary, multi-laboratory studies proved highly informative and served as an effective filter for promising treatments. One Sentence Summary: Confirmatory testing of exploratory findings in rigorous multi-laboratory settings reveals which hold up and what limits their translation.

Zusammenfassung: Die Polymyalgia rheumatica (PMR) ist eine häufige entzündlich-rheumatische Erkrankung im höheren Lebensalter, die durch bilaterale Schmerzen im Schulter- und Beckengürtel, Morgensteifigkeit sowie systemische Entzündungszeichen charakterisiert ist. Trotz ihrer Häufigkeit bleibt die PMR angesichts diagnostischer Unsicherheiten mit einem breiten Spektrum an Differenzialdiagnosen eine klinische Herausforderung. Zusätzlich erschweren die Überlappung mit der Riesenzellarteriitis sowie die aufgrund wiederholter Rezidive häufig erforderliche langfristige Glukokortikoidtherapie, die mit einem erhöhten Risiko für therapieassoziierte Nebenwirkungen einhergeht, das Management der Erkrankung. Entscheidend für die optimale Versorgung der Betroffenen ist eine frühzeitige Diagnosesicherung, eine strukturierte Patient:innenstratifizierung sowie das Einbeziehen individueller Risikofaktoren in die Therapieentscheidung.

Polymyalgia rheumatica is a common inflammatory disease characterized by pain and stiffness in the shoulders and hips. Glucocorticoids are the first-line treatment, but relapses and glucocorticoid-related toxic effects are common, which underscores the need for effective alternatives. Secukinumab is a fully human monoclonal antibody that selectively inhibits interleukin-17A. We enrolled patients with recently relapsed polymyalgia rheumatica and randomly assigned them, in a 1:1:1 ratio, to receive secukinumab at a dose of 300 mg (SEC-300 group), secukinumab at a dose of 150 mg (SEC-150 group), or placebo for 52 weeks. Patients in all the groups also received prednisone on a tapering schedule for 24 weeks. The primary outcome was sustained remission at week 52, defined as remission (the absence of signs or symptoms attributable to polymyalgia rheumatica and no new diagnosis of giant-cell arteritis that warranted escape or rescue treatment) that was sustained from week 12 until week 52. The annual cumulative glucocorticoid dose was a secondary outcome. Safety was also assessed. A total of 381 patients underwent randomization, and 127 were assigned to each group. At 52 weeks, sustained remission was observed in 41.2% (95% confidence interval [CI], 32.8 to 49.7) of the patients in the SEC-300 group, in 40.6% (95% CI, 32.2 to 49.0) of those in the SEC-150 group, and in 20.4% (95% CI, 13.6 to 27.2) of those in the placebo group (P<0.001 for the comparison of each secukinumab dose with placebo). The mean adjusted annual cumulative glucocorticoid dose was 1603.7 mg in the SEC-300 group, 1683.2 mg in the SEC-150 group, and 2093.0 mg in the placebo group. Serious adverse events occurred in 13.5% of the patients in the SEC-300 group, in 15.9% in the SEC-150 group, and in 14.2% in the placebo group. Nasopharyngitis, hypersensitivity reactions, urinary tract infections, fungal infections, and back pain were more common in the secukinumab groups than in the placebo group. Among patients with relapsed polymyalgia rheumatica, treatment with secukinumab plus a 24-week glucocorticoid taper resulted in a higher percentage of patients with remission and in lower cumulative glucocorticoid doses than a glucocorticoid taper alone. (Funded by Novartis; REPLENISH ClinicalTrials.gov number, NCT05767034.).

Patients and physicians eagerly await the day when the adverse effects of glucocorticoids will no longer be considered a ‘necessary evil’ in the treatment of inflammatory diseases. Research on novel glucocorticoid receptor (GR) ligands and combination therapies may bring us closer to this goal. We review the current status of novel approaches in rheumatology to reduce glucocorticoid toxicity, including the development of selective GR agonists and modulators, targeted delivery of glucocorticoid receptor ligands, and combination therapy of prednisone with an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. We also describe advances in optimizing glucocorticoid use to achieve an optimal benefit–risk ratio when conventional glucocorticoids are necessary. A priority in the treatment of inflammatory rheumatic musculoskeletal diseases must be to avoid the use of glucocorticoids whenever possible and to use the lowest effective dose when there is no alternative. In this regard, we emphasize glucocorticoid-sparing concepts, for which new options have emerged in recent years. It is also important that glucocorticoid toxicity is carefully and fully documented in both clinical trials and practice in order to justify the development and use of alternative drugs that truly avoid glucocorticoid toxicity. Although we have made good progress in recent years toward the optimal use of glucocorticoids, there is still much to be done.