Multicentre, 26-week, open-label phase 2 trial of the JAK inhibitor filgotinib in Behçet’s disease, idiopathic inflammatory myopathies and IgG4-related disease:DRIMID study protocol

Introduction:Research into novel therapies for rare, immune-mediated inflammatory diseases (IMIDs) faces significant challenges, including small patient populations, complex clinical trial design and difficulties in patient recruitment. Patients with Behçet’s disease (BD), idiopathic inflammatory myopathies (IIM) and IgG4-related disease (IgG4-RD) typically undergo treatment involving prolonged administration of high-dose glucocorticoids and immunosuppressants. Both are associated with an increased risk of infection. Additionally, glucocorticoids carry long-term toxicity risks. Thus, there is an urgent need to develop more targeted and effective anti-inflammatory treatments. Given the activation of the type 1 interferon pathway in BD, IIM and IgG4-RD, inhibition of the Janus kinase (JAK) STAT pathway emerges as a promising therapeutic strategy. The Drug Rediscovery in IMIDs (DRIMID) consortium aims to conduct a prospective pilot basket trial to investigate the effects of filgotinib, a JAK1 preferential inhibitor approved for ulcerative colitis and rheumatoid arthritis, on disease activity, quality of life and safety in patients with refractory BD, IIM and IgG4-RD. Methods and analysis: In this investigator-initiated, multicentre, open-label phase 2 study, up to 60 patients with rare IMIDs will be enrolled for a 26-week treatment period with filgotinib 200 mg once daily. The trial consists of two stages, each involving a consecutively treated cohort of up to 20 patients per disease. An interim analysis is conducted between these stages, where the trial will proceed only in diseases showing potential effectiveness. Baseline, 3-month and 6-month assessments will include data on quality of life, disease activity, corticosteroid toxicity and biomarkers. The coprimary endpoints are disease activity and quality of life across and within each disease. Ethics and dissemination: The study received approval from the Medical Research Ethics Committee in Utrecht, Netherlands. A Data Safety Monitoring Board has been established to monitor the trial’s safety and progress.</p

Recurrence risk of venous thromboembolism associated with systemic lupus erythematosus:A retrospective cohort study

BACKGROUND: Recurrence risk of systemic lupus erythematosus (SLE)‐associated venous thromboembolism (VTE) is unclear. AIM: To determine the recurrence risk of SLE‐associated VTE overall and by presence of provoking factors and SLE flares. METHODS: A multicenter, retrospective cohort study was conducted among patients with first SLE‐associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare–associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS. RESULTS: Eighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person‐years (PY; 95% confidence interval [CI], 0.1–3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9–8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%–21.7%) and 31.4% (95% CI, 6.3%–61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2–9.0) and 16.7 per 100 PY (95% CI, 4.5–42.7), with cumulative incidences of 33.7% (95% CI, 10.7%–58.9%) and 54.2% (95% CI, 10.7%–84.5%), respectively. Forty‐six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1–1.8) compared to those without flares at their index VTE. CONCLUSION: Antiphospholipid syndrome is the main determinant for recurrence risk of SLE‐associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare‐associated VTE has a lower recurrence risk

Paternal inflammatory arthritis is associated with a higher risk of miscarriage:results of a large multicentre study (iFAME-Fertility)

OBJECTIVES: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA.METHODS: We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA.RESULTS: In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = &lt;0.05). This increased risk was still present after adjusting for confounders [OR 2.03 (95% CI 1.12, 3.69) P = 0.015].CONCLUSIONS: This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates.</p

Multicentre, 26-week, open-label phase 2 trial of the JAK inhibitor filgotinib in Behçet’s disease, idiopathic inflammatory myopathies and IgG4-related disease: DRIMID study protocol

Introduction Research into novel therapies for rare, immune-mediated inflammatory diseases (IMIDs) faces significant challenges, including small patient populations, complex clinical trial design and difficulties in patient recruitment. Patients with Behçet’s disease (BD), idiopathic inflammatory myopathies (IIM) and IgG4-related disease (IgG4-RD) typically undergo treatment involving prolonged administration of high-dose glucocorticoids and immunosuppressants. Both are associated with an increased risk of infection. Additionally, glucocorticoids carry long-term toxicity risks. Thus, there is an urgent need to develop more targeted and effective anti-inflammatory treatments. Given the activation of the type 1 interferon pathway in BD, IIM and IgG4-RD, inhibition of the Janus kinase (JAK) STAT pathway emerges as a promising therapeutic strategy. The Drug Rediscovery in IMIDs (DRIMID) consortium aims to conduct a prospective pilot basket trial to investigate the effects of filgotinib, a JAK1 preferential inhibitor approved for ulcerative colitis and rheumatoid arthritis, on disease activity, quality of life and safety in patients with refractory BD, IIM and IgG4-RD. Methods and analysis In this investigator-initiated, multicentre, open-label phase 2 study, up to 60 patients with rare IMIDs will be enrolled for a 26-week treatment period with filgotinib 200 mg once daily. The trial consists of two stages, each involving a consecutively treated cohort of up to 20 patients per disease. An interim analysis is conducted between these stages, where the trial will proceed only in diseases showing potential effectiveness. Baseline, 3-month and 6-month assessments will include data on quality of life, disease activity, corticosteroid toxicity and biomarkers. The coprimary endpoints are disease activity and quality of life across and within each disease. Ethics and dissemination The study received approval from the Medical Research Ethics Committee in Utrecht, Netherlands. A Data Safety Monitoring Board has been established to monitor the trial’s safety and progress

Circulating calprotectin (S100A8/A9) is higher in rheumatoid arthritis patients that relapse within 12 months of tapering anti-rheumatic drugs

Objective To investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA) patients who are in stable remission on disease-modifying anti-rheumatic drugs (DMARDs) and serve as a marker for disease flare after DMARD tapering. Methods We used data from two trials. Patients from the IMPROVED study had early (< 2 years) RA, and when they achieved disease activity score remission (DAS44 < 1.6), they stopped methotrexate to attempt drug-free remission. Patients from the RETRO study had established RA in stable remission (DAS28 < 2.6) and either tapered by 50% or stopped (biological or conventional) DMARDs. Circulating calprotectin at the tapering time point was determined by ELISA, and its predictive value for flare (loss of remission) within 12 months of DMARD tapering/stopping was determined. Results In both IMPROVED (n = 104) and RETRO (n = 57), patients that flared within 12 months had higher calprotectin at the moment of DMARD tapering/stopping. Twofold higher calprotectin at the moment of DMARD tapering/stopping was associated with an increased risk (odds ratio) of flare of 1.07 (95% CI 0.98–1.18, p = 0.14) in the IMPROVED and 3.62 (95% CI 1.76–7.46, p < 0.001) in the RETRO. Correcting for clinical predictors of flare (DAS at study inclusion, anti-CCP2 positivity, gender) did not change these estimates. The area under the receiver operating curve of calprotectin levels for predicting flare within 12 months was 0.63 (95% CIs 0.51–0.76) in the IMPROVED study and 0.80 (95% CIs 0.69 to 0.92) in the RETRO study. Conclusion Circulating calprotectin levels in RA patients in remission on DMARDs are higher in patients that will flare upon DMARD tapering/stopping. Since the differences between the cohorts precluded definitive conclusions, more research is needed to determine whether calprotectin has prognostic value in predicting flare after attempting drug tapering in RA. Trial registration IMPROVED, ISRCTN11916566. RETRO, 2009-015740-42

Glucocorticoid discontinuation in patients with early rheumatoid and undifferentiated arthritis: a post-hoc analysis of the BeSt and IMPROVED studies

ObjectivesTo evaluate the success rate of glucocorticoid discontinuation and to study which factors are associated with successful discontinuation.MethodsData from two treat-to-target studies, BeSt (target Disease Activity Score (DAS) ≤2.4) and IMPROVED (target DAS &lt;1.6), were evaluated for all patients initially treated with a tapered high dose of prednisone with conventional synthetic disease-modifying antirheumatic drugs. Prednisone was discontinued when DAS ≤2.4 was maintained for 28 weeks in BeSt and as soon as DAS was &lt;1.6 in IMPROVED. Discontinuation was considered successful if the target was maintained at the next visit. Logistic regression analyses were performed to identify predictors of successful discontinuation. A mixed effects logistic regression model was used to assess whether primary versus secondary discontinuation was as successful.ResultsIn the BeSt study, 40% (47 of 93) of patients flared after primary prednisone discontinuation, and of the other 60% (56 of 93), 38% had to restart later. Of those who restarted (secondary discontinuation), 47% (17 of 35) again flared. In IMPROVED, after primary discontinuation 39% (158 of 400) flared, and of the other 61% (242 of 400), 40% had to restart later. After secondary discontinuation 49% (68 of 139) flared. Only in IMPROVED a secondary attempt was less successful (BeSt OR 0.71, p=0.45; IMPROVED OR 0.60, p=0.01). A lower DAS both at baseline and stop visit and male gender (in IMPROVED) were associated with successful primary discontinuation.ConclusionPrimary glucocorticoid discontinuation resulted in direct loss of disease control in approximately 40% and secondary in 50% of patients. ‘Standard’ baseline characteristics seem insufficient to personalise the duration of temporary glucocorticoid bridging, but the DAS at the time of discontinuation might provide guidance.</jats:sec

Adequately dosed aerobic physical activity in people with axial spondyloarthritis: associations with physical therapy

Abstract Introduction This study aimed to compare the engagement in moderate- and vigorous-intensity PA in axSpA patients with and without current physical therapy (PT). Methods In this cross-sectional study, a survey, including current PT treatment (yes/no) and PA, using the ‘Short QUestionnaire to ASsess Health-enhancing PA’ (SQUASH), was sent to 458 axSpA patients from three Dutch hospitals. From the SQUASH, the proportions meeting aerobic PA recommendations (≥ 150 min/week moderate-, ≥ 75 min/week vigorous-intensity PA or equivalent combination; yes/no) were calculated. To investigate the association between PT treatment and meeting the PA recommendations, odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using logistic regression models, adjusting for sex, age, health status and hospital. Results The questionnaire was completed by 200 patients, of whom 68%, 50% and 82% met the moderate-, vigorous- or combined-intensity PA recommendations, respectively. Ninety-nine patients (50%) had PT treatment, and those patients were more likely to meet the moderate- (OR 2.09 [95% CI 1.09–3.99]) or combined-intensity (OR 3.35 [95% CI 1.38–8.13]) PA recommendations, but not the vigorous-intensity PA recommendation (OR 1.53 [95% CI 0.80–2.93]). Aerobic exercise was executed in 19% of individual PT programs. Conclusion AxSpA patients with PT were more likely to meet the moderate- and combined-intensity PA recommendations, whereas there was no difference in meeting the vigorous-intensity PA recommendation. Irrespective of having PT treatment, recommendations for vigorous-intensity PA are met by only half of the patients. Implementation should thus focus on aerobic PA in patients without PT and on vigorous-intensity PA in PT programs. </jats:sec