Introduction
Janus kinase inhibitors (JAKis) are a class of drugs that differ from biologics in their mechanism of action and are rapidly gaining traction in the field of rheumatology. JAK, a protein kinase activated by various cytokines and hormones involved in inflammation, is found in different diseases, highlighting the potential of JAK inhibitors in treating immune-mediated inflammatory conditions. Clinical trials are underway to evaluate the efficacy and safety of JAKis in several rheumatic diseases, with comparable results to biologics. This article reviews the current status of JAKis in rheumatic diseases, their effectiveness, safety, and future applications for rare diseases. Rheumatology encompasses diseases characterized by painful musculoskeletal problems, often overlapping with other medical fields such as dermatology or gastroenterology. The pathophysiology involves autoimmune or autoinflammatory processes with unknown causes. While specific treatments for individual diseases are lacking, glucocorticoids remain the primary approach. However, the advent of biologics targeting specific inflammatory molecules has revolutionized rheumatic disease treatment and impacted other medical domains. JAKis have shown superior efficacy to biologics in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The oral administration of JAKis provides convenience for patients, distinguishing them from injectable biologics. Additionally, the mechanism of action of JAKis, selectively targeting JAKs as orally available small molecules, is conceptually complex but unique.
Interpretation of JAKis selectivity with efficacy and safety
Currently approved Janus kinase inhibitors (JAKis) have different categorizations based on their preferential inhibitory effects on JAK1/3, JAK1/2, pan-JAK, and JAK1. These categories determine their clinical characteristics. JAKis like tofacitinib (JAK1/3 inhibitor) have shown mild lymphopenia as a side effect, while baricitinib (JAK2 inhibitor) has demonstrated significant improvement in joint pain. JAK1 selective JAKis (upadacitinib and filgotinib) have similar efficacy and safety profiles to other JAKis. The mechanism of action of JAKis is complex, with selectivity against JAK1 appearing to be a common feature. However, the overall understanding of JAKis’ mechanism of action and their potential off-target effects is still limited. This review explores the use of JAKis for rheumatic diseases, examining their efficacy compared to biologics and addressing safety concerns. While they show promising initial therapeutic effects, the long-term safety and exposure data are still under investigation.
Status of JAK inhibitors in rheumatic diseases
Several Janus kinase inhibitors (JAKis) have been approved for the treatment of rheumatoid arthritis (RA), and they are also being studied in other diseases such as psoriatic arthritis (PsA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), and systemic lupus erythematosus (SLE). The development of JAKis is mainly focused on diseases where IL-6 or interferons play a role in the pathogenesis. Interestingly, JAKis have shown efficacy in diseases where IL-6 inhibition has failed and in conditions associated with interferon production. The complex mechanism of action of JAKis contributes to their potential therapeutic effects in various diseases, and additional clinical trials are ongoing to evaluate new JAKis.
Rheumatoid arthritis
Five Janus kinase inhibitors (JAKis) have been approved, demonstrating efficacy comparable to or higher than TNF inhibitors (TNFis). JAKis have shown effectiveness in patients with insufficient response to TNFis and other biologics. Some JAKis have even shown superiority to methotrexate (MTX) treatment alone. However, the cost and safety of JAKis are concerns. Infections, increased lipid levels, malignancy, and herpes zoster (HZ) are common adverse events associated with JAKis. HZ risk is increased by JAKis, but it is important to note that RA patients already have an increased risk of HZ. Circulating lipid concentration elevation and cardiovascular events are also considered, but long-term safety data show no clear difference compared to other DMARDs. Malignancy rates are a concern, especially with tofacitinib, but real-world data demonstrate similar frequencies to TNFis. The safety profile of JAKis requires long-term experience and risk assessment. HZ prophylaxis is important, and vaccination is recommended for RA patients, including those receiving JAKis.
Axial spondyloarthritis (axSpA)
Axial spondyloarthritis (axSpA) is an immune-mediated inflammatory disease that primarily affects the axial skeleton but can also involve peripheral joints, enthesitis, dactylitis, and other organs such as the eye, skin, and gut. The management of axSpA has advanced with the introduction of TNF inhibitors and more recently with biologics targeting the IL-23-IL-17 axis. JAK inhibitors, including tofacitinib, upadacitinib, filgotinib, deucravacitinib, and brepocitinib, have shown positive results in clinical trials for axSpA. These JAK inhibitors have demonstrated efficacy in patients with AS refractory to NSAIDs and biologics. The safety profile of JAK inhibitors in axSpA appears to be favorable, with no clear increase in serious adverse events. Additionally, JAK inhibitors have shown efficacy in psoriatic arthritis and other forms of peripheral SpA. The therapeutic options for SpA are rapidly evolving, with diverse treatment effects being observed beyond arthritis alone.
Systemic lupus erythematosus (SLE)
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex pathogenesis, and the inhibition of tyrosine kinases downstream of B-cell receptors or cytokine signaling has been explored as a potential therapy. Although JAK inhibitors have shown promise in animal models and phase I/II trials, they have not fully met the endpoints in phase III trials for SLE. However, there have been some positive results in phase II trials. Baricitinib, in a phase II trial, demonstrated resolution of SLE disease activity in patients with active arthritis or cutaneous lupus. However, the phase III trials for baricitinib did not achieve their primary endpoints. Tofacitinib, another JAK inhibitor, showed improvement in serological markers but did not improve disease activity in a phase I trial for SLE. Positive phase II trial results have been observed for filgotinib and deucravacitinib, warranting further investigation in phase III trials. Filgotinib showed promising results in lupus membranous nephropathy, and deucravacitinib demonstrated reductions in disease activity and improved clinical efficacy in active SLE patients.
Diseases with potential efficacy
JAK inhibitors have demonstrated potential in treating a range of autoimmune rheumatic diseases (AIRDs). Diseases associated with IL-6 inhibition have been studied due to the mechanism of JAKis inhibiting the IL-6 signaling pathway. Baricitinib and upadacitinib have shown efficacy in large vessel vasculitis, with promising results in phase II and phase III studies, respectively. Tofacitinib has shown tolerability in systemic sclerosis (SSc) patients, with improvement in skin lesions and prevention of worsening interstitial lung disease (ILD). In dermatomyositis (DM), JAK inhibitors have shown promising results in refractory cases, particularly in DM cases with autoantibodies against myeloma differentiation- associated gene-5 (MDA-5). JAK inhibitors have also been expected to be effective in refractory cases of adult-onset Still’s disease (AOSD). Autoinflammatory syndromes such as Behcet’s disease and Familial Mediterranean fever have shown varied treatment outcomes with JAK inhibitors. Interferonopathy, a genetic disorder involving the overproduction of type I interferon, has also shown some efficacy and tolerability with JAK inhibitor therapy. Despite these promising results, further validation in larger patient populations is still needed for widespread clinical application of JAK inhibitors in AIRDs.
Conclusions
JAK inhibitors (JAKis) are drugs that primarily target the JAK molecules, but their mechanism of action can lead to unexpected effects and adverse events such as MACE, VTE, and PE. Interestingly, the inhibition of multiple cytokines with a specific JAKi may be as effective or even more effective than targeting a single cytokine with biologics in certain diseases and measures. Understanding the distinct mechanism of action of JAKis, which differs from that of biologics, can improve our understanding of the underlying pathophysiology of each disease and potentially provide breakthroughs for incurable conditions. It is important to recognize the potential utility of JAKis in diseases that have limited treatment options. These overlooked conditions represent areas where patients can greatly benefit from the dedicated efforts of rheumatologists.
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