Reade

ObjectiveTo examine the effects of the Wim Hof Method (WHM), with cold exposure (WHM-C) and without (WHM-NC), on mental and physical health in individuals with chronic spinal cord injury (SCI).DesignRandomized-controlled trial.SettingRehabilitation center.ParticipantsSixty-two adults with chronic SCI (37% tetraplegia, 41% motor complete) were randomized into three groups: WHM-C, WHM-NC, and usual care (UC).InterventionThe intervention groups participated in a 7-week program involving weekly supervised sessions and daily home practice. WHM-NC included breathing exercises and mindset training, while WHM-C also incorporated cold exposure. UC participants received no intervention.Main measuresThe primary outcome was the Mental Health Inventory (MHI-5) score. Secondary outcomes included inflammatory and metabolic markers, pulmonary function, body composition, sleep quality, spasticity, chronic pain, and psychological stress.ResultsWHM-NC had eight dropouts, mostly due to motivation or unrelated medical issues, while WHM-C and UC had one dropout each. No significant differences in MHI-5 scores were observed between groups. However, WHM-C participants reported reduced pain interference in daily activities compared to UC (p=0.027). WHM-C also showed improvements in inspiratory parameters FIV1 (+27%, p=0.02) and PIF (+23%, p=0.02) and a significant reduction in fasting glucose concentration (-6%, p=0.006) compared to UC.ConclusionsWhile 44% of WHM-NC dropped out, WHM-C appears to be a feasible, effective intervention for improving aspects of physical health and pain perception in a broad group of individuals with chronic SCI, although no significant mental health benefits were observed.

The field of rheumatoid arthritis (RA) is moving towards identification of and intervention in people at risk of RA, but a validated risk stratification method is lacking. This work was undertaken to develop a risk stratification method for persons presenting with arthralgia considered to be at risk of RA. A joint European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) expert committee was established. Risk factor and outcome data from 10 arthralgia cohorts (including clinically suspect arthralgia and autoantibody-positive arthralgia) were studied. The work focused on differentiating the risk of progression to clinically apparent inflammatory arthritis (IA) within 1 year, using clinical and serologic variables, without and with subclinical joint inflammation detected by ultrasound (US) or magnetic resonance imaging (MRI). Developing RA according to the 2010 EULAR/ACR criteria within 1 year was a secondary outcome. A set of validated risk stratification criteria was developed. Using data from 2293 symptomatic at-risk individuals, a stratification method was derived consisting of 6 clinical and serologic variables (morning stiffness, patient-reported joint swelling, difficulty making a fist, C-reactive protein, rheumatoid factor, and anti-citrullinated peptide antibody) yielding an area under the curve (AUC) of 0.80 (95% CI, 0.77-0.83) for IA development. The inclusion of US variables did not increase the discriminative ability. When MRI-detected subclinical inflammation variables were included, the AUC was 0.87 (95% CI, 0.82-0.90). In the presence of clinical, serologic, and MRI variables, a sensitivity and specificity of >75% was achieved. For RA development, the AUC of the criteria with MRI was 0.93 (95% CI, 0.90-0.97). EULAR/ACR risk stratification criteria have been developed for people with arthralgia in secondary care who are considered at risk for RA. They can be applied in the absence or presence of imaging data and have been developed to define homogeneous risk groups for future prevention trials.

Treatment efficacy of patients receiving anti-TNF antibodies is limited by the formation of anti-drug antibodies. These are observed in most adalimumab-treated rheumatoid arthritis patients, despite the adjuvant-free and human sequence-derived nature of the antibody. The class switched phenotype and high affinity of these antibodies suggest CD4 T-cell involvement in their formation. In this study, we investigated the potential epitopes in the functional domain of adalimumab and assessed their actual HLA II presentation and induction of CD4 T-cell responses in exposed patients. The binding strength of overlapping adalimumab-derived peptides to 27 DR and 14 DQ HLA alleles was predicted in silico. 10 strong and 44 medium-binding 10-mer peptides were identified within the variable regions of the heavy and light chain of adalimumab. HLA-DR-mediated antigen presentation of selected peptides by monocyte-derived dendritic cells was determined by mass spectrometry of the peptide pool eluted from isolated HLA-DR complexes. Binding of the variable region peptides of heavy (H41-62) and light chains (L18-39) was demonstrated. The presence of adalimumab-specific CD4 T-cells in adalimumab-experienced patients was investigated via peptide stimulation of peripheral blood mononuclear cells and assessment of T-cell proliferation. Anti-adalimumab CD4 T-cell responses were observed against four variable region peptides in a group of adalimumab-experienced RA patients. Some of these responses were also present in healthy control donors. This study identifies immunologically relevant CD4 T-cell epitopes in the variable region of the human therapeutic antibody adalimumab based on RA patients' reactivity. Modification of these epitopes or concomitant therapy that targets or prevents adalimumab-specific T cell responses could be beneficial for patients with significant anti-drug responses.

BackgroundTo investigate a patient-level single imputation approach for patient reported outcomes (PROs) that express similar contents or associated PROs, where a PRO whose value is missing at a particular timepoint is substituted by another PRO whose value is available at the same timepoint.MethodsWe performed a simulation study on registry-based spondyloarthritis data to explore the potential interchangeability between the patient pain (PPA) and fatigue (PFA) assessment scores and relevant Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) individual questions, and between PPA, PFA and patient global assessment (PGA). Performance was assessed per imputation method in terms of relative bias and coverage. Sample size, level of missingness and missing data pattern were included as parameters in the simulations.ResultsAll applied scenarios to interchange PPA with BASDAI question 2 (axial pain), BASDAI question 3 (peripheral joint pain/swelling) or their average failed. Interchangeability between PFA and BASDAI question 1 (fatigue/tiredness) was acceptable for partially (up to 50%) missing data. When interchanging patient assessment scores (PPA, PFA and PGA), we observed inconsistent results in terms of performance. The performance of the applied methods depended on the sample size and the level of missingness, but not heavily on the underlying missing data pattern.ConclusionsInterchanging PFA and the BASDAI fatigue question was justified for partially missing data, while interchangeability between PPA, PFA and PGA, and between PPA and the BASDAI pain questions was not advised. Our findings suggest that registering patient assessment scores and BASDAI questions is recommended.

Pain in hand osteoarthritis (OA) is evaluated with repeated pain questionnaires. It is unclear whether these questionnaires adequately capture changes in pain recalled by patients. This study investigated whether changes on pain questionnaires (real-time evaluation) correspond to recalled pain. Data from hand OA patients from the HOSTAS cohort (four one-yearly) and HOPE trial (one six-week interval) were used. Pain was measured with the Australian/Canadian hand Osteoarthritis Index (AUSCAN, range 0-20) and a recall question (how is the pain compared with your last visit). Changes in AUSCAN pain were categorized into improved (≤-1), stable or worsened pain (≥1) and compared with the recall question using Cohen's kappa and percentage agreement. We determined concordance between measurement methods, and investigated associations of mental well-being and illness perceptions with concordance using generalized estimating equations (GEE). Of 708 intervals from HOSTAS (307 patients, 82% women, mean age 61.0 years, mean AUSCAN 9.1), AUSCAN changes and recall were concordant in 42% (Cohen's kappa 0.13). There was concordance in 47% of 86 intervals (Cohen's kappa 0.14) from the HOPE trial (86 patients, 80% women, mean age 63.5, mean AUSCAN 10.7). The most frequent recall answer was worsened pain in the HOSTAS (60%), improved pain in the HOPE trial (76%). In both studies, AUSCAN pain most frequently improved. Depression and anxiety showed no association with concordance. Changes in repeatedly measured AUSCAN pain often differ from the recalled course of pain over the same period. This has profound implications for evaluating patient-reported pain in clinical trials.

BackgroundThe variability in treatment response in people with rheumatoid arthritis (RA) warrants the prediction of patients at high risk of treatment failure. Identification of biomarkers linked to clinical remission in RA is currently a challenge. Metabolomics may help to identify such biomarkers as it allows for a comprehensive exploration of disease-related variations that extends beyond the genome and proteome. This hypothesis-free exploratory metabolomics study aimed to profile serum metabolic alterations in early RA to understand the metabolic changes associated with disease activity and therapeutic response.MethodsThe study included 220 early RA participants from the NORD-STAR study, randomized at baseline into four arms, ranging from conventional anti-rheumatic treatment to biological drugs: methotrexate combined with prednisolone (1), certolizumab (2), abatacept (3), or tocilizumab (4). Untargeted metabolomics was performed in serum samples at baseline and 24-week follow-up. Participants achieving clinical disease activity index remission at 24 weeks were defined as responders. Machine learning models for treatment response were constructed using random forest, logistic regression, support vector machine and extreme gradient boosting algorithms based on selected features.ResultsWe identified 278 metabolites, of which 39 were associated with baseline disease activity, including several acylcarnitines and amino acids. We also found 17 baseline metabolites associated with remission at 24 weeks in the overall cohort, including malic acid (β=-0.4), cytidine (β = 0.4), arginine (β = 0.3), and citrulline (β = 0.2), as well as specific metabolites and metabolic pathways associated with remission in the four treatment arms. Fifteen features were identified using machine learning-based multivariable selection. The best predictive model using logistic regression achieved AUC of 0.75 in training and 0.73 in the test set.ConclusionsOur study has identified several baseline metabolites and metabolic pathways associated with disease activity and response to different treatments in early RA. By integrating metabolomics and clinical data, we developed predictive models for response to treatment in early RA, though their predictive performance remains limited.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13075-025-03616-6.

ObjectivesTo investigate the course of restrictions in paid and unpaid work and corresponding societal costs in patients with hand osteoarthritis (OA). MethodsPatients with data of at least baseline and one follow-up moment (year one up to year eight) of the Dutch Hand OSTeoArthritis in Secondary care cohort (HOSTAS) were included. The Health and Labour Questionnaire (HLQ) was used to assess over the last two weeks hand OA-related restrictions for paid and unpaid work. Societal costs of productivity loss were estimated with Dutch government data on 2021. Results351 patients were included (mean age 60 years, 84% women). At baseline, 166/351 (47%) had paid work, decreasing to 54/164 (33%) at year eight. Loss of productive time over the two-week period was reported by 32/166 (19%) patients with paid work at baseline, 17/104 (16%) at year four, among whom 12/104 (11%) patients at both moments. Any restrictions over this two-week period were experienced by 89/166 patients (54%) at baseline and 41/104 (39%) at year four for those with paid work.Regarding unpaid work, 157/351 (45%) reported replacement of tasks by others at baseline and 72/164 (44%) at year eight. 205/351 (59%) reported restrictions at baseline, and 99/164 (60%) at year eight.Mean total societal costs for loss of paid and unpaid work were, per patient, €89/two weeks (95% confidence interval (CI) 52;127) at baseline, and €47/two weeks (26;69) at year eight. ConclusionsThe proportion of patients with paid work decreases during follow-up, but restrictions at paid and unpaid work seem mostly stable.Keywords