Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders

INTRODUCTION — The Janus kinases (JAKs) are protein tyrosine kinases (TYKs) that bind to transmembrane type 1 and type 2 cytokine receptors and mediate cellular responses to numerous cytokines and growth factors; these mediators are important in immune defense and in immune-mediated disease. Several pharmacologic JAK inhibitors (JAKi or Jakinibs) are commercially available for clinical use as oral and topical agents for immune-mediated and inflammatory diseases, although the availability of various JAK inhibitors varies among countries and regions.

JAK inhibitors are highly targeted molecules with relatively simple chemical structures in comparison to therapeutic agents made by recombinant deoxyribonucleic acid (DNA) techniques (and thus termed "biologics"), such as monoclonal antibodies and soluble truncated membrane receptors. Unlike biologics, the JAK inhibitors can be orally administered, although some are available for topical use.

Major established and investigational uses of JAK inhibitors include the treatment of several forms of inflammatory arthritis in adults and children (eg, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, spondyloarthritis, systemic lupus erythematosus) and other inflammatory disorders (eg, inflammatory bowel disease, atopic dermatitis, psoriasis, alopecia areata, vitiligo). They are also used in the management of hematologic disorders (eg, myelofibrosis, polycythemia vera, graft-versus-host disease) and in other conditions.

The biology and general considerations regarding the use of these agents for rheumatologic and other inflammatory disorders are presented here. The use of these agents for the treatment of specific inflammatory and autoimmune conditions, including the following and other conditions, is described in detail separately:

●(See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'JAK inhibitor therapy' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'JAK inhibitors'.)

●(See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Tofacitinib'.)

●(See "Treatment of psoriasis in adults", section on 'Emerging therapies'.)

●(See "Management of moderate to severe ulcerative colitis in adults", section on 'Janus kinase (JAK) inhibitors' and "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Small molecules' and "Management of the hospitalized child or adolescent with acute severe ulcerative colitis".)

●(See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Janus kinase inhibitors'.)

●(See "Psoriatic juvenile idiopathic arthritis: Management and prognosis", section on 'Spondylitis'.)

●(See "Treatment of atopic dermatitis (eczema)", section on 'JAK inhibitors'.)

JANUS KINASE BIOLOGY AND FUNCTION

Role of Janus kinases in receptor-mediated signaling — Janus kinases (JAKs) are members of a family of protein tyrosine kinases (TYKs) that facilitate cell signaling. Many of the major receptors that trigger the activation of immune cells are activated via protein phosphorylation, which is mediated by protein TYKs [1,2]. The JAKs are intracytoplasmic protein TYKs that bind to the cytoplasmic region of transmembrane cytokine receptors and promote signal transduction.

In particular, JAKs mediate signaling through type 1 and type 2 cytokine receptors [3]. Once the cytokine receptor interacts with a ligand, such as a cytokine or growth factor, JAKs associated with the receptor are activated, leading to tyrosine phosphorylation of the receptor, which then leads to activation of signal transducer and activators of transcription (STATs) (figure 1) [4]. The STATs translocate to the nucleus and modulate transcription of effector genes. Cellular responses to JAK/STAT signaling may thus include proliferation, differentiation, migration, apoptosis, and cell survival.

Janus kinase isoforms — There are four isoforms of JAKs: JAK1, JAK2, JAK3, and TYK2, which mediate signaling in pairs specifically associated with particular cytokine and growth-factor receptors:

●JAK1 – JAK1 is important for signaling of receptors activated by interleukin (IL) 6, IL-10, IL-11, IL-19, IL-20, IL-22, and interferon (IFN) alpha, IFN-beta, and IFN-gamma. JAK1 can be paired with any of the three other members of the JAK family, depending upon the associated receptor.

●JAK2 – JAK2 is important for signaling for hormone-like cytokines erythropoietin, thrombopoietin, growth hormone, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5. JAK2 can pair with JAK1, TYK2, or another JAK2 molecule, depending upon the associated receptor.

●JAK3 – JAK3 is expressed in hematopoietic cells and is activated when the relevant cytokine receptor for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 binds to its respective ligand. These cytokines are important for lymphocyte activation, function, and proliferation. JAK3 only signals in combination with JAK1.

●TYK2 – TYK2 pairs with either JAK1 or JAK2 or another TYK2 molecule to facilitate signaling for IL-12, IL-23, and type 1 IFNs.

The JAKs are not involved with signaling pathways for IL-1 or tumor necrosis factor (TNF).

MECHANISM OF ACTION OF JANUS KINASE INHIBITORS

Broad cytokine and growth factor inhibitory effects — Janus kinase (JAK) inhibitors are small, orally active drugs that are categorized as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). They suppress multiple cytokine and growth factor receptor signaling pathways, in contrast to biologic DMARDs (bDMARDs), which are designed to target a specific cytokine, cytokine receptor, or another cell surface molecule. The clinical efficacy and safety profiles of the JAK inhibitors when used for the treatment of rheumatoid arthritis are generally comparable with the bDMARDs, such as the tumor necrosis factor (TNF) inhibitors and interleukin (IL) 6 inhibitors.

The JAK inhibitors reversibly and irreversibly bind to JAK proteins inside cells, which prevents the JAKs from transphosphorylating the associated cytokine and growth factor receptor. As a result, the cytokine or growth factor receptor fails to activate the dedicated pair of signal transducer and activators of transcription (STATs) family members (STAT1-STAT6) [5]. The JAK inhibitors are thus also sometimes referred to as JAK/STAT inhibitors.

Their broad inhibitory properties have led to the use of JAK inhibitors in inflammatory arthritis of various types in both adults and children and in autoinflammatory diseases. JAK/STAT inhibition with these agents is also employed in disorders mediated by interferon (IFN) production (interferonopathies), including some disorders with recurrent infection and autoimmunity that result from gain-of-function variants in the STAT1 gene. T cell-mediated diseases, such as alopecia areata, vitiligo, and atopic dermatitis, have been explored or established as other potential indications for these agents. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)" and "Chronic mucocutaneous candidiasis", section on 'Signal transducer and activator of transcription (STAT1) dysfunction' and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'Autosomal dominant GOF STAT1 deficiency'.)

Effects mediated by inhibition of IL-6 signaling — JAK1 inhibition interferes with signaling through the interleukin (IL) 6 receptor, which probably accounts in part for its clinical efficacy in many clinical settings, as well as some of its side effects, such as neutropenia and hyperlipidemia, which are also associated with the use of IL-6 receptor monoclonal antibodies (eg, tocilizumab, sarilumab). (See 'Adverse effects' below.)

Selectivity of Janus kinase inhibitors for specific Janus kinases — JAK inhibitors available for clinical use differ in their selectivity for specific JAK isoforms. However, it is not clear how this apparent JAK selectivity in the laboratory and in experimental animal models extrapolates to meaningful differences among these agents in their clinical efficacy across the spectrum of chronic inflammatory diseases. At concentrations equivalent to clinically effective doses, the JAK inhibitors overall appear to be less selective for particular JAK isoforms than when evaluated in cellular and biochemical assays [5,6]. Tofacitinib, baricitinib, and peficitinib are considered pan-JAK inhibitors by regulatory authorities, while upadacitinib is considered a highly selective JAK1 inhibitor but also inhibits JAK2 and tyrosine kinase (TYK) 2. Filgotinib is a highly selective JAK1 inhibitor in biochemical and other cellular and whole blood laboratory testing [7].

Distinguishing characteristics of individual agents

Tofacitinib — Tofacitinib reversibly inhibits JAK1 and JAK3 in vitro and to a lesser extent inhibits JAK2 and TYK2 [6,8]. Tofacitinib, by inhibition of JAK3, inhibits cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; and by JAK1 inhibition, inhibits IL-6, type 1 IFNs, and IFN-gamma.

Tofacitinib is available as immediate-release and extended-release tablets, as well as an oral solution. Extended-release tablets are widely used because of their convenience, but there has been very little formal comparison of the immediate- and extended-release formulations in clinical trials [9]. Tofacitinib is approved for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and polyarticular juvenile idiopathic arthritis. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)

Baricitinib — Baricitinib reversibly inhibits JAK1 and JAK2, moderately inhibits TYK2, and only modestly inhibits JAK3 in in vitro and in animal models of arthritis in rats and mice [6,10]. It is administered orally in tablet form. With JAK1 inhibition, IL-6 and type 1 IFNs and IFN-gamma are inhibited. With JAK2 inhibition, growth factors erythropoietin, thrombopoietin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are inhibited. It is approved for use after conventional synthetic DMARD (csDMARD) failure in patients with rheumatoid arthritis outside of the United States and for use after TNF inhibitor failure in patients with rheumatoid arthritis in the United States. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Baricitinib'.)

In addition to immunomodulatory effects, the use of baricitinib in patients with coronavirus disease 2019 (COVID-19) is thought to have potential antiviral effects through interference of viral entry and has been approved for patients 18 years and older who are hospitalized and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). (See "COVID-19: Management in hospitalized adults", section on 'Baricitinib and JAK inhibitors'.)

JAK1/2 inhibitors such as baricitinib have been under investigation for treatment of autoinflammatory diseases mediated by IFN production and signaling (interferonopathies) because type 1 IFNs signal in part via JAK1. It is commercially available in Europe for atopic dermatitis, where IL-4, IL-5, and IL-13, cytokines preferentially inhibited by baricitinib, may play a role. Baricitinib has also been used to treat the autoimmune manifestations in chronic mucocutaneous candidiasis that is attributable to gain-of-function defects in signal transducer and activator of transcription 1 (STAT1). (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)", section on 'Treatment' and "Chronic mucocutaneous candidiasis", section on 'Treatment'.)

Upadacitinib — Upadacitinib demonstrates in vitro selectivity for JAK1 [11]. Thus, it effectively inhibits IL-6- and IFN-gamma-related signaling, with less effect on natural killer cell depletion compared with tofacitinib.

Upadacitinib is administered as a 15 mg oral tablet in a 24-hour extended-release formulation.

Similar to baricitinib, upadacitinib, a reportedly selective JAK1 inhibitor, is under investigation for treatment of autoinflammatory diseases mediated by IFN production and signaling (interferonopathies) based upon the rationale that type 1 IFNs signal in part via JAK1. It is approved for treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, atopic dermatitis, Crohn disease, and ulcerative colitis. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)", section on 'Therapeutic trial'.)

Other agents

●Filgotinib – Filgotinib is considered a highly selective JAK1 inhibitor. Filgotinib is approved for use in Europe and in Japan for the treatment of rheumatoid arthritis [12,13]. Its manufacturer did not seek approval in the United States for rheumatic diseases [14]. Filgotinib may be associated with a lower risk of herpes zoster when compared with other JAK inhibitors, although this feature has not been well established.

●Peficitinib – Peficitinib is an orally bioavailable, once-daily JAK inhibitor for the treatment of patients with rheumatoid arthritis with an inadequate response to DMARDs, including methotrexate. Peficitinib is a pan-JAK inhibitor that binds irreversibly to JAK1, JAK2, JAK3, and TYK2 [15,16]. Peficitinib, which binds irreversibly to the JAKs, appears to function as a pan-JAK inhibitor. Peficitinib is approved for use in Japan and Korea.

●Ruxolitinib – Ruxolitinib is a JAK1/2 inhibitor orally administered as a tablet. A topical form is available for the treatment of atopic dermatitis and vitiligo. It has been used primarily for the treatment of acute and chronic graft-versus-host disease, myelofibrosis, and polycythemia vera. In addition, oral JAK1 inhibitors such as ruxolitinib are under investigation for treatment of several different autoinflammatory diseases mediated by IFN production and signaling (interferonopathies) owing to their ability to interfere with type 1 IFN signaling pathways. Additionally, ruxolitinib has been used to treat chronic mucocutaneous candidiasis with associated autoimmunity due to gain-of-function defects in STAT1.

●Abrocitinib – Abrocitinib is a JAK1 inhibitor available for the treatment of atopic dermatitis in adults and adolescents. It is typically administered orally once daily. (See "Treatment of atopic dermatitis (eczema)", section on 'JAK inhibitors'.)

●Investigational agents – A number of JAK inhibitors in oral and topical formulations are under investigation but not available for routine clinical use. These include deucravacitinib, a selective TYK2 inhibitor that is under investigation for the treatment of psoriatic arthritis and systemic lupus erythematosus, and is approved for the treatment of psoriasis [17-19]; a TYK2/JAK1 inhibitor for psoriasis [18]; and a JAK1/TYK2 inhibitor for refractory dermatomyositis [20].

Various JAK inhibitors are also in development for the treatment of juvenile idiopathic arthritis (upadacitinib), systemic lupus erythematosus (upadacitinib), and alopecia areata (tofacitinib, ritlecitinib).

PRETREATMENT SCREENING AND PRECAUTIONS

Clinical and laboratory screening and evaluation — Similar testing protocols are appropriate for all of the available Janus kinase (JAK) inhibitors. We perform the following screening and evaluation before initiating treatment with a JAK inhibitor:

●Medical history – Patients should be screened for a history of conditions that may increase the risk for certain complications of JAK inhibitor therapy, including a history of diverticulitis, gastrointestinal tract perforation, thrombosis, current or past smoking and other cardiovascular risk factors, and malignancy (other than a successfully treated nonmelanoma skin cancer). A history of tumor necrosis factor (TNF) inhibitor use and the response to therapy should also be ascertained. (See 'Restrictions' below.)

●Laboratory testing – Patients are at risk for cytopenias, dyslipidemias, and liver injury, as well as reactivation of latent tuberculosis [21] and reactivation or exacerbation of hepatitis B [22,23] and possibly hepatitis C [24] (see 'Adverse effects' below). Thus, baseline laboratory studies should include:

•Complete blood count with differential white count and platelet count.

•Liver function tests, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), bilirubin, and alkaline phosphatase.

•Lipid panel, including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides.

•Screening for latent tuberculosis, hepatitis B (including testing for hepatitis B virus [HBV] surface antigen and HBV core antibody), and hepatitis C virus (HCV). (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)" and "Tuberculosis infection (latent tuberculosis) in children" and "Hepatitis B virus: Screening and diagnosis in adults" and "Screening and diagnosis of chronic hepatitis C virus infection".)

●Pregnancy testing and reproductive health counseling – Females of reproductive age should be screened for pregnancy before starting a JAK inhibitor and counseled appropriately with respect to reproductive risk. (See 'Restrictions' below and 'Reproductive health concerns' below and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tofacitinib' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Limited information'.)

Restrictions

●Concurrent treatment with other DMARDs – JAK inhibitors should not be given in combination with biologic disease-modifying antirheumatic drugs (bDMARDs) or potent immunosuppressants such as azathioprine and cyclosporine. Clinical trials testing tofacitinib in transplant patients in combination with mycophenolate/cyclosporine demonstrated increased adverse events, including post-transplant lymphoproliferative disease [25].

●Requirement for prior use of a TNF inhibitor – Overall, in the clinical trial programs for the JAK inhibitors approved for rheumatoid arthritis, safety signals other than increased herpes zoster risk were similar to approved biologics. However, in a phase 3B/4 US Food and Drug Administration (FDA)-mandated clinical trial (ORAL Surveillance) post tofacitinib approval, an imbalance with tofacitinib compared with etanercept/adalimumab was reported for the rate of malignancy and major adverse cardiovascular events (MACE) in a population of patients with rheumatoid arthritis who were over 50 years of age and enriched for cardiovascular risk factors. Additionally, an increased risk of venous thromboembolism in a dose-dependent fashion was reported [26]. Based upon this study, the FDA has advised limiting use of the JAK inhibitors tofacitinib, baricitinib, and upadacitinib to patients with immune-mediated inflammatory diseases, including rheumatoid arthritis, who have not adequately responded to or who are intolerant of a TNF inhibitor. The European Medicines Agency (EMA) originally recommended use of tofacitinib only in patients with increased malignancy, venous thromboembolism, or cardiovascular risk if no suitable alternative treatment option is available and did not extend this recommendation to the other JAK inhibitors. However, in October 2022, the EMA Pharmacovigilance Risk Assessment Committee (PRAC) expanded their recommendations to include all the JAK inhibitors based upon their final review of the ORAL Surveillance trial and preliminary review of a study evaluating patients with rheumatoid arthritis with similar high risk for cardiovascular events receiving treatment with baricitinib or TNF inhibitors [27].

●Cardiovascular risk factors – Given the potential increased risk of serious cardiac events (eg, myocardial infarction, stroke, venous thromboembolus, pulmonary embolus), the FDA has advised assessing whether the benefits outweigh the risks for the individual patient prior to initiating or continuing therapy with tofacitinib, baricitinib, and upadacitinib for arthritis and other inflammatory conditions, particularly in patients who are current or past smokers and those with other cardiovascular risk factors.

●Malignancy – Given the potential increased risk of malignancy (eg, lymphoma, lung cancer), the FDA and EMA have advised assessing whether the benefits outweigh the risks for the individual patient prior to initiating or continuing therapy with tofacitinib, baricitinib, upadacitinib, and filgotinib for arthritis and other inflammatory conditions, particularly in patients who develop a malignancy or who have a known malignancy other than a successfully treated nonmelanoma skin cancer [28]. The EMA PRAC specifically recommended that these medicines should be used in the following patients only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past, and those at increased risk of cancer [27].

●Patients ≥65 years (European recommendations) – The Pharmacovigilance Risk Assessment Committee (PRAC) of the EMA has recommended only using tofacitinib in patients over 65 years of age and in current or past smokers if no suitable treatment alternatives are available given the increased risk of serious infections, myocardial infarction, and malignancies with tofacitinib [29].

●Lymphopenia, neutropenia, and anemia – Initiation of JAK inhibitors should be avoided in patients with baseline absolute lymphocyte count (ALC) <500 cells/mm³ or absolute neutrophil count (ANC) <1000 cells/mm³ and in patients with baseline hemoglobin <8 g/dL (baricitinib, upadacitinib) or 9 g/dL (tofacitinib).

●Infection – Active infection should be excluded prior to initiation of JAK inhibitors, and treatment should be held for patients with active infection until resolved. For patients with clinically important active bacterial or viral infections, we withhold JAK inhibitors until the course of antibiotic or antiviral agent is complete and until patients appear to have clinical resolution of infection.

●Immunization – Live or live-attenuated vaccines should generally not be administered during treatment. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Timing of vaccination' and "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Live vaccines'.)

Recommendations regarding use of vaccines for COVID-19 infection are described separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

●Perioperative considerations – JAK inhibitor therapy may increase the risk of perioperative infection. The approach to perioperative medication management for patients using JAK inhibitors with rheumatic disease is described separately, and a similar approach is used for other conditions. (See "Preoperative evaluation and perioperative management of patients with rheumatic diseases", section on 'Medication management' and "Preoperative evaluation and perioperative management of patients with rheumatic diseases", section on 'Janus kinase inhibitors'.)

●Gastrointestinal disease – JAK inhibitors should be used with caution in patients at increased risk of gastrointestinal perforation, particularly patients with a history of diverticulitis. Alternative agents should be selected if available. If no alternative agents are available, patients should be educated regarding signs and symptoms of gastrointestinal perforation and counseled to seek care immediately if these develop. (See 'Gastrointestinal' below.)

●Thromboembolic disease – JAK inhibitors should be used with caution in patients with increased risk for or personal history of thrombosis. Alternative agents should be selected if available. If no alternative agents are available, patients should be educated regarding signs and symptoms of thrombosis and counseled to seek care immediately if these develop. (See 'Cardiovascular' below.)

●Pregnancy – Use should be avoided in pregnancy. Additional information regarding safety during pregnancy and breastfeeding is provided separately, including in the respective drug information topics for each agent. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tofacitinib' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Limited information'.)

Pretreatment vaccination — Patients preferably should be immunized appropriately prior to starting JAK inhibitor therapy because these agents increase the risk of certain infections, including herpes zoster [30] and streptococcal pneumonia [31]. Live and attenuated viral vaccines are avoided in patients under treatment with JAK inhibitors. The approach to immunization of patients with autoimmune and inflammatory rheumatic disease is described in detail separately. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

DOSING AND DRUG INTERACTIONS — Each of the Janus kinase (JAK) inhibitors is metabolized and transported in a unique fashion, and for each agent dosing may differ between different disorders and may be affected by renal and hepatic status and concomitant use of other medications.

●Dosing – The dosing for each agent is described in the topic reviews where the use of the medication for a given condition is discussed (see appropriate topic reviews). Dosing and adjustments for renal and hepatic dysfunction for these agents are described elsewhere. (See tofacitinib drug information; see baricitinib drug information; see upadacitinib drug information; see ruxolitinib drug information.)

●Drug interactions – The range of potential drug interactions differs between the individual agents, but some require dose modification or avoidance of particular drug combinations. Thus, patients receiving JAK inhibitors should have their medication regimen analyzed for drug interactions, particularly when initiating and adjusting therapy; this may be done by use of the Lexicomp drug interactions program included with UpToDate.

As examples, tofacitinib and upadacitinib metabolism is increased by rifampicin, a strong CYP3A4 inducer, whereas tofacitinib metabolism may be decreased by strong CYP3A4 inhibitors, such as ketoconazole, increasing levels of tofacitinib. Baricitinib may interact with organic anion transporter 3 inhibitors, such as probenecid, resulting in increased serum drug levels. Filgotinib is primarily metabolized by carboxylesterase 2, which is inhibited in vitro by drugs such as fenofibrate, carvedilol, diltiazem, and simvastatin, although the clinical relevance of this interaction is unknown [32].

ADVERSE EFFECTS

Overview of adverse effects — The most commonly reported adverse events associated with Janus kinase (JAK) inhibitors are generally not serious and have included upper respiratory infections, urinary tract infections, and nasopharyngitis, as well as nausea, headache, and occasional diarrhea. (See 'Infection' below and 'Gastrointestinal' below.)

However, an increased risk of serious infectious episodes, herpes zoster, tuberculosis, opportunistic infections, and gastrointestinal perforations has been described, although these and other major risks are generally similar (except for a greater risk of herpes zoster) to those for the biologic disease-modifying antirheumatic drugs (bDMARDs), such as interleukin (IL) 6 inhibitors and tumor necrosis factor (TNF) inhibitors, which are used in similar populations of patients with immune-mediated inflammatory diseases. (See 'Infection' below and 'Gastrointestinal' below and "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects", section on 'Adverse effects' and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

The ORAL Surveillance study reported a small increase in absolute risk of all-cause mortality, cardiovascular events, stroke, and malignancy with tofacitinib compared with TNF inhibitors in older patients with rheumatoid arthritis [26]. A post hoc analysis of the data reported greatest risk in patients with rheumatoid arthritis who were over age 65 and were previous or current smokers [33,34]. A possible increased risk of venous thromboembolism has also been observed with both baricitinib and tofacitinib. (See 'Cardiovascular' below and 'Malignancy' below.)

Most patients do not require any adjustment to therapy based on laboratory findings. Laboratory abnormalities include lymphopenia, neutropenia, anemia, dyslipidemia, and elevated liver enzymes; nonsignificant elevations of creatine phosphokinase and serum creatinine have also been noted [15,35-48]. (See 'Hematologic' below and 'Gastrointestinal' below.)

Infection — Overall, the risk of infection in patients treated with JAK inhibitors appears to be in line with what is seen for patients treated with bDMARDs, including TNF inhibitors, with the exception of the incidence of herpes zoster, which is increased with all the JAK inhibitors but not with the bDMARDs [49]. JAK inhibitors should not be given in combination with other biologic agents. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

●Herpes zoster – With tofacitinib, herpes zoster infections were reported at a rate of 3.4 per 100 patient-years, which is higher than what is seen with conventional synthetic DMARDs (csDMARDs) or bDMARDs [36,49,50]. Among patients with herpes zoster, 90.2 percent had herpes zoster in a single dermatome and 7.3 percent were considered to have serious herpes zoster infections. Use of glucocorticoids in conjunction with JAK inhibitors appears to further increase the incidence of herpes zoster.

Whenever possible, patients should be vaccinated for herpes zoster prior to initiation of a JAK inhibitor (see 'Pretreatment vaccination' above). For patients who develop herpes zoster while receiving a JAK inhibitor, it is the authors' practice to temporarily withhold the JAK inhibitor until the patient has shown clinical improvement and has completed a course of antiviral therapy. Patients with complicated herpes zoster or recurrent herpes zoster may be switched to an alternative therapy with a different mechanism of action or the patient may be treated with daily suppressive antiviral therapy indefinitely if the JAK inhibitor needs to be resumed.

●Tuberculosis – Tuberculosis has been reported in clinical trials of all of the JAK inhibitors. Incidence rates are similar to those seen with bDMARDs, 0.1 to 0.22 per 100 patient-years, and are primarily seen with their use in geographic areas endemic for tuberculosis [36,51]. Most cases of tuberculosis in clinical trials were primary infection, although there were cases of reactivation of latent tuberculosis [21].

Screening for latent tuberculosis should be performed prior to initiating JAK inhibitors (see 'Clinical and laboratory screening and evaluation' above). There are currently no established guidelines for duration of treatment of latent tuberculosis prior to initiation of JAK inhibitors. It is the author's practice to treat patients diagnosed with latent tuberculosis with antimicrobials as per World Health Organization (WHO) guidelines for at least two to four weeks prior to initiating JAK inhibitors. For patients with active tuberculosis, the JAK inhibitor should be held while treatment is initiated and until there is clear clinical improvement [36,49]. The decision of whether or when to resume JAK inhibitor therapy should be made on an individual basis, typically in consultation with an infectious disease specialist.

●Opportunistic infections – Opportunistic infections have been reported in patients treated with JAK inhibitors at rates of 0.1 to 0.3 per 100 patient-years, with rates similar to those seen in trials of bDMARDs. Opportunistic infections include multidermatomal herpes zoster, esophageal candidiasis, pneumocystis, cytomegalovirus (CMV), and cryptococcal infections [36,51,52]. JAK inhibitors should be held upon diagnosis of opportunistic infections, while treatment of the infection is initiated. Decisions regarding whether or when to resume JAK inhibitor therapy should be made on an individual basis in consultation with an infectious disease specialist, based upon the severity of infection, risk of morbidity and mortality due to infection, and risk of morbidity and mortality related to progression of the patient's underlying condition for which the JAK inhibitor was initiated.

Hematologic — The hematologic adverse events seen with JAK inhibitors are probably due in large part to inhibition of JAK1 and the resultant suppression of IL-6 signaling through its receptor [15,36-44,46,47,53]. Treatment should be temporarily interrupted in patients with an absolute neutrophil count (ANC) <1000 cells/mm³, absolute lymphocyte count (ALC) <500 cells/mm³, or hemoglobin <8 to 9 g/dL observed during routine patient monitoring, with subsequent dose reduction to maintain adequate levels if treatment is continued [32]. (See 'Infection' above.)

●Neutropenia – Modest neutropenia that is not clinically significant is seen with use of all JAK inhibitors, with rare grade 3/4 neutropenia (ANC <1000/ cells/mm³) and no association with increased infection risk.

●Lymphopenia – JAK3 inhibition is most likely responsible for lymphopenia, although this has been reported with all the JAK inhibitors. Grade 4 lymphopenia (ALC <500 cells/mm³) was rarely seen in the clinical trials of tofacitinib and was not associated with increased serious infectious risk. All the approved JAK inhibitors have warnings to not initiate treatment or discontinue treatment in patients with ALC <500 cells/mm3.

●Anemia – Significant anemia is unusual with JAK inhibitors.

Gastrointestinal — Patients treated with JAK inhibitors are at increased risk for abnormalities in liver function and gastrointestinal perforation.

●Elevated liver enzymes – Transaminase elevation has been observed with all JAK inhibitors, particularly when used in combination with methotrexate, with rates similar to adalimumab and methotrexate in clinical trials. Liver chemistry abnormalities typically resolve with dose reduction or discontinuation [15,36-44,46,47,53].

If transaminase elevations occur in patients who are also on methotrexate, it is the authors' practice to reduce or discontinue the methotrexate. Rarely it also may be necessary to reduce the dose of the JAK inhibitor.

●Gastrointestinal symptoms and gastrointestinal tract perforation – In clinical trials, nausea has been reported with all the JAK inhibitors, and diarrhea has been noted with tofacitinib in a small percentage of patients. Gastrointestinal perforations were described in a small number of patients in clinical trials of the JAK inhibitors. They were rare, occurring with an incidence rate of approximately 0.1 per 100 patient-years, which is similar to the frequency reported with IL-6 inhibitors [36]. Perforation events were primarily seen in patients concurrently treated with nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids.

JAK inhibitors should be avoided, if possible, in patients with a history of diverticulitis, given the increased risk of colon perforation in patients with diverticulitis [54]. In patients who develop perforation while on a JAK inhibitor, the authors avoid further use of JAK inhibitors.

Cardiovascular — Patients are at increased risk for dyslipidemia and may be at risk for thrombotic and other cardiovascular events.

●Dyslipidemia – Elevations in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) have been reported, typically in the range of 10 to 20 percent of patients [55,56]. The HDL/LDL ratio is generally unchanged. Elevations are usually noted within 12 weeks of starting treatment and are usually stable thereafter. Dyslipidemia should be managed according to available guidelines, using the same approaches as in patients not being treated with these agents. Studies have suggested this increase in cholesterol is associated with improvement in inflammation [55]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

●Cardiovascular and cerebrovascular – There is concern that JAK inhibitors may be associated with an increased risk of cardiovascular events, particularly among patients who already have risk factors. However, this has not been demonstrated consistently across studies.

A nationwide registry representing the population of France demonstrated an increased incidence of major adverse cardiovascular events (MACE, defined as cardiovascular death, myocardial infarction, stroke, and all-cause mortality), but the difference was not statistically significant (4.3 versus 3.6 per 1000 person-years, weighted hazard ratio [HR] 1.0, 95% CI 0.7-1.5) [57].

Similarly, the US Food and Drug Administration (FDA) reported an increase in nonfatal myocardial infarction (0.35 versus 0.16 events per 100 person-years, HR 2.20, 95% CI 1.02-4.75) and a trend towards an increase in MACE that did not reach statistical significance (0.98 versus 0.73 events per 100 person-years, HR 1.33, 95% CI 0.91-1.94).

Tofacitinib may be associated with an increased risk of cardiovascular events primarily among patients with a prior history of atherosclerotic disease. ORAL Surveillance was a large postmarketing open-label randomized trial with a median follow-up of four years. The study enrolled 4362 patients who were taking methotrexate, were at least 50 years old, and had at least one risk factor for heart disease [26]. A post-hoc analysis demonstrated an increased risk of MACE primarily among patients with a history of atherosclerotic disease. In patients without atherosclerotic disease, tofacitinib 5 mg twice daily was not associated with an increased risk of MACE when compared with TNF inhibitors [33].

The FDA and European Medicines Agency (EMA) have each issued guidance for use of these agents based upon the available data. (See 'Clinical and laboratory screening and evaluation' above and 'Restrictions' above.)

Venous thromboembolic events — JAK inhibitors may be associated with an increased risk of venous thrombotic events, especially pulmonary embolism. This risk may be highest for patients taking either tofacitinib or baricitinib.

A nationwide registry representing the population of Sweden observed an increased number of venous thrombolic events in patients treated with JAK inhibitors versus TNF inhibitors (11.3 versus 5.2 events per 1000 person-years) [58]. This increase was attributed to an increased risk of pulmonary embolism (adjusted HR 3.21, 95% CI 2.11-4.88). A nationwide registry representing the population of France also observed a higher number of venous thromboembolic events in patients treated with JAK inhibitors versus TNF inhibitors (6.0 versus 3.3 events per 1000 person-years), but the difference was not statistically significant (weighted HR 1.1, 95% CI 0.7-1.6) [57].

The risk of venous thrombolic events may be higher with specific JAK inhibitors. An increased risk of thrombosis was previously reported in the placebo-controlled trials of baricitinib [59]. The FDA reported a dose-dependent increased risk associated with tofacitinib compared with TNF inhibitors of venous thromboembolic events, including pulmonary embolism [26]. However, an increased risk has not been reported for upadacitinib or filgotinib [60-62].

Malignancy — In the clinical trial program for the approved JAK inhibitors, no increase in malignancies was reported compared with methotrexate and adalimumab [36,53,62]. However, in the ORAL Surveillance study in patients 50 years and older with elevated cardiovascular risk, the results suggested an increased risk of malignancy, particularly lung cancer and lymphoma, in the tofacitinib patients compared with the patients treated with a TNF inhibitor (1.13 versus 0.77 events per 100 person-years, HR 1.48, 95% CI 1.04-2.09) [26]. Lung cancer was seen particularly in current or past smokers.

The FDA and EMA have each issued guidance for use of these agents based upon the available data. (See 'Clinical and laboratory screening and evaluation' above and 'Restrictions' above.)

The underlying mechanism of the increased risk for venous thromboembolism, malignancy, or MACE is unknown. Prospective studies evaluating possible biomarkers associated with thrombosis are ongoing in patients treated with JAK inhibitors, as well as a large clinical trial with similar design to ORAL Surveillance evaluating baricitinib [63].

Reproductive health concerns

●Pregnancy and lactation – The JAK inhibitors are teratogens in animal models; studies in humans are lacking. Additional information regarding safety during pregnancy and breastfeeding is provided separately, including in the respective drug information topics for each agent. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tofacitinib' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Limited information'.)

●Male fertility – Preclinical studies suggested that filgotinib may impair male fertility; this appears to be an issue unique to filgotinib, and the mechanism remains unknown. In animal studies of filgotinib, adverse effects on male reproductive organs were observed, including impaired spermatogenesis and decreased fertility [64]. The potential effect of filgotinib on sperm production and male fertility in humans is unknown, as is the reversibility of these potential effects.

FDA concerns regarding male fertility, particularly with the 200 mg dose of filgotinib, influenced the FDA's decision not to approve filgotinib without additional studies. Initially, EMA package labeling for filgotinib includes a special warning regarding male fertility [32]. Studies on the impact of filgotinib on male spermatogenesis were conducted in patients with inflammatory bowel disease and rheumatoid arthritis. A press release of the data noted that there was no difference from placebo in spermatogenesis at 13 weeks treatment. Based upon further data review by the EMA, the warning of impact on male spermatogenesis has been removed from the package insert [65,66].

MONITORING — The approach to monitoring for drug toxicities is similar for all of the agents, although disease-specific concerns should also be considered. Janus kinase (JAK) inhibitors may have a disproportionate effect upon measures of inflammation and disease activity (eg, in rheumatoid arthritis) because of their suppressive effect on acute phase reactants, particularly on levels of C-reactive protein, that are independent of their clinical impact on arthritis disease activity (as measured by composite instruments that do not use acute phase measurements). This biologic effect is similar to the that of interleukin (IL) 6/IL-6R pathway inhibitors. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Disease Activity Score using 28 joints (DAS28)'.)

We generally perform the following monitoring for drug-related effects, similar to the approach in rheumatoid arthritis:

●Clinical monitoring – Patients should be monitored for the following [38] (see 'Adverse effects' above):

•Signs of infection, including viral infections, such as herpes zoster, and tuberculosis

•New onset of gastrointestinal symptoms that may suggest diverticulitis or gastrointestinal perforation

•Signs and symptoms of thrombosis or cardiovascular disease in patients at higher risk for these events

•Other adverse effects

●Laboratory monitoring – The approach to laboratory monitoring in patients being treated with a JAK inhibitor for a systemic inflammatory or rheumatologic disorder (eg, rheumatoid arthritis or psoriatic arthritis) is similar irrespective of the specific JAK inhibitor prescribed for these indications. Monitoring for patients with other conditions in which JAK inhibitors may also be used, such as hematologic disorders, may differ.

Laboratory monitoring in patients with a systemic inflammatory or rheumatologic disorder should include the following after baseline studies (see 'Clinical and laboratory screening and evaluation' above):

•Complete blood count with differential – Following baseline studies, a complete blood count and differential white blood cell count should be obtained after four to eight weeks of therapy, then every three months. Treatment should be temporarily interrupted in patients with an absolute neutrophil count (ANC) <1000 cells/mm³, absolute lymphocyte count (ALC) <500 cells/mm³, or hemoglobin <8 to 9 g/dL observed during routine patient monitoring, with dose reduction to maintain adequate levels if treatment is to be continued [32]. (See 'Infection' above and 'Hematologic' above.)

•Liver function tests – Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) are performed periodically following baseline studies. The authors typically obtain liver function tests after four to eight weeks of therapy, and then every three months.

•Lipids – A lipid panel including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, should be obtained 8 to 12 weeks after starting therapy and periodically thereafter, based upon usual guidance for screening and follow-up in patients not receiving JAK inhibitors. (See 'Gastrointestinal' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis" and "Society guideline links: Juvenile idiopathic arthritis" and "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY AND RECOMMENDATIONS

●Janus kinases (JAKs) are protein tyrosine kinases (TYKs) that bind to the intracellular domains of transmembrane cytokine receptors of several different cytokines and growth factors (figure 1). When the receptors are bound by their respective extracellular ligands, the JAKs become activated and phosphorylate both the receptor and the cognate signal transducer and activator of transcription (STAT) proteins, which in turn dimerize and enter the nucleus where they bind to transcriptional regulatory sites and mediate cellular responses important in immune defense, as well as immune-mediated disease. (See 'Janus kinase biology and function' above.)

●JAK inhibitors (JAKi or Jakinibs) are small, orally active drugs that are categorized as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) and have generally similar risks as the biologic DMARDs (bDMARDs) in treating immune-mediated inflammatory disease. However, a reported numeric increase in venous thromboembolisms, malignancy, and major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis treated with tofacitinib compared with tumor necrosis factor (TNF) inhibitors has resulted in a black box warning limiting use to patients with immune-mediated inflammatory diseases who have failed first-line biologic therapies, generally TNF inhibitors. Several agents are available for pharmacologic JAK inhibition, including tofacitinib, baricitinib, and upadacitinib. Filgotinib is approved in Europe and Japan. Peficitinib is available only in Japan and Korea. (See 'Mechanism of action of Janus kinase inhibitors' above and 'Adverse effects' above.)

●Baseline laboratory studies should include a complete blood count, differential, and platelet count; liver function tests; and a lipid panel. Patients should also be screened for latent tuberculosis and hepatitis B and C and cardiovascular and malignancy risk factors. Females of reproductive age should be screened for pregnancy. (See 'Pretreatment screening and precautions' above.)

●The most commonly reported adverse events associated with JAK inhibitors are upper respiratory infections, nausea, headache, nasopharyngitis, and diarrhea. Infections, particularly herpes zoster, are the most frequent serious adverse events reported. Venous thrombosis, thromboembolism, nonfatal myocardial infarction, lung cancer, and lymphoma may occur at an increased rate. Gastrointestinal perforation can rarely occur in adults. Laboratory abnormalities include neutropenia, thrombocytopenia, dyslipidemia, and elevated liver enzymes. (See 'Adverse effects' above.)

●JAK inhibitors should not be given in combination with other biologic agents and should be held in the presence of active infection. Patients should preferably be immunized with appropriate vaccines prior to therapy; live or live-attenuated vaccines are not recommended during treatment. (See 'Restrictions' above and 'Adverse effects' above and 'Pretreatment vaccination' above.)

●Patients should be monitored for signs or symptoms of infectious, gastrointestinal, or thrombotic complications. Laboratory monitoring includes blood counts, liver function tests, and lipid levels. (See 'Adverse effects' above and 'Monitoring' above.)