Risk of infection associated with Janus Kinase (JAK) inhibitors and biological therapies in inflammatory intestinal disease and rheumatoid arthritis. Prevention strategies

Immunomodulatory therapy for rheumatoid arthritis (RA) carries risk for infectious complications. Understanding the risks of different therapeutic options is essential for making treatment decisions and appropriately monitoring patients. This review examines data on the risks for serious infections and other key infections of interest for the major classes of agents in use for RA: glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologics and Janus kinase (JAK) inhibitors. Conventional synthetic DMARDs have an excellent safety profile with recent data available supporting the relative safety of methotrexate. Tumour necrosis factor (TNF) inhibitors are associated with an increase in the risk of serious infections. Risk with other biological agents and with JAK inhibitors varies somewhat but overall appears similar to that of TNF inhibitors, with JAK inhibitors also associated with a greater risk of herpes zoster. Glucocorticoids have a dose-dependent effect on serious infection risk—at higher doses risk of infection with glucocorticoids is substantially greater than with other immunomodulatory therapies, and even low-dose therapy carries a risk of infection that appears to be similar to that of biological therapies.

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P460 Evaluation of potential mechanisms underlying the safety observations of filgotinib in clinical studies in rheumatoid arthritis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.589 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S409-S409

Author(s):

A Clarke ◽

J Di Paolo ◽

B Downie ◽

A Meng ◽

N Mollova ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cell Proliferation ◽

Clinical Studies ◽

Nk Cell ◽

Janus Kinase ◽

Jak Inhibitor ◽

Jak Inhibitors ◽

Erythroid Progenitor ◽

Cell Counts

Abstract Background Inhibitors of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway have demonstrated efficacy in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Differences in selectivity of JAK inhibitors for JAK1, JAK2, JAK3 and TYK2 may influence their respective safety profiles, and the mechanisms responsible are not currently known. Filgotinib (FIL), a JAK1 inhibitor, did not negatively impact haemoglobin, LDL:HDL ratios or natural killer (NK) cell counts in clinical trials. Here, we compare the in vitro mechanistic profiles of four JAK inhibitors at clinically relevant doses. Methods JAK inhibitors (FIL, FIL metabolite [GS-829845], baricitinib [BARI], tofacitinib [TOFA], and upadacitinib [UPA]) were evaluated in vitro in human-cell-based assays. Growth of erythroid progenitors from human cord blood CD34+ cells was assessed using a HemaTox™ liquid expansion assay, NK cell proliferation was induced by IL-15 and LXR agonist-induced cholesteryl ester transfer protein (CETP) expression was assessed in the hepatic cell line, HepG2. Using assay-generated IC50 values and the reported human plasma concentrations from clinical studies, we calculated the target coverage for each JAK inhibitor at clinically relevant doses. The activity of FIL in humans was based on PK/PD modelling of FIL + GS-829845. Results Inhibition of cellular activity was calculated for each JAK inhibitor based on in vitro dose-response data, human exposure data and modelled PK/PD relationships. At clinically relevant doses, FIL resulted in lower calculated inhibition of NK cell proliferation compared with other JAK inhibitors. FIL 100 mg and 200 mg also reduced CETP expression, whereas other JAK inhibitors had no effect. There was no difference in the effect of FIL vs. other JAK inhibitors on erythroid progenitor cell differentiation or maturation. Conclusion FIL, a JAK1 inhibitor, resulted in less inhibition of NK cell proliferation compared with BARI, TOFA, and UPA. FIL also reduced LXR agonist-induced CETP expression, while the other inhibitors did not alter these levels. These results provide a potential mechanistic link between the observed reduction of CETP concentration following FIL treatment and the previously observed reduction in the LDL:HDL ratio in RA patients.

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BARICITINIB: NEW PHARMACOTHERAPY OPTIONS FOR RHEUMATOID ARTHRITIS AND OTHER IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES

Rheumatology Science and Practice ◽

10.14412/1995-4484-2020-304-316 ◽

2020 ◽

Vol 58 (3) ◽

pp. 304-316

Author(s):

E. L. Nasonov ◽

A. M. Lila

Keyword(s):

Rheumatoid Arthritis ◽

Rheumatic Diseases ◽

Janus Kinase ◽

Inflammatory Rheumatic Diseases ◽

Jak Inhibitors ◽

Oral Medications ◽

Immune Mediated ◽

Wide Range ◽

Promising Area ◽

Medical Advances

Deciphering the mechanisms of the pathogenesis of immune-mediated inflammatory rheumatic diseases (IMIRDs) in conjunction with designing a wide range of biological agents is one of the major medical advances in the 21st century. A new promising area of pharmacotherapy for IMIRDs is associated with the design of the so-called targeted oral medications that primarily include Janus kinase (JAK) inhibitors. The review presents new data on the efficacy and safety of the new JAK inhibitor baricitinib in treating rheumatoid arthritis and other IMIRDs.

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Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis: case presentation and literature review

Clinical Rheumatology ◽

10.1007/s10067-021-05911-4 ◽

2021 ◽

Author(s):

Shunsuke Mori ◽

Fumihiko Ogata ◽

Ryusuke Tsunoda

Keyword(s):

Rheumatoid Arthritis ◽

Diabetes Mellitus ◽

Risk Factors ◽

Pulmonary Embolism ◽

Venous Thromboembolism ◽

Disease Activity ◽

Janus Kinase ◽

Advanced Age ◽

Jak Inhibitors ◽

Increased Risk

AbstractJanus kinase (JAK) inhibitors have been developed as disease-modifying antirheumatic drugs. Despite the positive therapeutic impacts of JAK inhibitors, concerns have been raised regarding the risk of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE). A recent post hoc safety analysis of placebo-controlled trials of JAK inhibitors in rheumatoid arthritis (RA) reported an imbalance in the incidence of VTE for a 4-mg daily dose of baricitinib versus placebo. In a recent postmarketing surveillance trial for RA, a significantly higher incidence of PE was reported in treatment with tofacitinib (10 mg twice daily) compared with tofacitinib 5 mg or tumor necrosis factor inhibitors. We also experienced a case of massive PE occurring 3 months after starting baricitinib (4 mg once daily) for multiple biologic-resistant RA. Nevertheless, the evidence to support the role of JAK inhibitors in VTE risk remains insufficient. There are a number of predisposing conditions and risk factors for VTE. In addition to the known risk factors that can provoke VTE, advanced age, obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking can also contribute to its development. Greater VTE risk is noted in patients with chronic inflammatory conditions, particularly RA patients with uncontrolled disease activity and any comorbidity. Prior to the initiation of JAK inhibitors, clinicians should consider both the number and strength of VTE risk factors for each patient. In addition, clinicians should advise patients to seek prompt medical help if they develop clinical signs and symptoms that suggest VTE/PE. Key Points• Patients with rheumatoid arthritis (RA) are at increased risk of venous thromboembolism (VTE), especially those with uncontrolled, high disease activity and those with comorbidities.• In addition to the well-known risk factors that provoke VTE events, advanced age and cardiovascular risk factors, such as obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking, should be considered risk factors for VTE.• Although a signal of VTE/pulmonary embolism (PE) risk with JAK inhibitors has been noted in RA patients who are already at high risk, the evidence is currently insufficient to support the increased risk of VTE during RA treatment with JAK inhibitors.• If there are no suitable alternatives, clinicians should prescribe JAK inhibitors with caution, considering both the strength of individual risk factors and the cumulative weight of all risk factors for each patient.

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Efficacy and Safety of GSK3196165 (Otilimab) Versus Placebo and Sarilumab in Participants With Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Biological Disease-modifying Antirheumatic Drug (DMARDs) and/or Janus Kinase (JAK) Inhibitors

Case Medical Research ◽

10.31525/ct1-nct04134728 ◽

2019 ◽

Author(s):

Keyword(s):

Rheumatoid Arthritis ◽

Active Rheumatoid Arthritis ◽

Antirheumatic Drug ◽

Janus Kinase ◽

Inadequate Response ◽

Efficacy And Safety ◽

Jak Inhibitors ◽

Disease Modifying ◽

Disease Modifying Antirheumatic Drug

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AB0269 ARE INTERFERON-GAMMA RELEASE ASSAYS RELIABLE TO DETECT TUBERCULOSIS INFECTION IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH JANUS KINASE INHIBITORS?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2835 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1160.3-1161

Author(s):

C. Castellani ◽

E. Molteni ◽

A. Altobelli ◽

C. Garufi ◽

S. Mancuso ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Chest Radiography ◽

Kinase Inhibitors ◽

Clinical Manifestations ◽

Latent Tuberculosis ◽

Median Number ◽

Janus Kinase ◽

Tuberculosis Infection ◽

Jak Inhibitors ◽

Perfect Agreement

Background:The therapeutic armamentarium for patients with rheumatoid arthritis (RA) has recently been enriched with the family of Janus kinase (JAK) inhibitors. Because the risk of reactivation of latent tuberculosis infection (LTBI) following the use of these drugs seems to be similar to that seen with anti-TNF agents, screening for LTBI is recommended in patients with RA before starting treatment with JAK inhibitors. Interferon(IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. However, JAK inhibitors tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with this novel class of drugs.Objectives:To compare the performance of the QuantiFERON-TB Gold Plus (QFT-Plus) test with that of QuantiFERON-TB Gold In-tube (QFT-GIT) assay in RA patients before and during treatment with JAK inhibitors.Methods:A longitudinal, prospective study has been performed in RA patients (ACR/EULAR 2010 criteria) candidates for tofacitinib or baricitinib treatment. All patients underwent QFT-Plus and QFT-GIT at baseline (T0), and after 3 (T3) and 9/12 months (T9/12) of treatment with JAK inhibitors. The agreement of the two tests was calculated at all timepoints. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. Lastly, the variability of QTF-Plus results was assessed during follow-up.Results:Twenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled: among them, 22 were to start baricitinib (75.9%) and 7 tofacitinib (24.1%). A perfect agreement was found between QFT-Plus and QFT-GIT at all times of observation (κ=1). At baseline, no agreement was recorded between IGRAs and TST (κ=-0.08) and between TST and chest radiography (κ=-0.07), while a low agreement was found between QFT-Plus and chest radiography (κ=0.17). A variation of 33.3% in the results of the QFT-Plus test was recorded at T3 compared to T0, of 29.4% at T9/12 compared to T0, and of 11.8% at T9/12 compared to T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-Plus decreased after 3 months of treatment (1.59/4.72 IU/ml vs 3.08/7.68 IU/ml at baseline), followed by an increase after 9/12 months (2.25/4.61 IU/ml), but these differences were not significant. No significant change in the median number of circulating lymphocytes such as to explain the variation of the QFT-Plus results after 3 months of JAK inhibitor therapy was documented (1815/690/mm3 vs 2140/750/mm3 at baseline). At baseline, both QFT-Plus and QFT-GIT showed positive results in 5 patients (17.2%), negative in 19 (65.5%), and indeterminate in 5 (17.2%). Glucocorticoids intake was associated with a higher probability of negative or indeterminate result of IGRAs at baseline (p<0.0001).Conclusion:Our data show that a response to IGRAs is detectable in the course of treatment with JAK inhibitors. However, similarly to what has been observed during treatment with TNF antagonists, the results of QFT-GIT and QFT-Plus show some variability when longitudinally repeated. These fluctuations occur in the absence of correlation with clinical outcome, thus challenging their interpretation. Since we do not have a sufficiently sensitive test capable of detecting TB infection, an integrated evaluation of risk factors, clinical manifestations and multiple diagnostic tests should be considered for a proper evaluation of the risk of TB infection in immunosuppressed patients.Disclosure of Interests:None declared

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Janus kinase inhibitors for the treatment of rheumatoid arthritis

Journal of Korean Medical Association ◽

10.5124/jkma.2021.64.2.105 ◽

2021 ◽

Vol 64 (2) ◽

pp. 105-108

Author(s):

Sun Hee Jang ◽

Ji Hyeon Ju

Keyword(s):

Rheumatoid Arthritis ◽

Kinase Inhibitors ◽

Interleukin 1 ◽

Janus Kinase ◽

Jak Inhibitor ◽

Jak Inhibitors ◽

Biologic Dmards ◽

Signal Transducers ◽

Refractory Rheumatoid Arthritis ◽

Stat Signaling

Rheumatoid arthritis is a chronic inflammatory destructive disorder that affects the joints, muscles, and tendons accompanying various extra-articular manifestations. Traditional disease-modifying anti-rheumatic drugs (DMARDs) represent the basic treatment for rheumatoid arthritis. Over the last 20 years, biologic DMARDs (tumor necrosis factor inhibitors, interleukin-1 inhibitors, interleukin-6 inhibitors, T cell inhibitors, and B cell inhibitors) have been widely used as a novel class of DMARDs that have efficacy and efficiency. Discovery of the underlying pathogenesis of autoimmune disease enables us to develop new target therapies such as a Janus kinase (JAK) inhibitor. Activated JAK is known to activate signal transducers as well as activators of transcription (STAT) signaling. A JAK inhibitor is a type of medication that functions by inhibiting the JAK-STAT signaling pathway. In addition, it is easy to take a JAK inhibitor orally. In Korea, several JAK inhibitors have been approved. This review describes the types of JAK inhibitors, recommended doses, side effects, and updated European Alliance of Associations for Rheumatology guidelines. Clinicians should more often consider JAK inhibitors in the treatment of refractory rheumatoid arthritis in current rheumatology clinics

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Clinical significance of Janus kinase inhibitors in the therapy of rheumatoid arthritis: achievements and prospects

Modern Rheumatology Journal ◽

10.14412/1996-7012-2019-4-116-123 ◽

2019 ◽

Vol 13 (4) ◽

pp. 116-123 ◽

Cited By ~ 1

Author(s):

V. I. Mazurov ◽

I. B. Belyaeva

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Weight ◽

Intracellular Signaling ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Jak Inhibitors ◽

Janus Kinase Inhibitors ◽

Expected Effect ◽

Signaling Systems ◽

Disease Modifying

Significant successes in the use of biological agents (BA) have been achieved in the treatment of rheumatoid arthritis (RA); nonetheless, about 36% of patients cannot respond to therapy or achieve the expected effect. A new area in the treatment of RA is the use of Janus kinase (JAK) inhibitors, targeted synthetic disease-modifying anti-rheumatic drugs (chemical molecules with a molecular weight <1 kDa for oral administration) that inhibit the activity of intracellular signaling systems. The authors consider the clinical achievements and prospects, which open the use of JAK inhibitors in the treatment of RA.

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Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk?

Drug Safety ◽

10.1007/s40264-018-0651-5 ◽

2018 ◽

Vol 41 (7) ◽

pp. 645-653 ◽

Cited By ~ 54

Author(s):

Ian C. Scott ◽

Samantha L. Hider ◽

David L. Scott

Keyword(s):

Rheumatoid Arthritis ◽

Janus Kinase ◽

Jak Inhibitors

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Efficacy and safety of tofacitinib versus baricitinib in patients with rheumatoid arthritis in real clinical practice: analyses with propensity score-based inverse probability of treatment weighting

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-219699 ◽

2021 ◽

pp. annrheumdis-2020-219699

Author(s):

Yusuke Miyazaki ◽

Kazuhisa Nakano ◽

Shingo Nakayamada ◽

Satoshi Kubo ◽

Yoshino Inoue ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Practice ◽

Propensity Score ◽

Disease Activity ◽

Selection Bias ◽

Janus Kinase ◽

Jak Inhibitors ◽

Treatment Resistant ◽

Inverse Probability ◽

Resistant Group

ObjectivesThe differences of efficacy between each Janus kinase (JAK) inhibitors have not been clarified in the patients with rheumatoid arthritis (RA) in clinical practice. Here, we compared the efficacy between tofacitinib (TOFA) and baricitinib (BARI) in clinical practice.MethodsThe efficacy of TOFA (n=156) in patients with RA was compared with BARI (n=138). Selection bias was reduced to a minimum using propensity score-based inverse probability of treatment weighting (IPTW). The Clinical Disease Activity Index (CDAI) trajectory for patients who started TOFA or BARI was analysed using growth mixture modelling (GMM).ResultsNo significant difference was observed in patient characteristics between the TOFA and BARI groups in after adjustment by propensity score-based IPTW. The BARI group had a significantly higher rate of CDAI remission at week 24 after the introduction of JAK inhibitors than the TOFA group. The treatment-resistant group defined by GMM, comprising patients who did not achieve low disease activity at week 24, was more likely to include those who had received many biological disease-modifying antirheumatic drugs (bDMARDs) before the introduction of JAK inhibitors and those who received TOFA. Among patients with RA who received TOFA, those who had received ≥4 bDMARDs before the introduction of TOFA were more likely to be classified into the treatment-resistant group.ConclusionsBARI showed a similar safety profile and better clinical outcome when compared with TOFA after reduction to a minimum of selection bias. However, these were observed in a small population. Accordingly, further investigation is required in an accurately powered head-to-head trial.

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