scholarly journals Janus kinase inhibitors for the treatment of rheumatoid arthritis

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

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

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.

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

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

AB0345 EFFICACY OF JAK INHIBITORS IN REFRACTORY RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1472.1-1472
Author(s):  
M. Kamiya
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Disease Duration ◽  
Inhibitor Therapy ◽  
Cumulative Number ◽  
Jak Inhibitor ◽  
Continuation Rate ◽  
Jak Inhibitors ◽  
Refractory Rheumatoid Arthritis ◽  
Continuation Rates

Background:Disease-modifying antirheumatic drugs (DMARDs) have been the main agents for treating rheumatoid arthritis (RA) unless there are serious clinical restrictions or contraindications such as comorbidities. With inefficacy of conventional synthetic DMARDs (e.g., methotrexate), biological DMARDs (bDMARDs) are now available to suppress progression of joint destruction. However, bDMARDs cannot control disease activity in some patients, so JAK inhibitors targeting different cytokines are expected to be beneficial.Objectives:This study investigated factors associated with the efficacy and continuation of JAK inhibitor therapy in patients with refractory RA for whom disease activity was not adequately controlled even with multiple sequentially administered bDMARDs with different targets.Methods:We obtained the number of bDMARDs used and the various reasons for discontinuing therapy in our hospital from January 2005 to December 2019. Kaplan–Meier analysis was used to obtain the therapy continuation rate, and the log-rank test was used to examine the difference in therapy continuation rate. Refractory RA was defined as RA with inefficacy with 3 or more bDMARDs with different targets (1 or more tumor necrosis factor inhibitor, a selective costimulation modulator abatacept, and an interleukin 6 receptor inhibitor tocilizumab). We then examined patients with refractory RA who had received tofacitinib (TOF) or baricitinib (BAR) therapy after discontinuation of a series of bDMARDs due to unsatisfactory response. Various statistical tests were performed to identify predictors of ≥ 6-month continuation of JAK inhibitor therapy that achieves low disease activity without increases in prednisolone (PSL) use. Explanatory variables included characteristics of patients at initiation of TOF or BAR therapy: age, sex, disease duration, number of bDMARDs previously used, concomitant methotrexate dose, concomitant PSL dose, DAS28-ESR value, presence of rheumatoid factor or anti-CCP antibodies, and MMP-3 level.Results:A cumulative number of 782 bDMARDs were administered to 362 RA patients by December 2019. The most common reason for discontinuation was inefficacy (51.8%), followed by adverse events including deaths (30.1%), patients’ circumstances such as hospital transfer (9.2%), switch to biosimilars (5.2%), and remission (3.7%). The bDMARDs continuation rate and the number of bDMARDs used were 69.6% and 2.17 for 5 years and 53% and 2.83 for 10 years, respectively, if the switch was considered to be continuous due to insufficient effect. The 6-month continuation rates were not significantly different between TOF and BAR (60 patients [62.3%] vs. 39 patients [81.3%], respectively; P = 0.147). In patients with refractory RA, continuation rates were not significantly different between TOF and BAR (19 patients [42.1%] vs. 11 patients [54.5%], respectively; P = 0.86). Only TOF-treated patients, not BAR-treated patients, showed significant differences in disease duration (226.1 months in the continued group vs. 111.8 months in the discontinued group; P = 0.035) and concomitant PSL dose (0.71 mg vs. 4.0 mg, respectively, P = 0.045).Conclusion:There are not a few patients with refractory rheumatoid arthritis. These findings, albeit retrospective, suggest that low concomitant PSL dose and long disease duration at the time of TOF therapy initiation were factors for TOF continuation. Therapy continuation rate was decreased in patients with refractory RA, and further study on switching therapy between different JAK inhibitors is anticipated.References:[1]Souto A, Maneiro JR & Gomez-Reino JJ. Rate of diccontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care database. Rheumatology (Oxford), 55, 523-534, 2016Disclosure of Interests:None declared

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

2019 ◽  
Vol 13 (4) ◽  
pp. 116-123 ◽  
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.

scholarly journals O27 Early experience with JAK inhibitor prescribing in the UK: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA)

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Lianne Kearsley-Fleet ◽  
Rebecca Davies ◽  
Kath Watson ◽  
Mark Lunt ◽  
Kimme L Hyrich ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitors ◽  
Patient Characteristics ◽  
Median Number ◽  
Outcome Data ◽  
Janus Kinase ◽  
Oral Disease ◽  
British Society ◽  
Biologic Dmards ◽  
The Uk

Abstract Background In 2017, a new class of oral disease modifying anti-rheumatic drugs (DMARDs), janus kinase inhibitors (JAKi), were licensed for rheumatoid arthritis (RA): baricitinib and tofacitinib. In the UK, they are approved for use in patients with high disease activity with or without methotrexate, following failure of conventional synthetic (cs) DMARDs or biologic DMARDs, the latter when rituximab is contraindicated. As a new therapy option, it is currently unclear how and when these drugs are being prescribed in patients with RA. This analysis aims to describe the characteristics of patients starting JAKi and registered with the BSRBR-RA. Methods The BSRBR-RA aims to capture exposure and outcome data in patients with RA receiving biologics, biosimilars and targeted synthetic DMARDs. At the start of therapy, demographic and clinical data, including past treatment data, are collected. Characteristics of all patients receiving a JAKi for the first time with data recorded in the BSRBR-RA up to 31/03/2019 are described. Results To 31/03/2019, 698 patients in the BSRBR-RA have been treated with a JAKi; 596 patients baricitinib and 110 tofacitinib (Table 1). A quarter of patients received a JAKi with no prior biologic exposure; 148 (25%) baricitinib and 16 (15%) tofacitinib. Of these, 15% had a prior malignancy history. Of those with prior biologic exposure, the median number of previous biologics was 3 (IQR 2-4), the majority had prior TNFi (91%) or rituximab (51%), and 50% were receiving concurrent methotrexate. Conclusion To date, more patients have been recruited starting baricitinib than tofacitinib, likely owing to the later licensing of tofacitinib. Two groups are emerging with a quarter of patients receiving JAKi immediately after csDMARDs and a majority as a later stage alternative following multiple biologics. Further recruitment and follow-up patients will allow for analysis of real-world safety and effectiveness, but differences in patient characteristics will need to be considered in any comparative effectiveness analyses. Disclosures L. Kearsley-Fleet None. R. Davies None. K. Watson None. M. Lunt None. K.L. Hyrich Honoraria; AbbVie. Grants/research support; UCB, Pfizer, BMS.

scholarly journals Janus Kinase Inhibitors for the Treatment of Rheumatoid Arthritis

2017 ◽  
Vol 52 (10) ◽  
pp. 667-668 ◽  
Author(s):  
Senir Turan ◽  
Scot Walker
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Reactions ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Oral Drugs ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Janus Kinase Inhibitors ◽  
Skin Conditions

Rheumatoid arthritis (RA) is a disease where the immune system attacks the linings of the joints, resulting in joint pain, stiffness, swelling, and destruction. Although many products are available for the treatment of RA, limitations such as adverse reactions and tolerance greatly affect adherence. Many of the current biologic disease-modifying antirheumatic drugs on the market are injectables, leaving a void to be filled for a product that can be taken orally. The most advanced of these approaches, the Janus kinase (JAK) inhibitors, are oral drugs that have not only made a breakthrough in RA, but also other skin conditions.

scholarly journals Potential Adverse Events Reported With the Janus Kinase Inhibitors Approved for the Treatment of Rheumatoid Arthritis Using Spontaneous Reports and Online Patient Reviews

2022 ◽  
Vol 12 ◽  
Author(s):  
Yun-Kyoung Song ◽  
Junu Song ◽  
Kyungim Kim ◽  
Jin-Won Kwon
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Events ◽  
Kinase Inhibitors ◽  
Proportional Reporting Ratio ◽  
Gastrointestinal Disorder ◽  
Interstitial Lung Diseases ◽  
Janus Kinase ◽  
Reporting Odds Ratio ◽  
Jak Inhibitors ◽  
Spontaneous Reports

The aim of this study was to analyze the potential adverse events (AEs) caused by Janus kinase (JAK) inhibitors, including tofacitinib, baricitinib, and upadacitinib, used to treat rheumatoid arthritis using spontaneous AE reports from the FDA (FAERS) and interpreting them in correlation with those from Korea (KAERS) and an online patient review (WebMD). Potential AEs were identified based on a disproportionality analysis using the proportional reporting ratio (PRR), reporting odds ratio (ROR), and the information component (IC). A total of 23,720 reports were analyzed from FAERS database, of which 91.5% were reports on tofacitinib. Potentially important medical AEs related to infections were reported frequently, as well as thromboembolism-related AEs. The AEs, such as malignancy, interstitial lung diseases, myocardial infarction, and gastrointestinal disorder, also reported. In an online patient review report, the ineffectiveness of the drug and gastrointestinal AEs were frequently reported. Infection with baricitinib and symptoms related to pain or edema due to upadacitinib were the main discomfort experienced by patients. In conclusion, the results of this study highlight the possible safety issues associated with JAK inhibitors. Routine clinical observations and further research using various real-world databases are needed.

scholarly journals More Unnecessary Imaginary Worlds - Part 1: The Institute for Clinical and Economic Review’s Evidence Report on Janus Kinase (JAK) Inhibitors in Rheumatoid Arthritis

2020 ◽  
Vol 11 (1) ◽  
pp. 2
Author(s):  
Paul Langley
Keyword(s):  
Quality Of Life ◽  
Rheumatoid Arthritis ◽  
Incremental Cost ◽  
Measurement Theory ◽  
Janus Kinase ◽  
Measurement Means ◽  
Normal Science ◽  
Jak Inhibitor ◽  
Jak Inhibitors

Previous commentaries in the Formulary Evaluation section of INNOVATIONS in Pharmacy have pointed to the lack of credibility in modeled claims for cost-effectiveness and associated recommendations for pricing by the Institute for Clinical and Economic Review (ICER). The principal objection to ICER reports has been that their modeled claims fail the standards of normal science: they are best seen as pseudoscience. The purpose of this latest commentary is to consider the recently released ICER evidence report for Janus Kinase (JAK) Inhibitors. As ICER continues, in the case of JAK Inhibitors, to apply its modeled cost utility framework with consequent recommendations for pricing adjustments, these recommendations also lack credibility. In contrast with previous ICER evidence reports, the present report adopts only a 12-month timeframe, one due, in large part, to ICER being unable to justify assumptions to drive its construction of imaginary worlds beyond 12 months. This commentary emphasizes again, why the ICER methodology fails to meet the standards of normal science. Claims made by ICER for the competing JAK Inhibitor therapies lack credibility, are impossible to evaluate, let alone replicate across treatment settings. Even so, it is important to examine a number of key elements in the ICER invention of the 12-month JAK Inhibitor imaginary world. While this does not imply any degree of acceptance of the ICER methodology, one element that merits particular attention is the failure of the ICER modeling to meet logically defensible measurement standards in its application of generic health related quality of life (HRQoL) ordinal metrics to create its QALY claims. The failure to meet the required standards of fundamental measurement means that the cost-per-QALY claims are invalid. This raises the issue of the application of Rasch Measurement Theory (RMT) in instrument development and the potential role of patient centric outcome (PCO) instruments that represent the patient voice in value claims. The case made here is that the ICER approach should be abandoned as an unnecessary distraction. If we are to meet standards for the discovery of new facts in therapy response then our focus must be on proposing credible, evaluable and replicable claims within disease states. Instruments, such as the Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire that build on the common construct that QoL is the extent to which human needs are fulfilled should be the basis for value claims.  HRQoL Instruments that are clinically focused and reflect the value calculus of providers and not patients in measuring response by symptoms and activity limitations are irrelevant.   This puts to one side the belief that incremental cost-per-QALY models, the construction of imaginary worlds are, in any sense, a ‘gold standard’; a meme embraced by the health technology assessment profession. Claims for incremental cost per QALY outcomes and recommendations for pricing and access driven by willingness to pay thresholds are irrelevant to formulary decisions.   Article Type: Commentary

scholarly journals Topical Tofacitinib: A Janus Kinase Inhibitor for the Treatment of Vitiligo in an Adolescent Patient

2021 ◽  
pp. 190-194
Author(s):  
Sineida Berbert Ferreira ◽  
Rachel Berbert Ferreira ◽  
Afonso Cesar Neves Neto ◽  
Silvana Martins Caparroz Assef ◽  
Morton Scheinberg
Keyword(s):  
Case Report ◽  
Skin Disease ◽  
Kinase Inhibitor ◽  
Effective Therapy ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Adolescent Patient ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitor ◽  
History Of

Vitiligo is an autoimmune skin disease presenting with areas of depigmentation. Recent reports suggest that Janus kinase (JAK) inhibitors may be an effective therapy. In this case report, we show our experience with an adolescent patient with a long history of generalized and refractory vitiligo, for which treatment with topical tofacitinib, a JAK inhibitor, associated with phototherapy for 9 months, resulted in near complete repigmentation.

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