Rheumatic and musculoskeletal diseases are chronic, heterogeneous conditions shaped by complex interactions between immune, metabolic, behavioural, and environmental factors. Despite substantial advances in pharmacological therapies, many patients continue to have pain, fatigue, functional impairment, and accumulating comorbidity burden, highlighting the need for complementary strategies beyond inflammation control. Prehabilitation is a proactive and multimodal approach aimed at optimising physical, metabolic, and psychological health before periods of increased vulnerability. Although originally developed in surgical and oncological settings, its principles might be relevant across the continuum of chronic inflammatory diseases. Psoriatic disease represents a particularly attractive model given its identifiable preclinical phases, heterogeneous course, and strong influence of modifiable lifestyle factors. In this Personal View, we discuss the rationale for translating prehabilitation to psoriatic disease, explore potential windows of opportunity and intervention domains across the disease continuum, and consider the conceptual challenges, current evidence gaps, and uncertainties surrounding its application in this clinical setting.
BACKGROUND:Outcome measures for lupus arthritis that are not sensitive to change might contribute to misleading results in systemic lupus erythematosus (SLE) trials. We aimed to optimise lupus arthritis assessment by developing a novel composite disease activity measure, derived against ultrasound synovitis and incorporating participant-reported outcomes. METHODS:In this cohort study we derived the Lupus Arthritis and Musculoskeletal Disease Activity (LAMDA) score from baseline data in a prospective, longitudinal, multicentre study (USEFUL) of participants with SLE receiving intramuscular glucocorticoid therapy for lupus arthritis recruited from seven hospitals in England. Penalised multiple quantile (median) regression of total combined grey scale and power Doppler scores from bilateral hand and wrist joint ultrasounds on inflammatory arthritis core set variables defined by the American College of Rheumatology (tender joint count in 68 joints, swollen joint count in 66 joints, Health Assessment Questionnaire Disability Index, erythrocyte sedimentation rate [ESR], and visual analogue scales [VAS] for patient's musculoskeletal pain and disease activity and physician's musculoskeletal disease activity), and early morning stiffness severity VAS was used to derive the score. We assessed convergent construct validity, known groups validity, and responsiveness. We established thresholds of meaning for trial entry, minimal disease activity, participant acceptable symptom state, and minimal clinically important improvement using receiver operating characteristic curve analysis. A separate external validation cohort was recruited from Leeds Teaching Hospitals NHS Trust, clinical outcomes and treatment intention were collected by clinicians who were not involved in the USEFUL study. The construct validity of LAMDA within this external validation cohort was assessed, including discrimination of treatment intention and participant acceptable symptom state. People with lived experience of SLE were involved in the design and delivery of both the USEFUL study and the present study. FINDINGS:133 participants recruited between Oct 20, 2016, and Dec 20, 2018, were included from the USEFUL study; mean age was 47·0 years (IQR 35·0-55·0), 126 (95%) were female, seven (5%) were male, and 82 (62%) were White. The model retained four variables in the LAMDA score: swollen joint count in 66 joints, ESR, VAS for physician musculoskeletal disease activity, and participant musculoskeletal pain. High intraclass correlation (>0·99) supported directly substituting swollen joint count in 28 joints for swollen joint count in 66 joints to improve feasibility. LAMDA showed good construct validity, correlating with conventional disease activity measures, ultrasound findings, and patient-reported outcomes. LAMDA was responsive, yielding a medium-to-large early treatment effect following glucocorticoid therapy (effect size 0·40, p<0·0001). Provisional thresholds of meaning showed good logical consistency with participant characteristics and patient-reported change in musculoskeletal pain. The external validation cohort included 44 participants, recruited between Nov 15, 2017, and July 23, 2020; median age was 48·5 years (IQR 39·0-56·0), 38 (86%) were female, six (14%) were male, and 32 (73%) were White. The findings from the external validation cohort were supportive of the initial findings. LAMDA was correlated with multiple participant reported outcome measures and the proposed thresholds of meaning outperformed swollen joint counts alone in discriminating treatment intention and participant acceptable symptom state. INTERPRETATION:LAMDA is a novel ultrasound-derived clinical disease activity measure that should improve the assessment of lupus arthritis in clinical trials and real-world practice. Further validation is underway in large multinational randomised controlled trials. FUNDING:None.
Systemic lupus erythematosus (SLE) guidelines predominantly focus on common major organ involvement. An international taskforce from three SLE expert groups (European Reference Network on Connective Tissue and Musculoskeletal Diseases, Systemic Lupus International Collaborating Clinics, and the European Lupus Society) previously developed consensus therapeutic strategies for 24 rare SLE manifestations. Here, 77 participants contributed to the development of consensus therapeutic strategies for 22 additional rare SLE manifestations, including diffuse pulmonary haemorrhage, rare cutaneous manifestations (bullous lupus, chilblain lupus, lupus tumidus, erythema multiforme, and toxic epidermal necrolysis-like lupus erythematosus), renal manifestations (interstitial nephritis and lupus podocytopathy), rare neurological manifestations (chorea, small fibre neuropathy, catatonia, and intracranial hypertension), rare gastrointestinal manifestations (protein-losing enteropathy, lupus hepatitis, intestinal pseudo-obstruction, and peritonitis), musculoskeletal manifestations (myositis and Jaccoud's arthropathy), and other rare manifestations such as uveitis, angioedema due to anti-C1 esterase inhibitor antibodies, interstitial cystitis, and lupus mastitis. These expert-based therapeutic strategies provide a framework for guiding therapeutic decisions where evidence-based recommendations might be insufficient.
Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disease primarily affecting children and adolescents. The condition is characterised by bone pain, hyperostosis, and bone deformities, impacting patients' quality of life. Although CNO is the second most common inflammatory rheumatic disease in childhood, no licensed treatments exist. Clinical trials have been challenged by the absence of validated classification criteria and inclusion and exclusion criteria, a shortage of well-validated tools to measure treatment response, and a small market for commercialisation. Clinical trials are urgently needed to generate evidence and allow licensing of medications. Since 2022, long-standing challenges, previously hindering trial design and delivery in CNO, have been addressed through the development of classification criteria, expert consensus on inclusion and exclusion criteria, and the development of outcome measures. Applying a platform trial design testing treatments against a common comparator promises to deliver several key benefits for patients with CNO, families, and health-care services. This Viewpoint summarises treatments currently used to treat CNO alongside promising future candidates, outlining challenges in trial design and how these have, partly, been overcome.
BACKGROUND:Despite widespread use of ultrasound in rheumatology, interpretation of findings is predicated on the assumption that healthy individuals show no gradable differences in all joints and across all age ranges. To define the age-related ultrasound thresholds in small joints, this study sought to systematically grade three ultrasound abnormalities (ie, synovial hypertrophy, Doppler signal, and synovial effusion) in the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints of healthy individuals aged 18-80 years. METHODS:This multicentre, cross-sectional, observational study recruited healthy individuals from 20 centres across 13 countries in Europe, South America, Asia, and the Middle East. Participants included individuals aged 18-80 years from a range of backgrounds, including university and hospital research staff, health-service workers, students, and volunteers from local advertising or national cohorts. Main exclusion criteria were individuals with previous or current inflammatory joint disease, clinical joint inflammation, recent history of joint trauma, hand osteoarthritis, joint pain, and use of corticosteroids or non-steroidal anti-inflammatory drugs. Participants were classified into three age groups (18-39, 40-59, and 60-80 years) representing young, middle, and older age groups. Clinical and ultrasound assessment of bilateral metacarpophalangeal 1-5, proximal interphalangeal 1-5, wrist, and metatarsophalangeal 1-5 joints were conducted according to European Alliance of Associations for Rheumatology guidelines and severity of ultrasound joint abnormalities was graded using the European Alliance of Associations for Rheumatology-Outcome Measure for Rheumatology synovitis score. The age-related threshold for each joint type was identified using the cumulative 95% prevalence rule. People with lived experience of inflammatory arthritis were involved in the study design and interpretation of results. FINDINGS:Participants were recruited from Feb 7, 2017, to July 30, 2019. 802 participants were included in the final analysis. 351 (44%) of 802 participants were aged 18-39 years, 302 (38%) were aged 40-59 years, and 149 (19%) were aged 60-80 years. 578 (72%) of 802 participants were female, 224 (28%) were male, 644 (81%) of 799 were White, and the median age was 42 years (IQR 30-56). Of 28 735 joints scanned, 3728 (13%) had at least one ultrasound finding higher than grade 0. The highest proportion of ultrasound findings higher than grade 0 was in metatarsophalangeal 1 (45%), followed by metatarsophalangeal 2 (39%). Doppler signal activity in the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints and synovial hypertrophy in proximal interphalangeal 2-5, metacarpophalangeal 5, and metatarsophalangeal 5 was minimal in all age ranges. Synovial effusion findings differed by joint type predominantly, but not by age. INTERPRETATION:Doppler signal in any metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints are likely to be abnormal in all age groups. Normal ultrasound thresholds for synovial effusion and synovial hypertrophy differed by joint type and age. The development of age-specific and joint-specific reference values is an important step towards precision medicine using ultrasound imaging in rheumatology. FUNDING:None.
BACKGROUND:General practitioner (GP) delay is the main cause of referral delay for rheumatoid arthritis in the Netherlands due to insufficient experience with joint examination. This delay led to the launch of the early arthritis recognition clinic, in which rheumatologists screen patients for clinical arthritis using joint examination. Because the long-term effectiveness of this intervention is unknown, we measured functional disability and sustained disease-modifying antirheumatic drug (DMARD)-free remission in patients with rheumatoid arthritis to establish its effectiveness. METHODS:In this single-centre, longitudinal, comparative effectiveness cohort study, patients with rheumatoid arthritis who fulfilled the 1987 criteria, the 2010 criteria, or both of the American College of Rheumatology or European Alliance of Associations for Rheumatology and who were referred through the early arthritis recognition clinic (recruited between 2010 and 2020) were compared with similar patients with rheumatoid arthritis (at least one swollen joint and symptom duration of less than 2 years) referred through regular routes (recruited between 2006 and 2009). Both groups received similar treatment and follow-up for 5 years at the Leiden Early Arthritis Clinic. Outcomes were assessed in all patients. The long-term outcomes of Disease Activity Score (DAS) and functional disability-as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI)-were analysed by a linear mixed model, and the long-term outcome of sustained DMARD-free remission was analysed with Cox regression. Patients with lived experience of rheumatoid arthritis were involved in the study. FINDINGS:Between Aug 31, 2010, and Jan 2, 2020, 2081 patients were seen via the early arthritis recognition clinic pathway, 818 patients had clinical arthritis and 132 patients with rheumatoid arthritis were eligible. 10 patients were lost to follow-up and 122 were included in the study (72 [59%] female and 50 [41%] male). Between Jan 5, 2006, and De 22, 2009, 690 patients were referred via the regular referral pathway with clinical arthritis of whom 342 had rheumatoid arthritis and were included in the study (225 [66%] female and 117 [34%] male. Patients referred via the early arthritis recognition clinic had lower disease activity (DAS-44) over 5 years (β=0·26 [95% CI 0·12-0·41]; p=0·0003), less functional disability (HAQ-DI) over 5 years (0·14 [0·02-0·25]; p=0·021), and higher rates of sustained DMARD-free remission (hazard ratio 2·1 [95% CI 1·34-3·16]; p=0·0010) compared with regularly referred patients. Patients with rheumatoid arthritis identified via the early arthritis recognition clinic had a lower median GP delay than regularly referred patients (median 5·14 weeks [IQR 1·86-11·43] vs 9·00 weeks [5·00-20·14], p<0·0001). INTERPRETATION:Implementing an EARC screening clinic improved long-term outcomes and reduced referral delays in patients with rheumatoid arthritis. This study is one of the first to indicate that active intervention to accelerate diagnosis seems effective in improving long-term outcomes in patients with rheumatoid arthritis. FUNDING:The Dutch Arthritis Society.
BACKGROUND:Obesity is common in patients with rheumatoid arthritis and is associated with poorer disease outcomes. We aimed to evaluate the association between BMI and clinical response to Janus kinase (JAK) inhibitors in patients with rheumatoid arthritis using individual patient data from the JAK inhibitor randomised controlled trial programmes. METHODS:In this individual patient data meta-analysis, ClinicalTrials.gov was searched from database inception to Jan 13, 2025, for phase 3, randomised controlled trials of tofacitinib, baricitinib, upadacitinib, and filgotinib in adult patients with rheumatoid arthritis, with a placebo or active comparator. Individual patient data were obtained via the Vivli data-sharing platform. The primary outcomes were a 20% improvement based on American College of Rheumatology (ACR) core set variables (ACR20) and Disease Activity Score based on the evaluation of 28 joints and C-reactive protein (DAS28-CRP), at the trial-defined primary efficacy timepoint. BMI was analysed as a continuous and categorical variable using one-stage mixed-effects models, and validated using a two-stage individual patient data meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. There was no involvement of people with lived experience in the study design or conduct. This study is registered with PROSPERO (CRD420251180005). FINDINGS:16 trials contributed individual patient data from 11 883 participants (9588 [80·7%] women and 2293 [19·3%] men, and two with missing sex data). Mean age was 52·9 years (SD 12·3). 8493 (71·5%) of 11 883 participants were White, 2142 (18·0%) were Asian, 439 (3·7%) were Black, and 809 (6·8%) were of other ethnicity. 7765 received tofacitinib, upadacitinib, or baricitinib. Filgotinib trials were excluded due to insufficient variables. Median BMI was 26·8 kg/m2 (IQR 23·2-31·3) and 3676 (30·9%) patients had class 1-3 obesity. Higher BMI was associated with reduced JAK inhibitor efficacy across all endpoints. Compared with patients with healthy weight, adjusted relative risk for ACR20 response was 0·94 (95% CI 0·91-0·98) for patients with overweight (25 to <30 kg/m2), 0·92 (0·89-0·96) for class 1 obesity (30 to <35 kg/m2), 0·88 (0·81-0·96) for class 2 obesity (35 to <40 kg/m2), and 0·78 (0·71-0·85) for class 3 obesity (≥40 kg/m2). For DAS28-CRP, adjusted mean differences compared with healthy weight were 0·14 (95% CI 0·06-0·22) for overweight, 0·21 (0·12-0·31) for class 1 obesity, 0·30 (0·16-0·44) for class 2 obesity, and 0·54 (0·37-0·70) for class 3 obesity. No corresponding BMI gradient was observed in the placebo group. Between-study heterogeneity was low to moderate (I2=0-40%). Overall risk of bias in individual studies was low. INTERPRETATION:Higher BMI was associated with poorer response and a reduced treatment benefit with JAK inhibitors, with obesity acting as an effect modifier. These findings support integration of weight management into routine care for rheumatoid arthritis and improved BMI representation in future trials. FUNDING:None.
Autoantibodies are central to the diagnosis, classification, and stratification of many autoimmune diseases, particularly those characterised by B-cell activation and MHC class II associations. However, a substantial proportion of patients have historically been labelled as seronegative, creating diagnostic uncertainty and suggesting either technical limitations in autoantibody detection or genuinely distinct pathogenic mechanisms. Advances in laboratory assays, encompassing the adoption of recombinant antigens, high-throughput autoantibody profiling, and autoantigen discovery, have progressively reduced the boundaries of seronegativity across several autoimmune diseases. In this Personal View, we discuss how improved autoantibody detection and the identification of novel specificities have reshaped concepts of seronegative disease across different clinically relevant examples of autoimmune diseases. We further examine how autoantibodies inform patient stratification, influence cancer-associated autoimmunity, and even reverse translational immunology implications and pathogenic hints, while highlighting contexts in which genuinely seronegative autoimmunity might still exist.
Although the diagnosis of rheumatoid arthritis can usually be made once clinical arthritis appears, this moment does not represent the biological onset of disease. Rheumatoid arthritis develops over a period of years in preclinical phases that precede the emergence of persistent joint inflammation. In this narrative Review, we examine how chronicity develops along this trajectory by integrating temporal and tissue perspectives. We discuss early disease phases characterised by the emergence and maturation of autoimmunity and systemic inflammatory shifts, followed by stages marked by subclinical and subsequently clinical joint inflammation, in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis. We consider how some immune perturbations could resolve in some individuals, while others progress to self-sustaining disease, highlighting that reversibility might differ across disease trajectories. Lastly, we examine how evolving multi-hit hypotheses, recent omics studies, and results from prevention trials inform the identification of checkpoints at which progression to chronic disease might still be modifiable.
BACKGROUND:The TREAT EARLIER trial showed that a time-limited intervention with 12 months of methotrexate in individuals with arthralgia at risk of rheumatoid arthritis improved inflammatory burden but did not prevent rheumatoid arthritis after 2 years. Long-term follow-up is needed to assess the durability of the effects. In addition, heterogeneity in pathophysiological subtype (with or without anti-citrullinated protein antibodies [ACPA]) and disease risk was not considered in the 2-year analysis. Therefore, we investigated the long-term effect of methotrexate in reducing disease burden and progression to rheumatoid arthritis in ACPA-positive and ACPA-negative individuals at increased risk of rheumatoid arthritis. METHODS:The TREAT EARLIER trial was a randomised, placebo-controlled trial of participants aged 18 years or older, with clinically suspect arthralgia and subclinical joint inflammation. Participants were recruited from 13 rheumatology outpatient clinics in the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (methylprednisolone 120 mg) followed by a 1-year course of methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment for at least 2 years. Follow-up continued for 5 years. The two primary endpoints in this 5-year follow-up analysis were disease burden (physical disability) and development of rheumatoid arthritis, assessed on an intention-to-treat basis. Patients were stratified for ACPA; only those at increased predicted risk (>10%) were included in the 5-year analysis. People with lived experience of clinically suspect arthralgia or rheumatoid arthritis were involved in the study design. This trial is registered with EudraCT (2014-004472-35) and the Netherlands Trial Register (NTR4853-trial-NL4599), and is complete. FINDINGS:Between April 16, 2015, and Sept 11, 2019, we enrolled 236 participants; 119 were assigned to active treatment and 117 to placebo. 215 (91%) participants completed the 5-year follow-up. 120 participants at increased predicted risk of rheumatoid arthritis were analysed at 5 years, of whom 66 (55%) were ACPA-negative and 54 (45%) were ACPA-positive. Mean age was 48 (SD 12) years, 72 (60%) of 120 participants were female, and 48 (40%) were male. Over 5 years, ACPA-negative participants in the active treatment group (n=35) had sustained improvement in physical disability compared with ACPA-negative participants in the placebo group (n=31; mean difference in Health Assessment Questionnaire disability index [HAQ] -0·16 [95% CI -0·29 to -0·04], p=0·0082) whereas, in ACPA-positive participants, the previously reported benefit in physical disability at 2 years in the treatment group versus placebo group was not sustained (-0·12 [-0·26 to 0·03], p=0·12). Three (9%) of 35 ACPA-negative participants in the treatment group developed rheumatoid arthritis compared with ten (32%) of 31 in the placebo group over 5 years (hazard ratio [HR] 0·24 [95% CI 0·07 to 0·87], p=0·018), corresponding to a number needed to treat of four. In ACPA-positive participants, 18 (58%) of 31 in the treatment group developed rheumatoid arthritis versus 15 (65%) of 23 in the placebo group (HR 0·75 [0·38-1·49], p=0·41). In the full trial cohort of 236 participants, physical disability in the treatment group improved durably over 5 years compared with the placebo group (mean difference in HAQ -0·06 [95% CI -0·14 to -0·05], p=0·048), though development of rheumatoid arthritis was not prevented, with 26 (22%) of 119 participants developing rheumatoid arthritis in the treatment group and 31 (27%) of 117 in the placebo group (HR 0·79 [95% CI 0·47 to 1·34], p=0·38). INTERPRETATION:Secondary prevention with a single intramuscular glucocorticoid injection and 1 year of methotrexate has different long-term effects on developing rheumatoid arthritis in ACPA-positive participants and in ACPA-negative participants. ACPA-negative participants had a long-term reduction in inflammatory disease burden and development of rheumatoid arthritis whereas there was no sustained improvement with ACPA-positive participants. These results imply that different treatment strategies are needed for ACPA-positive and ACPA-negative individuals with arthralgia who are at risk of rheumatoid arthritis. FUNDING:Dutch Research Council (NWO), Dutch Arthritis Society.
