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Objectives: We investigated whether local joint swelling recurs in the same joints over time in patients with rheumatoid arthritis (RA) who are treated to target., Methods: Patients with newly diagnosed RA participating in the Behandel-Strategieën, "treatment strategies" (BeSt) study (n=508) were followed for median 10 years while receiving Disease Activity Score (DAS) ≤2.4 steered treatment. Every 3 months 68 joints were assessed for the presence of swelling. We evaluated whether baseline local joint swelling was predictive for swelling in the same joint during follow-up using a multilevel mixed-effect logistic regression model. Different strategies were used to account for missing data. A permutation test was performed to assess if joint swelling was better predicted by baseline swelling of the joint itself than by baseline swelling of randomly selected other joints., Results: In 46% of the joints that were swollen at baseline, joint swelling later recurred at least once during follow-up. Joint swelling at baseline was statistically significantly associated with swelling in the same joint during follow-up (OR 2.37, 95% CI 2.30 to 2.43, p<0.001), and also specifically with recurrent swelling in the same joint (OR 1.73, 95% CI 1.37 to 1.59, p<0.001). Local joint swelling was better predicted by baseline swelling of that particular joint than by baseline swelling of other joints (p<0.001)., Conclusion: Joint swelling tends to recur locally in the joints swollen at RA onset. This suggests that local factors influence the manifestation of joint inflammation over time., Competing Interests: Competing interests: The original BeSt study was funded by a research grant from the Dutch College of Health Insurances with additional funding from Schering-Plough BV and Centocor Inc., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients in clinical practice are transitioned from originator etanercept (OR-ETA) to biosimilar etanercept (BS-ETA), but some subsequently retransition. Insights into the incidence of and reasons for retransitioning and the characteristics of these patients could help clinicians successfully introduce biosimilars., Objective: Our objective was to assess the incidence of and reasons for retransitioning from BS-ETA to OR-ETA in patients with a rheumatic disease (RD) and to explore the determinants thereof., Methods: This cohort study included all patients with RD who had transitioned from OR-ETA to BS-ETA in a large hospital in the Netherlands in 2016. The incidence of retransitioning to OR-ETA and the 1-year persistence with BS-ETA were assessed using the Kaplan-Meier estimator. Reasons for retransitioning were classified as related to (1) efficacy, (2) adverse events, (3) the administration device, and (4) other. Determinants for retransitioning, including baseline and treatment characteristics, were assessed in a nested case-control study using conditional logistic regression., Results: We included 342 patients (median age 57.8 years; 53.5% females). At 1 year after transitioning, 9.4% of patients had retransitioned to OR-ETA and 69.7% were persistent with BS-ETA. At the end of follow-up (median 4.4 years), 47 patients (13.7%) had retransitioned to OR-ETA. The median time until retransitioning was 0.55 years (interquartile range 0.2-1.3). Most patients (n = 34 [72.3%]) retransitioned because of a (perceived) loss of effect, followed by adverse events (23.4%). In total 3.8% of patients switched to another biological treatment or a Janus kinase inhibitor; 17.1% of patients discontinued BS-ETA without retransitioning or switching within the first year. Univariate determinants for retransitioning included initiating corticosteroids or intensifying immunomodulator treatment (odds ratio [OR] 2.37; 95% confidence interval [CI] 1.03-5.45) and the number of visits to the rheumatology department (OR 2.06; 95% CI 1.55-2.74). In the multivariate analysis, only the number of visits to the rheumatology department remained significantly associated with retransitioning (OR 2.19; 95% CI 1.60-3.01)., Conclusion: When introducing a biosimilar in clinical care, clinicians should anticipate that one in seven patients will retransition to the originator. A (perceived) loss of effect was the most frequently reported reason for retransitioning. Patients who visited the rheumatology department more frequently had an increased risk of retransitioning, which is likely to be related to patients reporting a loss of effect and to adverse events resulting in more visits to the rheumatology department., (© 2021. The Author(s).)

Aim: To assess gender differences in ankylosing spondylitis (AS) patients in relation to tumor necrosis factor alpha inhibitor (TNFi) drug survival and occurrence of adverse events in daily practice in a large peripheral hospital., Method: Retrospective data were collected from AS patients treated with etanercept, infliximab and adalimumab between January 2004 and January 2014. Kaplan-Meier survival curves were conducted to describe the drug survival and occurrence of adverse events in time., Results: Overall, 122 AS patients (60.7% male) were included over a 10-year time period, with a mean treatment period of 51 months (1-127 months). In total, 21 (17.2%) patients stopped the TNFi, mainly due to inefficacy (52.4%). Female patients showed a significant shorter treatment period compared to males (33.4 vs. 44.9 months). In addition, female patients switched more between TNFi compared to males (26.9% vs. 16.3%) and had a significantly higher risk at developing infections compared to male patients (26% vs.19%)., Conclusion: Females stayed on the same TNFi for a significantly shorter period compared to males (33.4 vs. 44.9 months) and the most important reason to stop or switch the drug was inefficacy. Moreover, females seemed to be more prone to infections during TNFi treatment than males., (© 2018 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Treat-to-target therapy is effective for patients with rheumatoid arthritis (RA), but long-term results of continued targeted treatment are lacking., Objective: To evaluate long-term outcomes in patients with early RA after 10 years of targeted treatment in 4 treatment strategies., Design: Randomized trial. (Nederlands Trial Register: NTR262 and NTR265)., Setting: The Netherlands., Patients: 508 patients with early active RA., Intervention: Sequential monotherapy (strategy 1), step-up combination therapy (strategy 2), or initial combination therapy with prednisone (strategy 3) or with infliximab (strategy 4), all followed by targeted treatment aiming at low disease activity., Measurements: Functional ability (Health Assessment Questionnaire [HAQ] score) and radiographic progression (Sharp-van der Heijde score) were primary end points. Survival in the study population was compared with the general population using the standardized mortality ratio., Results: 195 of 508 of patients (38%) dropped out of the study (28% in strategy 4 vs. 40% to 45% in strategies 1 to 3, respectively). At year 10, mean HAQ score (SD) was 0.57 (0.56); 53% and 14% of patients were in remission and drug-free remission, respectively, without differences among the strategies. Over 10 years, mean HAQ scores were 0.69, 0.72, 0.64, and 0.58 in strategies 1 to 4, respectively (differences not clinically relevant). Radiographic damage was limited for all strategies, with mean Sharp-van der Heijde estimates during follow-up of 11, 8, 8, and 6 in strategies 1 to 4, respectively (P = 0.15). Standardized mortality ratio was 1.16 (95% CI, 0.92 to 1.46) based on 72 observed and 62 expected deaths, with similar survival among the 4 strategies (P = 0.81)., Limitation: Dropout rate varied by strategy., Conclusion: In patients with early RA, initial (temporary) combination therapy results in faster clinical improvement and targeted treatment determines long-term outcomes. Drug-free remission, with prevention of functional deterioration and clinically relevant radiographic damage, and normalized survival are realistic outcomes., Primary Funding Source: Dutch College of Health Insurance Companies, Schering-Plough, and Janssen.

Objective: To identify subgroups of pain trajectories in patients with symptomatic knee osteoarthritis (OA), and to explain these different trajectories by patient characteristics, lifestyle, and coping factors, as well as radiographic features., Methods: Longitudinal data of pain severity (0-10) from 5 years of followup of the CHECK (Cohort Hip and Cohort Knee) study was used. Latent class growth analysis identified homogeneous subgroups with distinct trajectories of pain. Multinomial regression analysis was used to examine different lifestyle and coping characteristics between the trajectories., Results: In longitudinal pain data of 5 years of followup in 705 participants, 3 pain trajectories were identified: marginal, mild, and moderate pain trajectories. Compared with the marginal pain trajectory, the mild and moderate pain trajectories can be characterized by the following baseline variables: body mass index (BMI) > 25, additional hip pain, low education level, using the coping strategy "worrying," and having ≥ 3 comorbidities. Moderate pain trajectory can be supplemented with the Kellgren-Lawrence grading scale grade ≥ 2 radiological change., Conclusion: Three trajectories of pain were identified. Participants with a BMI > 25, secondary school as highest education level, having at least 3 comorbidities, additional hip pain, and/or whose coping style is worrying are more likely to develop a moderate or mild pain trajectory compared with those without these characteristics. In the management of knee pain in people with early symptomatic OA, attention should also be given to additional factors such as hip pain, other comorbidities, passive coping strategy, and obesity.

Objective: To evaluate to what extent radiographic features of knees and hips that are normally related to osteoarthritis (OA) represent characteristics of an individual in addition to OA severity., Methods: We studied a cohort of individuals (n = 1002) with very early signs of hip and knee OA, from the Cohort Hip and Cohort Knee (CHECK) study. Baseline radiographs were evaluated by digital analyses, using Holy's and Knee Images Digital Analysis (KIDA) software, providing distinct quantitative measures of radiographic OA features. In addition, conventional Kellgren and Lawrence (KL) grading was performed. Digital parameters were evaluated for correlations within participants between contralateral (left vs. right hip and left vs. right knee), ipsilateral (e.g. left hip vs. left knee), and diagonal joints (e.g. left hip vs. right knee). Analyses were performed separately for participants with KL grade 0-I and those with evident radiographic OA (KL grade II-III). Regression analyses determined whether demographic characteristics were related to radiographic features., Results: Correlations between digital parameters and KL grade were moderate, and within each KL grade large variation was found. Within participants strong correlations were found for digital parameters between joints in individuals with KL grade 0-I (R = 0.60-0.89), strongest for contralateral comparison, but no statistically significant correlations were found for participants with KL grade II-III. The demographic characteristics age, gender, height, and weight were, to a limited extent (R(2) = 0.01-0.20) but statistically significant, related to radiographic characteristics., Conclusion: Using digital analyses of radiographic OA, strong correlations between joints within participants were found. These correlations diminished when OA became evident. This has implications for monitoring joint damage in (very) early OA with digital analyses.

Objective: To compare nine disease activity indices and the new American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) remission criteria in rheumatoid arthritis (RA) and to relate these to physical function and joint damage progression., Methods: Five-year data from the BeSt study were used, a randomised clinical trial comparing four treatment strategies in 508 patients with recent-onset RA. Every three months disease activity was assessed with nine indices (Disease Activity Score (DAS), DAS-C reactive proteine (DAS-CRP), Disease Activity Score in 28 joints (DAS-28), DAS28-CRP, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and three DAS versions with adjusted tender joint scores) and categorized into remission, low, moderate and high disease activity (LDA, MDA, HDA). In addition, the recent ACR/EULAR clinical trial and practice remission was assessed 3-monthly with 28 and 68/66 joint counts. For each index, Generalized Estimating Equations analyses were performed to relate disease activity levels and the absence/presence of remission to 3-monthly assessments of physical functioning and annual radiological progression., Results: From the composite indices, CDAI and SDAI were the most stringent definitions of remission and classified more patients as LDA. DAS28 and DAS28-CRP had the highest proportions of remission and MDA and a smaller proportion of LDA. ACR/EULAR remission percentages were comparable to CDAI/SDAI: remission percentages. The variant including CRP and 68/66 joint counts was the most stringent. For all indices, higher levels of disease activity were associated with decreased physical functioning and more radiological damage progression. Despite differences in classification between the indices, no major differences in relation to the two outcomes were observed., Conclusion: The associations of nine composite indices and ACR/EULAR remission criteria with functional status and joint damage progression showed high accordance, whereas the proportions of patients classified in the disease activity levels differed.

Objective: To assess the relationship between a decrease in disease activity score (DAS) and functional ability during 5 years of DAS-steered treatment in recent-onset rheumatoid arthritis (RA) patients, taking into account absolute DAS levels and follow-up duration., Methods: Data from the BeSt study were used, in which treatment was aimed at achieving DAS ≤2.4. The longitudinal relationship between 3-monthly measured DAS and health assessment questionnaire (HAQ) score was assessed using linear mixed modelling during 5 years of treatment, with DAS and HAQ 3 months earlier, change in DAS in last 3 months (delta DAS), time (log-transformed) and their interactions as determinants., Results: Predictors for HAQ were: previous DAS, delta DAS, ln time, the interaction previous DAS×delta DAS, and previous HAQ. The interaction ln time×delta DAS was non-significant, indicating that the association between delta DAS and HAQ was independent of follow-up duration. A decrease from a higher DAS was associated with a smaller HAQ decrease than for a similar decrease from a lower DAS, indicating a non-linear relationship between DAS and HAQ., Conclusion: At any time during 5 years of follow-up, a decrease in DAS was associated with a better functional ability. The magnitude of HAQ improvement depends on the DAS decrease and on the absolute DAS level.

Objective: To predict the 2-year course of activity limitations in patients with early knee and/or hip osteoarthritis (OA)., Methods: The Cohort Hip & Cohort Knee (CHECK) study is a prospective followup study. The CHECK cohort, comprising participants (n = 1,002) with early OA-related knee and/or hip symptoms, was followed for 2 years. Participants completed questionnaires and underwent physical, laboratory, and radiographic examination. Regression models were used to examine whether baseline variables predicted the course of activity limitations as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Analyses were performed separately for participants with knee symptoms and participants with hip symptoms., Results: After 2 years of followup, activity limitations slightly decreased. Large between-subject variation was observed in WOMAC change scores. In participants with knee symptoms, young age, non-Western ethnicity, bilateral hip pain, morning stiffness in the knee, high comorbidity count, high body mass index, high bodily pain, poor general health perception, and pain coping strategy were associated with a poor 2-year outcome on activity limitations. In participants with hip symptoms, few activity limitations at baseline, bilateral hip pain, morning stiffness in the knee, high comorbidity count, low active hip flexion, poor general health perception, and pain coping strategy were associated with a poor 2-year outcome on activity limitations., Conclusion: After 2 years of followup, large between-subject variation was observed in the course of activity limitations. The course of activity limitations is to some extent already predictable at an early stage of knee and hip OA.

Objective: To describe the osteoarthritis study population of CHECK (Cohort Hip and Cohort Knee) in comparison with relevant selections of the study population of the Osteoarthritis Initiative (OAI) based on clinical status and radiographic parameters., Methods: In The Netherlands a prospective 10-year follow-up study was initiated by the Dutch Arthritis Association on participants with early osteoarthritis-related complaints of hip and/or knee: CHECK. In parallel in the USA an observational 4-year follow-up study, the OAI, was started by the National Institutes of Health, on patients with or at risk of symptomatic knee osteoarthritis. For comparison with CHECK, the entire cohort and a subgroup of individuals excluding those with exclusively hip pain were compared with relevant subpopulations of the OAI., Results: At baseline, CHECK included 1002 participants with in general similar characteristics as described for the OAI. However, significantly fewer individuals in CHECK had radiographic knee osteoarthritis at baseline when compared with the OAI (p<0.001). In contrast, at baseline, the CHECK cohort reported higher scores on pain, stiffness and functional disability (Western Ontario and McMaster osteoarthritis index) when compared with the OAI (all p<0.001). These differences were supported by physical health status in contrast to mental health (Short Form 36/12) was at baseline significantly worse for the CHECK participants (p<0.001)., Conclusion: Although both cohorts focus on the early phase of osteoarthritis, they differ significantly with respect to structural (radiographic) and clinical (health status) characteristics, CHECK expectedly representing participants in an even earlier phase of disease.

Objective: To evaluate the efficacy of infliximab plus methotrexate (MTX) as induction therapy in patients with early rheumatoid arthritis (RA)., Methods: Disease-modifying antirheumatic drug (DMARD)-naive patients with active, early RA who were included as group 4 of the BeSt study were initially treated with infliximab (3 mg/kg) in combination with MTX (25 mg/week). The Disease Activity Score (DAS) was measured every 3 months. In patients with persistent low disease activity (DAS 2.4, the infliximab dosage was increased (maximum 10 mg/kg), and they were subsequently switched to another DMARD. Except for intraarticular administration, corticosteroids were not permitted. Functional ability and the modified Sharp/van der Heijde score were determined after 2 years of therapy., Results: Of the 120 patients, 67 responders (56%) had persistent low disease activity and discontinued infliximab after a median of 9.9 months, with a median MTX dosage of 10 mg/week after 2 years. Ten other patients experienced a disease flare after discontinuation and resumed infliximab after a median of 3.7 months. Thirteen patients did not achieve persistent low disease activity and received infliximab at various dosages. Treatment was unsuccessful in 30 patients. In the 67 responders, the progression of joint damage was lower than in the 30 patients in whom treatment failed., Conclusion: Fifty-six percent of patients with active early RA, initially treated with infliximab plus MTX, could discontinue infliximab after achieving a DAS of

To investigate the potential anti-inflammatory effects of sesame oil, which is present in the injectable gold preparation Auromyose, the synthesis of tumour necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) by in vitro stimulated blood cells was measured before, during and after 12 weeks of dietary supplementation with 18 g of sesame oil daily in 11 healthy male volunteers. Neither TNF-alpha, PGE2 nor LTB4 production levels showed statistically significant changes during the 12 weeks of dietary supplementation with sesame oil. These results do not suggest an anti-inflammatory effect of sesame oil as present in injectable gold preparations which are used in the treatment of rheumatoid arthritis.

Objective: To assess the effect of resumption of second line drugs in patients with rheumatoid arthritis (RA) that flared after treatment discontinuation., Methods: RA patients were studied whose RA flared up after discontinuation of second line treatment while being in remission and who received a second course of the drug. Disease activity parameters were prospectively assessed at the time of treatment discontinuation, during the period when the disease flared up, and three months thereafter. Furthermore the medical charts were reviewed at 12 months after treatment resumption., Results: There were 51 patients included in the study: 25 patients treated with antimalarial drugs, 10 with parenteral gold, four with d-penicillamine, eight with sulphasalazine, two with azathioprine, and two with methotrexate. Disease activity parameters showed significant improvement within three months of treatment resumption, but remained significantly worse when compared with that measured before treatment discontinuation. Within three months 47% of the patients fulfilled 20% response criteria. Disease activity 12 months after treatment resumption was considered to be absent in 35%, mild in 43%, and moderate or active in 22% of the patients. In four (8%) patients the resumed treatment was stopped because of lack of efficacy. Side effects were recorded in four patients, which did not result in treatment discontinuation., Conclusions: Resumption of second line drugs in RA patients whose disease flared up after discontinuation of treatment is effective and safe in most patients. Half of the patients responded within three months after resumption of the second line drug.

Background: Continuous therapy with low-dose ranitidine (150 mg b.d.) is known to be effective for the prevention of recurrent nonsteroidal anti-inflammatory drug (NSAID)-associated duodenal ulcer but not for gastric ulcer., Aim: To investigate, in a double-blind placebo-controlled study, the preventive effect of a high dose of ranitidine (300 mg b.d.) on the recurrence of both duodenal ulcers and gastric ulcers in rheumatoid arthritis patients with a continuous need for NSAIDs., Methods: Rheumatoid arthritis patients with a history of peptic ulcer disease were randomized to receive either ranitidine 300 mg b.d. or placebo for 12 months. Endoscopy was performed at study entry and after 6 and 12 months. End-point was the recurrence of gastric or duodenal ulcers., Results: The study was stopped after a blinded interim analysis; at that time 10 of the 15 included patients in each treatment group were evaluable. Recurrent duodenal ulcers had occurred in four patients treated with placebo and none of the patients treated with ranitidine (Fisher's exact one-tailed P = 0.04; 95% CI, - 0.70 to -0.10). Recurrent gastric ulcers had occurred in six patients in the placebo group and three patients in the ranitidine group (Fisher's exact one-tailed P = 0.18; 95% CI, -0.72 to 0.12). Two patients in the placebo group had developed both duodenal ulcers and gastric ulcers. No adverse events were observed., Conclusions: High dose ranitidine is effective for the prevention of recurrent duodenal ulcer but not for recurrent gastric ulcer in rheumatoid arthritis patients taking NSAIDs.

Background: A favourable benefit/risk ratio for treatment of rheumatoid arthritis (RA) with second-line drugs has been established only in short-term studies. The present investigation addresses the question of whether RA patients with a good response to long-term treatment with second-line drugs benefit from continuation of such treatment., Methods: A 52-week randomised double-blind placebo-controlled multicentre study was conducted to assess the effect of stopping second-line therapy in 285 RA patients with a good long-term therapeutic response. The patients either continued the second-line drug (n = 142) or received a placebo (n = 143). The endpoint was a flare, defined as recurrence of synovitis., Findings: At entry into the study median duration of second-line drug therapy was 5 years (range 2-33). At 52 weeks the cumulative incidence of a flare was 38% for the placebo group and 22% for the continued therapy group (p = 0.002). The risk of a flare was 2.0 times higher for patients receiving placebo than for those continuing the second-line drug (95% CI 1.27 to 3.17). The same trend was found for each second-line drug separately, with the exception of d-penicillamine. Side-effects that necessitated dose reduction or discontinuation occurred in 2 patients in each group., Interpretation: Second-line drugs continue to be effective in RA patients who have responded well to initial treatment.

To assess possible associations between human leucocyte antigens (HLA) and the achievement of remission during gold treatment, HLA typing was performed in 67 rheumatoid arthritis (RA) patients with a gold-induced remission and in 25 control RA patients who discontinued gold therapy because of lack of efficacy. Both groups of RA patients showed a significantly higher frequency of DR4 antigen and lower frequency of DR6 than a control population. There were no significant differences in HLA antigens between remission-responders and non-responders. It is concluded that HLA typing is not helpful in predicting the therapeutic response to parenteral gold therapy.

Objectives: To assess prospectively the influence of intramuscular gold therapy on Helicobacter pylori serology in patients with rheumatoid arthritis (RA)., Methods: Fifty patients with RA were started on intramuscular gold or chloroquine, as the control group and were followed serologically for H pylori infection for 12 months., Results: Twelve patients treated with gold and eight control patients treated with chloroquine, all with serological evidence for H pylori infection, showed no significant decline of IgA and IgG anti-H pylori antibody levels or serum pepsinogen A and C levels. Total serum IgA and IgG levels declined significantly during gold therapy, while they remained unchanged during chloroquine therapy., Conclusions: Intramuscular gold therapy in patients with RA does not influence the serological parameters of H pylori infection.

Many HLA-associated diseases occur in patients not carrying the putative predisposing antigen. The suggestion that this might be due to disease heterogeneity is not sufficiently supported by available data. We hypothesise that HLA-DR4-associated genetic susceptibility to rheumatoid arthritis is due to an effect of DR4 on T-cell receptor repertoire expression and that the presence of antigen in the mother is capable of producing this effect in her children, even when DR4 is not inherited by them. To investigate this possibility we HLA typed 94 rheumatoid arthritis patients and their parents and 86 control families. An increased frequency, compared with controls, of non-inherited maternal HLA-DR4 was found predominantly in the mothers of DR4-negative patients. Unexpectedly, we also found an increased frequency of non-inherited maternal HLA-DR6 and a decreased frequency of non-inherited maternal HLA-DR3 in the mothers of DR4-positive patients. The results of our analyses are consistent with our hypothesis.

In recent studies from Sweden an increased prevalence of HLA-B27 associated diseases and of HLA-B27 was found in an unselected group of men with permanently implanted pacemakers and with a heart block. Furthermore, a significantly increased prevalence of HLA-B27 was found in men with a pacemaker who had no clinical or radiological signs of HLA-B27 associated disease. To obtain more insight into the association between HLA-B27 and heart block, and the possible role of HLA-B27 in causing this block, a study was made of 35 patients with a pacemaker and heart block of unknown cause, selected from a total group of 350 men with pacemakers who were still alive at the time of the study. One of these 35 men had ankylosing spondylitis and two patients had an asymptomatic sacroiliitis, but all three were HLA-B27 negative. HLA-B27 was present in five (14%) patients, which is a significantly higher prevalence than in healthy controls (17/292, 6%). This percentage is equal to the percentage of HLA-B27 positivity found in the Swedish study on unselected men with an implanted pacemaker, in whom the presence of an HLA-B27 associated disease had been excluded. It suggests that factors other than HLA-B27 are important in the pathogenesis of heart block in most patients.