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
Schenning, L.C.M.; Ottevanger, R.; Quint, K.D.; Tas, S.W. 2024
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
Pol, J.A. van der; Akdemir, G.; Broek, M. van den; Dirven, L.; Kerstens, P.J.S.M.; Lems, W.F.; ... ; Allaart, C.F. 2023
Objectives: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. Methods: Eight-year follow-up... Show moreObjectives: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. Methods: Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)<= 2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative Delta SHS in an individual joint, seen by >= 3 out of 4 readers and persisting >= 2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS. Results: Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses. Conclusion: After 8 years of treatment to target DAS <= 2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair. Show less
Pol, J.A. van der; Akdemir, G.; Broek, M. van den; Dirven, L.; Kerstens, P.J.S.M.; Lems, W.F.; ... ; Allaart, C.F. 2023
Objectives To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this.Methods Eight-year follow-up... Show moreObjectives To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this.Methods Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)≤2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative ΔSHS in an individual joint, seen by ≥3 out of 4 readers and persisting ≥2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS.Results Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses.Conclusion After 8 years of treatment to target DAS≤2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair. 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
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 formed... 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
Objectives: The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase... Show moreObjectives: The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi. Methods: This is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders. Results: 365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies. Conclusions: After failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi. Show less
Objectives The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase... Show moreObjectives The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi.Methods This is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders.Results 365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies.Conclusions After failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi. Show less
Kay, J.; Harigai, M.; Rancourt, J.; Dickson, C.; Melby, T.; Issa, M.; ... ; Kremer, J.M. 2020
Objective To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.Methods Data were pooled from eight randomised clinical trials (four phase 3,... Show moreObjective To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.Methods Data were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).Results Mean absolute neutrophil counts decreased (-1.36x10(9)/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30x10(9)/L) within 1 month, then decreased to baseline (weeks 12-24). Mean platelet counts increased at week 2 (+51x10(9)/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (-0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).Conclusions Moderate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation. Show less
