To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid ...arthritis (RA) and inadequate response to MTX.
In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response.
Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100 or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported.
Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated.
NCT01888874.
To develop recommendations for the management of medium to high-dose (ie, >7.5 mg but ≤100 mg prednisone equivalent daily) systemic glucocorticoid (GC) therapy in rheumatic diseases. A ...multidisciplinary EULAR task force was formed, including rheumatic patients. After discussing the results of a general initial search on risks of GC therapy, each participant contributed 10 propositions on key clinical topics concerning the safe use of medium to high-dose GCs. The final recommendations were selected via a Delphi consensus approach. A systematic literature search of PubMed, EMBASE and Cochrane Library was used to identify evidence concerning each of the propositions. The strength of recommendation was given according to research evidence, clinical expertise and patient preference. The 10 propositions regarded patient education and informing general practitioners, preventive measures for osteoporosis, optimal GC starting dosages, risk-benefit ratio of GC treatment, GC sparing therapy, screening for comorbidity, and monitoring for adverse effects. In general, evidence supporting the recommendations proved to be surprisingly weak. One of the recommendations was rejected, because of conflicting literature data. Nine final recommendations for the management of medium to high-dose systemic GC therapy in rheumatic diseases were selected and evaluated with their strengths of recommendations. Robust evidence was often lacking; a research agenda was created.
Abstract
Objectives
To investigate whether MTX should be combined with an additional DMARD and bridging glucocorticoids as initial treatment for patients with early RA to induce an effective ...long-term response.
Methods
The Care in early RA study is a two-year investigator-initiated pragmatic multicentre randomized trial. Early RA patients, naïve to DMARDs and glucocorticoids, were stratified based on prognostic factors. High-risk patients were randomized to COBRA-Classic (n = 98): MTX, sulfasalazine, prednisone step-down from 60 mg; COBRA-Slim (n = 98): MTX, prednisone step-down from 30 mg; or COBRA-Avant-Garde (n = 93): MTX, leflunomide, prednisone step-down from 30 mg. Low-risk patients were randomized to COBRA-Slim (n = 43); or Tight Step Up (TSU) (n = 47): MTX without prednisone. Clinical/radiological outcomes at year 2, sustainability of response, safety and treatment adaptations were assessed.
Results
In the high-risk group 71/98 (72%) patients achieved a DAS28-CRP < 2.6 with COBRA-Slim compared with 64/98 (65%) with COBRA-Classic and 69/93 (74%) with COBRA-Avant-Garde (P = 1.00). Other clinical/radiological outcomes and sustainability of response were similar. COBRA-Slim treatment resulted in less therapy-related adverse events compared with COBRA-Classic (P = 0.02) or COBRA-Avant-Garde (P = 0.005). In the low-risk group, 29/43 (67%) patients on COBRA-Slim and 34/47 (72%) on TSU achieved a DAS28-CRP < 2.6 (P = 1.00). On COBRA-Slim, low-risk patients had lower longitudinal DAS28-CRP scores over 2 years, a lower need for glucocorticoid injections and a comparable safety profile compared with TSU.
Conclusion
All regimens combining DMARDs with glucocorticoids were effective for patients with early RA up to 2 years. The COBRA-Slim regimen, MTX monotherapy with glucocorticoid bridging, provided the best balance between efficacy and safety, irrespective of patients’ prognosis.
Trial registration
ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01172639.
The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a ...long-term, open-label extension study (ClinicalTrials.gov: NCT02065700).
Eligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies.
Of 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data.
Filgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy.
To develop and validate a screening tool to identify patients with a high likelihood for Spondyloarthritis (SpA) in the Democratic Republic of the Congo (DR Congo).
The development of the SpA ...Screening questionnaire in Sub Saharian Africa (SpASSS) questionnaire followed 3 steps: The item generation was carried out by a systematic literature review according to the PRISMA guidelines on the clinical manifestations of SpA, interviewing clinical experts and the classification criteria for Spondyloarthritis. The candidate questions were tested in a population of 50 consecutive patients with confirmed diagnosis of spondyloarthritis, in a control population of rheumatic disease excluding SpA and in a group of 200 non-rheumatic participants, randomly chosen in the general population for question reduction and validation. Descriptive statistical analyses were performed to assess socio-demographic characteristics and response distribution for each item. Their diagnostic performance was investigated using ROC curves. For validation, principal component analysis was performed using factor analysis. Referral strategy score for SpA was determined by adjusted Cronbach's alpha coefficient.
Mean ± SD age of SpA cases was 41.8 ± 14.4 years, 56% were men compared to diseased controls 60.0 ± 12.5 years, 28.7% men (p < 0.001). 14/20 items showed a statistically significant difference (p < 0.05) between SpA cases and control groups. All items were factorable and 6 components were identified. Only the two first components (C1 with 8 items, C2 with 3 items) showed a significant threshold for reliability in detection of suspected SpA with a Cronbach's alpha of 0.830 and 0.708. All validated items of these two components showed the global reliability threshold with α-adjusted Cronbach calculated at 66.9%. The performance for correctly screening SpA was demonstrated with an area under the curve of 0.938 (0.884-0.991) and 0.794 (0.728-0.861) for C1 and C2 respectively.
This validation and item reduction of the SpASSS questionnaire for SpA might identify patients to refer for case ascertainment and will help conducting future epidemiological and clinical studies in the DR Congo.
• To the best of our knowledge, this is the first study in Sub-Saharan Africa based on local data to develop a screening tool for SpA in the population for epidemiological and clinical use. • Referral strategies based on context-specific data are necessary to provide accurate case definition and epidemiological data, thus reducing methodological bias. • In the SpA group, no discrimination was made regarding SpA subtypes, disease duration, activity and severity.
To systematically review the impact of tapering targeted therapies (bDMARDs or JAKis) on the risk of serious infections and severe adverse events (SAEs) in patients with rheumatoid arthritis (RA) or ...axial spondyloarthritis (axSpA) in remission or low disease activity (LDA) state.
A meta-analysis based on a systematic review of PubMed, Embase, Cochrane, until August 2019, as well as relevant databases of international conferences, was used to evaluate the risk difference (RD) at 95% confidence interval (95% CI) of incidence density of serious infections, SAEs, malignancies, cardiovascular adverse events (CV AEs), or deaths after tapering (dose reduction or spacing) compared to continuation of targeted therapies.
Of the 1957 studies initially identified, 13 controlled trials (9 RA and 4 SpA trials) were included in the meta-analysis. 1174 patient-years were studied in the tapering group (TG) versus 1086 in the usual care group (UC). There were 1.7/100 patient-year (p-y) serious infections in TG versus 2.6/100 p-y in UC (RD (95% CI) 0.01 (0.00 to 0.02), p = 0.13) and 7.4/100 p-y SAEs in TG versus 6.7/100 p-y in UC (RD 0.00 (- 0.02 to 0.02), p = 0.82). The risk of malignancies, CV AEs, or deaths did not differ between the tapering and the usual care groups. Subgroup analysis (RA and SpA) detected no significant differences between the two groups.
We could not show significant impact of tapering bDMARD or JAKi over continuation concerning the risk of serious infections, SAEs, malignancies, CV AEs, or deaths in RA and SpA patients in remission or LDA state.
Background The Patient-Reported Outcomes Measurement Information System (PROMIS®) is a new, state-of-the-art assessment system for measuring patient-reported health and well-being of adults and ...children that has the potential to be more valid, reliable and responsive than existing PROMs. The PROMIS items can be administered in short forms or, more efficiently, through computerized adaptive testing. This paper describes the translation of 563 items from 17 PROMIS item banks (domains) for adults from the English source into Dutch–Flemish. Methods The translation was performed by FACITtrans using standardized methodology and approved by the PROMIS Statistical Center. The translation included four forward translations, two back-translations, three to five independent reviews (at least two Dutch, one Flemish) and pre-testing in 70 adults (age range 20–77) from the Netherlands and Flanders. Results A small number of items required separate translations for Dutch and Flemish: physical function (five items), pain behaviour (two items), pain interference (one item), social isolation (one item) and global health (one item). Challenges faced in the translation process included: scarcity or overabundance of possible translations, unclear item descriptions, constructs broader/smaller in the target language, difficulties in rank ordering items, differences in unit of measurement, irrelevant items or differences in performance of activities. By addressing these challenges, acceptable translations were obtained for all items. Conclusion The methodology used and experience gained in this study can be used as an example for researchers in other countries interested in translating PROMIS. The Dutch–Flemish PROMIS items are linguistically equivalent. Short forms will soon be available for use and entire item banks are ready for cross-cultural validation in the Netherlands and Flanders.
Objective:To develop evidence-based recommendations for the management of systemic glucocorticoid (GC) therapy in rheumatic diseases.Methods:The multidisciplinary guideline development group from 11 ...European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist–epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference.Results:The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy (ie, non-steroidal anti-inflammatory drugs, gastroprotection and cyclo-oxygenase-2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice (ie, adrenal insufficiency, pregnancy, growth impairment).Conclusion:Ten key recommendations for the management of systemic GC-therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence (ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC-replacement) and need further research; therefore also a research agenda was composed.
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