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Introduction: While modern treatments can prevent progressive bone destruction in patients with rheumatoid arthritis (RA) achieving clinical remission, it is unclear whether residual clinical activity may cause or be associated with progressive joint damage. This post hoc analysis evaluated the association between clinical disease activity and structural progression in patients with RA treated with filgotinib (FIL) in FINCH 1 (NCT02889796). Methods: Patients with RA and inadequate response to methotrexate (MTX) use were randomized 3:3:2:3 to FIL 200 mg (FIL200) or FIL 100 mg (FIL100) once daily, adalimumab 40 mg biweekly, or placebo, all with background MTX. We evaluated the change from baseline (CFB) in modified total Sharp score (mTSS), erosion score, and joint space narrowing score among patients achieving Clinical Disease Activity Index (CDAI) remission (CDAI ≤ 2.8), low disease activity (LDA; 2.8 < CDAI ≤ 10), medium disease activity (MDA; 10 < CDAI ≤ 22), and high disease activity (HDA; CDAI > 22) at 24 weeks. Results: At week 24, the least squares (LS) mean CFB in mTSS was similarly low across treatments among patients who achieved CDAI remission (range 0.00–0.11) or LDA (n = 285 and 575, respectively). In patients with MDA and HDA (n = 471 and 157, respectively), smaller LS mean CFB in mTSS was seen in the FIL200 group vs. the placebo group (P < 0.05 for both). Conclusions: RA clinical remission and LDA achievement were associated with suppressed progression of joint destruction over 24 weeks in all treatment groups. Only FIL200 significantly inhibited joint damage compared with placebo in patients with MDA or HDA, indicating an uncoupling of clinical disease activity and structural progression in patients receiving FIL200. Trial Registration: NCT02889796. [ABSTRACT FROM AUTHOR]

Introduction: High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations. Methods: Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models. Results: Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200 mg + MTX/csDMARD exhibited consistently better responses after 12 weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population. Conclusion: The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA. Trial Registration: Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728. Plain Language Summary: Rheumatoid arthritis is a disease that results in swollen and painful joints. There is currently no method to determine which treatment will work best for an individual patient. However, there may be identifying markers found in the blood that could indicate how a patient will respond to treatment. One of these possible markers is a ratio of two types of white blood cells, neutrophils and lymphocytes, which are part of the body's immune system and help the body detect and fight infection and other diseases. This ratio is referred to as the neutrophil-to-lymphocyte ratio. The current study evaluated whether the neutrophil-to-lymphocyte ratio at the beginning of treatment was associated with rheumatoid arthritis treatment outcomes. Blood test results were used from 3365 patients receiving filgotinib (a medicine used to treat rheumatoid arthritis) or other therapies as part of the FINCH clinical trials. Patients were classified as having a high or low neutrophil-to-lymphocyte ratio at the start of treatment. Patients receiving filgotinib over 24 weeks who had a high neutrophil-to-lymphocyte ratio showed less disease activity than patients whose ratio was low. This study provides support for the use of the neutrophil-to-lymphocyte ratio as a way to help determine whether a patient would benefit from filgotinib as part of their rheumatoid arthritis treatment and may help improve rheumatoid arthritis treatment outcomes. [ABSTRACT FROM AUTHOR]

Introduction: This post hoc analysis of the phase 3 rheumatoid arthritis (RA) filgotinib clinical trial program assessed the effect of filgotinib on body mass index (BMI) in patients with RA and the impact of BMI on the efficacy and safety of filgotinib. Methods: FINCH 1–3 were randomized, double-blind, active- or placebo-controlled phase 3 trials of filgotinib 100 and 200 mg in patients with RA (N = 3452). BMI assessments included the mean change from baseline in BMI and the proportion of patients whose BMI increased by incremental thresholds. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 response and low disease activity/remission according to Disease Activity Score 28 using C-reactive protein. The exposure-adjusted incident rate (EAIR) of adverse events (AEs) was assessed by baseline BMI, using integrated data from the FINCH 1–4 and the phase 2 DARWIN 1–3 studies (total filgotinib exposure = 8085 patient-years). Results: Mean change from baseline in BMI over time was similar across treatment arms. In most patients, BMI increased by ≤ 1 or 2 kg/m2 at both weeks 12 and 24, regardless of treatment group or baseline BMI; few patients had increases of ≥ 4 kg/m2. For most efficacy measures, filgotinib 200 mg was more efficacious than filgotinib 100 mg or active comparators or placebo across BMI subgroups. For the higher filgotinib dose, the EAIR of serious treatment-emergent AEs, venous thrombotic and embolic events, and major adverse cardiovascular events increased with increasing BMI. Conclusions: Filgotinib did not lead to substantial changes in BMI, and BMI did not appear to affect the efficacy of filgotinib. Trial Registration: ClinicalTrials.gov identifiers: NCT02889796, NCT02873936, NCT02886728, NCT03025308, NCT01888874, NCT01894516, NCT02065700. Plain Language Summary: Some rheumatoid arthritis treatments cause patients to gain weight or are less effective in patients with obesity than in patients without obesity. Also, obesity can make rheumatoid arthritis worse. Filgotinib is a rheumatoid arthritis treatment that was evaluated in seven randomized clinical studies (FINCH 1–4 and DARWIN 1–3). We investigated whether filgotinib causes changes in weight and whether body mass index (BMI) affects the efficacy or safety of filgotinib. We analyzed how the BMI of patients who participated in FINCH 1, 2, or 3 changed over time. Most patients had a small increase in BMI (around 1–2 kg/m2) after 24 weeks of filgotinib treatment. This change in BMI was not affected by patients' BMI at baseline. Baseline BMI did not impact the efficacy of filgotinib, which was assessed using standard measures of disease activity. Filgotinib was more effective than other rheumatoid arthritis treatments and placebo in all patients, regardless of BMI subgroup. Using safety data from all seven clinical studies (FINCH 1–4 and DARWIN 1–3), we found that some adverse events occurred more often in patients with obesity (a BMI of ≥ 30 kg/m2) than in those without obesity. The increased adverse events included venous thrombotic and embolic events and major adverse cardiovascular events, for which obesity is a known risk factor. These results show that filgotinib did not substantially change BMI (which increased by around 1–2 kg/m2 in most patients), and that baseline BMI did not affect the efficacy of filgotinib. [ABSTRACT FROM AUTHOR]

Filgotinib is an oral preferential Janus kinase 1 inhibitor that demonstrated significant reductions in radiographic progression, with an acceptable tolerability and safety profile, vs placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR; FINCH 1) and vs MTX in MTX-naïve patients with RA (FINCH 3). International treatment guidelines identify multiple poor prognostic factors (PPFs) associated with worse disease outcomes among patients with RA. However, questions remain both about the clinical utility of considering PPFs and about which PPFs should drive treatment decisions. Additionally, the role of radiographic findings in clinical practice continues to be discussed and to evolve. This review examines radiographic results from post hoc analyses of phase 3 trials of filgotinib that examined subgroups with 4 PPFs or with baseline estimated rapid radiographic progression (e-RRP). In MTX groups, there were trends toward greater progression among patients with 4 PPFs or e-RRP, suggesting these subgroups may comprise a higher-risk population. Results show general consistency for the efficacy of filgotinib 200 mg plus MTX vs placebo plus MTX/MTX monotherapy on radiographic assessments, including change from baseline in modified total Sharp score and proportions without radiographic progression, even among MTX-IR or MTX-naïve patients with 4 PPFs or e-RRP who may be at higher risk of bone damage. Multivariate analysis identified multiple factors associated with baseline e-RRP status. This summary of the current understanding of benefits associated with filgotinib on radiographic progression and the relevance of baseline factors to these benefits may help inform treatment decisions for patients facing high risk of radiographic progression. [ABSTRACT FROM AUTHOR]

Introduction: Global clinical trials in rheumatoid arthritis (RA) often do not recruit enough patients from diverse racial and ethnic backgrounds to identify any potential differences in treatment outcome across such groups. To overcome this limitation, using data from five previous clinical trials and two ongoing trial extensions, this study aimed to assess the efficacy and safety of filgotinib in patients with RA across geographic regions. Methods: This was a post hoc, exploratory analysis of data from male and female patients with RA meeting the 2010 RA criteria as defined by the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology. Data were analyzed from phase 2 (DARWIN 1–2) and phase 3 (FINCH 1–3) clinical trials, as well as two long-term extension studies (DARWIN 3, FINCH 4), of filgotinib. Efficacy endpoints included ACR 20%/50%/70% improvement (ACR20/50/70) responses, disease activity score in 28 joints using C-reactive protein [DAS28(CRP)], Clinical Disease Activity Index scores, Boolean remission, and change from baseline in Health Assessment Questionnaire–Disability Index (HAQ-DI). Safety data were presented as exposure-adjusted incidence rates per 100 patient-years of exposure of treatment-emergent adverse events. Results: Compared with placebo, at week 12 a greater proportion of patients receiving filgotinib 200 mg (FIL200) or 100 mg (FIL100) achieved ACR20 (p < 0.01), with similar outcomes in most regions. Overall, the reduction in HAQ-DI with FIL200 or FIL100 was greater than with placebo (p < 0.05) at week 12. Compared with placebo, at week 24 the proportions of patients achieving DAS28(CRP) ≤ 3.2 were greater for both doses of FIL, as seen in most regions (p < 0.01). Safety outcomes did not indicate regional or ethnic differences in the safety profile of filgotinib. Conclusion: Filgotinib efficacy and safety in patients with RA were generally consistent across geographic regions. ClinicalTrials.gov Trial Registration Numbers: NCT02889796; NCT02873936; NCT02886728; NCT03025308; NCT01888874; NCT01894516; NCT02065700. Plain Language Summary: Clinical trials in rheumatoid arthritis recruit too few patients from diverse ethnic backgrounds to be able to identify differences in treatment outcomes. In adults with moderate-to-severe active rheumatoid arthritis who do not tolerate or have responded poorly to other advanced treatments, the Janus kinase inhibitor filgotinib can be used alone or in combination with the immunosuppressant methotrexate. Using data from 4695 patients with rheumatoid arthritis from five previous clinical trials and two ongoing trial extensions, this paper examined the efficacy and safety of filgotinib in patients with rheumatoid arthritis across geographic locations worldwide. Patients were grouped by region: North America, South and Central America, Western Europe, Eastern Europe, East Asia, South and Southeast Asia, and Other (South Africa, New Zealand, Australia, and Israel). The efficacy of filgotinib in treating the symptoms of rheumatoid arthritis was assessed using several measures of disease activity, with changes in patient quality of life determined using a health assessment questionnaire. Safety data were reported as the rates of side effects experienced by patients. Across different geographic regions, no major differences in filgotinib treatment response were observed. Rheumatoid arthritis disease activity levels were consistently lower in patients receiving filgotinib than in patients receiving placebo. Across the regions examined, quality-of-life scores also improved to a greater degree in patients receiving filgotinib compared with placebo. The rates of side effects, including infections, were similar irrespective of region. The number of deaths was low, mostly resulting from cardiovascular events, infections, and malignancies. This study demonstrates that the efficacy and safety of filgotinib are consistent in patients with rheumatoid arthritis from a broad range of geographic regions and ethnic backgrounds. [ABSTRACT FROM AUTHOR]

Introduction: We conducted a post hoc analysis of efficacy and safety of filgotinib stratified by estimated radiographic progression rate before baseline (BL) in patients with rheumatoid arthritis (RA) who had inadequate response to methotrexate (MTX; FINCH 1; NCT02889796) or were naïve to it (FINCH 3; NCT02886728). Methods: Radiographic progression rate was BL-Modified Total Sharp Score (mTSS) divided by RA duration (BL mTSS/year); estimated rapid radiographic progression (e-RRP) was BL change in mTSS/year ≥ 5; and estimated nonrapid radiographic progression (e-NRRP) was BL mTSS/year < 5. Efficacy and safety were compared between subgroups. All p-values are nominal. Results: In FINCH 1 and FINCH 3, 558/1755 (31.8%) and 787/1249 (63.0%) patients, respectively, had BL e-RRP. BL characteristics were generally similar between subgroups within each trial. At week (W) 24, in FINCH 1, proportions achieving a Disease Activity Score 28 for rheumatoid arthritis with C-reactive protein < 2.6 were significantly greater with filgotinib 200 (FIL200) and 100 mg (FIL100) versus placebo among e-RRP and e-NRRP subgroups. In each study, proportions of FIL-treated patients achieving Clinical Disease Activity Index ≤ 2.8 and Simple Disease Activity Index ≤ 3.3 were similar between subgroups. In FINCH 3, disease activity measures were at least numerically improved among patients receiving FIL versus MTX monotherapy. At W24, mTSS changes from BL (CFB) were greater among patients with e-RRP in FINCH 1 and FINCH 3 versus e-NRRP (0.81 versus 0.19, p = 0.001; 0.67 versus 0.25, p = 0.31, respectively). At W52, in FINCH 1, mTSS CFBs were smaller among e-RRP patients treated with FIL200 (0.40; p < 0.001) and FIL100 (0.77; p = 0.024) versus adalimumab (ADA; 1.46). In FINCH 3 at W52, mTSS CFBs were significantly smaller with FIL200 versus MTX among e-RRP patients. Rates of treatment-emergent adverse events (AEs) were comparable between subgroups and across treatment arms. Conclusions: Patients with previous e-RRP who received standard care tended to progress radiographically. FIL200 demonstrated persistent, consistent benefit for disease activity control among e-RRP and e-NRRP subgroups, and AE profiles were similar between subgroups. Although filgotinib efficacy was somewhat reduced among patients with e-RRP, filgotinib treatment slowed radiographic progression in both subgroups. Trial Registration: Clinicaltrials.gov NCT02889796, NCT02886728. [ABSTRACT FROM AUTHOR]

Introduction: This exploratory analysis of FINCH 1 (NCT02889796) examined filgotinib (FIL) efficacy and safety in a subgroup of patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX; MTX-IR) who had four poor prognostic factors (PPFs). Methods: Patients with MTX-IR received placebo up to week (W)24 or FIL200 mg, FIL100 mg, or adalimumab up to W52; all received MTX. Efficacy and safety data were stratified by four PPFs versus fewer than four PPFs: seropositivity, high-sensitivity C-reactive protein (CRP) ≥ 6 mg/L, Disease Activity Score in 28 joints with CRP > 5.1, and erosions on X-rays. Results: At baseline, 687/1755 patients had four PPFs. At W12, whether with four PPFs or fewer than four PPFs, response rates on all American College of Rheumatology (ACR) measures were significantly greater with FIL200 and FIL100 versus placebo. At W52, FIL200 ACR20/50/70 response rates remained at least numerically higher versus adalimumab in both subgroups. At W52, FIL200 reduced modified total Sharp score (mTSS) change versus adalimumab in patients with four or fewer than four PPFs. Conclusions: In high-risk (four PPFs) patients with MTX-IR RA, FIL200 and FIL100 showed similar reductions in disease activity versus placebo at W12 as in patients with fewer than four PPFs. mTSS in patients receiving FIL200 changed little from W24 to W52, while that in patients receiving FIL100 progressed comparably to patients who received adalimumab. Tolerability was comparable across treatment arms and subgroups. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) is a chronic debilitating illness, usually associated with mental health ailments. Literature reports contradictory observations about the association between recent RA pharmacotherapies and mental health. We systematically reviewed RA randomized control trials to synthesize the association between Janus kinases (JAK) inhibitors therapy and mental health. Methods: We systematically searched clinical trials of JAK inhibitor intervention reporting mental health outcomes using short form-36 (SF-36) in PubMed, Embase, and Scopus databases from inception to February 2021. We have selected the studies and extracted the data, adhering to Preferred Reporting Items of Systematic reviews and Meta-Analysis (PRISMA) guidelines. We have pooled the mean change of SF-36 mental component score (MCS) between JAK inhibitors and comparator therapy with a 95% confidence interval. Results: Of the 2915 searched studies for systematic review, 19 studies involving 14,323 individuals were included for the meta-analysis. The pooled mean reduction in SF-36 MCS scores (after minus before) with JAK inhibitors was 4.95 (4.41–5.48). The pooled mean difference of incremental mean change in SF-36 MCS score between JAK monotherapy and comparator was 1.53 (0.88–2.18). The improvement in SF-36 MCS scores with JAK inhibitor therapy is greater than the minimum clinically important difference (MCID) value of 2.5. However, on separate analysis with comparator drugs like methotrexate and standard treatment, the MCS scores did not exceeded the MCID value and were also not statistically significant. Conclusions: JAK inhibitors results in clinically meaningful improvement in the mental health scores of the RA patients. PROSPERO Registration ID: 2021 CRD42021234466. [ABSTRACT FROM AUTHOR]

Introduction: The Janus kinase (JAK) inhibitor therapeutic class has shown significant clinical benefit in the treatment of rheumatoid arthritis (RA). We sought to gain insight into the mode of action and immunological effects of filgotinib, a JAK1 selective inhibitor, in active RA by analyzing secreted and cell-based biomarkers key to RA pathophysiology in two phase 2b trials of filgotinib in active RA. Methods: Immune cell subsets and 34 serum biomarkers were analyzed longitudinally over 12 weeks using blood samples collected from patients with active RA receiving filgotinib (100 or 200 mg once daily) or placebo (PBO) in the two phase 2b trials (DARWIN 1, on a background of methotrexate, and DARWIN 2, as monotherapy). Results: Consistently across both studies, filgotinib treatment decreased multiple immune response biomarkers that have key roles in RA for immune response, and decreased markers that promote matrix degradation, angiogenesis, leukocyte adhesion, and recruitment. Filgotinib did not significantly modulate T and natural killer (NK) lymphoid subsets, but slightly increased B cell numbers after 12 weeks. Multiple correlations were observed for changes in biomarkers with disease activity score 28-CRP. MIP1β showed modest predictivity at baseline for ACR50 response at 12 weeks in the 100 mg filgotinib dose across both studies (AUROC, 0.65 and 0.67, p < 0.05). Conclusions: Filgotinib regulates biomarkers from multiple pathways, indicative of direct and indirect network effects on the immune system and the stromal response. These effects were not associated with reductions of major circulating lymphoid populations. Trial Registration: ClinicalTrials.gov, NCT01888874, NCT01894516. [ABSTRACT FROM AUTHOR]