One-year effectiveness of long-term exercise therapy in people with axial spondyloarthritis and severe functional limitations.

OBJECTIVE: To evaluate the effectiveness of long-term, personalized, supervised exercise therapy on functional ability compared with usual care in people with axial spondyloarthritis (axSpA) and severe functional limitations. METHODS: Participants were randomly 1:1 assigned to the intervention(maximal 64 sessions, with 14 additional optional sessions of supervised active exercise therapy(e.g. aerobic and muscle strengthening) with individualized goal-setting, education and self-management regarding physical activity) or usual care(care determined by clinician(s) and participants themselves). Primary end point was the change in the Patient-Specific Complaints activity ranked 1 (PSC1 (0-10)) at 52 weeks. Secondary endpoints were the PSC activities ranked 2 and 3, the Bath Ankylosing Spondylitis Functional Index, 6-min walk test, Patient Reported Outcome Measurement Information System-Physical Function-10 and the Short Form-36 Physical and Mental Component Summary Score (SF-36 PCS and MCS). Statistical comparisons comprised independent student t-tests and linear mixed models, based on intention-to-treat. RESULTS: 214 participants(49% female, age 52 (SD 12) years), were randomized to the intervention (n = 110) or usual care (N = 104) group. In the intervention group 93% started treatment, using on average 40.5 sessions (SD 15.1). At 52 weeks, the difference in change in PSC1 between groups favored the intervention group (mean difference [95% CI]; -1.8 [-2.4 to -1.2]). additionally, all secondary outcomes, except the SF-36 MSC, showed significantly greater improvements in the intervention group with effect sizes ranging from 0.4-0.7. CONCLUSION: Long-term, supervised exercise therapy proved more effective than usual care in improving functional disability and physical quality of life in people with axSpA and severe functional limitations. CLINICAL TRIAL REGISTER NUMBER: Netherlands Trial Register NL8238, included in the International Clinical Trial Registry Platform (ICTRP) (https://trialsearch.who.int/Trial2.aspx?TrialID=NL8238).

Day-to-day fluctuations of fatigue severity in individuals with knee osteoarthritis: an ecological momentary assessment approach.

Objective: The variable course of fatigue adds to the disease burden of patients with OA yet it has been poorly understood. This study aimed to describe within-person fluctuations of fatigue severity and explore its associations with pain, positive affect, negative affect, sleep, and perceived exertion of physical activity. Methods: Individuals with chronic knee pain or a clinical diagnosis of knee OA ≥40 years of age completed daily assessments about fatigue, pain, positive affect, negative affect, sleep, perceived exertion of physical activity (numeric rating scale 0-10), and overwhelming fatigue (yes/no) on a smartphone over 14 days. Within-person fluctuations of fatigue severity were described by the probability of acute changes (PACs) and s.d.s. Associations with pain, positive affect, negative affect, sleep, and perceived exertion of physical activity were explored using multilevel models. Results: Forty-nine individuals were included (mean age 63.4 years; 82% female). PACs and s.d.s of within-person daily fatigue fluctuations ranged from 0.00 to 0.80 and 0.35 to 2.95, respectively. Within-person associations of fatigue severity were moderate for positive affect [ß = -0.57 (95% CI -0.67, -0.47)], weak for pain [ß = 0.41 (95% CI 0.29, 0.53)] and negative affect [ß = 0.40 (95% CI 0.21, 0.58)], and negligible for sleep [ß = -0.13 (95% CI -0.18, -0.08)] and perceived exertion of physical activity [ß = 0.18 (95% CI 0.09, 0.26)]. Conclusion: Some individuals showed almost stable day-to-day levels of fatigue severity, whereas others experienced a substantial number of clinically relevant fluctuations. To reduce the burden of daily fatigue fluctuations, our results suggest that pain, positive and negative affect rather than sleep and perceived exertion of physical activity should be considered as potential targets.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis: protocol of a randomized, placebo-controlled, double-blind clinical trial (COMPLETE-PsA).

BACKGROUND: Both methotrexate (MTX) and leflunomide (LEF) are registered and regularly prescribed as first-line treatments for the use in patients with psoriatic arthritis (PsA) and they are occasionally used in combination. However, evidence about their individual, and especially combined efficacy, in PsA is lacking. The aim of this study is to compare the effectiveness and safety of MTX and LEF combination therapy to MTX monotherapy in patients with PsA. METHODS: COMPLETE-PsA is a randomized, placebo-controlled, double-blind clinical trial. Disease-modifying antirheumatic drug (DMARD)-untreated patients (n = 78) with clinical diagnosis of active (i.e. ≥2 swollen joints) PsA will be randomized 1:1 (stratified for high disease activity, Psoriatic Arthritis Disease Activity Score [PASDAS] ≥ 5.4) to the combination or monotherapy. The intervention group receives MTX 25 mg (oral or subcutaneous) once weekly plus LEF 20 mg daily, and the control group receives the same but with placebo instead of LEF daily. Primary endpoint is between-group difference in PASDAS at 16 weeks, adjusted for baseline PASDAS. Key secondary parameters include between-group comparisons in change in Disease Activity in Psoriatic Arthritis (DAPSA) score, skin score, enthesitis score, dactylitis score, and swollen/tender joint count, as well as the proportion of patients fulfilling minimal disease activity (MDA), American College of Rheumatology (ACR) 20/50/70 response criteria at week 16. Furthermore, safety, function and quality of life (Health Assessment Questionnaire [HAQ], Psoriatic Arthritic Impact of Disease [PSAID], Short Form 12 [SF-12]) will be assessed. DISCUSSION: This is, to our knowledge, the first randomized, placebo-controlled, double-blind clinical trial assessing the effectiveness of MTX and LEF combination therapy in patients with PsA. The study will provide important information for treatment strategies and treatment recommendations. TRIAL REGISTRATION: Dutch Trial Register NTR7632 (3 December 2018). CMO NL66544.091.18 (19 November 2018).

Dose reduction and withdrawal strategy for TNF-inhibitors in psoriatic arthritis and axial spondyloarthritis: design of a pragmatic open-label, randomised, non-inferiority trial.

BACKGROUND: Tumour necrosis factor inhibitors (TNFi) are effective in the treatment of patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). However, these drugs come with some disadvantages such as adverse events, practical burden for patients and high costs. Dose optimisation of TNFi after patients have reached low disease activity (LDA) has been shown feasible and safe in rheumatoid arthritis (RA). However, data on TNFi dose optimisation in PsA and axSpA are scarce, especially pragmatic, randomised strategy studies. METHODS: We developed an investigator-driven, pragmatic, open-label, randomised, controlled, non-inferiority trial (DRESS-PS) to compare the effects of a disease activity-guided treat-to-target strategy with or without a tapering attempt in patients with SpA (PsA and axSpA combined), ≥ 16 years of age, who are being treated with TNFi, and have had at least 6 months of low disease activity. The primary outcome is the percentage of patients in LDA after 12 months of follow up. Patients are assessed at baseline, 3, 6, 9, and 12 months of follow up. Bayesian power analyses with a weakened prior based on a similar study performed in RA resulted in a sample size of 95 patients in total. DISCUSSION: More knowledge on disease activity-guided treatment algorithms would contribute to better treatment choices and cost savings and potentially decrease the risk of side effects. In this article we elucidate some of our design choices on TNFi dose optimisation and its clinical and methodological consequences. TRIAL REGISTRATION: Dutch Trial Register, NL6771. Registered on 27 November 2018 (CMO NL66181.091.18, 23 October 2018).

Long-term efficacy of low-dose radiation therapy on symptoms in patients with knee and hand osteoarthritis: follow-up results of two parallel randomised, sham-controlled trials.

BACKGROUND: Low-dose radiation therapy is commonly used as treatment for benign diseases, including osteoarthritis, in some countries (eg, Germany). We have previously presented our 3-month follow-up results of two randomised sham-controlled trials, in which no substantial effects of low-dose radiation therapy on clinical outcomes were seen in patients with knee and hand osteoarthritis. Here we report the 6-month and 12-month results of these studies. METHODS: In one randomised sham-controlled trial, patients with knee osteoarthrosis were recruited, and in the other trial patients with hand osteoarthritis were recruited. All patients were recruited from the department of rheumatology of Sint Maartenskliniek (Nijmegen, The Netherlands) and the trials were undertaken in parallel. Patients were eligible if they had knee or hand osteoarthritis according to American College of Rheumatology (ACR) criteria, had a pain score of 5 or more on a 0-10 scale for at least 15 of the past 30 days, and did not meet 2011 modified ACR criteria for fibromyalgia. In each study, patients were randomly assigned (1:1), stratified by pain score (<8 vs ≥8) using a computer-generated randomisation list and stratified block randomisation, to low-dose radiation therapy (six fractions of 1 Gy low-dose radiation therapy in 2 weeks) or sham (six sessions with 0 Gy of radiation therapy in 2 weeks) intervention. Patients and researchers involved in patient contact or assessments were masked to group allocation, whereas the radiotherapy technologist who did the treatment was unmasked. Patients completed questionnaires (numeric rating scale of patients' global assessment and validated measures for pain and functioning) at baseline and at 1, 2, 3, 6, and 12 months after starting treatment. The primary outcome was the proportion of participants who responded according to the Outcome Measures in Rheumatology Osteoarthritis Research Society International responder criteria at 3 months, which has been reported previously. Here we report the proportion of participants who responded at 6 months and 12 months, and other clinical outcomes of pain, functioning, and patients' global assessment of their symptoms. We used logistic and linear mixed-models analyses to assess differences in number of responders and continuous outcomes. Safety was assessed in all participants who received at least one fraction of low-dose radiation or sham treatment. This study is registered with the Netherlands Trial Registry, NTR4574, and is closed to accrual. FINDINGS: Between Oct 14, 2015, and May 3, 2017, 213 patients were screened for inclusion for the knee osteoarthritis study, of whom 55 were eligible and randomly assigned to low-dose radiation therapy (n=27) or sham intervention (n=28). In parallel, for the hand osteoarthritis study, 368 patients were screened and 56 were randomly assigned low-dose radiation (n=28) or sham intervention (n=28). Some minor imbalances in baseline demographic characteristics in terms of sex and age were seen in both the knee and hand cohorts. In the knee osteoarthritis cohort, 48 patients were assessible at 6 months and 50 were assessible at 12 months, and in the hand osteoarthritis cohort 52 patients were assessible at 6 and 12 months. We found no significant differences at 6 or 12 months in the proportion of participants who had a response for both groups. In the knee osteoarthritis group, at 6 months, the number of responders was nine (41%) of 22 patients who received low-dose radiation therapy versus nine (35%) of 26 patients who received the sham intervention (difference in proportion 7% [95% CI -20 to 33]; odds ratio [OR] 1·34 [95% CI 0·41 to 4·42]); and at 12 months, 13 (52%) of 25 patients versus 11 (44%) of 25 patients responded (difference in proportion 8% [-19 to 35]; OR 1·41 [0·45 to 4·48]). In the hand osteoarthritis group, at 6 months, the number of responders was seven (28%) of 25 patients who received low-dose radiation therapy versus 11 (31%) of 27 patients who received the sham intervention (difference in proportion 12% [-38 to 13]; OR 0·57 [0·18 to 1·81]); and at 12 months, eight (31%) of 26 patients versus seven (27%) of 26 patients responded (difference in proportion 4% [-20 to 29]; OR 1·23 [0·37 to 4·12]). We did not find any difference between groups in other clinical outcomes at 6 or 12 months. Three participants with knee osteoarthritis in the sham intervention group and two participants with hand osteoarthritis in the low-dose radiation therapy group had serious adverse effects, none of which were considered to be related to the intervention. INTERPRETATION: We did not find evidence of a delayed effect of low-dose radiation therapy for patients with knee and hand osteoarthritis. Our placebo-controlled results suggest that the large effects of low-dose radiation therapy reported in clinical practice and observational studies can probably be explained by a regression to the mean effect and response to placebo. FUNDING: Dutch Arthritis Foundation and Stichting Landelijk Katholiek Reumacentrum, Netherlands.

Short-term clinical worsening is a clear predictor for worsening at 2 years in established knee and hip osteoarthritis.

OBJECTIVES: Our aim was to estimate the proportion of knee and hip OA patients showing worsening at 2 years, and to examine the additional predictive value of failure of optimised non-surgical treatment during 3 months for worsening at 2 years. METHODS: Data of patients participating in the longitudinal CONTROL-PRO study (patients fulfilling clinical ACR criteria for knee or hip OA) were used. Measurements of pain, functioning and patient global assessments were performed at baseline, 3 months and 2 years. Worsening at 2 years was defined as fulfilling the recently validated clinical worsening criteria for knee and hip OA, or total joint replacement (TJR). Logistic regression was performed with worsening at 2 years as the dependent variable. RESULTS: The 297 included patients were predominantly women (66%) with a mean age of 55 years. At 2 years, 61% showed worsening (knee 59%; hip 71%) and 24% had undergone a TJR (knee 19%; hip 51%). Clinical worsening at 3 months appeared to be a clear independent predictor for worsening at 2 years (OR 2.8 95% CI 1.5-5.2) with a moderate discriminative ability (AUC 0.68 95% CI 0.57-0.70). Similar results were obtained when only TJR at 2 years was used as the outcome measure (OR 4.1 95% CI 2.0-8.4) with good AUC (0.82 95% CI 0.76-0.87). CONCLUSIONS: Our findings suggest that re-assessment of symptoms after optimised non-surgical treatment could be meaningful in clinical decision making for TJR. Furthermore, this information could be used to identify subgroups of patients potentially eligible for novel and advanced treatment options.

Effectiveness of low-dose radiation therapy on symptoms in patients with knee osteoarthritis: a randomised, double-blinded, sham-controlled trial.

OBJECTIVES: Low-dose radiation therapy (LDRT) for benign disorders such as knee osteoarthritis (OA) is widely used in some parts of the world, despite absence of controlled studies. We evaluated the effect of LDRT on symptoms and inflammation in patients with knee OA. METHODS: In this randomised, double-blinded, sham-controlled clinical trial (RCT), we recruited patients with knee OA (clinical ACR criteria) in the Netherlands, aged ≥50 years, pain score ≥5/10 and non-responding to analgesics and exercise therapy. Patients were randomised 1:1 to receive LDRT (1 Gray per fraction) or sham intervention six times in 2 weeks, stratified by pain (<8 versus ≥8/10). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months postintervention. Secondary outcomes included pain, function and inflammatory signs assessed by ultrasound, MRI and serum inflammatory markers. RESULTS: We randomly assigned 55 patients: 27 (49%) to LDRT and 28 (51%) to sham. At 3 months postintervention, 12/27 patients (44%; 95% CI 26% to 63%) in the LDRT vs 12/28 patients (43%; 95% CI 25% to 61%) in the sham group responded; difference 2% (95% CI 25% to 28%), OR adjusted for the stratifying variable was 1.1 (95% CI 0.4 to 3.2). Also, for clinical and any of the inflammatory signs, no differences were observed. CONCLUSIONS: We found no substantial beneficial effect on symptoms and inflammatory signs of LDRT in patients knee OA, compared with sham treatment. Therefore, based on this RCT and the absence of other high-quality evidence, we advise against the use of LDRT as treatment for knee OA. TRIAL REGISTRATION NUMBER: NTR4574.

Patient Acceptable Symptom State in Knee Osteoarthritis Patients Succeeds Across Different Patient-reported Outcome Measures Assessing Physical Function, But Fails Across Other Dimensions and Rheumatic Diseases.

OBJECTIVE: The aims of this study are (1) to establish the Patient Acceptable Symptom State (PASS) cutoff values of different patient-reported outcome measures (PROM) assessing physical function in patients with knee osteoarthritis (OA), and (2) to assess the influence of sex, age, duration of symptoms, and presence of depressive feelings on being in PASS. METHODS: Patients fulfilling the clinical American College of Rheumatology knee OA criteria received standardized nonsurgical treatment and completed different questionnaires at baseline and 3 months assessing physical function: Knee Injury and Osteoarthritis Outcome Score, Lequesne Algofunctional Index, Lower Extremity Functional Scale, numerical rating scale, and the physical function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index. PASS values were defined as the 75th percentile of the score of questionnaires for those patients who consider their state acceptable. RESULTS: Of the 161 included patients, 62% were women with a mean age of 59 years (SD 9) and body mass index of 30 kg/m2 (SD 5). Standardized PASS values (95% CI) for different questionnaires for physical function varied between 48 (44-54) and 54 (50-56). Female patients and patients feeling depressed were found to have a lower probability to be in PASS for physical function, with OR (95% CI) varying from 0.45 (0.23-0.91) to 0.50 (0.26-0.97) and from 0.27 (0.14-0.55) to 0.38 (0.19-0.77), respectively. CONCLUSION: PASS cutoff values for physical function are robust across different PROM in patients with knee OA. Our results indicate that PASS values are not consistent across dimensions and rheumatic diseases, and that the use of a generic PASS value for patients with OA or even patients with other rheumatic diseases might not be justifiable.

The clinical burden of generalized osteoarthritis represented by self-reported health-related quality of life and activity limitations: a cross-sectional study.

The involvement of multiple joints is common in osteoarthritis (OA), often referred to as generalized osteoarthritis (GOA). However, since research and practice mainly focus on a specific OA localization, the health status of patients with GOA is largely unknown. Therefore, we aimed to describe the clinical burden of GOA in terms of self-reported health-related quality of life (HRQoL) and activity limitations. In this cross-sectional study, individuals clinically diagnosed with GOA and referred to multidisciplinary treatment, completed questionnaires on socio-demographics, joint involvement, HRQoL (SF-36) and activity limitations (HAQ-DI). SF-36 physical (PCS) and mental component summary scores (MCS) were calculated using norm-based data. The patient's specific most important activity limitations were linked to the International Classification of Functioning, Disability and Health. A total of 147 patients participated [85 % female; mean (SD) age 60 (8) years]. The majority (93 %) had symptomatic OA in both the upper and lower extremities. Predominant joints with symptomatic OA were the hands (85 %) and knees (82 %). Mean (SD) SF-36 PCS and MCS scores were 37 (7) and 48 (10), respectively, showing a broad impact of GOA on the physical component of health. The mean (SD) HAQ-DI score was 1.27 (0.50) indicating moderate to severe functional limitations. Activities concerning mobility and domestic life were considered most important activity limitations, especially walking. The results show a high clinical burden of GOA in terms of HRQoL and activity limitations. This study points to the need of developing non-pharmacological interventions for patients with GOA that should target on improving the physical component of health and mobility limitations.

Measurement properties of the Health Assessment Questionnaire Disability Index for generalized osteoarthritis.

OBJECTIVE: Generalized OA (GOA) is highly prevalent in OA. Individuals with GOA typically suffer from limitations of both upper and lower extremity function, yet we lack a validated instrument to assess their activity limitations. An appropriate instrument might be the HAQ Disability Index (HAQ-DI). Therefore the aim of this study was to evaluate the measurement properties of the HAQ-DI in GOA. METHODS: Data were used from a randomized controlled trial comparing the effectiveness of two multidisciplinary treatment programmes for patients with GOA. One hundred and thirty-seven of 147 included patients completed a standardized set of questionnaires before and after treatment. Interpretability, validity, reliability and responsiveness of the HAQ-DI were assessed using the Consensus-Based Standards for the Selection of Health Status Measurement Instruments checklist (COSMIN). RESULTS: Floor and ceiling effects were present. The content validity was questionable since the HAQ-DI encompasses activities that are either not relevant or too easy to perform as judged by patients and experts. Construct validity was good since 90% of the hypotheses were confirmed. Factor analysis confirmed the unidimensionality of the HAQ-DI (root mean square error of approximation = 0.057, χ(2)/df ratio = 1.48). Cronbach's α was 0.90, confirming internal consistency and the ICC was 0.81, reflecting good reliability. The minimal important change was 0.25 and the smallest detectable change was 0.60. We could not establish the responsiveness of the HAQ-DI. CONCLUSION: The HAQ-DI showed good construct validity, internal consistency and reliability, whereas its content validity and responsiveness were limited. We recommend updating the items of the HAQ-DI in future research focusing on functional limitations in GOA. TRIAL REGISTRATION: Dutch Trial Register NTR2137, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2137.

Rituximab treatment in patients with refractory inflammatory myopathies.

OBJECTIVE: To assess the efficacy of rituximab on disease activity and muscle strength in patients with inflammatory myopathies refractory to conventional therapy. METHODS; Thirteen patients were treated with rituximab 1000 mg i.v., twice, with a 2-week interval and followed for a median of 27 months. Primary outcomes were disease activity measured by creatine phosphokinase (CPK), lactate dehydrogenase (LDH) levels and muscle strength measured by hand-held dynamometry and manual muscle testing (MMT). Secondary outcomes were improvement in secondary laboratory measures, global assessment of general health, disease activity and pain, CS dose, functional ability, health-related quality of life and safety. Retreatment with rituximab was conducted if disease activity relapsed. RESULTS; The median levels of CPK and LDH were significantly reduced by 93.2 and 39.8%, respectively, compared with baseline after 34.6 months. The median muscle strength measured by hand-held dynamometry was significantly improved by 21.5% after 24 months. The median increase in muscle strength measured with MMT was 7.0% after 24 months of follow-up, although this did not reach statistical significance. Secondary outcomes improved as well. CONCLUSION; Rituximab is an effective treatment in refractory inflammatory myopathies, showing a decrease in CPK and LDH, an increase in muscle strength and improvement in scores of disease activity, general health, functional ability and health related quality of life with sustained effect during a median of 27.1 months of follow-up.