Objectives To assess whether prednisone use and/ or disease activity score (DAS) are associated with the development of hyperglycaemia and diabetes in rheumatoid arthritis (RA). Methods We included... Show moreObjectives To assess whether prednisone use and/ or disease activity score (DAS) are associated with the development of hyperglycaemia and diabetes in rheumatoid arthritis (RA). Methods We included 504 non-diabetic early RA patients from the BeSt study (Dutch acronym for treatment strategies). Patients were randomised to four DASsteered treatment arms and followed for 10 years. The associations between DAS and prednisone use with glucose levels and the occurrence of hyperglycaemia over time were assessed with linear and logistic mixed effects regression models. Development of diabetes was analysed with Cox regression. Sensitivity analyses were performed in patients who had a first episode of hyperglycaemia. Results 31 of 504 patients (6.2%) with a mean age of 54 years developed diabetes during follow-up; 11 of these (35%) had received prior treatment with prednisone. Prednisone use was not associated with development of hyperglycaemia or diabetes after correction for multiple testing in main or sensitivity analyses. In the main analyses, DAS was significantly associated with development of diabetes (HR 1.802 per 1 point DAS increase, 95%CI 1.284 to 2.529) but not with glucose levels nor hyperglycaemia. In patients with previous hyperglycaemia, DAS was associated with glucose levels, recurrence of hyperglycaemia and diabetes. Conclusions In non-diabetic early RA patients, the use of prednisone was not associated with developing hyperglycaemia or diabetes. However, high DAS increased the risk of diabetes. Potential risks associated with prednisone use may have been mitigated by its effect on DAS Show less
ObjectivesTo assess disease outcomes after 20 and 12 years of patients with RA or undifferentiated arthritis (UA), treated-to-target in the BeSt and IMPROVED trials.MethodsIn BeSt (inclusion 2000... Show moreObjectivesTo assess disease outcomes after 20 and 12 years of patients with RA or undifferentiated arthritis (UA), treated-to-target in the BeSt and IMPROVED trials.MethodsIn BeSt (inclusion 2000–02, duration 10 years), 508 patients with early RA were randomized to: 1. sequential monotherapy, 2. step-up combination therapy, 3. initial csDMARD combination therapy, 4. initial bDMARD/csDMARD combination therapy. The treatment target was low disease activity (DAS ≤ 2.4).In IMPROVED (inclusion 2007–10, duration 5 years), 610 patients with early RA/UA started MTX with prednisone bridging. The treatment target was remission (DAS < 1.6). Patients not in early remission were randomized to 1. csDMARD combination therapy or 2. bDMARD/csDMARD combination therapy.Between 2019 and 22, these patients were invited for long-term follow-up.ResultsOne-hundred-fifty-three ex-Best and 282 ex-IMPROVED patients participated in the follow-up study after a median of 12 and 20 years since the study started.In ex-BeSt and ex-IMPROVED patients, the rate of low disease activity was 91%, and 68% were in DAS remission. Median SHS was 14.0 in ex-BeSt (IQR 6.0–32.5; progression since end BeSt 6.0, IQR 2.0–12.5) and 8 in ex-IMPROVED participants (IQR 3–16; progression since end IMPROVED 4, IQR 2–9). Mean HAQ was 0.8 ± 0.6 in ex-BeSt (change since end BeSt: 0.3 ± 0.5) and 0.6 ± 0.6 in ex-IMPROVED participants (change since end IMPROVED: 0.06 ± 0.5).ConclusionAt 12/20 years after treatment started, the majority of RA and UA patients who had been treated to target low DAS or DAS remission were in DAS remission and had limited functional disability. Radiographic damage progression was mild although not completely suppressed. Show less
Background In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those... Show moreBackground In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept.Objective Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population.Methods Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the ‘JAK-pot’ collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi.Results Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97).Conclusion While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design. Show less
Heckert, S.L.; Maassen, J.M.; Cessie, S. le; Goekoop-Ruiterman, Y.P.M.; Güler-Yüksel, M.; Lems, W.; ... ; Allaart, C.F. 2023
Objectives To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).Methods The BeSt ... Show moreObjectives To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).Methods The BeSt (BehandelStrategieen) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)<= 2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed.Results Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy.Conclusions After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor. Show less
BackgroundThe aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain.MethodsIn the BeSt-for... Show moreBackgroundThe aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain.MethodsIn the BeSt-for-Kids-study 92 DMARD-naïve JIA-patients were randomized in 3 treatment-strategies: 1) initial sequential DMARD-monotherapy 2) initial methotrexate (MTX)/prednisolone-bridging or 3) initial MTX/etanercept. Potential differences in VAS pain scores (0-100 mm) over time between treatment-strategies were compared using linear mixed models with visits clustered within patients. A multivariable model was used to assess the ability of baseline characteristics to predict the chance of high pain-scores during follow-up.ResultsPain-scores over time reduced from mean 55.3 (SD 21.7) to 19.5 (SD 25.3) mm after 24 months. On average, pain-scores decreased significantly with β -1.37 mm (95% CI -1.726; -1.022) per month. No significant difference was found between treatment-strategies (interaction term treatment arm*time (months) β (95% CI) arm 1: 0.13 (-0.36; 0.62) and arm 2: 0.37 (-0.12; 0.86) compared to arm 3). Correction for sex and symptom duration yielded similar results. Several baseline characteristics were predictive for pain over time. Higher VAS pain [β 0.44 (95% CI 0.25; 0.65)] and higher active joint count [0.77 (0.19; 1.34)] were predictive of higher pain over time, whereas, low VAS physician [ -0.34 (-0.55; -0.06)], CHQ Physical [ -0.42 (-0.72; -0.11)] and Psychosocial summary Score [ -0.42 (-0.77; -0.06)] were predictive of lower pain.ConclusionsTreatment-to-target seems effective in pain-reduction in non-systemic JIA-patients irrespective of initial treatment-strategy. Several baseline-predictors for pain over time were found, which could help to identify patients with a high risk for development of chronic pain. Show less
Spekking, K.; Anink, J.; Boer, P. de; Bergstra, S.A.; Berg, J.M. van den; Schonenberg-Meinema, D.; ... ; Muller, P.C.E.H. 2023
BackgroundThe aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain.MethodsIn the BeSt-for... Show moreBackgroundThe aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain.MethodsIn the BeSt-for-Kids-study 92 DMARD-naïve JIA-patients were randomized in 3 treatment-strategies: 1) initial sequential DMARD-monotherapy 2) initial methotrexate (MTX)/prednisolone-bridging or 3) initial MTX/etanercept. Potential differences in VAS pain scores (0-100 mm) over time between treatment-strategies were compared using linear mixed models with visits clustered within patients. A multivariable model was used to assess the ability of baseline characteristics to predict the chance of high pain-scores during follow-up.ResultsPain-scores over time reduced from mean 55.3 (SD 21.7) to 19.5 (SD 25.3) mm after 24 months. On average, pain-scores decreased significantly with β -1.37 mm (95% CI -1.726; -1.022) per month. No significant difference was found between treatment-strategies (interaction term treatment arm*time (months) β (95% CI) arm 1: 0.13 (-0.36; 0.62) and arm 2: 0.37 (-0.12; 0.86) compared to arm 3). Correction for sex and symptom duration yielded similar results. Several baseline characteristics were predictive for pain over time. Higher VAS pain [β 0.44 (95% CI 0.25; 0.65)] and higher active joint count [0.77 (0.19; 1.34)] were predictive of higher pain over time, whereas, low VAS physician [ -0.34 (-0.55; -0.06)], CHQ Physical [ -0.42 (-0.72; -0.11)] and Psychosocial summary Score [ -0.42 (-0.77; -0.06)] were predictive of lower pain.ConclusionsTreatment-to-target seems effective in pain-reduction in non-systemic JIA-patients irrespective of initial treatment-strategy. Several baseline-predictors for pain over time were found, which could help to identify patients with a high risk for development of chronic pain. Show less
Ouwerkerk, L. van; Verschueren, P.; Boers, M.; Emery, P.; Jong, P.H.P. de; Landewé, R.B.M.; ... ; Bergstra, S.A. 2023
Objectives To compare the use of glucocorticoids (GC) over time in patients with rheumatoid arthritis (RA) who were or were not treated initially with GC bridging therapy.Methods Data from the BeSt... Show moreObjectives To compare the use of glucocorticoids (GC) over time in patients with rheumatoid arthritis (RA) who were or were not treated initially with GC bridging therapy.Methods Data from the BeSt, CareRA and COBRA trials were combined in an individual patient data (IPD) meta-analysis. We compared GC use between bridgers and non-bridgers at 12, 18 and 24 months from baseline with mixed-effects regression analysis. Secondary outcomes were mean cumulative GC dose until 24 months after baseline with and without the bridging period, Disease Activity Score based on 28 joints (DAS28) over time and number of disease-modifying antirheumatic drug (DMARD) changes.Results 252/625 patients (40%) were randomised to GC bridging (bridgers). Excluding the period of bridging, later GC use was low in both groups and cumulative doses were similar. Mean DAS28 was similar between the groups, but bridgers improved more rapidly (p<0.001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio 0.59 (95% CI 0.38 to 0.94)). GC use was higher in the bridgers at t=12 months (OR 3.27 (95% CI 1.06 to 10.08)) and the bridging schedules resulted in a difference in cumulative GC dose of 2406 mg (95% CI 1403 to 3408) over 24 months.Conclusion In randomised trials comparing GC bridging and no GC bridging, bridgers had a more rapid clinical improvement, fewer DMARD changes and similar late use of GC compared with non-bridgers. GC bridging per protocol resulted, as could be expected, in a higher cumulative GC dose over 2 years. Show less
Liem, S.I.E.; Bergstra, S.A.; Ciaffi, J.; Meulen, C. van der; Ueckert, D.A.; Schriemer, M.R.; ... ; Vries-Bouwstra, J.K. de 2023
Objective: The Health Assessment Questionnaire-Disability Index is an important outcome measure reflecting functional disability, but knowledge on its course over time in patients with systemic... Show moreObjective: The Health Assessment Questionnaire-Disability Index is an important outcome measure reflecting functional disability, but knowledge on its course over time in patients with systemic sclerosis is scarce. Therefore, we investigated the long-term course of the Health Assessment Questionnaire-Disability Index and its association with baseline characteristics in systemic sclerosis patients. Methods: Systemic sclerosis patients, fulfilling the European League Against Rheumatism and the American College of Rheumatology 2013 criteria, were included from the Leiden Combined Care in Systemic Sclerosis cohort with annual assessments including the Scleroderma Health Assessment Questionnaire-Disability Index (range = 0-3). The course of the Health Assessment Questionnaire-Disability Index was evaluated over the total follow-up (baseline to last available Health Assessment Questionnaire-Disability Index) and between yearly visits. Based on a minimal clinical important difference of 0.22, courses were categorized into worsening, stable or improvement. The course of the Health Assessment Questionnaire-Disability Index over time was evaluated with linear mixed models. Baseline characteristics were compared between patients with a worsening or improvement of the Health Assessment Questionnaire-Disability Index over the total follow-up period with logistic regression analyses. Results: A total of 517 systemic sclerosis patients were included, with a median follow-up of 7 years (interquartile range = 4-9; 2649 visits) and a baseline Health Assessment Questionnaire-Disability Index of 0.625 (interquartile range = 0.125-1.25). On group level, the Health Assessment Questionnaire-Disability Index is stable with an annual increase of 0.019 (95% confidence interval = 0.011 to 0.027). Looking at subgroups, patients >65 years or who died/were physically unable to come during follow-up had a worse mean Health Assessment Questionnaire-Disability Index. In individual courses from baseline to the last follow-up, the proportions of patients with a clinically meaningful worsening, stable or improved Health Assessment Questionnaire-Disability Index were 35%, 42% and 23%, respectively. Patients with immunosuppressants (odds ratio = 0.5, 95% confidence interval = 0.3 to 0.9) or gastrointestinal involvement (odds ratio = 0.6, 95% confidence interval = 0.4 to 0.9) at baseline showed a reduced chance of worsening of the Health Assessment Questionnaire-Disability Index over the total follow-up period. Conclusion: Over time, the average course of the Health Assessment Questionnaire-Disability Index was stable in systemic sclerosis patients. However, individual courses vary, with worsening occurring in one-third. Worsening occurred less often in individuals using immunosuppressants or with gastrointestinal involvement at baseline. Show less
Objective:Age at rheumatoid arthritis (RA) onset varies by geographical latitude. We have investigated to what extent differences in patient-specific factors and country-level socioeconomic... Show moreObjective:Age at rheumatoid arthritis (RA) onset varies by geographical latitude. We have investigated to what extent differences in patient-specific factors and country-level socioeconomic indicators explain this variability. Methods: Patients with RA from the worldwide METEOR registry were included. Bayesian multilevel structural equation models were used to study the relationship between the absolute value of (hospital) geographical latitude and age at diagnosis (as a proxy for age at RA onset). We examined to what extent this effect is mediated by individual patient characteristics and by country-specific socioeconomic indicators and disentangled whether the observed effects occurred at the patient, hospital, or country levels. Results: We included 37 981 patients from 93 hospitals in 17 geographically widespread countries. Mean age at diagnosis per country ranged from 39 (Iran) to 55 (Netherlands) years. Per degree increase in country latitude (between 9.9 degrees and 55.8 degrees), mean age at diagnosis increased by 0.23 years (95% credibility interval: 0.095 to 0.38) (reflecting >10 years difference in age at RA onset). For hospitals within a country, this latitude effect was negligible. Inclusion of patient-specific factors (eg, gender, anticitrullinated protein antibodies status) in the model augmented the main effect from 0.23 to 0.36 years. Inclusion of country-level socioeconomic indicators (eg, gross domestic product per capita) in the model almost effaced the main effect (from 0.23 to 0.051 (-0.37 to 0.38)). Conclusions: Patients living closer to the equator get RA at a younger age. This latitude gradient was not explained by individual patient characteristics, but rather by countries' socioeconomic status, providing a direct link between countries' level of welfare and the clinical onset of RA. Show less
Objectives: We studied patterns of joint inflammation in juvenile idiopathic arthritis (JIA) to assess whether joint activity recurs locally in the same joints. Methods: Joints of 91 patients of... Show moreObjectives: We studied patterns of joint inflammation in juvenile idiopathic arthritis (JIA) to assess whether joint activity recurs locally in the same joints. Methods: Joints of 91 patients of the BeSt for Kids study, a treat-to-target trial for children with recent-onset oligoarticular, rheumatoid factor-negative polyarticular and psoriatic JIA, were clinically assessed during 2 years (10 study visits). The association between joint inflammation at baseline and later inflammation in the same joint was assessed using a multilevel mixed-effects logistic regression model at joint level. With a Poisson model, the association between baseline joint inflammation and the number of study visits at which the same joint was recurrently inflamed was tested. Results: Of the 6097 joints studied, 15% (897) was clinically inflamed at baseline. In 42% (377/897) of those joints, inflammation recurred during follow-up. Joint inflammation at baseline was statistically significantly associated with joint inflammation during follow-up in the same joint (OR 3.9, 95% CI 3.5 to 4.4) and specifically with the number of episodes of recurrent joint inflammation (IRR 1.6, 95% CI 1.2 to 2.1). Conclusion: In JIA, joint inflammation has the tendency to recur multiple times in joints that are clinically inflamed at disease onset. This indicates that local factors might play a role in the processes contributing to the occurrence of JIA flares. Show less
Objectives To investigate whether in rheumatoid arthritis (RA) frequency of local joint inflammation is associated with radiographic joint damage progression in that joint. Methods: Data from 473... Show moreObjectives To investigate whether in rheumatoid arthritis (RA) frequency of local joint inflammation is associated with radiographic joint damage progression in that joint. Methods: Data from 473 patients with RA and available radiographs from the BeSt study were used. Patients were treated to target (Disease Activity Score of <= 2.4) for a median of 10 years. At each study visit every 3 months, joints were assessed for swelling and tenderness. Radiographs of hands and feet were made yearly. A generalised linear mixed model was used to assess the association between the percentage of study visits at which clinical inflammation was observed in a joint (cumulative inflammation) and radiographic joint damage in that same joint. Clinical inflammation was primarily defined as joint swelling (with or without joint tenderness). For secondary analyses, we also investigated joint tenderness without joint swelling. Damage was measured as the percentage of the maximum possible Sharp-Van der Heijde score in a particular joint. Results: Cumulative local joint swelling was associated with local progression of radiographic damage in the same joint (beta=0.14, 95% CI 0.13 to 0.15). This association was also found in a subset of joints that were swollen at least once. Cumulative local joint tenderness without concurrent local joint swelling was less strongly associated with local radiographic joint damage progression (beta=0.04, 95% CI 0.03 to 0.05). Conclusions: In RA, long-term cumulative local joint inflammation is associated with joint damage progression in the same joint. Show less
Ouwerkerk, L. van; Boers, M.; Emery, P.; Jong, P.H.P. de; Landewe, R.B.M.; Lems, W.; ... ; Bergstra, S.A. 2022
Objectives: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may... Show moreObjectives: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may affect this. Methods: Data from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (>= 3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome. Results: The probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended. Conclusions Based on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low. Show less
Khidir, S.J.H.; Boonstra, M.; Bergstra, S.A.; Boerrigter, G.W.M.; Voog-van der Harst, E.M.; Ninaber, M.K.; ... ; Vries-Bouwstra, J.K. de 2022
Objective: Decreased maximal mouth opening is a common and disabling manifestation in systemic sclerosis patients. We aimed to study the course of maximal mouth opening, determinants of smaller... Show moreObjective: Decreased maximal mouth opening is a common and disabling manifestation in systemic sclerosis patients. We aimed to study the course of maximal mouth opening, determinants of smaller maximal mouth opening over time and the burden of smaller maximal mouth opening on mouth handicap. Methods: Consecutive systemic sclerosis patients participating in the prospective Leiden Combined Care in systemic sclerosis cohort were included. Annual clinical assessment included maximal mouth opening measurement and mouth handicap evaluation (Mouth Handicap in Systemic Sclerosis scale). Presence of microstomia (maximal mouth opening < 30 mm) was studied. Maximal mouth opening over time was assessed on group level and for all patients individually. Baseline characteristics were analysed for their association with smaller maximal mouth opening over time (linear mixed-effects models). Furthermore, cross-sectional association between maximal mouth opening with Mouth Handicap in Systemic Sclerosis scale was assessed (linear regression analysis). Results: A total of 382 systemic sclerosis patients were studied with median follow-up time of 2.0 years (interquartile range = 0.0-3.0). At baseline, mean maximal mouth opening was 42.2 +/- 8.0 mm and 7% suffered from microstomia. Annual decrease of > 5.0 mm in maximal mouth opening during follow-up occurred in 63 patients and was accompanied by increase in disease severity. Disease characteristics at baseline independently predictive for smaller maximal mouth opening over time were: more extended skin subtype; peripheral vasculopathy; pulmonary, renal and gastrointestinal involvement. Smaller maximal mouth opening was significantly associated with more reported mouth handicap. Conclusion: The course of maximal mouth opening is stable in a majority of systemic sclerosis patients. Still, maximal mouth opening over time was smaller in patients with more severe organ involvement. Although microstomia was infrequent, a smaller maximal mouth opening was significantly associated with more mouth handicap, indicating the importance to address maximal mouth opening in routine care of systemic sclerosis patients. Show less
Khidir, S.J.H.; Boonstra, M.; Bergstra, S.A.; Boerrigter, G.W.M.; Voog-van der Harst, E.M.; Ninaber, M.K.; ... ; Vries-Bouwstra, J.K. de 2022
Objective:Decreased maximal mouth opening is a common and disabling manifestation in systemic sclerosis patients. We aimed to study the course of maximal mouth opening, determinants of smaller... Show moreObjective:Decreased maximal mouth opening is a common and disabling manifestation in systemic sclerosis patients. We aimed to study the course of maximal mouth opening, determinants of smaller maximal mouth opening over time and the burden of smaller maximal mouth opening on mouth handicap.Methods:Consecutive systemic sclerosis patients participating in the prospective Leiden Combined Care in systemic sclerosis cohort were included. Annual clinical assessment included maximal mouth opening measurement and mouth handicap evaluation (Mouth Handicap in Systemic Sclerosis scale). Presence of microstomia (maximal mouth opening < 30 mm) was studied. Maximal mouth opening over time was assessed on group level and for all patients individually. Baseline characteristics were analysed for their association with smaller maximal mouth opening over time (linear mixed-effects models). Furthermore, cross-sectional association between maximal mouth opening with Mouth Handicap in Systemic Sclerosis scale was assessed (linear regression analysis).Results:A total of 382 systemic sclerosis patients were studied with median follow-up time of 2.0 years (interquartile range = 0.0–3.0). At baseline, mean maximal mouth opening was 42.2 ± 8.0 mm and 7% suffered from microstomia. Annual decrease of > 5.0 mm in maximal mouth opening during follow-up occurred in 63 patients and was accompanied by increase in disease severity. Disease characteristics at baseline independently predictive for smaller maximal mouth opening over time were: more extended skin subtype; peripheral vasculopathy; pulmonary, renal and gastrointestinal involvement. Smaller maximal mouth opening was significantly associated with more reported mouth handicap.Conclusion:The course of maximal mouth opening is stable in a majority of systemic sclerosis patients. Still, maximal mouth opening over time was smaller in patients with more severe organ involvement. Although microstomia was infrequent, a smaller maximal mouth opening was significantly associated with more mouth handicap, indicating the importance to address maximal mouth opening in routine care of systemic sclerosis patients. Show less
Bergstra, S.A.; Sepriano, A.; Kerschbaumer, A.; Heijde, D. van der; Caporali, R.; Edwards, C.J.; ... ; Landewe, R.B.M. 2022
This systematic literature review (SLR) regarding the efficacy, duration of use and safety of glucocorticoids (GCs), was performed to inform the 2022 update of the EULAR recommendations for the... Show moreThis systematic literature review (SLR) regarding the efficacy, duration of use and safety of glucocorticoids (GCs), was performed to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). Studies on GC efficacy were identified from a separate search on the efficacy of disease-modifying antirheumatic drugs (DMARDs). A combined search was performed for the duration of use and safety of GCs in RA patients. Dose-defined and time-defined GC treatment of any dose and duration (excluding intra-articular GCs) prescribed in combination with other DMARDs were considered. Results are presented descriptively. Two included studies confirmed the efficacy of GC bridging as initial therapy, with equal efficacy after 2 years of initial doses of 30 mg/day compared with 60 mg/day prednisone. Based on a recently performed SLR, in clinical trials most patients starting initial GC bridging are able to stop GCs within 12 (22% patients continued on GCs) to 24 months (10% patients continued on GCs). The safety search included 12 RCTs and 21 observational studies. Well-known safety risks of GC use were confirmed, including an increased risk of osteoporotic fractures, serious infections, diabetes and mortality. Data on cardiovascular outcomes were Inconsistent. Overall, safety risks increased with increasing dose and/or duration, but evidence on which dose is safe was conflicting. In conclusion, this SLR has confirmed the efficacy of GCs in the treatment of RA. In clinical trials, most patients have shown to be able to stop GCs within 12-24 months. Well-known safety risks of GC use have been confirmed, but with heterogeneity between studies. Show less
Sepriano, A.; Kerschbaumer, A.; Bergstra, S.A.; Smolen, J.S.; Heijde, D. van der; Caporali, R.; ... ; Landewe, R.B.M. 2022
ObjectivesTo perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the... Show moreObjectivesTo perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). MethodsSLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used. ResultsFifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi. ConclusionThe safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation. Show less
Kerschbaumer, A.; Sepriano, A.; Bergstra, S.A.; Smolen, J.S.; Heijde, D. van der; Caporali, R.; ... ; Landewe, R.B.M. 2022
Objectives:To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology... Show moreObjectives:To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA). Methods:This systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022. Results: Of 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission. Conclusion: The results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA. Show less
Smolen, J.S.; Landewe, R.B.M.; Bergstra, S.A.; Kerschbaumer, A.; Sepriano, A.; Aletaha, D.; ... ; Heijde, D. van der 2022
Objectives: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. Methods: An international task force was... Show moreObjectives: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. Methods: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. Results: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. Conclusions: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost. Show less
