Efficacy and safety of JAK inhibitors in connective tissue disease-associated interstitial lung disease

Interstitial lung disease (ILD) encompasses diverse conditions, including fibrotic lung diseases characterized by cellular proliferation, interstitial inflammation, and fibrosis. ILD can arise from numerous causes, including connective tissue diseases (CTDs) such as systemic sclerosis (SSc), rheumatoid arthritis (RA), idiopathic inflammatory myopathy (IIM), Sjögren’s syndrome (SS), and systemic lupus erythematosus (SLE), with SSc, RA, and IIM being more prevalent. The reported prevalence of ILD varies widely across studies owing to differences in inclusion criteria, research methodologies, and follow-up durations. For instance, the prevalence of ILD in SSc can reach 30%, with a 10-year mortality rate of up to 40%.[1] The exact prevalence of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains uncertain, ranging from 1% to 58% based on different study methodologies.[2] The global prevalence of ILD in polymyositis and dermatomyositis (PM/DM) is approximately 41%, with a higher prevalence in Asian populations.[3] ILD profoundly affects the treatment approaches, quality of life, morbidity, and mortality in patients with rheumatic diseases. The overlapping pathological and clinical features of ILDs complicate diagnosis and pose significant challenges in the management of CTD-ILDs. Overview of pathogenesis in CTD-ILD: ILD has emerged as a significant cause of morbidity and mortality in patients with CTDs. The pathogenesis of ILD primarily involves inflammation and damage to the alveolar epithelium, leading to the activation of pulmonary interstitial fibroblasts. Activated fibroblasts and myofibroblasts produce excessive extracellular matrix proteins that contribute to scar formation in the lungs. Interactions among various cell types can influence the patterns and severity of fibrosis. Autoantibodies, as well as components of both innate and adaptive immunity, are crucial in regulating CTD-ILD progression [Figure 1].[4]Figure 1: Pathogenesis of RA-ILD, MDA5+ DM-ILD, and SSc-ILD and the associated JAK-STAT pathway. Under the influence of various factors, AT II differentiates into lung myofibroblasts through the EMT process, while lung fibroblasts differentiate into lung myofibroblasts via the FMT process. This differentiation results in ECM secretion, which contributes to the development of ILD. TGF-β1, through the JAK2/STAT3 pathway, can induce EMT, whereas IL-6 and TGF-β1, via the JAK/STAT pathway, can induce FMT. In the pathogenesis of RA-ILD, the presence of plasma cells secreting anti-CCP antibodies or producing RF in RA patients stimulates NETs. This, in turn, induces lung fibroblasts to differentiate into lung myofibroblasts via FMT. In the pathogenesis of MDA5+ DM-ILD, pDCs and mDCs produce IFN-β. IFN-β activates monocytes and macrophages, leading to the production of additional mDCs and increased IFN-β expression. IFN-β can induce ROS-mediated mitochondrial dysfunction in DM, with ROS subsequently activating TGF-β1, thereby contributing to ILD development. In the pathogenesis of SSc-ILD, autoimmune and inflammatory responses, along with pathogens and environmental factors, may induce endothelial and epithelial injury, activate the immune system, recruit fibroblasts, and lead to the phenotypic transformation of fibroblasts into myofibroblasts. Anti-CCP: Anti-cyclic citrullinated peptide; AT II: Alveolar type II cell; DM: Dermatomyositis; ECM: Extracellular matrix components; EMT: Epithelial to mesenchymal transition; FMT: Fibroblast to mesenchymal transition; IFN-β: Interferon-β; IL: Interleukin; ILD: Interstitial lung disease; JAK/STAT: Janus kinase and signal transducer and activator of transcription; JAKi: JAK inhibitors; MDA5+ DM-ILD: Anti-MDA5 antibody-positive dermatomyositis-associated ILD; mDCs: Myeloid dendritic cells; NE: Neutrophil; NETs: Neutrophil extracellular traps; pDCs: Plasmacytoid dendritic cells; RA-ILD: Rheumatoid arthritis-associated interstitial lug disease; RF: Rheumatoid factor; RF-IgG: Rheumatoid factor-immunoglobulin; ROS: Reactive oxygen species; SSc-ILD: Systemic sclerosis-associated interstitial lung disease; TGF-β1: Transforming growth factor β1.Mechanism of Janus kinase inhibitors (JAKi) application in CTD-ILD: The JAK and signal transducer and activator of transcription (STAT) signaling pathways regulate numerous cellular processes, many of which are implicated in inflammation and autoimmune diseases. Currently, five JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib) are approved for clinical use in RA. Evidence indicates that the JAK/STAT signaling pathway is involved in the pathogenesis of interstitial pneumonia. This pathway is activated by profibrotic and pro-inflammatory cytokines, including interleukin (IL)-6, IL-11, and IL-13, which are upregulated in various ILDs. Additionally, certain growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor (FGF), are overexpressed in ILD and can activate the JAK/STAT pathway through typical or atypical pathways. These observations suggest a pivotal role of JAK/STAT signaling in ILD. Nevertheless, further research is needed to fully elucidate the involvement of the JAK/STAT pathway in these diseases [Figure 1].[5–7] Glucocorticoids (GCs) combined with immunosuppressive therapy can be used to treat certain CTD-ILD cases. However, traditional treatments are often ineffective for refractory, rapidly progressing-ILD (RPILD), and relapsed ILD. JAKi offer a novel therapeutic option for CTD-ILD. Among these, tofacitinib (a JAK1/JAK3 inhibitor) and baricitinib (a JAK1/JAK2 inhibitor) are currently the most extensively used drugs for the management of rheumatic diseases. Efficacy of JAKi in RA-ILD: RA is a chronic systemic inflammatory disorder characterized by persistent symmetrical erosive synovitis. It may also present with extra-articular manifestations, one of the most common of which is ILD, a significant contributor to the high mortality of patients with RA.[8] The current treatment options differ. Tofacitinib, the first JAKi approved for the treatment of RA, has an uncertain effect on RA-ILD. Nevertheless, phase II and III clinical trials for RA have demonstrated its efficacy and safety. It has a short half-life and a rapid onset of action. It has been shown to mitigate the progression of zymosan-induced ILD in SKG mice. Compared with the controls, tofacitinib significantly inhibited ILD progression by expanding myeloid-derived suppressor cells and suppressing the proliferation and differentiation of T helper 17 (Th17) cells. These findings suggest possible therapeutic benefits of tofacitinib in RA-ILD.[9] In a cohort study involving 28,559 patients with RA, treatment with tofacitinib was associated with a 4% reduction in the incidence of ILD compared with all classes of biologic disease-modifying anti-rheumatic drugs (bDMARDs). Additionally, tofacitinib is associated with a reduced risk of ILD in patients with RA.[10] A retrospective analysis of 43 patients with RA-ILD treated with JAKi suggested that JAKi may be a safe short-term treatment option that stabilizes high-resolution computed tomography (HRCT) findings.[11] Another study assessed pulmonary function before and after tofacitinib treatment in 18 patients with RA-ILD. After one year, the percentage of forced vital capacity increased by 3.0% from baseline, whereas the percentage of forced expiratory volume in one second remained stable. These results suggest that pulmonary function in patients with RA-ILD treated with tofacitinib could remain relatively stable over a one-year period, supporting the potential efficacy of JAKi for RA-ILD.[12] However, a study involving 36 patients with RA treated with JAKi demonstrated a 5.6% deterioration rate in ILD imaging and an 18.2% deterioration rate in those with pre-existing ILD. Notably, no new cases of ILD were reported, suggesting that JAKi may be a viable treatment option for patients with RA.[13] Efficacy of JAKi in dermatomyositis-associated interstitial lung disease (DM-ILD): ILD is the most common pulmonary manifestation of IIM and can occur at any stage of the disease with high morbidity and mortality rates.[14] Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are associated with dermatomyositis (DM) and are considered risk factors for acute or subacute interstitial pneumonia. RPILD is the strongest independent predictor of mortality in patients with IIM-ILD. The current standard treatment for RPILD associated with anti-MDA5-positive DM includes high-dose GCs in combination with calcineurin inhibitors with or without cyclophosphamide. When combined immunosuppressive therapies are ineffective against IIM-ILD, JAKi are an alternative treatment option.[15] In 2018, Kurasawa et al[16] demonstrated that tofacitinib was effective in treating refractory RPILD associated with anti-MDA5 antibody-positive DM. In 2019, Chen et al[17] conducted a single-center prospective clinical study to assess the efficacy of tofacitinib in patients with early anti-MDA5 antibody-positive amyopathic dermatomyositis-ILD (ADM-ILD). Their results indicated that, following ILD onset, the 6-month survival rate in the prospective group (18/18, 100%) was significantly higher than that in the control group (25/32, 78%), suggesting that early intervention with JAKi is critical for the treatment of ADM-ILD before severe pulmonary function deterioration occurs. Furthermore, related case reports have supported the therapeutic efficacy of tofacitinib in IIM-ILD, with dose escalation demonstrating its effectiveness. Considering these findings, a larger prospective study is required to confirm these results. Efficacy of JAKi in systemic sclerosis-associated interstitial lung disease (SSc-ILD): SSc is a rheumatic disease characterized by vasculopathy, inflammation, and extensive fibrosis affecting multiple organs. It is often complicated by ILD, which is a significant cause of morbidity and mortality. Current treatments for SSc-ILD include cyclophosphamide, mycophenolate, anti-IL-6 agents (tocilizumab), anti-B-cell therapies (rituximab), and antifibrotic drugs (nintedanib). JAKi were demonstrated to impede the fibrosis pathway in a mouse model of SSc by interfering with the TGF-β1-mediated JAK/STAT signaling pathway. Currently, JAKi are used in conjunction with GCs and other immunosuppressants to mitigate inflammation and manage severe rheumatic conditions.[18] In a study involving nine patients treated with tofacitinib for ≥6 months, significant improvements were observed in diffusing capacity of the lungs for carbon monoxide (DLCO), reduction of ground-glass opacities and pleural thickening on HRCT, and decreased pulmonary fibrosis scores compared with 35 patients receiving conventional therapy. This suggests that tofacitinib enhances sclerosis and addresses early radiological abnormalities in SSc-ILD.[19] Given the dual effects of JAKi on both inflammatory and fibrotic components of the disease, early treatment with JAKi before the onset of fibrosis may lead to improved outcomes. However, larger cohort studies and randomized controlled trials (RCTs) are required to validate these preliminary findings. Safety of JAKi in CTD-ILD: JAKi are new small-molecule agents of varying types, but their safety profiles generally overlap. Common adverse effects include nasopharyngitis, upper respiratory tract infections, headaches, and diarrhea, with a notable incidence of viral infections, such as herpes zoster. Studies indicate that JAKi elevate the risk of non-opportunistic respiratory tract infections (including upper and lower respiratory infections, influenza, and pneumonia) compared with placebo, whereas opportunistic respiratory infections, ILD, venous thromboembolism, and lung neoplasms are rare. Tofacitinib, which is metabolized and excreted by the liver and kidneys, may lead to adverse events in patients with severe liver or renal impairment, necessitating dose reduction.[20] An interim report from Japan’s post-marketing surveillance program highlighted infection as the most frequent adverse event, with serious infections, including herpes zoster and pneumonia/bacterial pneumonia.[21] Patients with RA treated with JAKi have a lower risk of developing ILD.[22] Another study comparing the safety of JAKi and rituximab for RA-ILD found that JAKi treatment did not increase the risk of hospitalization or mortality due to respiratory causes compared with rituximab. Therefore, JAKi may be a safe treatment option for patients with RA-ILD.[23] In a retrospective study, patients with RA-ILD treated with tofacitinib showed a higher incidence of severe infections requiring drug discontinuation, especially lower respiratory tract infections, than patients with RA without ILD who were also treated with tofacitinib.[12] In conclusion, whether JAKi increase the risk of infections in patients with CTD-ILD and their safety in other CTD-ILDs (such as SSc-ILD and DM-ILD) requires further validation through large-scale clinical studies. Summary and prospects: JAKi have certain disadvantages, including an increased risk of infections, particularly viral diseases such as herpes zoster, and a risk of developing new ILD, although the incidence remains low. Furthermore, JAKi are less selective than biological agents, as they can inhibit cytokine signaling pathways, and their targeting specificity is not absolute. Despite these limitations, JAKi have been used to treat autoimmune diseases, such as RA. Some studies have confirmed their effectiveness in managing CTD-ILD. JAKi are considered particularly effective when the conventional triple therapy (high-dose GCs, cyclophosphamide, and calcineurin inhibitors) is ineffective against CTD-ILD. These represent a viable treatment option for CTD-ILD and introduce a new therapeutic strategy for rheumatic diseases. Currently, research on the use of JAKi in the treatment of CTD-ILD is limited. This review focused on the safety and efficacy of JAKi in RA-ILD, DM-ILD, and SSc-ILD. Further studies are needed to explore the potential applications of JAKi in other CTD-ILDs, such as SLE-ILD and SS-ILD. Ongoing and recently concluded clinical trials are investigating the use of JAKi for the treatment of CTD-ILD (ChiCTR2100047938, ChiCTR2000031389, NCT04311567, NCT05177471, and NCT05246293). The results of these studies may provide valuable insights for the clinical diagnosis and treatment of CTD-ILDs in the future; however, large-scale RCTs are necessary to thoroughly evaluate their efficacy and safety. Conflicts of interest None.