Own experience uses Janus kinase inhibitors 1 type (Ranvek) in a patient with seronegative RA. Clinical observation

Combination Treatment with JAK2 and PI3K Inhibitors in Myeloproliferative Neoplasms

The ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis. We retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups. After PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67-7.42) for malignancy and 3.03 (95% CI: 0.77-15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23-2.97). The IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.

Reply: Calm before the storm: Understanding the role of Janus kinase inhibitors in COVID-19

BackgroundClinical feature of Janus kinase (JAK) inhibitor is recognized as not only suppress inflammation but also improve patient-reported outcomes (PRO) such as pain and health assessment questioner (HAQ) in patients...

ObjectivesRecently, a number of studies have explored the possible attenuation of the immune response by disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Our study objective was to investigate the presumed attenuated humoral response to vaccination against SARS-CoV-2 in patients with RA treated with Janus kinase (JAK) inhibitors with or without methotrexate (MTX). The immune responses were compared with controls without RA.MethodThe humoral vaccination response was evaluated by determining titres of neutralising antibodies against the S1 antigen of SARS-CoV-2. One hundred and thirteen fully vaccinated individuals were included at 6 ± 1 weeks after second vaccination (BioNTech/Pfizer (69.9%), AstraZeneca (21.2%), and Moderna (8.9%)). In a cross-sectional and single-centre study design, we compared titres of neutralising antibodies between patients with (n = 51) and without (n = 62) medication with JAK inhibitors.ResultsTreatment with JAK inhibitors led to a significantly reduced humoral response to vaccination (P = 0.004). A maximum immune response was seen in 77.4% of control patients, whereas this percentage was reduced to 54.9% in study participants on medication with JAK inhibitors (effect size d = 0.270). Further subanalyses revealed that patients on combination treatment (JAK inhibitors and MTX, 9 of 51 subjects) demonstrated an even significantly impaired immune response as compared to patients on monotherapy with JAK inhibitors (P = 0.028; d = 0.267).ConclusionsJAK inhibitors significantly reduce the humoral response following dual vaccination against SARS-CoV-2. The combination with MTX causes an additional, significant reduction in neutralising IgG titres. Our data suggest cessation of JAK inhibitors in patients with RA in the context of vaccination against SARS-CoV-2. Key Points• It was shown that DMARD therapy with JAK inhibitors in patients with rheumatoid arthritis leads to an attenuation of the humoral vaccination response against SARS-CoV-2.• The effect under medication with JAK inhibitors was significant compared to the control group and overall moderate.• The combination of JAK inhibitors with MTX led to an additive and significant attenuation of the humoral response.

Background Recently, there have been clinical reports of hepatitis B virus reactivation (HBVr) related with Janus kinase (JAK) inhibitors. However, there were no studies to investigate the association between HBVr and different JAK inhibitors. Research design and methods This study was a retrospective review utilizing the FAERS pharmacovigilance database and a systematic literature search for all cases of HBVr reported with JAK inhibitors. Disproportionality analysis and Bayesian analysis were used in data detection to screen the suspected HBVr after the administration of different JAK inhibitors, based on the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database from Q4 2011 to Q1 2022. Results There were a total number of 2097 (0.02%) reports of HBVr in FAERS, of which 41 (1.96%) were associated with JAK inhibitors. Baricitinib appeared to have the strongest signal among four JAK inhibitors, based on the highest reporting odds ratio (ROR = 4.45, 95% confidence interval [CI] 1.67–11.89). Ruxolitinib also showed signals, whereas no signals were detected among Tofacitinib and Upadacitinib. Conclusion While there may be an association between JAK inhibitors and HBVr, it appears to be a numerically uncommon occurrence. Further studies are needed to optimize the safety profiles of JAK inhibitors.

Topical Janus kinase (JAK) and phosphodiesterase-4 (PDE4) inhibitors are novel treatment approaches for atopic dermatitis (AD). This study aimed to compare the efficacy and safety of JAK and PDE4 inhibitors for AD treatment. The databases of PubMed, EMBASE, Web of Science, and Cochrane Library were searched until June 2021 for eligible studies of AD patients treated with topical JAK and PDE4 inhibitors. Baseline and follow-up data were extracted. Efficacy of JAK inhibitors was evaluated using Investigator's Global Assessment (IGA) achieving "clear" or "almost clear", with 2 points or more improvement from baseline at the end of treatment, referred to as "IGA response"). A Bayesian multiple treatment network meta-analysis with fixed effects was performed. Odds ratio (OR) with 95% credibility interval (CrI) were used for comparing the efficacy of JAK and PDE4 inhibitors with placebo for AD. A total of 10 randomized controlled trials of topical JAK and PDE4 inhibitors with 4689 patients were included for analysis. A total of three topical JAK inhibitors and two topical PDE4 inhibitors were included. Compared with placebo, all JAK and PDE4 inhibitors had higher IGA response at 4weeks of treatment. Notably, with similar safety profile, tofacitinib 2% b.i.d., ruxolitinib 1.5% b.i.d., and delgocitinib 3% b.i.d. showed favorable IGA response compared with topical tacrolimus and corticosteroids. Ranking analysis suggested that among all included JAK and PDE4 inhibitors, tofacitinib 2% b.i.d. had the highest probability of achieving IGA response (SUCRA=0.880). Besides, JAK and PDE4 inhibitors showed non-inferior safety profile with placebo. This study confirmed that topical JAK and PDE4 inhibitors had promising treatment efficacy and safety for AD patients. Tofacitinib 2% b.i.d., ruxolitinib 1.5% b.i.d. and delgocitinib 3% b.i.d. showed superior efficacy over other JAK and PDE4 inhibitors.

BackgroundFor the past 20 years, biologic (b)DMARDs have been the main treatment option for children and young people with JIA where an initial conventional-synthetic DMARD has not been effective. Since...

BackgroundAlthough impacting hundreds of thousands of people in Western nations each year, hepatitis E virus (HEV) is an under-reported health problem (1). HEV usually is a self-limiting disease, but especially...

BackgroundThe types of bone damage in rheumatoid arthritis (RA) include joint erosion, periarticular osteoporosis, and systemic osteoporosis. Janus kinase (JAK) inhibitors ameliorate inflammation and joint erosion in RA, but their effect on the three types of bone loss have not been reportedly explored in depth. We aimed to clarify how JAK inhibitors influence the various types of bone loss in arthritis by modulating osteoclastic bone resorption and/or osteoblastic bone formation.MethodsCollagen-induced arthritis (CIA) mice were treated with a JAK inhibitor after the onset of arthritis. Micro-computed tomography (μCT) and histological analyses (bone morphometric analyses) on the erosive calcaneocuboid joint, periarticular bone (distal femur or proximal tibia), and vertebrae were performed. The effect of four different JAK inhibitors on osteoclastogenesis under various conditions was examined in vitro.ResultsThe JAK inhibitor ameliorated joint erosion, periarticular osteopenia and systemic bone loss. It reduced the osteoclast number in all the three types of bone damage. The JAK inhibitor enhanced osteoblastic bone formation in the calcaneus distal to inflammatory synovium in the calcaneocuboid joints, periarticular region of the tibia and vertebrae, but not the inflamed calcaneocuboid joint. All the JAK inhibitors suppressed osteoclastogenesis in vitro to a similar extent in the presence of osteoblastic cells. Most of the JAK inhibitors abrogated the suppressive effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells, while a JAK inhibitor did not affect this effect due to less ability to inhibit IFN-γ signaling.ConclusionsThe JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting osteoclastogenesis and promoting osteoblastogenesis. These results indicate that the effect of JAK inhibitors on osteoclastogenesis and osteoblastogenesis depends on the bone damage type and the affected bone area. In vitro studies suggest that while JAK inhibitors inhibit osteoclastic bone resorption, their effects on osteoclastogenesis in inflammatory environments vary depending on the cytokine milieu, JAK selectivity and cytokine signaling specificity. The findings reported here should contribute to the strategic use of antirheumatic drugs against structural damages in RA.

Janus kinase (JAK) inhibitors tofacitinib and upadacitinib are effective therapies for inflammatory bowel disease and rheumatologic disorders but currently possess a warning for increased venous thromboembolism (VTE) risk. Some patients with a history of VTE may benefit from a JAK inhibitor, but the risk of recurrent VTE with JAK inhibitor use is unclear. Our goal was to observe rates of new VTE events after starting JAK inhibitor therapy in patients with a prior VTE, and observe whether concurrent anticoagulation (AC) reduces this risk. We conducted a review of adults prescribed tofacitinib or upadacitinib between January 1, 2000, and June 30, 2023, with a prior history of VTE. Patient charts were reviewed for demographic data, disease type, and VTE date(s), and to verify duration of JAK inhibitor use along with any concurrent AC. VTEs following JAK inhibitor initiation were identified by International Classification of Diseases-Tenth Revision code and verified by physician documentation and imaging. We identified 79 patients with a documented VTE history before initiating JAK inhibitors, 47 of whom began a JAK inhibitor with concurrent AC. Of these, 15 patients discontinued AC while receiving JAK inhibitors. In total, 5 new VTE events were observed during 55.42 patient-years of JAK inhibitor treatment without concurrent AC (9.0 events per 100 patient-years), while no new VTE events occurred during 65.2 patient-years of JAK inhibitor treatment with concurrent AC, demonstrating a lower risk of recurrent VTE (P = .020). These results suggest that for patients with a prior VTE history there is a high risk for recurrent VTE while receiving JAK inhibitors. Concurrent use of AC with JAK inhibitors appears to be protective against recurrent VTEs in this population.

Janus kinase (JAK) inhibitors are being increasingly used in inflammatory bowel diseases (IBDs). In the present review we raise a series of practical questions on JAK inhibitors in IBD and provide clear and concise answers. We performed a bibliographic search to identify studies assessing the role of JAK inhibitors in IBD. The key conclusions are summarized as follows. Upadacitinib has shown favorable efficacy outcomes in ulcerative colitis relative to other JAK inhibitors, although this conclusion requires confirmation through randomized trials. Extended induction can benefit patients with partial response. Real-world data support the use of JAK inhibitors in pediatric and older adults with IBD. JAK inhibitor efficacy appears unaffected by body mass index. JAK inhibitors may offer considerably high colectomy-free rates in acute severe ulcerative colitis. Interruption of therapy should be cautious, as maintenance seems key to sustained remission. Dose re-escalation can recapture response in over half of patients with loss of efficacy. Switching between JAK inhibitors, especially from tofacitinib to upadacitinib, is a viable strategy. Upadacitinib appears promising in the treatment of refractory perianal fistulizing Crohn's disease. JAK inhibitors may also be an option in refractory pouchitis. Combination therapy with JAK inhibitors and biologics may be beneficial in refractory IBD, though more studies are needed. JAK inhibitors appear effective in some extraintestinal dermatologic manifestations. Pretreatment screening for latent tuberculosis is advised. JAK inhibitors cause reversible, dose-dependent cholesterol increases without consistent evidence of a clear impact on cardiovascular risk, but monitoring is advised. Use in pregnancy is discouraged due to potential risks, and breastfeeding is contraindicated because of drug excretion in milk.

The aim of this study was to compare the risk of major cardiovascular events (MACE) and venous thromboembolic events (VTE) between tumour necrosis factor (TNF) and Janus kinase (JAK) inhibitors in patients with rheumatoid arthritis (RA). We researched PubMed, Scopus, Cochrane Library, and clinicaltrials.gov until December of 2023 for randomised controlled trials (RCTs) and observational studies. The outcomes studied were MACE (stroke, heart attack, myocardial infarction, sudden cardiac death) and VTE (deep vein thrombosis, pulmonary embolism). We pooled data using random effects model. Risk for the reported outcomes was expressed as odds ratio (OR) with a 95% confidential interval (CI). We performed a subgroup analysis based on study design. We identified 23 studies, 20 of which compared the odds for MACE and 14 the odds for VTE between JAK and TNF inhibitors in RA patients. Ten studies were RCTs and the rest were observational. Regarding MACE risk we pooled data from a total of 215,278 patients (52,243 were treated with JAK inhibitors, while the rest 163,035 were under TNF inhibitors). Compared with TNF inhibitors, the OR for JAK inhibitors in regards with MACE risk was 0.87 (0.64-1.17, p<0.01). Regarding VTE, a total of 176,951 patients were analysed (41,375 JAK inhibitors users and 135,576 TNF inhibitors users). The OR for VTE for JAK inhibitors compared with TNF inhibitors was 1.28 (0.89-1.84, p<0.01). According to our results, there is no statistically significant difference for MACE or VTE in RA patients who receive either JAK or TNF inhibitors.

Background: Janus kinase (JAK) inhibitors have emerged as a progressively utilized therapeutic approach for the management of rheumatoid arthritis (RA). However, the complete determination of their cardiovascular safety remains inconclusive. Hence, the primary objective of this network meta-analysis is to meticulously assess and juxtapose the cardiovascular risks linked to distinct JAK inhibitors employed in RA patients.Methods: A systematic review and network meta-analysis were meticulously conducted, encompassing a collection of randomized controlled trials (RCTs) that focused on investigating the incidence of major adverse cardiovascular events (MACE) and all-cause mortality associated with Janus kinase (JAK) inhibitors administered to patients with rheumatoid arthritis (RA). Extensive exploration was performed across multiple electronic databases, incorporating studies published until March 2023. To be included in this analysis, the RCTs were required to involve adult participants diagnosed with RA who received treatment with JAK inhibitors. To ensure accuracy, two authors independently undertook the selection of eligible RCTs and meticulously extracted aggregate data. In order to examine the outcomes of MACE and all-cause mortality, a frequentist graph theoretical approach within network meta-analyses was employed, utilizing random-effects models. Third study has been registered on PROSPERO under the reference CRD42022384611.Findings: A specific selection encompassing a total of 14 meticulously chosen randomized controlled trials was undertaken, wherein 13,524 patients were assigned randomly to distinct treatment interventions. The analysis revealed no notable disparity in the occurrence of major adverse cardiovascular events (MACE) between the interventions and the placebo group. However, in comparison to adalimumab, the employment of JAK inhibitors exhibited an association with higher rates of all-cause mortality [odds ratio (OR): 1.7, 95% confidence interval (CI): 1.02–2.81]. This observed increase in risk primarily stemmed from the usage of tofacitinib (OR: 1.9, 95% CI: 1.12–3.23). None of the other JAK inhibitors exhibited a statistically significant variance in all-cause mortality when compared to adalimumab.Interpretation: Our study suggests that JAK inhibitors may not increase the risk of MACE in RA patients but may be associated with a higher risk of all-cause mortality compared to adalimumab, primarily due to tofacitinib use. Rheumatologists should carefully consider the cardiovascular risks when prescribing JAK inhibitors, particularly tofacitinib, for RA patients.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384611, CRD42022384611.

Janus kinase (JAK) inhibitors are novel treatment approaches for atopic dermatitis (AD). This study was aimed to compare the efficacy of JAK inhibitors for AD treatment. The database of PubMed, EMBASE, Web of Science, and Cochrane Library were searched until March 28, 2021, for randomized control trials (RCTs) of AD patients treated with JAK inhibitors. Baseline and follow-up data were extracted. Efficacy of JAK inhibitors was evaluated using 50% improvement in Eczema Area and Severity Index (EASI-50). A Bayesian multiple treatment network meta-analysis with fixed effects was performed. Odds ratio (OR) with 95% credibility interval (CrI) were used for comparing the efficacy of JAK inhibitors with placebo for AD. A total of seven RCTs of JAK inhibitors with 2530 patients were included for analysis. After excluded one study with high risk of bias, a total of six JAK inhibitors with 17 different formulations and doses were analyzed. The severity of atopic dermatitis of included patients was almost moderate to severe (93.4%). Compared with placebo, all JAK inhibitors had higher EASI-50 at 4 weeks of treatment, except for baricitinib with 1mg once daily (QD) (OR: 1.4, 95% Crl: 0.9-2.1), ruxolitinib with 0.15% QD (OR: 2.3, 95% Crl: 0.8-11.4), and ruxolitinib with 0.5% QD (OR: 3.4, 95% Crl: 0.9-18.1). Among all included, upadacitinib had the highest probability of being the best treatment (SUCRA value of 0.936). In topical JAK inhibitors, delgocitinib 3% twice a day (BID) had the highest probability of being the best treatment (SUCRA value of 0.849). JAK inhibitors had promising treatment efficacy for AD patients. Upadacitinib with 30 mg QD had the best efficacy among all included JAK inhibitors, and delgocitinib 3% BID showed superior efficacy over other topical JAK inhibitors for AD treatment.