Therapeutic Advances in Musculoskeletal Disease最新文献

Background: Systemic sclerosis (SSc) is a heterogeneous autoimmune disease, where autoantibody profiling plays a central role in defining disease subsets and guiding personalized management.

Objectives: To investigate the clinical phenotype and long-term outcomes of anti-Th/To positive SSc patients in an international cohort, focusing on interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), malignancy association, organ damage accrual, and mortality within a precision medicine framework.

Design: Multicenter case-control study.

Methods: Data prospectively collected from 28 European Scleroderma Trial and Research centers were analyzed (CP144). For each anti-Th/To+ case, two anti-Th/To- controls were matched by sex, age at onset, and disease duration to enable detailed phenotypic comparisons.

Results: A total of 102 anti-Th/To+ patients were compared to 204 anti-Th/To- matched controls. Anti-Th/To+ patients had a higher prevalence of concomitant anti-Ro52+, lower frequency of diffuse cutaneous involvement, digital ulcers, pitting scars, and telangiectasias. ILD on high-resolution computed tomography and ILD functional progression events were less frequent in anti-Th/To+ patients, and anti-Th/To positivity was not independently associated with ILD in multivariable analysis. Instead, ILD presence was significantly associated with anti-Topoisomerase-1 (anti-Topo1) and anti-Ro52 positivity, and lack of anticentromere antibodies. Similarly, myocarditis was less frequently observed in anti-Th/To+ cases, although myositis had a higher rate than in anti-centromere+ or other lcSSc patients. Other SSc manifestations, including PAH, and malignancies synchronous to SSc onset had similar frequencies between cases and controls. Anti-Th/To+ patients accrued mild organ damage during the disease course, with lower damage index scores than anti-Topo1+ matched controls. No SSc-related deaths occurred in anti-Th/To+ patients, who had survival curves slightly better, although not significantly different, than matched controls.

Conclusion: Anti-Th/To+ SSc patients are characterized by low prevalence of major organ involvement, including ILD, when compared to matched controls, mild organ damage, and good survival. These results reinforce the ongoing use of autoantibody profiling-including rarer antibodies-in precision medicine for SSc.

Background: Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis associated with psoriasis, affecting multiple domains, including peripheral joints, axial skeleton, enthesis, dactylitis, and skin. Several multinational organizations, including European Alliance of Associations for Rheumatology (EULAR), Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), and Pan American League of Associations for Rheumatology (PANLAR), have established treatment recommendations to optimize patient care. However, differences may exist in their guidelines, reflecting methodology regional differences, expert consensus, and evolving evidence.

Design and objectives: This review compares the treatment recommendations for PsA established by EULAR, GRAPPA, and PANLAR, highlighting similarities, differences, and challenges in achieving standardized treatment strategies worldwide.

Methods: A comparative literature review analyzing key aspects of each guideline was performed. A systematic evaluation of the latest three multinational treatment recommendations was conducted, focusing on pharmacological and nonpharmacological management approaches. Differences in treatment sequencing, targeted therapies, and emphasis domains were examined.

Results: While all three organizations emphasize a multidisciplinary and personalized approach to PsA treatment, some variations exist in the preferred sequencing of therapies, the role of targeted synthetic disease-modifying antirheumatic drugs, and the approach to extra-musculoskeletal manifestations. PANLAR provides a regional perspective with emphasis on access constraints, EULAR integrates real-world evidence and long-term safety data, and GRAPPA emphasizes domain-based treatment.

Conclusion: While PANLAR, EULAR, and GRAPPA guidelines align in core treatment principles, key differences persist, influencing clinical decision-making. Greater international collaboration may enhance the harmonization of treatment recommendations, ensuring optimal patient outcomes globally.

Background: Despite widespread use of tumor necrosis factor inhibitors (TNFi) as first-line therapy in rheumatoid arthritis (RA), up to 40% of patients fail initial treatment. Subsequent therapeutic choices remain poorly structured, with limited evidence-based guidance to inform individualized post-TNFi decision-making.

Objective: To develop evidence-informed, profile-based recommendations to guide treatment selection after inadequate response to a first TNFi in RA, combining evidence and expert consensus.

Design: Delphi-based consensus study informed by a PRISMA-guided scoping review (ScR) and nominal group methodology.

Methods: A PRISMA-guided ScR of biologic and targeted synthetic biologic disease-modifying antirheumatic drug (tsDMARDs) after TNFi failure was conducted. Patient profiles were identified by a steering committee, and draft recommendations were evaluated through an anonymized Delphi process. A profile-based decision tree integrated direct and indirect evidence, with evidence strength graded using the Oxford Centre for Evidence-Based Medicine approach.

Results: The ScR included 43 studies, mostly exploratory analyses of randomized trials. Scenarios included age ⩾65 years; failure of ⩾2 TNFi; monotherapy; rheumatoid factor/anti-citrullinated peptide antibody status; prominent systemic inflammation; interstitial lung disease (ILD); rheumatoid vasculitis; high cardiovascular (CV) risk or prior CV event; venous thromboembolism (VTE) risk; obesity; high infection risk; osteoporosis; nociplastic pain, depression and fatigue; prior solid cancer; hematologic cancer/lymphoproliferative disease; non-melanoma skin cancer; and pregnancy.Seventeen recommendations were formulated; 15 achieved consensus. Agreed positions included caution with JAK inhibitors (JAKi) in older patients and in those with CV/VTE risk; preference for IL-6 receptor inhibitors or JAKi for monotherapy or prominent systemic inflammation; in RA-ILD, use a b/tsDMARD with a non-TNFi mechanism; rituximab as first choice in rheumatoid vasculitis; abatacept in infection-prone patients; discouraging JAKi in prior malignancy; and TNFi as acceptable during pregnancy. Two statements did not reach consensus: preferential use of non-TNFi in obesity and heightened caution with tofacitinib in osteoporosis or fracture risk.

Conclusion: This Delphi-validated, profile-based framework provides a practical tool to support evidence-informed clinical decision-making.

Background: Knee osteoarthritis (KOA) is a major global cause of disability. Traditional burden metrics quantify disease magnitude but may overlook system-level outcomes. The Chronic Disease Quality of Life Index (CD-QoLI) was developed to capture these broader impacts.

Objectives: To assess the global impact of KOA using the CD-QoLI, focusing on long-term trends, regional disparities, and future projections.

Design: A global population-based modelling study.

Methods: KOA data were obtained from the Global Burden of Disease Study and included incidence, prevalence, and years lived with disability (YLDs) across 204 countries and territories. CD-QoLI was derived from two standardized epidemiological ratios to reflect system-level outcomes. Temporal trends were quantified using annual average percentage change (AAPC), and forecasting models projected values to 2040. Analyses were stratified by sex, age, and Sociodemographic Index (SDI) regions.

Results: Globally, KOA incidence, prevalence, and YLDs increased substantially over the study period. Over the same period, CD-QoLI declined from 0.812 to 0.700 (AAPC: -0.50); in this study, lower CD-QoLI values indicate a relatively more favorable system-level balance between KOA burden and outcomes, and declines were more pronounced in high- and middle-SDI regions. Females and older adults consistently showed lower scores, while individuals aged 15-49 years exhibited a reversal from decline to improvement after 2014. Low-SDI regions displayed persistently higher or rising CD-QoLI values. Spatial analyses indicated marked cross-national heterogeneity, with several high-income countries showing increasing CD-QoLI trajectories over time, whereas others experienced notable declines. Overall, CD-QoLI levels were strongly inversely correlated with SDI (ρ = -0.884). Projections to 2040 indicate persistent disparities, particularly among younger populations and low-SDI areas.

Conclusion: Although KOA burden continues to rise, improvements in system-level outcomes remain uneven across regions, age groups, and development levels, emphasizing the need for targeted and equitable chronic care strategies.

Background: Obesity is a major risk factor for musculoskeletal disorders. Glucagon-like peptide-1 receptor (GLP-1R)-based agonists facilitate weight loss and may influence musculoskeletal health. However, whether GLP-1R based agonists are associated with the musculoskeletal adverse events during the treatment remains unclear.

Objectives: To assess the association between the use of GLP-1R agonists (GLP-1RA) and the spontaneous reports of musculoskeletal adverse events based on RCT safety data.

Design: A systematic review and meta-analysis of RCTs.

Methods: PubMed, Embase, the Cochrane Center Register of Controlled Trials for Studies, and Clinicaltrial.gov website were searched for RCTs of GLP-1R-based agonists from the inception to June 2025. The primary endpoint was the association between GLP-1R-based agonists and the reported musculoskeletal adverse events, expressed as risk ratio with the 95% confidence interval (CI) using a random-effect model.

Results: A total of 43 RCTs with 100,488 participants were included. No significant difference was observed between users of GLP-1RAs and the control group in the reporting of the prespecified musculoskeletal adverse events, including gouty arthritis, rheumatoid arthritis, osteoarthritis, osteoporotic fracture, synovitis, or intervertebral disc protrusion. However, a higher proportion of male participants was associated with fewer reports of osteoarthritis (β = -0.015, 95% CI, -0.029 to -0.001) in GLP-1R-based agonist users.

Conclusion: GLP-1RAs were not associated with the spontaneously reported events of gouty arthritis, rheumatoid arthritis, osteoarthritis, osteoporotic fracture, synovitis, or intervertebral disc protrusion. A higher percentage of male participants was associated with fewer reports of osteoarthritis among GLP-1RA users.

Background: Obesity has been proposed as a risk factor for the development of rheumatoid arthritis (RA). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for weight reduction and glycemic control and have been shown to exert immunomodulatory effects. However, the association between GLP-1RA use and the onset of RA remains unclear.

Objectives: To investigate the association between GLP-1RA exposure and new-onset RA in a large population-based study.

Design: Retrospective, population-based case-control study.

Methods: We analyzed data from a nationwide health provider database. All adults diagnosed with RA were matched with controls (1:5) by age, sex, and socioeconomic status. The primary exposure was GLP-1RA use within the 10 years preceding RA diagnosis. Multivariable logistic regression models were used to estimate the association between GLP-1RA use and new onset RA, adjusting for age, body mass index (BMI), smoking status, and diabetes mellitus (DM). Duration of GLP-1RA exposure was stratified according to length of exposure (⩽6 vs >6 months).

Results: The study included 4535 RA cases and 22,675 matched controls. In univariate analyses, subcutaneous semaglutide and liraglutide were significantly associated with new onset RA, while dulaglutide showed a non-significant trend. These associations remained significant in multivariable models adjusted for potential confounders. Higher BMI categories and DM were independently associated with new onset RA. When GLP-1RA exposure was stratified according to length of exposure (⩽6 vs > 6 months), shorter exposure, but not longer exposure, was associated with new onset RA.

Conclusion: GLP-1RA use was associated with new onset RA. However, prolonged treatment appeared to attenuate this association, potentially reflecting the beneficial effects of GLP-1RAs on BMI and glycemic control, which are independently associated with new onset RA.

What is this summary about? Gout is a painful inflammatory form of arthritis that happens when urate levels build up in the blood for a long time. This causes urate crystals to form in the joints, tendons, and soft tissues, causing swelling and pain. Some patients have "uncontrolled gout" when conventional, oral medications do not work well or cause side effects. Pegloticase is an intravenously administered treatment for uncontrolled gout. It uses a modified enzyme to change urate into a substance called allantoin, which the body can easily remove via the kidneys. Patients take pegloticase with a medicine called methotrexate, which prevents their immune systems from making pegloticase ineffective. The MIRROR study investigated how well pegloticase worked with and without methotrexate in treating uncontrolled gout and how safe it was when used for a year. Afterward, the number of patients who went into remission, meaning their gout was well controlled, was investigated. There were two definitions of remission: one was more complex with six criteria and the other was simpler with three criteria. After 1 year of pegloticase treatment, 43% of patients met the complex definition and 70% met the simpler definition. These results show that pegloticase helped many people with long-term uncontrolled gout reach remission. The results also show that the simpler definition of uncontrolled gout is a practical way for doctors to see how well treatments work in managing uncontrolled gout. What were the results? Using the six-criteria remission definition (adapted from de Lautour 2016), 43% of included patients achieved gout remission after 52 weeks of pegloticase treatment. Using the three-criteria remission definition (adapted from G-CAN), 70% of included patients achieved gout remission after 52 weeks of pegloticase treatment. What do the results mean? All patients in the MIRROR RCT had uncontrolled gout, and patients had experienced gout for an average of approximately 14 years. These analyses showed that lowering serum urate levels with pegloticase for 12 months put gout into remission in a large proportion of these patients with hard-to-treat disease. Importantly, these findings indicate that the simplified criteria adapted from the G-CAN definition were practical to use in routine clinical care and could be used to see how well treatment is working in patients with uncontrolled gout.

Background: Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA), and folic acid is routinely co-prescribed to prevent folate deficiency. However, no consensus exists regarding the optimal dose and frequency of folic acid supplementation.

Objectives: This study aimed to compare the incidence of major adverse cardiovascular events (MACE) in RA patients receiving high versus low doses of folic acid alongside MTX.

Design: A population-based retrospective cohort study.

Methods: RA patients using MTX without baseline MACE were recruited retrospectively from a citywide database in Hong Kong between 2006 and 2015 and followed until 2018. The primary outcome was the first occurrence of MACE. Cox regression analyses with time-varying covariates were used to assess the association between folic acid dosage and incident MACE, adjusting for demographics, traditional cardiovascular risk factors, markers of inflammation and anti-rheumatic drug use.

Results: A total of 8405 RA patients on MTX were identified. Of these, 6854 (78.5%) were female and the mean age was 56.0 ± 13.5 years. Among the cohort, 2967 patients (35.3%) received ⩾5 mg of folic acid daily, while 5438 (64.7%) received 0-<5 mg. After a median follow-up of 9 years (interquartile range: 5 years), 504 patients (6.0%) developed MACE. Multivariable analyses showed that the use of folic acid ⩾5 mg daily was associated with a significantly higher risk of MACE (adjusted hazard ratios were 1.34 (95% confidence interval (CI) 1.09-1.64) in the erythrocyte sedimentation rate model and 1.39 (95% CI 1.14-1.71) in the C-reactive protein model) compared to lower doses. The association remained significant after inverse probability treatment weighting and machine-learning gradient boosted regression modelling.

Conclusion: High-dose folic acid supplementation may be associated with an increased risk of MACE in RA patients taking MTX.

Background: Giant cell arteritis (GCA) is a chronic inflammatory vasculopathy associated with an increased risk of cardiovascular and thromboembolic complications, including acute coronary syndrome (ACS). Early identification of high-risk subgroups is essential for targeted prevention. This scoping review summarizes the demographic and clinical characteristics of patients with GCA who are at elevated risk for ischemic cardiac events.

Design: Scoping review.

Methods: We systematically searched PubMed, Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL), and EMBASE (Ovid interface) for studies evaluating the association between GCA and ACS, applying predefined eligibility criteria. Eligible studies included adults aged ⩾50 years with confirmed GCA and reported ACS outcomes. Data were synthesized qualitatively, and key quantitative variables were extracted.

Results: Nine studies met inclusion criteria, encompassing 14,484 patients with GCA. Of these, 71.5% were women, 77% had a new GCA diagnosis, and 9.8% experienced an ischemic cardiac event during follow-up. Consistently reported predictors of ACS included the early post diagnosis period, male sex, and older age at diagnosis. Other potential risk factors such as hypertension, corticosteroid use, and concomitant polymyalgia rheumatica were inconsistently reported or lacked statistical significance. Substantial heterogeneity in study design, definitions, and follow-up duration precluded pooled analysis.

Conclusion: Older age, male sex, and the period shortly after GCA diagnosis appear to confer the highest risk for ACS, though current evidence is limited by methodological variability and incomplete reporting. Prospective studies with standardized definitions, detailed treatment data, and longitudinal follow up are needed to refine cardiovascular risk stratification in GCA. Meanwhile, clinicians should maintain heightened vigilance for cardiac events in high-risk patients, particularly early in the disease course.

Background: Systemic lupus erythematosus (SLE) is a major underlying disease of glucocorticoid-associated osteonecrosis of the femoral head (ONFH). Despite its clinical significance, no prophylactic treatment has been established to prevent ONFH in patients receiving systemic glucocorticoid therapy.

Objectives: To investigate the efficacy and safety of a three-drug combination therapy consisting of clopidogrel sulfate, pitavastatin calcium hydrate, and tocopherol acetate, administered concurrently with initial glucocorticoid therapy to prevent ONFH in patients with SLE.

Design: A multicenter, single-arm, interventional clinical trial conducted as an advanced medical treatment approved by the Ministry of Health, Labor and Welfare of Japan.

Methods: This study was conducted at 12 sites in Japan between August 2014 and March 2024. Patients with SLE who required initial glucocorticoid therapy (⩾0.5 mg/kg/day of prednisolone) received the three study drugs concurrently with glucocorticoids for 90 days. Magnetic resonance imaging of both hip joints was performed 180 days after initiation of glucocorticoid therapy to determine ONFH occurrence. The primary endpoint was ONFH incidence, and safety and potential risk factors were also evaluated using logistic regression analysis.

Results: Of the 50 enrolled patients, 43 completed the 90-day regimen. ONFH was identified in 8 of 43 patients (18.6%), which was below the threshold incidence of 25% based on the historical control, suggesting a potential signal of reduced incidence (p = 0.1664). Treatment-emergent adverse events were observed in 19 patients; the only severe adverse event was a drug eruption in one patient. The exploratory analysis identified the period of drinking as a significant risk factor for ONFH occurrence.

Conclusion: The findings demonstrate the feasibility and acceptable safety of this three-drug combination therapy. Although the results should be regarded as preliminary and hypothesis-generating, they suggest a potential signal that warrants further investigation in adequately powered randomized controlled trials.

Trial registration: Clinical trial for the control of osteonecrosis of the femoral head secondary to the initial corticosteroid treatment in patients with systemic lupus erythematosus (UMIN000008230; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009636).