Objectives ACPA-positive and ACPA-negative RA differ in underlying risk factors but have a similar clinical presentation at RA diagnosis. It is unknown what the ACPA-associated differences or... Show moreObjectives ACPA-positive and ACPA-negative RA differ in underlying risk factors but have a similar clinical presentation at RA diagnosis. It is unknown what the ACPA-associated differences or similarities are during the symptomatic at-risk stage of RA, i.e. clinically suspect arthralgia (CSA). To deepen insights into these differences/similarities, we compared the course of symptoms/impairments and subclinical joint inflammation in the CSA phase during progression to inflammatory arthritis (IA) or to CSA resolution.Methods A total of 845 CSA patients were followed for a median of 24 months; 136 patients developed IA and an additional 355/505 patients had resolution of CSA according to rheumatologists. Patient burden (pain, morning stiffness, fatigue, functional disabilities, presenteeism) was assessed at baseline and 4, 12 and 24 months and at IA development. Subclinical joint inflammation in the hands and feet was assessed over time with 1.5T MRI. Linear and Poisson mixed models were used.Results In both ACPA-positive and ACPA-negative patients, patient burden increased towards IA development and decreased towards CSA resolution. However, patient burden was lower in ACPA-positive vs ACPA-negative disease at all timepoints. Conversely, subclinical joint inflammation tended to increase more rapidly during development of ACPA-positive IA [incidence rate ratio (IRR) 1.52 (95% CI 0.94, 2.47), P = 0.089] and remained higher over time in ACPA-positive CSA patients achieving resolution compared with ACPA-negative patients [IRR 1.52 (95% CI 1.07, 2.15), P = 0.018]. Although correlation coefficients between changes in patient burden and subclinical joint inflammation during progression to IA were weak, they were consistently higher in ACPA-positive than ACPA-negative disease, e.g. rho = 0.29 vs 0.12 for functional disabilities.Conclusion During RA development and CSA resolution, ACPA-positive CSA patients have lower patient burden but more subclinical joint inflammation than ACPA-negative CSA patients. These data strengthen the notion that the development of ACPA-positive and ACPA-negative RA is pathophysiologically different and encourage further research on these differences. Show less
Manaï, M.; Middendorp, H. van; Pol, J.A. van der; Allaart, C.F.; Dusseldorp, E.; Veldhuijzen, D.S.; ... ; Evers, A.W.M. 2024
Medication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce... Show moreMedication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce. This proof-of-principle double-blind randomized clinical trial examined whether treatment effects in recent-onset rheumatoid arthritis (RA) can be optimized through pharmacological conditioning. After four months of standardized treatment (n = 46), patients in clinical remission (n = 19) were randomized to the Control group (C), continuing standardized treatment (n = 8), or the Pharmacological Conditioning (PC) group, receiving variable treatment according to conditioning principles (n = 11). After eight months, treatment was tapered and discontinued linearly (C) or variably (PC). Standard treatment led to large improvements in disease activity and HRQoL in both groups. The groups did not differ in the percentage of drug-free clinical remission obtained after conditioning or continued standard treatment. The PC group did show a larger decrease in self-reported disease activity (Cohen's d = 0.9) and a smaller increase in TNF-alpha levels (Cohen's d = 0.7) than the C group. During all phases, more differences between groups were found for the patients who followed protocol than for the intention-to-treat sample. Although the results are not conclusive, pharmacological conditioning may have some advantages in terms of disease progression and stability, especially during the conditioning phase, compared with standard clinical treatment. The effects may be particularly beneficial for patients who show a good initial response to increased medication dosages. Show less
Winchow, L.L.; Tikly, M.; Musenge, E.; Chopra, A.; Huizinga, T.W.J.; Salomon-Escoto, K.; ... ; Govind, N. 2023
Background: We investigated sensitivity to change of three scoring methods of the Health Assessment Questionnaire (HAQ) in relation to change in disease activity in patients with active rheumatoid... Show moreBackground: We investigated sensitivity to change of three scoring methods of the Health Assessment Questionnaire (HAQ) in relation to change in disease activity in patients with active rheumatoid arthritis (RA).Patients and Methods: Adult RA-patients with complete data in the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology database with respect to the 20 HAQ questions and disease activity score with 28-joint count using the erythrocyte sedimentation rate (DAS28-ESR) for 2 visits, at least 6-12 months apart, and high disease activity (DAS28-ESR >5.1) at visit 1. Changes in HAQ scored by the (1) conventional method (HAQ-8), (2) HAQ-Tomlin method (HAQ-T), and (3) HAQ-20-item method (HAQ-20) were analyzed in relation to the European League Against Rheumatism (EULAR) RA response criteria, dichotomized to good/moderate and no response.Results: In 421 patients, mean standard deviation (SD) DAS28-ESR declined significantly (6.1 [0.8]-4.8 [1.6], P < 0.0001), over a mean period (SD) of 8.7 (1.9) months. Median HAQ scores improved by all three scoring methods, HAQ-8 (1.6-1.4); HAQ-T (1.2-0.7); and HAQ-20 (1.2-0.9) with similar effect sizes of 0.97, 0.96, and 0.95, respectively. The proportion who achieved a HAQ minimally clinically important improvement (MCII) of >= 0.22 was significantly higher in 47% of patients with EULAR good/moderate score compared to the no response patients (64% vs. 11%, P < 0.0001). Good/moderate EULAR response, higher baseline DAS28, and higher baseline HAQ (7.11, 1.55, and 1.06, respectively) were independent predictors of achieving a HAQ-MCII.Conclusion: Three HAQ scoring methods performed similarly in sensitivity to change with no advantage of alternative scoring methods compared to the conventional HAQ-8 method. A good/moderate EULAR response, despite long disease duration, was associated with a significant likelihood of achieving a HAQ-MCII. Show less
Fleischmann, R.M.; Heijde, D. van der; Strand, V.; Atsumi, T.; Mcinnes, I.B.; Takeuchi, T.; ... ; Weinblatt, M.E. 2023
Objectives To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.Methods Two phase 3,... Show moreObjectives To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.Methods Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. Primary endpoint: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12.Results The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. Primary endpoint: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups.Conclusions Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. Show less
Mayboroda, O.A.; Lageveen-Kammeijer, G.S.M.; Wuhrer, M.; Dolhain, R.J.E.M. 2023
Rheumatoid arthritis (RA) Is a highly prevalent autoimmune disease that affects the joints but also various other organs. The disease is characterized by autoantibodies that are often already... Show moreRheumatoid arthritis (RA) Is a highly prevalent autoimmune disease that affects the joints but also various other organs. The disease is characterized by autoantibodies that are often already observed pre-disease. Since the 1980s, it has been known that antibody glycosylation is different in RA as compared to control individuals. While the literature on glycosylation changes in RA is dominated by reports on serum or plasma immunoglobulin G (IgG), our recent studies have indicated that the glycosylation changes observed for immunoglobulin A (IgA) and total serum N-glycome (TSNG) may be similarly prominent, and useful in differentiating between the RA patients and controls, or as a proxy of the disease activity. In this study, we integrated and compared the RA glycosylation signatures of IgG, IgA and TSNG, all determined in the pregnancy-induced amelioration of rheumatoid arthritis (PARA) cohort. We assessed the association of the altered glycosylation patterns with the disease, autoantibody positivity and disease activity. Our analyses indicated a common, composite glycosylation signature of RA that was independent of the autoantibody status. Show less
To detail the unmet clinical and scientific needs in the field of rheumatology. After a 2-year hiatus due to the SARS-CoV-2 pandemic, the 22nd annual international Advances in Targeted Therapies... Show moreTo detail the unmet clinical and scientific needs in the field of rheumatology. After a 2-year hiatus due to the SARS-CoV-2 pandemic, the 22nd annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. Breakout sessions were convened with experts in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and connective tissue diseases (CTDs). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research, as well as highlight recent progress in meeting formerly identified unmet needs. Clinical trial design innovation was emphasised across all disease states. Within RA, developing therapies and trials for refractory disease patients remained among the most important identified unmet needs and within lupus and spondyloarthritis the need to account for disease endotypes was highlighted. The RA group also identified the need to better understand the natural history of RA, pre-RA states and the need ultimately for precision medicine. In CTD generally, experts focused on the need to better identify molecular, cellular and clinical signals of early and undifferentiated disease in order to identify novel drug targets. There remains a strong need to develop therapies and therapeutic strategies for those with treatment-refractory disease. Increasingly it is clear that we need to better understand the natural history of these diseases, including their 'predisease' states, and identify molecular signatures, including at a tissue level, which can facilitate disease diagnosis and treatment. As these unmet needs in the field of rheumatic diseases have been identified based on consensus of expert clinicians and scientists in the field, this document may serve individual researchers, institutions and industry to help prioritise their scientific activities. Show less
D'Onofrio, B.; Helm-van Mil, A. van der; Huizinga, T.W.J.; Mulligen, E. van 2022
Introduction: Drug-free remission (DFR) and its maintenance have been defined as the most desirable outcome for rheumatoid arthritis (RA) patients. DFR is linked to resolution of arthritis-related... Show moreIntroduction: Drug-free remission (DFR) and its maintenance have been defined as the most desirable outcome for rheumatoid arthritis (RA) patients. DFR is linked to resolution of arthritis-related symptoms and restoration of normal functioning. However, there is currently no consensus if an optimal strategy, upon the initiation of treatment to the proper drugs withdrawal, is enough to induce it, or whether it is a predetermined condition related to patients' intrinsic characteristics. Areas covered: This review focuses on two key concepts around DFR. First, we analyze patients' intrinsic factors that may increase the chance of DFR, regardless of therapeutic choices. Second, we discuss on the evidence that it can be induced thanks to adequate, extrinsic disease management. Finally, we provide a glimpse into consequences of drugs discontinuation .Expert opinion: The early initiation of DMARD and the subsequent strict monitoring and drug adjustments are of primary importance to allow patients to achieve DFR, irrespective of initial treatment strategy. Once remission is obtained and maintained, it is possible to gradually taper and discontinue drugs with no dramatic consequences on the disease course. Among those who stop medication, ACPA-negative patients more often maintain the remission. Thus, DFR might depend on a combination of intrinsic and extrinsic factors. Show less
Background: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the... Show moreBackground: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6R alpha antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. Methods: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. Results: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. Conclusions: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers. Show less
Khidir, S.J.H.; Boeren, A.M.P.; Boonen, A.; Jong, P.H.P. de; Mulligen, E. van; Helm-van Mil, A.H.M. van der 2022
Objectives: Cross-sectional studies have shown that rheumatoid arthritis is more prevalent among people with a lower educational attainment. No longitudinal data are present on educational... Show moreObjectives: Cross-sectional studies have shown that rheumatoid arthritis is more prevalent among people with a lower educational attainment. No longitudinal data are present on educational attainment in the at-risk phase of clinically suspect arthralgia (CSA). We therefore analysed the association between educational attainment and progression from CSA to inflammatory arthritis (IA), and performed mediation analysis with subclinical joint inflammation to elucidate pathways of this association. Methods: A total of 521 consecutive patients presenting with CSA were followed for IA development during median 25 months. Educational attainment was defined as low (lower secondary vocational education), intermediate or high (college/university education). Subclinical inflammation in hand and foot joints was measured at presentation with contrast enhanced 1.5 T-MRI. Cox-regression was used to analyse IA development per educational attainment. A three-step mediation analysis evaluated whether subclinical joint inflammation was intermediary in the path between educational attainment and IA development, before and after age correction. Association between educational attainment and IA development was verified in an independent CSA cohort. Results: Low educational attainment was associated with increased IA development (HR = 2.35, 95% CI = 1.27, 4.33, P = 0.006), independent of BMI and current smoking status (yes/no). Moreover, patients with a low educational attainment had higher levels of subclinical inflammation, which also was associated with IA development. Partial mediation effect of subclinical inflammation was observed in the relationship between education and IA development. Low educational attainment was also associated with increased IA development in the validation cohort (HR = 5.72, 95% CI = 1.36, 24.08, P = 0.017). Conclusion: This is the first study providing evidence that lower educational attainment is associated with a higher risk of progressing from arthralgia to IA. This effect was partially mediated by subclinical joint inflammation. Show less
Multivalent scaffolds that carry multiple molecules with immunophenotyping or immunomodulatory properties areinvaluable tools for studying and modulating specific functions ofhuman immune responses... Show moreMultivalent scaffolds that carry multiple molecules with immunophenotyping or immunomodulatory properties areinvaluable tools for studying and modulating specific functions ofhuman immune responses. So far, streptavidin-biotin-basedtetramers have been widely used for B-cell immunophenotypingpurposes. However, the utility of these tetramers is limited by theirtetravalency, the inherent immunogenicity of streptavidin (abacterial protein that can potentially be recognized by B cells),and the limited feasibility to functionalize these reagents. This has rendered tetramers suboptimal for studying rare, in particular,antigen-specific B-cell populations in the context of clinical applications. Here, we used polyisocyanopeptides (PICs), multivalentpolymeric scaffolds functionalized with around 50 peptide antigens, to detect autoreactive B cells in the peripheral blood of patientswith rheumatoid arthritis. To explore the potential immunomodulatory functionalities, we functionalized PICs with autoantigenicpeptides and a trisaccharide CD22 ligand to inhibit autoreactive B-cell activation through interference with the B-cell receptoractivation pathway, as evidenced by reduced phospho-Syk expression upon PIC binding. Given the possibilities to functionalizePICs, our data demonstrate that the modular and versatile character of PIC scaffolds makes them promising candidates for futureclinical applications in B-cell-mediated diseases Show less
Tanaka, Y.; Takeuchi, T.; Kato, D.; Kaneko, Y.; Fukuda, M.; Izutsu, H.; ... ; Heijde, D. van der 2022
Objective To determine the efficacy of peficitinib in reducing joint damage and predictive factors affecting treatment response in Japanese patients with rheumatoid arthritis. Methods This post hoc... Show moreObjective To determine the efficacy of peficitinib in reducing joint damage and predictive factors affecting treatment response in Japanese patients with rheumatoid arthritis. Methods This post hoc analysis used data from a placebo-controlled, phase 3 trial (RAJ4) of peficitinib in patients with rheumatoid arthritis and inadequate response to methotrexate. Erosion and joint space narrowing (JSN) were assessed at baseline and at Week 28/early termination of treatment using the van der Heijde-modified Sharp method. A univariate logistic regression analysis of change from baseline in a modified total Sharp score identified predictive factors with significant treatment interaction; the effects of these factors on treatment response were further evaluated using a multivariate model. Results The analyses included 481 patients. For most joint groups, peficitinib demonstrated a reduced change from baseline at Week 28/early termination in erosion and JSN scores versus placebo; a numerically greater effect was observed with peficitinib 150 mg versus 100 mg. Baseline C-reactive protein (CRP) and prednisolone dose were identified as clinically significant negative predictive factors: the treatment effect decreased as CRP or prednisolone dose increased for both peficitinib doses. Conclusions Peficitinib 100 mg and 150 mg reduced joint damage versus placebo, across almost all joint groups. Higher baseline CRP and/or prednisolone dose were associated with reduced peficitinib efficacy. ClinicalTrials.gov identifier NCT02305849 Show less
BackgroundThe accumulation of risk for the development of rheumatoid arthritis (RA) is regarded as a continuum that may start with interacting environmental and genetic factors, proceed with the... Show moreBackgroundThe accumulation of risk for the development of rheumatoid arthritis (RA) is regarded as a continuum that may start with interacting environmental and genetic factors, proceed with the initiation of autoimmunity, and result in the formation of autoantibodies such as anti-citrullinated peptide antibodies (ACPA). In parallel, at-risk individuals may be asymptomatic or experience joint pain (arthralgia) that is itself non-specific or clinically suspicious for evolving RA, even in the absence of overt arthritis. Optimal strategies for the management of people at-risk of RA, both for symptom control and to delay or prevent progression to classifiable disease, remain poorly understood. MethodsTo help address this, groups of stakeholders from academia, clinical rheumatology, industry and patient research partners have collaborated to advance understanding, define and study different phases of the at-risk state. In this current report we describe different European initiatives in the field and the successful effort to build a European Registry of at-risk people to facilitate observational and interventional research. ResultsWe outline similarities and differences between cohorts of at-risk individuals at institutions spanning several countries, and how to best combine them within the new database. Over the past 2 years, besides building the technical infrastructure, we have agreed on a core set of variables that all partners should strive to collect for harmonization purposes. ConclusionWe emphasize to address this process from different angles and touch on the biologic, epidemiologic, analytic, and regulatory aspects of collaborative studies within a meta-database of people at-risk of RA. Show less
Hollander, N.K. den; Verstappen, M.; Sidhu, N.; Mulligen, E. van; Reijnierse, M.; Helm-van Mil, A.H.M. van der 2022
Objectives: Identifying patients that will develop RA among those presenting with undifferentiated arthritis (UA) remains a clinical dilemma. Although MRI is helpful according to EULAR... Show moreObjectives: Identifying patients that will develop RA among those presenting with undifferentiated arthritis (UA) remains a clinical dilemma. Although MRI is helpful according to EULAR recommendations, this has only been determined in UA patients not fulfilling 1987 RA criteria, while some of these patients are currently considered as RA because they fulfil the 2010 criteria. Therefore, we studied the predictive value of MRI for progression to RA in the current UA population, i.e. not fulfilling RA classification criteria (either 1987 or 2010 criteria) and not having an alternate diagnosis. Additionally, the value of MRI was studied in patients with a clinical diagnosis of UA, regardless of the classification criteria. Methods: Two UA populations were studied: criteria-based UA as described above (n = 405) and expert-opinion-based UA (n = 564), i.e. UA indicated by treating rheumatologists. These patients were retrieved from a large cohort of consecutively included early arthritis patients that underwent contrast-enhanced MRI scans of hand and foot at baseline. MRIs were scored for osteitis, synovitis and tenosynovitis. Patients were followed for RA development during the course of 1 year. Test characteristics of MRI were determined separately for subgroups based on joint involvement and autoantibody status. Results: Among criteria-based UA patients (n = 405), 21% developed RA. MRI-detected synovitis and MRI-detected tenosynovitis were predictive for progression to RA. MRI-detected tenosynovitis was independently associated with RA progression (odds ratio (OR) 2.79; 95% CI 1.40, 5.58), especially within ACPA-negative UA patients (OR 2.91; 95% CI 1.42, 5.96). Prior risks of RA development for UA patients with mono-, oligo- and polyarthritis were 3%, 19% and 46%, respectively. MRI results changed this risk most within the oligoarthritis subgroup: positive predictive value was 27% and negative predictive value 93%. Similar results were found in expert-opinion-based UA (n = 564). Conclusion: This large cohort study showed that MRI is most valuable in ACPA-negative UA patients with oligoarthritis; a negative MRI could aid in preventing overtreatment. Show less
Objectives: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have... Show moreObjectives: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA. Methods: We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA. Results: In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = <0.05). This increased risk was still present after adjusting for confounders [OR 2.03 (95% CI 1.12, 3.69) P = 0.015]. Conclusions: This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates. Show less
Wissen, M.A.T. van; Teuwen, M.M.H.; Ende, C.H.M. van den; Vlieland, T.P.M.V.; Broeder, A.A. den; Hout, W.B. van den; ... ; Weely, S.F.E. van 2021
Objectives Research on effectiveness and cost-effectiveness of longstanding exercise therapy in patients with axial SpondyloArthritis (axSpA) or Rheumatoid Arthritis (RA) is scarce, and mainly... Show moreObjectives Research on effectiveness and cost-effectiveness of longstanding exercise therapy in patients with axial SpondyloArthritis (axSpA) or Rheumatoid Arthritis (RA) is scarce, and mainly concerned patients with a relatively favorable health status. We aim to evaluate the effectiveness and cost-effectiveness of longstanding exercise therapy compared to usual care in the subgroup of patients with axSpA or RA and severe limitations in functioning. Methods In two separate, parallel randomized controlled trials the effectiveness and cost-effectiveness of longstanding, active exercise therapy (52 weeks) compared with usual care (1:1) will be evaluated. The longstanding, active exercise therapy will focus on improving individual limitations in daily activities and participation and will be given by a trained physical therapist in the vicinity of the participant. For each diagnosis, 215 patients with severe limitations in activities and participation will be included. Assessments are performed at baseline, 12, 26, and 52 weeks. The primary outcome measure of effectiveness is the individual level of functioning (activities and participation), as measured with the Patient-Specific Complaints instrument at 52 weeks. For cost-effectiveness analyses, the EuroQol (EQ-5D-5L) and questionnaires on healthcare use and productivity will be administered. The economic evaluation will be a cost-utility analysis from a societal perspective. After 52 weeks, the patients in the usual care group are offered longstanding, active exercise therapy as well. Follow-up assessments are done at 104, 156, and 208 weeks. Conclusion The results of these studies will provide insights in the effectiveness and cost-effectiveness of longstanding exercise therapy in the subgroup of axSpA and RA patients with severe functional limitations. Show less
Tanaka, Y.; Takeuchi, T.; Soen, S.; Yamanaka, H.; Yoneda, T.; Tanaka, S.; ... ; Heijde, D. van der 2021
Objective. To evaluate the safety and efficacy of long-term denosumab 60 mg every 6 months (Q6M) or every 3 months (Q3M) in patients with rheumatoid arthritis (RA). Methods. This 12-month,... Show moreObjective. To evaluate the safety and efficacy of long-term denosumab 60 mg every 6 months (Q6M) or every 3 months (Q3M) in patients with rheumatoid arthritis (RA). Methods. This 12-month, randomized, double-blind, placebo-controlled, multicenter, phase III trial with an open-label extension period from 12 to 36 months (DESIRABLE) enrolled Japanese patients with RA treated with placebo (P) for 12 months followed by either denosumab Q6M (P/Q6M) or denosumab Q3M (P/Q3M) for 24 months; denosumab Q6M for 36 months (Q6M/Q6M); or denosumab Q3M for 36 months (Q3M/Q3M). Efficacy was assessed by van der Heijde modified total Sharp score (mTSS), bone erosion score (BES), and joint space narrowing (JSN) score. Results. Long-term treatment better maintained mTSS and BES suppression in the P/Q3M and Q3M/ Q3M vs P/Q6M and Q6M/Q6M groups; changes from baseline in total mTSS (standard error) at 36 months were 2.8 (0.4) and 1.7 (0.3) vs 3.0 (0.4) and 2.4 (0.3), respectively, and corresponding changes in BES were 1.3 (0.2) and 0.4 (0.2) vs 1.4 (0.2) and 1.1 (0.2), respectively. No JSN effect was observed. Bone mineral density consistently increased in all groups after denosumab initiation, regardless of concomitant glucocorticoid administration. Serum C-terminal telopeptide of type I collagen decreased rapidly at 1 month postdenosumab administration (in both the initial 12-month [Q3M and Q6M groups] and long-term treatment [P/Q3M and P/Q6M groups] phases). Adverse event incidence leading to study drug discontinuation was similar across treatment groups. Conclusion. Denosumab treatment maintained inhibition of progression of joint destruction up to 36 months. Based on effects on BES progression, higher dosing frequency at an earlier treatment stage may be needed to optimize treatment. Denosumab was generally well tolerated. (ClinicalTrials.gov: NCT01973569). Show less
Hartman, L.; Cutolo, M.; Bos, R.; Opris-Belinski, D.; Kok, M.R.; Griep-Wentink, H.J.R.M.; ... ; Boers, M. 2021
Objectives. Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to... Show moreObjectives. Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to pill count. GLORIA is an ongoing two-year trial on the addition of low-dose (5 mg/d) prednisolone or placebo to standard care in older people (65+ years) with RA. During the entire trial, adherence is measured with electronic caps, and with pill counts. The objective is to describe medication adherence patterns, and to compare the adherence results of the two methods.Methods. The recorded adherence patterns of patients (blinded for treatment group) were classified according to descriptive categories. The cutoff for good adherence was set at 80% of prescribed pills taken.Results. Trial inclusion closed in 2018 at 451 patients, but trial follow-up is ongoing; the current dataset contains adherence data of 371 patients. Mean number of recorded 90-day periods per patient was 4 (range 1-8). Based on pill count over all periods, 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user (<20% of days an opening) and 40% as irregular user (different adherence patterns, in or between periods).Conclusion. In our trial of older people with RA, the majority appeared to be adherent to medication according to pill count. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so. Show less
Sidhu, N.; Wouters, F.; Niemantsverdriet, E.; Helm-van Mil, A.H.M. van der 2021
Objectives: New onset undifferentiated large joint inflammatory arthritis can be diagnostically challenging. It is unknown how often these patients progress to RA, and how they can be identified at... Show moreObjectives: New onset undifferentiated large joint inflammatory arthritis can be diagnostically challenging. It is unknown how often these patients progress to RA, and how they can be identified at first presentation. We assessed clinical and serological features associated with RA development in patients with an undifferentiated mono- or oligo-articular large joint arthritis, and with keen interest in whether an MRI of the small joints of the hand and foot would aid diagnosis. Methods: Leiden Early Arthritis Clinic includes 4018 patients; this prospective study follows 221 consecutively included patients with new onset undifferentiated large joint arthritis. Baseline clinical data and serology were obtained. Forty-five patients had MRIs (hand and foot). MRIs were scored according to the OMERACT RAMRIS. Univariable and multivariable logistic regression were assessed. Test characteristics, predictive values and net reclassification index (NRI) for RA were determined. Results: Patients mostly presented with knee or ankle mono-arthritis. During the 12 months' follow-up 17% developed RA. Autoantibody positivity (ACPA and/or RF) and MRI-detected synovitis in hands and feet were independently associated with RA development in multivariable analyses [odds ratio 10.29 (P = 0.014) and 7.88 (P = 0.017), respectively]. Positive predictive value of autoantibodies, MRI-detected synovitis and combination of both features was 63%, 55% and 100%, respectively. The addition of MRI-detected synovitis to autoantibody status improved diagnostic accuracy (NRI 18.1%). Conclusion: In patients presenting with undifferentiated large joint arthritis, 17% will develop RA. Autoantibody positivity and subclinical synovitis are independent predictors. The data suggest MRI of small joints is beneficial for early identification of RA in large joint arthritis. Show less
Objective. To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.Methods. Daily practice... Show moreObjective. To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset.Methods. Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis <45 years, 45-65 years, >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders.Results. The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of -0.02 and -0.05 DAS points and, -0.01 and 0.02 HAQ points per month in the <45 and 45-65 years age-groups as compared with the >65 year age group, a difference that did not seem clinically relevant.Conclusion. In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ. Show less
Krijbolder, D.I.; Wouters, F.; Mulligen, E. van; Helm-van Mil, A.H.M. van der 2021
Objectives: Morning stiffness (MS) is characteristic of RA and associates with markers of systemic and local inflammation in RA patients. In patients with arthralgia, MS is a cardinal symptom to... Show moreObjectives: Morning stiffness (MS) is characteristic of RA and associates with markers of systemic and local inflammation in RA patients. In patients with arthralgia, MS is a cardinal symptom to recognize arthralgia at-risk for RA development [i.e. clinically suspect arthralgia (CSA)]. In CSA, MS is also assumed to reflect inflammation, but this has never been studied. Therefore we aimed to study whether MS in CSA patients is associated with systemic and subclinical joint inflammation. Methods: A total of 575 patients presenting with CSA underwent laboratory investigations and contrast-enhanced 1.5 T MRI of the hand and forefoot (scored according to the Rheumatoid Arthritis MRI Score method). Associations of MS (duration >= 60 min) with the presence of subclinical joint inflammation (synovitis, tenosynovitis and osteitis) and increased CRP (>= 5 mg/l) were determined with logistic regression. Additionally, the effect of MS duration (>= 30, >= 60 and >= 120 min) was studied. Results: A total of 195 (34%) CSA patients experienced MS. These patients more often had subclinical synovitis [34% vs 21%; odds ratio (OR) 1.95 (95% CI 1.32, 2.87)], subclinical tenosynovitis [36% vs 26%; OR 1.59 (95% CI 1.10, 2.31)] and increased CRP [31% vs 19%; OR 1.93 (95% CI 1.30, 2.88)] than patients without MS. In multivariable analyses, subclinical synovitis [OR 1.77 (95% CI 1.16, 2.69)] and CRP [OR 1.78 (95% CI 1.17-2.69)] remained independently associated with MS. In CSA patients who later developed RA, and thus in retrospect were 'pre-RA' at the time of CSA, MS was more strongly associated with subclinical synovitis [OR 2.56 (95% CI 1.04, 6.52)] and CRP [OR 3.86 (95% CI 1.45, 10.24)]. Furthermore, associations increased with longer MS durations. Conclusion: Inflammation associates with MS in the CSA phase that preceded clinical arthritis. These results increase our understanding of MS when assessing arthralgia in clinical practice. Show less
