JAK inhibitors in rheumatology

Abstract Janus kinase inhibitors (JAKis) are a group of drugs with a different mechanism of action from biologics and are most rapidly uptaken in the rheumatology field. JAK is a protein kinase activated in the cytoplasm by multiple cytokines and hormones involved in inflammatory pathology. The expression of JAK has been observed in various diseases, indicating the utility of JAK inhibitors in a wide variety of immune-mediated inflammatory diseases. Clinical trials are underway for a number of different rheumatic diseases based on the therapeutic efficacy of JAKis, which is comparable to that of biologics. This article will review the current status of JAKis for rheumatic diseases in terms of efficacy and safety and extend to future clinical applications for rare diseases.


Introduction
Janus kinase (JAK) was first discovered as a nonreceptor cytoplasmic tyrosine kinase forming the JAK family consisting of JAK1, JAK2, JAK3, and TYK2 [1]. Deficiency or functional insufficiency of JAKs has been demonstrated to widely affect the acquired immune system. Particularly, the discovery of the deficiency or dysfunction of JAK3 leading to severe combined immunodeficiency both in humans and mouse led to the development of a JAK inhibitor (JAKi) [2][3][4].
Rheumatology is a field in medicine that covers diseases presenting with painful musculoskeletal problems encompassed as rheumatic diseases. Therefore, rheumatic diseases overlap with other fields such as dermatology or gastroenterology which are also covered in a different section of this special issue. The pathophysiology involves autoimmunity and/or autoinflammation of unknown causes. Due to unknown etiology, specific treatment for a specific disease does not exist and glucocorticoid (GC) is still the primary treatment tool for most of the diseases. Unfortunately, aiming cure for rheumatic diseases is still not a realistic treatment goal. However, targeting specific molecules involved in the inflammatory process with biologics has revolutionized the treatment of rheumatic diseases which also lead to revolutionary change in other medical fields. The most recent advance in rheumatology is the efficacy of JAKis for rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) which demonstrated superiority over biologics.
The convenience of an orally available JAKis as opposed to biologics that require parenteral injection is innovative from the patient's perspective. Another aspect of JAKis that makes it unique is that the mechanism of action is conceptually selective to JAKs as an orally available small molecule compound however, very complex.

Interpretation of JAKis selectivity with efficacy and safety
Currently approved JAKis are categorized depending on their preferential inhibitory effect on JAK1/3 (tofacitinib), JAK1/2 (baricitinib), pan-JAK (peficitinib), and JAK1 (upadacitinib, filgotinib) which is occasionally depicted as 1st generation JAKis with broad and 2nd generation with rather a narrow target. Owing to this preferential inhibitory effect of each JAKis there are some clinical characteristics. Tofacitinib is the only JAKi considered to act on JAK3 which is a well-known molecule essential in lymphocyte development, proliferation, and homeostasis. Therefore, long-term treatment has demonstrated mild lymphopenia from baseline without correlation with infectious adverse events [5]. Baricitinib is known for its effect on JAK2 which plays important role in a series of hormone and cytokine signaling pathways. Major factors involved in the inflammatory pathology of RA and strongly influenced by the inhibition of JAK2 are erythropoietin (EPO) and granulocyte-macrophage colonystimulating factor (GM-CSF). Although biologics targeting GM-CSF have not been approved, an antirheumatic effect was demonstrated similar to tumor necrosis factor inhibitors (TNFis) that legitimate the inhibition of JAK2. The other interesting finding through these clinical trials was that improvement of joint pain was statistically superior to TNFis [6][7][8]. The pain relief effect of JAKis has received attention but has not been clearly understood. Inhibition of EPO could not only lead to anemia but also has the potential to exacerbate the preexisting anemia related to chronic inflammation often observed in RA patients. However, anemia was not observed in approved doses presumably due to the improvement of chronic inflammation [9,10]. The JAK1 selective JAKis (upadacitinib and filgotinib) have demonstrated similar efficacy and safety with other JAKis. These compounds are of interest since they require approximately 10 times the different doses to demonstrate selectivity against JAK1 with similar effects on clinical benefit, dyslipidemia, and creatine kinase elevation with a numerical difference in infectious adverse events [11,12]. Why could this be? We do not have an answer for this and it indicates the complex mechanism of action of JAKis. But what have we learned from these clinical trials is that selectivity against JAK1 seems to be the common action among the 5 JAKis indicating that JAK1 is the key molecule involved in the inflammatory pathway through interleukin (IL)-6 and interferon (IFN)s. These are major inflammatory cytokines whose inhibition is related to infectious adverse events especially herpes zoster in the case of IFN inhibition. However, JAK1 is involved in number of other inflammatory signaling pathways such as IL-2, IL-4, IL-7, IL-15, IL-21, leukocyte inhibitor factor, oncostatin M and others which makes the mechanism of action of JAKis a complicated story with more questions than answers.
Depending on the categorization of targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD) does not guarantee specific molecule targeting. The basis for classification as a tsDMARD is its development process targeting a specific molecule, not because it has a molecular-specific mechanism of action [13]. The common mechanism of all 5 JAKis is inhibiting JAK activation by competitive binding to the adenosine triphosphate (ATP) pocket with ATP. Most of the kinases share this activation mechanism and possess an ATP binding pocket which is suggesting that each JAKi always can possess a different off-target effect. Hence interpreting the clinical effect of JAKis based on their selectivity against each JAKs may not lead to the correct understanding of drug characteristics. We should bear in mind that tsDMARDs are not specific but rather selective compared to bDMARDs.
The characteristics of tsDMARDs should be considered from the perspective of the effects of long-term exposure on patients. The common perception of JAKis in clinical practice is the early therapeutic effect similar to or even superior to that of biologics and that there is a lack of sufficient long-term exposure information in terms of adverse events. This review will focus on the development of JAKis for rheumatic diseases and safety issues from the recent clinical trials that have been publicized and also real-world evidence.

Status of JAK inhibitors in rheumatic diseases
The number of approved JAKis varies from country to country, but 5 JAKis have been approved to date for the treatment of RA (Table 1). Other diseases that has been approved or in phase 3 clinical trial include PsA, AS, axial spondyloarthritis (axSpA), polyarticular juvenile idiopathic arthritis (pJIA), and systemic JIA (sJIA). Due to the well-known involvement of JAK in the IL-6 intracellular signaling pathway, the main direction of development seems to be emphasized to diseases effective with IL-6 inhibition. Anti-IL-6 receptor antibody is approved for the treatment of sJIA, pJIA, adult-onset Still's disease, and Takayasu arteritis and more recently efficacy against polymyalgia rheumatica has been demonstrated which can also be seen in the development pathway of JAKis [14]. It is interesting to note that JAKis have shown efficacy also in diseases where IL-6 inhibition has failed to show efficacy such as AS and PsA where TNF, IL-17, and IL-23 inhibition has been efficacious. Another direction can be seen in diseases where interferons play a role in those pathogeneses. A typical example is systemic lupus erythematosus (SLE), where anti-type I interferon (IFN) receptor antibody is approved for treatment. IFN is a cytokine that can be produced in a variety of diseases with intractable conditions with limited treatment choices such as idiopathic inflammatory myositis, sarcoidosis, and IFNopathy. The complexity of the mechanism of action of JAKi can be seen just by looking at the development process of these JAKis, including the diseases mentioned in other sections. Therefore, unlike biologics, JAKis are expected to have therapeutic effects on a wide variety of diseases and additional JAKis clinical trials are underway with new agents in addition to existing approved JAKis (Table 1).

Rheumatoid arthritis
Five JAKis have already been approved, all with efficacy comparable to or significantly higher than that of TNFis (Table 1) [15][16][17][18][19]. In addition, JAKis has proven their efficacy in patients with insufficient response to TNFi (mostly adalimumab) and other biologics [20][21][22][23]. The interesting efficacy is that some JAKis have demonstrated superiority against MTX treatment by JAKi monotherapy, which has only been demonstrated by IL-6 inhibitor among the biologics [24][25][26]. These results have led many clinicians to expect early therapeutic effects in an early phase of the disease i.e., prior to MTX initiation. The major issue of JAKis for its position in the treatment scheme is its cost and safety. The medical cost of burden of JAKis is nothing comparable to MTX. MTX has been used for over 40 years with long-standing proof of efficacy and cost-effectiveness. However, it is known that patients can be hesitant with poor adherence to MTX in real-world practice [27,28]. A large clinical trial that investigated the anti-atherosclerotic effect of MTX (CIRT trial) revealed the gastrointestinal side effects in healthy individuals which was relevant to the discontinuation of the study [29]. In addition, MTXrelated lymphoproliferative disease is known to be an adverse event with a considerable racial difference [30]. Post-marketing surveillance study of JAKis revealed that many cases are often treated without concomitant MTX and some were treated without prior use of MTX. In addition, the majority of the use of JAKis in clinical practice has been observed in patients who have had an inadequate response to more than one biologic. These data indicate that many patients that can be classified as difficult-to-treat RA are treated with JAKi monotherapy [31]. On that note, it should be emphasized that JAKis exert maximum therapeutic effect with concomitant MTX. Treatment efficacy of JAKis can be observed from early to late phases of the RA treatment presumably due to its complex mechanism of action, inhibiting multiple cytokines, and unintended inhibitory effects, so-called off-target effects, are assumed. The recent treatment recommendation suggests considering the use of JAKis after inadequate response to treatment with classical conventional DMARDs methotrexate (MTX) or biologics the TNFis. Based on this information, the recent trend in the use of JAKis is to start with concomitant MTX and reduce/discontinue MTX following the achievement of sufficient therapeutic effect. However, not only the socioeconomic but also the patient economic burden should take into consideration with shared decision making to which drug should prioritize to be tapered.
Safety issues of JAKis have been raised in numerous clinical trials. Infections including herpes zoster (HZ), malignancy, increased circulating lipid concentration, and creatine phosphokinase elevation are common adverse events. Infections (largely upper respiratory tract, nasopharyngitis, and urinary tract) are a common adverse event also observed across other DMARDs and no unexpected increase has been observed with JAKis. Among the known adverse events, HZ is commonly increased by JAKis compared to any other DMARDs and is presumably related to the mechanism of action which is caused by inhibition of the type I IFN pathway. Although HZ has received increased attention due to JAKis, it should be recognized that HZ frequency has been increased in RA compared to healthy individuals before the use of JAKis [32]. Furthermore, it should be noted that HZ is on the rise in recent years among healthy individuals regardless of race [33]. In Japan, a rise of HZ cases has been observed in the thirties, forties, and sixties through eighties following the initiation of the varicella immunization program for children in 2014. Varicella cases in children have decreased by 78.1% in 2018 compared App P3 (Jan '22 a ) n a n a n a n a n a n a n a PsA App na na App Terminated P3 (Oct '26 a ) P2 (Jan '21 a ) n a n a AS P3 (Aug '20 a )  na  na  App  Terminated  na  na  na  na  Systemic JIA P3 (Nov '24 a ) P3 (Aug '23 a ) n a n a n a n a n a n a Axial SpA P2 (Dec '23 a ) na na P3 (Jul '25 a ) n a n a n a n a n a PMR P2 (May '22 a ) P2 (Apr '24 a ) n a n a n a n a n a n a n a SLE P1 (Mar '24 a ) Terminated na P2 (Jul '22 a ) na P2 (Oct '24 a ) P2 (Sep '23 a ) n a n a CLE P1/2 (Mar '24 a ) na na na P2 (Dec '19 a ) n a n a n a n a Lupus nephritis na na na na P2 (Feb '20 a ) n a n a n a n a SjS P1/2 (Sep '24 a ) P2 (May '24 a ) na na P2 (Oct '19 a ) n a n a n a n a SSc n a n a TA P4 (Dec '25 a ) na na P3 (Aug '27 a ) n a n a n a n a n a GCA na P2 (Apr '21 a ) na P3 (Nov '24 a ) n a n a n a n a n a Sarcoidosis P1 (Jun '21 a ) n a n a n a n a n a n a n a n a IFNopathy na P2/3 (Oct '23 a ) n a n a n a n a n a n a n a to 2000 through 2010 indicating the rise of HZ is related to notably decreased exposure to varicella in these generations. These generations are most likely to develop RA and receive DMARDs which are known to increase HZ. It should be noted that complications such as postherpetic neuralgia, Ramsay-Hunt Syndrome, and ocular issues will significantly affect the quality of life and should not be underestimated. Therefore, the importance of HZ prophylaxis in RA patients should be reaffirmed. Unlike live vaccines, the latest HZ subunit vaccine can be administered while on DMARDs, steroids, and other immunosuppressants. The efficacy of the HZ subunit vaccine under the use of DMARDs or JAKis is uncertain but it is effective in immune-mediated inflammatory diseases [34]. A major concern of this subunit vaccine is that it contains an adjuvant system; AS01B. Adjuvants are potent activators of the innate immune system and can induce experimental arthritis in animals which makes one concern of RA flare in humans. The most recent report on this topic analyzed the claims database and revealed that the disease flare rate did not change following HZ subunit vaccination [35]. Therefore, it would be ideal to vaccinate RA patients in general, especially those receiving or planning to receive JAKis.
Treatment-associated increased circulating lipid concentration is an adverse event that has been first raised by tocilizumab, the IL-6 inhibitor. JAK is involved in the IL-6 signaling pathway and therefore this identical adverse event is considered caused by IL-6 inhibition. In consideration of RA is associated with a greater burden of atherosclerotic events and cardiovascular disease, an increase in vascular events, including venous thromboembolism (VTE) and major cardiovascular event (MACE) would be a major issue. Two randomized clinical trials assessed this issue in direct comparison with TNFis with RA patients with more than one cardiovascular risk factor. The ENTRACTE study, directly compared cardiovascular safety by assessing the time to the first occurrence of MACE between eternacept and tocilizumab and demonstrated non-inferiority of tocilizumab [36]. On the other hand, the ORAL Surveillance study directly compared the event rate of MACE and malignancy between tofacitinib and TNFis (adalimumab or eternacept) where non-inferiority of tofacitinib was not demonstrated with a numerical increase of MACE in tofacitinib treated patients [37]. This has raised the sense of urgency regarding the long-term safety of tofacitinib and other JAKis. However, meta-analysis, long-term follow-up of JAKis clinical trials, and real-world data have demonstrated no clear difference between MACE with preexisting biologics [12,[38][39][40][41][42]. On top of these results, it is theoretically difficult to explain how inhibition of JAKs would directly relate to hypercoagulation causing MACE. JAKs activated by thrombopoietin, where inhibition would lead to adverse events that are the opposite of MACE. In retrospect, the MACE/VTE issue was first raised by the baricitinib clinical trial with six cases of VTE in the 4 mg QD group alone and none in the placebo and 2 mg QD group [43]. Most of these patients had high BMI, some had a history or family history of VTE and in the long-term extension study where all patients received baricitinib 2 mg or 4 mg QD, there was no clear increase in VTE. Yet, it should be noted that JAKis may be avoided or used with care for those with cardiovascular risks based on the notion from the aforementioned clinical trials.
Malignancy rate is a common concern for DMARDs. The more effective the DMARDs are, the more concern there is about their inhibitory effect on anti-tumor immunity. If one can recall the time when TNFis were first approved, the sense of urgency on carcinogenesis was considerable. Over 2 decades of experience in real-world clinical practice is dispelling concerns about the carcinogenicity of biologics. Similar to MACE, non-inferiority of malignancy was also not demonstrated in the ORAL Surveillance. The importance of this result is that not only a numerical increase, but a statistically significant increase was observed when treatment with tofacitinib 5 mg and 10 mg twice a day (BID) were combined and compared with TNFis. The frequency of malignancy with TNFis in ENTRACTE and ORAL Surveillance both conducted at a similar period were similar which was numerically lower which one could consider that TNFis can reduce malignancy events compared to tofacitinib (Table  2). Importantly, real-world data has also demonstrated a similar frequency of malignancy with TNFis with some increase in those with larger exposure (Table 3). Due to the indispensable role of JAKs in the development and activation of the acquired immune system related to anti-tumor immunity, involvement in carcinogenesis is not difficult to imagine. On that note, when and at what stage the malignancies were diagnosed is a unknown caveat. Malignancy diagnosed early after administration of tofacitinib would indicate the pre-existence of malignancy but if this was already in the late stage with metastasis would indicate not carcinogenesis, but induction of metastasis. ORAL surveillance has raised numerous discussions on the interpretation of its results and RA treatment recommendation update by EULAR has been announced emphasizing the importance of risk assessment in the use of JAKis. It seems that the questions currently being raised about the safety of JAKis can only be answered by experience with long-term use, similar to the path taken by biologics.
Other JAKis are still on their way to data collection for safety and may be too early to note that MACE and malignancies are a class-effect rather than a drug-effect [12,41,44]. However, HZ is an obvious class effect, and initiation of JAKis should be done with caution followed by risk assessment and prophylaxis.

Axial spondyloarthritis (axSpA)
Axial spondyloarthritis (axSpA) is an immune-mediated inflammatory disease that predominantly affects the axial skeleton but also peripheral joints with enthesitis, and dactylitis. It can also affect the eye, skin, and gut such as uveitis, psoriasis, and inflammatory bowel disease. Therefore, axSpA is considered ankylosing spondylitis (AS) as the mainstay with a group of diseases that is a possible cause of spondyloarthritis. Diagnosis from the early phase of the disease is emerging with non-detectable changes by modalities termed non-radiographic SpA. Management of axSpA has progressed in the recent 2 decades with TNFis and more recently IL-23-IL-17 axis has become an apparent target with 3 biologics (secukinumab, ixekizumab, brodalumab) targeting IL-17 and 3 biologics (ustekinumab, guselkumab, risankizumab) targeting IL-23. The latest development with JAKis has been conducted with tofacitinib, upadacitinib, filgotinib, deucravacitinib and brepocitinib with different selectivity against JAKs (Table 1). In a phase II trial of tofacitinib for axial SpA including AS, among several different doses, 5 mg/day twice achieved the primary endpoint and the adverse events were similar among treatment groups [45]. The positive results obtained in this trial led to a phase III trial for AS refractory to NSAIDs, in which the tofacitinib group was superior to the placebo group in achieving the treatment effect (Assessment in AS response criteria: ASAS20) at 16 weeks that was maintained at 48 weeks [46]. Similarly, other JAK inhibitors showed positive results: for patients with NSAID-or bDMARD-refractory AS, upadacitinib 15 mg/day achieved the primary endpoint and demonstrated a superior improvement in ASAS40 at 14 weeks [47,48]. Filgotinib 200 mg/day in its phase III trial, achieved the primary endpoint with the improvement of ASDAS (AS disease activity score) at 12 weeks compared with the placebo. In a phase III trial of these JAK inhibitors, no clear increase in serious AEs was observed [49]. Unfortunately, filgotinib has been terminated due to risk-benefit concerns which was also a concern in RA ending unapproved in the United States.
Efficacy against psoriatic arthritis can also be interpreted as an effect against peripheral SpA  which will be discussed in a different section of this special issue. The SpA encompasses a wide range of diseases and is an area that its therapeutic option is rapidly developing, as diverse therapeutic effects have been verified without limiting it to arthritis.

Systemic lupus erythematosus (SLE)
Systemic lupus erythematosus (SLE) is a typical autoimmune disease with a diverse pathogenic background, and inhibition of tyrosine kinases downstream of B-cell receptors or cytokine signaling has been considered a promising therapy. Therefore, the therapeutic effect of JAK inhibitors has been strongly expected, however, despite positive results in animal models or phase I/II trials, there is no fully achievement of the endpoints in phase III trials [50].
The application of JAK inhibitors in SLE has been the subject of their success in RA and atopic dermatitis, with particular emphasis on the potential therapeutic effect in the treatment of skin lesions and arthritis in SLE. The phase II trial of baricitinib in SLE, which has the largest number of trial data to date, showed that the patients with active arthritis or with cutaneous lupus had a resolution of the SLE disease activity index (SLEDAI)-2K-defined activities at week 24 that were the primary endpoint of the trial [51]. The frequency of serious infections and SAEs was increased in the 4 mg group, but the frequency of total AEs did not differ among groups indicating the tolerability of the drug. However, the results of the two phase III trials (BRAVE I, BRAVE 2) were somewhat disappointing. In BRAVE I, the primary endpoint of SRI-4 improvement at 52 weeks was achieved with 4 mg of baricitinib, but in BRAVE2, the primary endpoint was not achieved with any of the doses. None of the key secondary endpoints were achieved in either trial [52].
The efficacy of tofacitinib in SLE was evaluated in a phase I trial compared with the placebo group [53]. According to the results, there was an improvement in serological markers at day 84, but no improvement in disease activity as assessed by SLEDAI-2K, British Isles Lupus Assessment Index (BILAG), or physician global assessment (PGA).
Positive phase II trial results have been obtained for filgotinib and deucravacitinib, which phase III trial is warranted. In the phase II trial of filgotinib with a small number of patients (n ¼ 5) compared with the spleen kinase inhibitor lanraplenib in lupus membraneous nephropathy [54], there was a median reduction of 50.7% in 24-h urine protein and the stable median Safety of Estrogens in Lupus Erythmatosus National Assessment (SELENA)-SLEDAI in the filgotinib group. Filgotinib treatment was well tolerated. Deucravacitinib, a selective Tyk2 inhibitor, in a phase II trial has shown reductions in disease activity compared to placebo in multiple measures at both 32 and 48 weeks [55]. In patients with active SLE, deucravacitinib showed statistically significant and sustained clinical efficacy in disease activity by SRI [4], as well as improvement across multiple composites and organ-specific measures up to 48 weeks, and was well tolerated.

Diseases with potential efficacy
Some other autoimmune rheumatic diseases (AIRDs) have shown promise for JAK inhibitors treatment.
Owing to the mechanism of JAKis inhibiting IL-6 signaling pathway, diseases that has been suggested with IL-6 inhibition has been studied. Efficacy in large vessel vasculitis is anticipated with baricitinib and upadacitinib in phase II and phase III study respectively. Refractory giant cell arteritis patients were treated with baricitinib in an open-label phase II study. Only 1 patient out of 14 patients relapsed with other 13 patients achieving glucocorticoid free remaining in disease remission during the 52-week study [56]. Phase III clinical trials with upadacitinib for treating giant cell arteritis and Takayasu arteritis are underway. Tofacitinib demonstrated tolerability in systemic sclerosis (SSc) patients in a phase I/II trial with no increase in severe AEs [57]. A systematic literature review of observational studies reported that treatment with a JAK inhibitor resulted in significant improvement of skin lesions in 52/59 (88%) of SSc patients [58]. Additionally in this report, worsening of interstitial lung disease (ILD) was avoided in 28/29.
Owing to distinct type 1 IFN-signaling pathway activation in dermatomyositis (DM), JAK inhibitor has been studied with promising results in refractory cases. In a literature review, a total of 145 cases, mainly relapsed/refractory cases, were analyzed and revealed that 94-100% of the patients were successfully treated for skin, muscle, ILD, etc [59]. In particular, DM with autoantibodies against myeloma differentiation-associated gene-5 (MDA-5) often presents rapid-progressing ILD with poor prognosis that pathogenesis strongly associated with the cytokine abnormalities including type I IFN. The disease for which the effect of JAK inhibitors is expected to be a breakthrough [60].
Adult-onset Still's disease (AOSD) is another well-known disease in which multiple cytokines productions are the root of pathogenesis, and JAK inhibitors have been expected to be effective in refractory cases. Although there are only several case reports of a small number of patients, a systematic literature review reported that 84.6% of the patients were successfully treated, and 91.7% were able to reduce glucocorticoid dose [61].
Treatment outcomes in autoinflammatory syndromes have also been reported, including 13 patients with Behcet's disease treated with tofacitinib as an additional therapy [62] revealing that 6/13 (61.5%) patients achieved a partial response and 38.5% resulted with no response. Two patients out of 13 (15.4%) developed herpes zoster, but no other apparent treatment-related AEs were noted. A Literature review of the JAK inhibitor treatment of the Familial Mediterranean fever, another well-known autoinflammatory syndrome, reported a total of 6 cases in multiple reports [61]. All patients received tofacitinib alone or in combination with glucocorticoids or immunosuppressive agents. Fifty percent of the patients achieved complete remission, and the remaining 50% had 'partial remission' with residual inflammatory response but no worsening of symptoms without AEs.
Interferonopathy is a genetic disorder centered on the persistent overproduction of type I interferon.
Although there have been several reports showing the efficacy and tolerability of JAK inhibitor therapy, they are mainly case reports with only few cases [63,64].
As mentioned above, there are several AIRD in which multiple cytokine abnormalities, including type I interferon, are at the root of the pathogenesis, and although clinical application of JAK inhibitors is expected, validation in a large number of patients is still awaited.

Conclusions
JAKis are a category of drugs that predominantly inhibit the JAK molecule(s). However, due to its mechanism of action, it is always possible that these drugs could exert an unexpected effect, which includes adverse events such as MACE, VTE, and PE. It is also intriguing that multiple cytokine inhibition with a subspecific JAKi is equally or even better in specific diseases and specific measures compared to highly specific single cytokine inhibition by biologics. Therefore, clarifying the mechanism of action of JAKi, which is clearly different from that of biologics, will lead to a better understanding of the pathophysiology of each disease, and will help to break through the current situation in which these drugs cannot cure the diseases. Not to be forgotten is the suggested utility of JAKi in diseases for which treatment options are extremely scarce. These diseases, including those that are overlooked, are areas in which patients can benefit greatly from the energetic efforts of rheumatologists.

Author contributions
KY and KO have substantially contributed to the conception and design of the work revising the manuscript critically for updated information. Both authors have approved the version submitted.

Funding
None.