Rheumatoid arthritis (RA) is one of the most common chronic inflammatory diseases, primarily affecting the joints and presenting with extra-articular manifestations such as rheumatoid nodules, lung involvement or vasculitis, as well as other systemic comorbidities [1]. This disease causes a decline in physical function, reduced work capacity, and decreased social participation, leading to reduced quality of life and increased cumulative risk of comorbidities, representing a significant burden for both the individual and society [2].

The incidence of RA in Italy is 0.5–1%, with an apparent decrease from North to South and from urban to rural areas [3]. A positive family history increases the risk of RA by approximately 3–5 times, implicating genetic factors in the pathogenesis, as confirmed by increased concordance rates in twins [4].

Nowadays, treatment goals include rapid achievement of remission or low disease activity to prevent structural damage and consequent disability. The early initiation of therapy in the course of the disease can prevent radiographic progression, most of which occurs within the first few months of disease onset. The primary role of disease-modifying antirheumatic drugs (DMARDs) is well established, with conventional synthetic DMARDs (csDMARDs, such as methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine) still used as first-line therapy today, in addition to their non-selective immunosuppressive mechanism of action. The introduction of biologic DMARDs (bDMARDs) in the 1990s represented a major change in the management of RA. They can be used as monotherapy or in combination with csDMARDs, with a sensible improvement in achieving remission or obtaining low disease activity of RA. They are specific, targeting a precise pathway of the immune system, and are used as second-line therapy. The most representative class of bDMARDs is the tumor necrosis factor (TNF) inhibitors (TNF-i), such as infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol. While only 30% of patients treated with csDMARDs achieve remission, up to 50.0% of those treated with TNF-i in a treat-to-target strategy achieve remission at 6–12 months. However, despite treatment with csDMARDs and bDMARDs, up to 20–30% of patients with RA do not achieve or fail to maintain a good response over time [5].

In recent years, the development and authorization of Janus kinase (JAK) inhibitors (JAKis), small molecules belonging to the class of targeted synthetic DMARDs (tsDMARD), have further improved treatment options for RA.

JAKis are cytoplasmic proteins that link cytokine signaling from membrane receptors to transcription factors, known as signal transducers and activators of transcription (STATs). This allows for optimal control of the inflammatory response, making it a valuable resource for the management of autoimmune diseases [6]. There are four members in the JAK family (JAK1, JAK2, JAK3, and tyrosine kinase 2, TYK2), and seven types of STATs (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6), that can be targeted by JAKis [7].

In addition to their good efficacy and safety profiles, other important advantages of JAKis are their oral route of administration and lower production costs compared to bDMARDs [7].

Four JAKis—tofacitinib, baricitinib, upadacitinib, and filgotinib (FIL)—have been approved in Europe for the treatment of moderate-to-severe RA after failure of first- and second-line therapy [8]. Tofacitinib and baricitinib are considered pan-JAK inhibitors, being able to simultaneously interact with different JAKis, blocking their downstream signaling pathway, while upadacitinib and FIL are preferentially blockers of JAK1 over the other molecules.

FIL is a competitive and reversible inhibitor of adenosine triphosphate in the JAK family, and is currently indicated in the EU both as monotherapy and also in combination with methotrexate for the treatment of moderate-to-severe active RA in adults with an inadequate response or intolerance to one or more DMARDs [9]. Specifically, FIL has been shown to preferentially inhibit JAK1/3, JAK1/2, and JAK1/TYK2 (Tyrosine Kinase 2), with a functional selectivity for cytokine receptors that signal via JAK2 or JAK2/TYK2 pairs [10].

The efficacy of FIL in the treatment of moderate-to-severe active RA was initially investigated in the phase II DARWIN 2 trial [11], as well as in the phase II DARWIN 1 trial [12] in combination with methotrexate (MTX), demonstrating an improvement in symptoms among patients with an inadequate response to methotrexate.

Subsequently, its efficacy was further evaluated in phase III trials, including: (a) FINCH 1 [10], which assessed the efficacy of FIL versus placebo or adalimumab in patients with inadequate response to MTX; (b) FINCH 2 [13], which showed a significantly greater proportion of patients achieving clinical response at week 12 in patients with active RA who had an inadequate response or intolerance to one or more bDMARDs; and (c) FINCH 3 [14], which demonstrated the efficacy of FIL plus or without MTX compared to MTX alone. Notably, FINCH 3 also showed a rapid decrease in pain after only 2 weeks of treatment, which was maintained up to 24 weeks.

FIL was generally well tolerated in patients with RA across clinical trials, with the most frequently reported adverse reactions being nausea, upper respiratory tract infection (URTI), urinary tract infection (UTI), and dizziness. Moreover, the frequency of serious infection associated with FIL remained low and stable with longer-term exposure [15]. However, patients in real-world clinical practice often differ from those selected for registration trials. For this reason, real-world clinical data on efficacy, safety, and adherence are particularly valuable. To date, however, data supporting the efficacy and safety of FIL in patients with RA from real-life studies are still scarce [16, 17].

On this basis, our study aims to further evaluate the effectiveness and safety of FIL in real-world patients with RA from a large Italian cohort. To our knowledge, this is the first real-world study to assess the effectiveness of FIL in patients with RA with an 18-month follow-up. Thanks to its large sample size and the involvement of multiple centers across Italy, this study offers a comprehensive snapshot of FIL’s effectiveness in clinical practice nationwide.