[Temporomandibular dysfunction and bruxism in patients with early rheumatoid arthritis and at-risk patients: a cross-sectional study]. / Temporomandibulaire disfunctie en bruxisme bij patiënten met vroege reumatoïde artritis en risicopatiënten: een cross-sectioneel onderzoek.

What is the prevalence of temporomandibular dysfunction in patients with early rheumatoid arthritis and individuals at risk of rheumatoid arthritis? 3 groups (of 50 participants each) were examined for a possible TMD diagnosis: 1. patients with early rheumatoid arthritis, 2. at-risk individuals, and 3. healthy controls. A possible association with bruxism, determined on the basis of self-reporting and clinical features, was also examined. At-risk patients had a higher prevalence of TMD pain diagnoses compared to healthy controls (p = 0.046). Within the early rheumatoid arthritis group, seronegative patients had a higher prevalence of TMD pain diagnoses than seropositive patients (p = 0.048). No further differences in the prevalence of TMD diagnoses were found between the groups. Participants with a TMD pain diagnosis were more often diagnosed with probable sleep bruxism than those without a TMD pain diagnosis. The prevalence of TMD pain is increased in individuals at risk of rheumatoid arthritis and seronegative early rheumatoid arthritis patients, and is associated with signs of bruxism.

Construct validity of the PROMIS PF-10 in patients with inflammatory rheumatic diseases and severe limitations in physical functioning.

OBJECTIVE: Assessing the construct validity of the Patient-Reported Outcomes Measurement Information System Physical Function 10-Item Short Form (PROMIS PF-10) in a subpopulation of rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) patients with severe limitations in physical functioning (PF). METHOD: RA/axSpA patients with severe functional limitations completed the PROMIS PF-10, Health Assessment Questionnaire - Disability Index (HAQ-DI for RA) or Bath Ankylosing Spondylitis Functional Index (BASFI for axSpA), 36-item Short Form Health Survey (SF-36), EuroQol 5-dimensions 5-level (index score, EQ-VAS), and performed the Six-Minute Walk Test (6MWT). Construct validity was assessed by computing Spearman rank or Pearson correlation coefficients and testing hypotheses about correlations between the PROMIS PF-10 and measures of PF and quality of life. RESULTS: Data from 316 patients (180 RA/136 axSpA, 91.7%/47.8% female, mean ± sd age 58.6 ± 13.2/54.0 ± 11.3 years) were analysed. The median (IQR) PROMIS PF-10 score was 34.5 (31.4-37.6) in RA and 36.0 (32.8-38.3) in axSpA patients. The PROMIS PF-10 correlated strongly with the HAQ-DI, BASFI, and EQ-5D-5L index score (r > 0.6), moderately with the SF-36 Physical Component Summary score, EQ-VAS, and 6MWT (0.30 ≤ r ≤ 0.60), and weakly with the SF-36 Mental Component Summary score (r < 0.30). Five of six hypotheses (83%) were confirmed in both groups. CONCLUSION: The overall strong correlation of the PROMIS PF-10 with measures of PF and moderate to weak correlations with outcomes measuring different constructs were confirmed in subpopulations of RA and axSpA patients with severe functional limitations, supporting its construct validity.

The Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire: predicting clinical arthritis development.

OBJECTIVE: There is a need to better define symptom characteristics associated with arthritis development in individuals at risk of rheumatoid arthritis (RA). We investigated whether reported symptoms in at-risk individuals could predict arthritis development and whether predictive symptoms differed between seropositive and seronegative at-risk individuals. METHOD: At-risk individuals from four cohorts (Netherlands, UK, Sweden, and Switzerland) completed the Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire. Participants had either (i) anti-citrullinated protein antibodies and/or rheumatoid factor, or (ii) relevant symptoms with or without RA antibodies. Follow up was ≥ 24 months or until clinical arthritis development. Stepwise forward selection created SPARRA prediction models for the combined group and for a seropositive subgroup. RESULTS: Of 214 participants, the mean age was 50 years, 67% were female, and 27% (n = 58) developed clinical arthritis after a median time of 7 months. Four symptoms predicted arthritis development: self-reported joint swelling, joint pain moving from side to side (combined group only), feeling pins and needles in the joints, and often feeling fatigued (predicting non-arthritis). CONCLUSION: Specific symptoms can provide useful information to estimate a person's RA risk. Differences in predictive symptoms between seropositive and seronegative at-risk individuals need to be further investigated. Future research is needed to determine whether changes in symptoms over time improve prediction and to determine the value of SPARRA in optimizing the selection of individuals who need to consult a rheumatologist.

Patient perspective on remission in rheumatoid arthritis: Validation of patient reported outcome instruments to measure absence of disease activity.

OBJECTIVE: Patients have identified pain, fatigue and independence as the most important domains that need to be improved to define remission in rheumatoid arthritis (RA). This study identified and validated instruments for these domains and evaluated their added value to the ACR/EULAR Boolean remission definition. METHODS: Patients with a 28-joint Disease Activity Score (DAS28) ≤3.2 or in self-perceived remission (declaring their disease activity 'as good as gone') from the Netherlands, Portugal, Australia, and Canada, were assessed at 0, 3 and 6 months for patient-reported outcomes and the WHO-ILAR RA core set. Instrument validity was evaluated cross-sectionally, longitudinally and for the ability to predict future good outcome in terms of physical functioning. Logistic regression quantified the added value to Boolean remission. RESULTS: Of 246 patients, 152 were also assessed at 3, and 142 at 6 months. Most instruments demonstrated construct validity and discriminative capacity. Pain and fatigue were best captured by a simple numerical rating scale (NRS). Measurement of independence proved more complex, but a newly developed independence NRS was preferred. NRS for pain, fatigue and independence, in addition to or instead of patient global assessment did not add enough information to justify modification of the current Boolean definition of remission in RA. CONCLUSION: Key elements of the patient perspective on remission in RA can be captured by NRS pain, fatigue, and independence. Although this study did not find conclusive evidence to improve the current definition of remission in RA, the information from these instruments adds value to the physician's assessment of remission and further bridges the gap between physician and patient.

Symptoms in first-degree relatives of patients with rheumatoid arthritis: evaluation of cross-sectional data from the symptoms in persons at risk of rheumatoid arthritis (SPARRA) questionnaire in the PRe-clinical EValuation of Novel Targets in RA (PREVeNT-RA) Cohort.

BACKGROUND: First-degree relatives (FDRs) of people with rheumatoid arthritis (RA) have a fourfold increased risk of developing RA. The Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire was developed to document symptoms in persons at risk of RA. The aims of this study were (1) to describe symptoms in a cohort of FDRs of patients with RA overall and stratified by seropositivity and elevated CRP and (2) to determine if patient characteristics were associated with symptoms suggestive of RA. METHODS: A cross-sectional study of FDRs of patients with RA, in the PREVeNT-RA study, who completed a study questionnaire, provided a blood sample measured for rheumatoid factor, anti-CCP and CRP and completed the SPARRA questionnaire. Moderate/severe symptoms and symmetrical, small and large joint pain were identified and described. Symptoms associated with both seropositivity and elevated CRP were considered suggestive of RA. Logistic regression was used to determine if symptoms suggestive of RA were associated with patient characteristics. RESULTS: Eight hundred seventy participants provided all data, 43 (5%) were seropositive and 122 (14%) had elevated CRP. The most frequently reported symptoms were sleep disturbances (20.3%) and joint pain (17.9%). Symmetrical and small joint pain were 11.3% and 12.8% higher, respectively, in those who were seropositive and 11.5% and 10.7% higher in those with elevated CRP. In the logistic regression model, seropositivity, older age and feeling depressed were associated with increased odds of small and symmetrical joint pain. CONCLUSIONS: This is the first time the SPARRA questionnaire has been applied in FDRs of patients with RA and has demonstrated that the presence of symmetrical and small joint pain in this group may be useful in identifying people at higher risk of developing RA.

Long-term effects on bone mineral density after four years of treatment with two intensive combination strategies, including initially high-dose prednisolone, in early rheumatoid arthritis patients: the COBRA-light trial.

In this study, no difference in bone loss was observed between patients with early RA initially treated with COmbinatietherapie Bij Reumatoide Artritis (COBRA) (including initially 60 mg/day prednisolone) and patients treated with COBRA-light (including initially 30 mg/day prednisolone) during 4-year observation. PURPOSE: To assess changes in bone mineral density (BMD) after 4 years in early rheumatoid arthritis (RA) patients initially treated with COBRA-light or COBRA therapy. METHODS: In a 1 year, open-label, randomised, non-inferiority trial, patients were assigned to COBRA-light (methotrexate 25 mg/week plus initially prednisolone 30 mg/day) or COBRA (methotrexate 7.5 mg/week, sulfasalazine 2 g/day plus initially prednisolone 60 mg/day) therapy. After 1 year, antirheumatic treatment was at the discretion of treating rheumatologists. BMD was measured at baseline and after 1, 2 and 4 years at hips and lumbar spine with dual-energy X-ray absorptiometry. BMD changes between treatment strategies on average over time were compared with GEE analysis. RESULTS: Data from 155 out of 162 patients could be analysed: 68% were female with a mean age of 52 (SD 13) years. Both COBRA-light and COBRA therapy showed declines in BMD at the total hip of -3.3% and -1.7%, respectively (p = 0.12), and the femoral neck, -3.7% and -3.0%, respectively (p = 0.95). At the lumbar spine, both treatment groups showed minor decline in BMD over 4 years: -0.5% and -1.0%, respectively (p = 0.10). CONCLUSION: In a treat-to-target design in early RA, over 4 years, no differences between groups were found in change in BMD at total hip, femoral neck and the lumbar spine. At the hip, bone loss was around 3% in both groups, while mild bone loss was observed at lumbar spine, both in patients starting prednisolone 60 and 30 mg/day. These data suggest that the well-known negative effects of prednisolone can be modulated by modern treatment of RA.

Increased primary care use for musculoskeletal symptoms, infections and comorbidities in the years before the diagnosis of inflammatory arthritis.

OBJECTIVES: Little is known about relevant events in the at-risk phase of rheumatoid arthritis before the development of clinically apparent inflammatory arthritis (IA). The present study assessed musculoskeletal symptoms, infections and comorbidity in future IA patients. METHODS: In a nested case-control study using electronic health records of general practitioners, the frequency and timing of 192 symptoms or diseases were evaluated before a diagnosis of IA, using the International Classification of Primary Care coding system. Cases were 2314 adults with a new diagnosis IA between 2012 and 2016; controls were matched 1:2. The frequency of primary care visits was compared using logistic regression. RESULTS: The frequency of visits for musculoskeletal symptoms (mostly of shoulders, wrists, fingers and knees) and carpal tunnel syndrome was significantly higher in IA patients vs controls within the final 1.5 years before diagnosis, with ORs of 3.2 (95% CI 2.8 to 3.5), 2.8 (95% CI 2.5 to 3.1) and 2.5 (95% CI 2.2 to 2.8) at 6, 12 and 18 months before diagnosis, respectively. Also, infections (notably of the genital and urinary tracts), IA-comorbidities and chronic diseases were more prevalent in cases than controls, but more evenly spread out over the whole 6-year period before IA. A decision tree was created including all symptoms and diseases. CONCLUSION: There was an increased frequency of primary care visits for musculoskeletal symptoms, infections and comorbidities prior to the diagnosis of IA. This diverging trend is present for 4-6 years, but becomes statistically significant 1.5 years before the diagnosis. Validation of these results is warranted.

Temporomandibular joint function, periodontal health, and oral microbiome in early rheumatoid arthritis and at-risk individuals: a prospective cohort study protocol.

OBJECTIVES/AIMS: Rheumatoid arthritis (RA) is an autoimmune disease affecting the joints, including the temporomandibular joint (TMJ). Early diagnosis and treatment can alleviate symptoms and prevent progression. Predictors for disease outcome in individuals at risk for RA are therefore valuable. While limited information is available on the prevalence of TMJ involvement in early RA, previous studies suggest that RA, periodontitis and the oral microbiome are interrelated. Predictive factors for RA development may thus be present in the oral cavity. Our two aims are: (1) to assess the prevalence of TMJ involvement in early RA, and (2) to investigate the predictive value of oral factors in RA development. MATERIALS AND METHODS: We will include 150 individuals in this multi-center, prospective cohort study: 50 patients with early RA, 50 at-risk individuals, and 50 healthy controls. At baseline, the TMJ, periodontal health, and the oral microbiome will be examined. The general health will be followed over time, on four occasions up to 3 years. DISCUSSION: Our results will provide insight into the prevalence and clinical characterization of TMJ involvement in early RA. For at-risk individuals, oral factors can be studied as possible predictors for the development of RA.

An add-on training program involving breathing exercises, cold exposure, and meditation attenuates inflammation and disease activity in axial spondyloarthritis - A proof of concept trial.

OBJECTIVES: The primary objective of this trial was to assess safety and anti-inflammatory effects of an add-on training program involving breathing exercises, cold exposure, and meditation in patients with axial spondyloarthritis. METHODS: This study was an open-label, randomised, one-way crossover clinical proof-of-concept trial. Twenty-four patients with moderately active axial spondyloarthritis(ASDAS >2.1) and hs-CRP ≥5mg/L were included and randomised to an intervention (n = 13) and control group (n = 11) group that additionally received the intervention after the control period. The intervention period lasted for 8 weeks. The primary endpoint was safety, secondary endpoints were change in hs-CRP, serum calprotectin levels and ESR over the 8-week period. Exploratory endpoints included disease activity measured by ASDAS-CRP and BASDAI, quality of life (SF-36, EQ-5D, EQ-5D VAS), and hospital anxiety and depression (HADS). RESULTS: We found no significant differences in adverse events between groups, with one serious adverse event occurring 8 weeks after end of the intervention and judged 'unrelated'. During the 8-week intervention period, there was a significant decline of ESR from (median [interquartile range] to 16 [9-26.5] to 9 [5-23] mm/hr, p = 0.040, whereas no effect was found in the control group (from 14 [8.3-27.3] to 16 [5-37] m/hr, p = 0.406). ASDAS-CRP declined from 3.1 [2.5-3.6] to 2.3 [1.9-3.2] in the intervention group (p = 0.044). A similar trend was observed for serum calprotectin (p = 0.064 in the intervention group versus p = 0.182 in the control group), but not for hs-CRP. CONCLUSIONS: This proof-of-concept study in axial spondyloarthritis met its primary endpoint with no safety signals during the intervention. There was a significant decrease in ESR levels and ASDAS-CRP upon the add-on training program in the intervention group. These findings warrant full-scale randomised controlled trials of this novel therapeutic approach in patients with inflammatory conditions. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02744014.

Suboptimal cardiovascular risk management in rheumatoid arthritis patients despite an explicit cardiovascular risk screening programme.

Objective: In 2011, we started to offer cardiovascular (CV) risk screening to rheumatoid arthritis (RA) patients with a high CV risk. After 1 year, we assessed whether patients labelled as high CV risk had started preventive treatment when indicated, and whether the CV risk score had changed. Methods: CV risk screening was performed in both a large outpatient rheumatology clinic and a general hospital in the Netherlands, and the general practitioner or the internist was informed about the results of the CV screening, including specific advice on the initiation or adjustment of cardiopreventive drugs. National guidelines were used to assess how many patients were eligible for preventive treatment. After 1 year, CV risk, lifestyle, and treatment were re-evaluated. Patients with a history of CV disease at baseline or who experienced a CV event during follow-up were excluded from the analyses. Results: A high 10 year CV risk (> 20%) was present in 58%, and 55% had an indication for anti-hypertensives, statins, or both. At follow-up, cardiopreventive drug treatment had been started or adjusted in only one-third of patients with an indication for treatment. After screening, 42% of patients reported having changed their lifestyle, through more exercise (24%), diet adaption (20%), and weight loss (11%). Conclusion: Despite clear guidelines to improve CV risk, the results of a programme comprising active screening, targeted advice, and referral to the general practitioner or internist prove that primary prevention remains a major challenge in high-risk RA patients.

Predictors of sick leave and improved worker productivity after 52 weeks of intensive treatment in patients with early rheumatoid arthritis.

Objective: To identify predictors of sick leave and improved worker productivity in patients with early rheumatoid arthritis (RA) treated for 52 weeks with intensive combination strategies. Methods: Patients with early RA were included in the COmbinatietherapie Bij Reumatoïde Artritis (COBRA)-light trial and followed for 52 weeks. As the COBRA-light strategy proved to be non-inferior to the COBRA strategy, all patients were pooled. Predictors for sick leave and improved worker productivity were assessed through a 3 month time-lag multivariable logistic generalized estimating equations model. Results: At baseline, 97 patients had a paid job, 59 had no job, and for six patients the work status was unknown. During the trial, 13 patients stopped working (8%) and six started working (4%). Only sick leave in the past 3 months predicted sick leave. By excluding this variable, patient global assessment and actual hours of sick leave became predictors. Increased worker productivity was predicted by higher patient global assessment levels, Sharp van der Heijde score ≥ 1, actual hours on sick leave, and higher worker productivity in the past 3 months. Conclusion: Sick leave and improved worker productivity were mainly predicted by non-disease-specific variables. Both outcomes can be predicted on a 3 month basis, using the outcome over the past 3 months for the next 3 months. By applying this model in daily practice, decisions for therapy change could be based not solely on disease activity but also taking into account a possible high risk for sick leave in the upcoming 3 months.

One Year Effects of a Workplace Integrated Care Intervention for Workers with Rheumatoid Arthritis: Results of a Randomized Controlled Trial.

Purpose To evaluate the effectiveness of a workplace integrated care intervention on at-work productivity loss in workers with rheumatoid arthritis (RA) compared to usual care. Methods In this randomized controlled trial, 150 workers with RA were randomized into either the intervention or control group. The intervention group received an integrated care and participatory workplace intervention. Outcome measures were the Work Limitations Questionnaire, Work Instability Scale for RA, pain, fatigue and quality of life (RAND 36). Participants filled out a questionnaire at baseline, and after 6 and 12 months. We performed linear mixed models to analyse the outcomes. Results Participants were on average 50 years of age, and mostly female. After 12 months, no significant intervention effect was found on at-work productivity loss. We also found no significant intervention effects on any of the secondary outcomes. Conclusions We did not find evidence for the effectiveness of our workplace integrated care intervention after 12 months of follow up. Future studies should focus on investigating the intervention in groups of workers with severe limitations in work functioning, and an unstable work situation.

Process Evaluation of a Workplace Integrated Care Intervention for Workers with Rheumatoid Arthritis.

Purpose To perform a process evaluation of the implementation of a workplace integrated care intervention for workers with rheumatoid arthritis to maintain and improve work productivity. The intervention consisted of integrated care and a participatory workplace intervention with the aim to make adaptations at the workplace. Methods The implementation of the workplace integrated care intervention was evaluated with the framework of Linnan and Steckler. We used the concepts recruitment, reach, dose delivered, dose received, fidelity and satisfaction with the intervention. Data collection occurred through patient questionnaires and medical records. Results Participants were recruited by sending a letter including a reply card from their own rheumatologist. In total, we invited 1973 patients to participate. We received 1184 reply cards, and of these, 150 patients eventually participated in the study. Integrated care was delivered according to protocol for 46.7 %, while the participatory workplace intervention was delivered for 80.6 %. Dose received was nearly 70 %, which means that participants implemented 70 % of the workplace adaptations proposed during the participatory workplace intervention. The fidelity score for both integrated care and the participatory workplace intervention was sufficient, although communication between members of the multidisciplinary team was limited. Participants were generally satisfied with the intervention. Conclusions This process evaluation shows that our intervention was not entirely implemented as intended. The integrated care was not delivered to enough participants, but for the intervention components that were delivered, the fidelity was good. Communication between members of the multidisciplinary team was limited. However, the participatory workplace intervention was implemented successfully, and participants indicated that they were satisfied with the intervention.

Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis.

OBJECTIVE: Findings from previous studies have suggested that subclinical inflammation of the synovium does not coincide with the appearance of rheumatoid arthritis (RA)-specific autoantibodies. This study was undertaken to examine the relationship between the presence of autoantibodies, changes in the synovium, and development of arthritis over time in a markedly larger, prospective study. METHODS: Fifty-five individuals who were IgM rheumatoid factor positive and/or anti-citrullinated protein antibody (ACPA) positive (detected by the anti-cyclic citrullinated peptide antibody test) and who were without any evidence of arthritis upon physical examination were included in the study. ACPAs were subsequently also detected using a multiplex chip-based assay. All individuals underwent magnetic resonance imaging and mini-arthroscopic synovial biopsy sampling of a knee joint at inclusion and were prospectively followed up. Proportional hazards regression analysis was performed to investigate whether changes in the synovium were associated with the onset of arthritis. RESULTS: Fifteen individuals (27%) developed arthritis after a median followup time of 13 months (interquartile range 6-27 months; range 1-47 months). No overt synovial inflammation was observed, but CD3+ T cell numbers in the biopsy tissue showed a borderline association with subsequent development of clinically manifest arthritis (hazard ratio 2.8, 95% confidence interval [95% CI] 0.9-9.1; P = 0.088). In addition, the presence of CD8+ T cells was associated with ACPA positivity (odds ratio [OR] 16.0, 95% CI 1.7-151.1) and with the total number of ACPAs present (OR 1.4, 95% CI 1.0-1.8). CONCLUSION: These findings confirm and extend previous results showing the absence of clearcut synovial inflammation in individuals having systemic autoimmunity associated with RA. However, subtle infiltration by synovial T cells may precede the signs and symptoms of arthritis in preclinical RA.

Avidity maturation of anti-citrullinated protein antibodies in rheumatoid arthritis.

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and are present years before the onset of symptoms. The avidity of autoantibodies can have a strong impact on their effector potency. This study was undertaken to analyze the avidity of ACPAs in serum samples obtained from ACPA-positive healthy individuals (predisease), patients with early disease, and patients with established RA as well as the avidity maturation over time in samples from healthy subjects who later developed RA. METHODS: We measured ACPA avidity in serum samples from ACPA-positive healthy individuals, symptomatic individuals, and patients with established RA in 5 collections from The Netherlands, Canada, and Austria. We determined the dynamics of avidity maturation of ACPAs from the predisease stage to established disease in 1 case from the native North American population and in 10 cases from a Dutch blood donor cohort. RESULTS: The overall ACPA response was characterized by low-avidity antibodies. Higher-avidity ACPAs were observed in symptomatic patients only, while low-avidity ACPAs were observed in both healthy subjects and patients. In longitudinal samples obtained from subjects prior to disease onset, ACPA avidity increased over time until disease onset. No further avidity maturation was observed after disease onset. CONCLUSION: Our findings indicate that avidity maturation of the ACPA response takes place prior to disease onset.

Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study.

OBJECTIVE: To describe the disease course after the cessation of infliximab in early rheumatoid arthritis patients with disease activity score (DAS)-steered treatment and to identify predictors of persistent low disease activity. METHODS: In a post-hoc analysis of the BeSt study, disease activity and joint damage progression were observed in patients treated with methotrexate plus infliximab, who discontinued infliximab after achieving low disease activity (DAS ≤2.4) for 6 months. Predictors were identified using Cox regression analysis. RESULTS: 104 patients discontinued infliximab, of whom 77 had received infliximab plus methotrexate as initial treatment. Mean DAS at the time of infliximab cessation was 1.3, median symptom duration was 23 months and median Sharp/van derHeijde score was 5.5. The median follow-up was 7.2 years. Infliximab was re-introduced after loss of low disease activity in 48%, after a median of 17 months. The joint damage progression rate did not increase in the year after cessation, regardless of flare. After re-introduction of infliximab, 84% of these patients again achieved a DAS ≤2.4. In the multivariable model, smoking, infliximab treatment duration ≥18 months and shared epitope (SE) were independently associated with the re-introduction of infliximab: 6% of the non-smoking, SE-negative patients treated <18 months needed infliximab re-introduction. CONCLUSION: Cessation of infliximab was successful in 52%, with numerically higher success rates in patients initially treated with infliximab. Of the 48% who flared, 84% regained low disease activity. The joint damage progression rate did not increase in the year after cessation. Smoking, long infliximab treatment duration and SE were independently associated with re-introduction of infliximab.