Search

Introduction : Treatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50–100 × 109/L) are reported. Patients and Methods : Patients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety. Results : Of 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were −20.5% (−55.8% to 38.5%, n=51) and −39.8% (−98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3). Conclusion : A starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) intracellular signaling pathway is implicated in the pathogenesis of a number of inflammatory dermatoses. Clinical trials and other studies have demonstrated the efficacy of JAK inhibitors in the treatment of a variety of dermatologic conditions. Here we review JAK inhibitors currently under investigation for the treatment of alopecia areata, vitiligo, sarcoidosis, necrobiosis lipoidica, granuloma annulare, and systemic lupus erythematosus with a special emphasis on safety and the implications of JAK inhibitors during the novel coronavirus 2019 pandemic.

Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT‐PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure‐response relationships for efficacy and safety endpoints using data from the SELECT‐PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure‐response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure‐response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure‐response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure‐response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.

BACKGROUND Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present final data from OCTAVE Open, an open-label, long-term extension study. AIMS The primary objective of OCTAVE Open was to assess the safety and tolerability of long-term tofacitinib in patients with ulcerative colitis; evaluating efficacy was a secondary objective. METHODS Eligible patients included OCTAVE Induction 1&2 non-responders and OCTAVE Sustain completers/treatment failures. Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. Incidence rates (unique patients with events/100 patient-years) for adverse events of special interest were calculated; ≤7.0 years of observation. Efficacy endpoints derived from Mayo score were reported ≤36 months (last scheduled endoscopy visit). RESULTS In OCTAVE Open, 769 of 944 patients (81.5%) initially received tofacitinib 10 mg b.d. Among all patients (2440.8 patient-years of exposure), incidence rates (IRs; 95% confidence intervals) for deaths and adverse events of special interest were: deaths, 0.25 (0.09-0.54); serious infections, 1.61 (1.14-2.20); herpes zoster (non-serious and serious), 3.16 (2.47-3.97); opportunistic infections, 0.87 (0.54-1.33); major adverse cardiovascular events, 0.16 (0.04-0.42); malignancies (excluding non-melanoma skin cancer), 1.03 (0.67-1.52); non-melanoma skin cancer, 0.75 (0.45-1.19); deep vein thrombosis, 0.04 (0.00-0.23); pulmonary embolism, 0.21 (0.07-0.48). At Month 36, 66.9% and 40.3% showed clinical response, 64.6% and 37.1% had endoscopic improvement, and 58.9% and 33.7% maintained or achieved remission, with tofacitinib 5 and 10 mg b.d. respectively. CONCLUSION Tofacitinib demonstrated consistent safety up to 7.0 years. Data collected up to Month 36 support long-term efficacy beyond the 52-week maintenance study.

Human lives and nations’ economies have been adversely affected worldwide by the COVID-19 pandemic. The hyperinflammatory state associated with the disease may be related to mortality. Systemic glucocorticoid is the first-line therapy for cytokine storm. Various immunomodulatory drugs such as tocilizumab and baricitinib have been used in those not responding to glucocorticoid monotherapy. Amid the peak crisis of COVID-19 in India, there was an extreme paucity of medications, oxygen, and hospital beds. We describe three patients with COVID-19 who received low-dose tofacitinib (an oral Janus kinase inhibitor) in addition to moderate-dose glucocorticoid. These patients were treated at their homes, as the hospitals were short of beds. Rapid reduction in hypoxemia along with gradual resolution of other signs of the disease were observed. The results are reassuring regarding the feasibility of managing of severe COVID-19 outside the hospital setting when healthcare resources are overwhelmed by pandemic-related caseload.

Rheumatoid arthritis (RA) is a chronic autoimmune disease requiring long-term treatment. Upadacitinib (UPA), a Janus kinase (JAK) inhibitor, is a new treatment for RA. The benefit–risk profile of a medication is best understood by evaluating the number needed to treat (NNT) and the number needed to harm (NNH). This analysis evaluated the comparative risk–benefit of UPA versus adalimumab (ADA). Post-hoc analyses were performed using data from the SELECT-COMPARE trial of UPA versus placebo (PBO) and UPA versus ADA among patients with active RA who remained on stable methotrexate (MTX) treatment and had an inadequate response; patients who failed to achieve response were rescued by predefined criteria—PBO or ADA switch to UPA, and UPA switch to ADA (all patients on PBO were switched to UPA at week 26). This analysis assessed efficacy and adverse events of special interest (AESIs) at week 26, 48, and 156 (3 years). NNT and NNH (95% confidence intervals) values were calculated between UPA versus ADA for all time points, and between UPA versus PBO for week 26. NNT and NNH values were applied to a hypothetical cohort of 100 patients to estimate the comparative efficacy and safety profiles. UPA consistently showed greater efficacy than ADA, as evidenced by NNT values

Background This meta-analysis of randomized controlled trials (RCTs) investigated the usefulness of Janus kinase (JAK) inhibitors among hospitalized patients with COVID-19. Methods PubMed, Web of Science, the Cochrane Library, and Ovid MEDLINE were searched for RCTs published before 7 September 2021. Only RCTs that compared the clinical efficacy and safety of JAK inhibitors with other alternative treatments or placebos in the treatment of hospitalized patients with COVID-19 were included. Results Overall, patients receiving JAK inhibitors exhibited a lower 28-day mortality rate than the control group (risk ratio [RR], 0.60; 95% CI, 0.47–0.77; I2 = 0%). Compared with the control group, the study group also had a lower 14-day mortality rate (RR, 0.60; 95% CI, 0.42–0.85; I2 = 0%), a higher rate of clinical improvement (RR, 1.05; 95% CI, 1.02–1.09; I2 = 0%), and less need of mechanical ventilation or extracorporeal membrane oxygenation (RR, 0.64; 95% CI, 0.50–0.84; I2 = 0%). Finally, JAK inhibitor use was associated with a similar risk of adverse events and infections as that observed in the control group. Conclusions JAK inhibitors can help reduce mortality and improve clinical outcomes among hospitalized patients with COVID-19. Additionally, JAK inhibitors can be used safely in this clinical entity.

Background Coronavirus disease 2019 (COVID-19) has spread worldwide and is also an important disease in Japan. Thus, the optimal treatment strategy for severe COVID-19 should be established urgently. The effects of combination treatment with baricitinib—a Janus kinase inhibitor, remdesivir, and dexamethasone (BRD) are unknown. Methods Patients who received combination therapy with BRD at the Japanese Red Cross Medical Center were enrolled in the study. All patients received baricitinib (≤14 d), remdesivir (≤10 d), and dexamethasone (≤10 d). The efficacy and adverse events were evaluated. Results In total, 44 patients with severe COVID-19 were enrolled in this study. The 28-d mortality rate was low at 2.3% (1/44 patients). The need for invasive mechanical ventilation was avoided in most patients (90%, 17/19 patients). Patients who received BRD therapy had a median hospitalization duration of 11 d, time to recovery of 9 d, duration of intensive care unit stay of 6 d, duration of invasive mechanical ventilation of 5 d, and duration of supplemental oxygen therapy of 5 d. Adverse events occurred in 15 patients (34%). Liver dysfunction, thrombosis, iliopsoas hematoma, renal dysfunction, ventilator-associated pneumonia, infective endocarditis, and herpes zoster occurred in 11%, 11%, 2%, 2%, 2%, 2%, and 2% of patients, respectively. Conclusions Combination therapy with BRD was effective in treating severe COVID-19, and the incidence rate of adverse events was low. The results of the present study are encouraging; however, further randomized clinical studies are needed.

Spondyloarthritis (SpA) comprises a group of chronic inflammatory diseases with overlapping clinical, genetic and pathophysiological features including back pain, peripheral arthritis, psoriasis, enthesitis and dactylitis. Several cytokines are involved in the pathogenesis of SpA, variously contributing to each clinical manifestation. Many SpA-associated cytokines, including IL-23, IL-17, IL-6, type I/II interferon and tumour necrosis factor signal directly or indirectly via the Janus kinase (JAK)–signal transducer and activator of transcription pathway. JAK signalling also regulates development and maturation of cells of the innate and adaptive immune systems. Accordingly, disruption of this signalling pathway by small molecule oral JAK inhibitors can inhibit signalling implicated in SpA pathogenesis. Herein we discuss the role of JAK signalling in the pathogenesis of SpA and summarize the safety and efficacy of JAK inhibition by reference to relevant SpA clinical trials.

Long-term real-world management of inflammatory rheumatic diseases remains unclear, especially with the advent of new treatment options. This study characterizes the number of advanced treatments used by patients with selected rheumatic diseases (rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing spondylitis, juvenile idiopathic arthritis) and provides a contemporary portrait of treatment patterns and therapeutic sequencing among patients with RA and PsA.Patients were selected from a large US claims database and classified into disease subsamples based on the latest rheumatic diagnosis recorded before/on the day of initiation of the first advanced treatment (index date). The total number of advanced treatments was assessed within the first 5 years following the index date. Treatment patterns and therapeutic sequencing were assessed over the first 2 years.Approximately 20% of patients received ≥2 distinct advanced treatments during the first year following index date - the proportion increased to almost 50% among patients with 5 years of observation. Most patients (RA: 76.8%; PsA: 88.7%) initiated a tumor necrosis factor as the first advanced treatment. Over the first 2 years after the index date, 1/3 of RA and PsA patients switched to another advanced treatment. More than 50% initiated a second treatment with the same mechanism of action (MOA). A small proportion of patients received a biosimilar.Despite advent of treatments with different MOA, cycling between treatments with the same MOA was common. Further studies with longer data follow-up would be needed to assess the impact of higher adoption of biosimilars on treatment patterns/sequencing.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs). AIMS: To report an analysis of PMS case safety reports for tofacitinib in patients with UC METHODS: Worldwide tofacitinib PMS reports received in the Pfizer safety database from 30 May 2018 (first regulatory approval) to 25 August 2020 were analysed. The type and estimated reporting rate (RR) of serious AEs of interest, including infection, gastrointestinal, vascular, respiratory, neoplasm and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate- or extended-release formulations. RESULTS: During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8916 PY. Overall, 4226 case reports were received and included 12 103 AEs, of which 1839 were serious AEs (SAEs). Among the cases reported, 1141 (27.0%) included an SAE and 18 (0.4%) were fatal. The RR (per 100 PY) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 3.28 for infections, 1.26 for vascular disorders, 0.74 for respiratory disorders, 0.55 for neoplasms and 0.50 for cardiac disorders. CONCLUSIONS: The types of AEs were consistent with those reported in tofacitinib clinical trials. Most reported AEs were non-serious. Limitations of PMS reports and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results. ispartof: ALIMENTARY PHARMACOLOGY & THERAPEUTICS vol:55 issue:3 pages:302-310 ispartof: location:England status: published

The Janus kinase inhibitor ruxolitinib is approved for the treatment of myelofibrosis (MF) and improved overall survival (OS) versus control therapy in the phase 3 COMFORT trials. The aim of this retrospective analysis was to examine the real-world impact of ruxolitinib on OS in patients with MF. The US Medicare Fee-for-Service claims database (parts A/B/D) was used to identify patients with ≥ 1 inpatient or ≥ 2 outpatient claims with an MF diagnosis (January 2010–December 2017). Eligible patients with MF were ≥ 65 years old (intermediate-1 or higher risk based on age). Patients were divided into 3 groups based on ruxolitinib approval status at diagnosis and ruxolitinib exposure: (1) preapproval, ruxolitinib-unexposed; (2) post-approval, ruxolitinib-unexposed; and (3) post-approval, ruxolitinib-exposed. In total, 1677 patients with MF were included (preapproval [all ruxolitinib-unexposed], n = 278; post-approval, n = 1399 [ruxolitinib-unexposed, n = 1127; ruxolitinib-exposed, n = 272]). Overall, median age was 78 years, and 39.8% were male. Among patients with valid death dates (preapproval, n = 119 [42.8%]; post-approval, ruxolitinib-unexposed, n = 382 [33.9%]; post-approval ruxolitinib-exposed, n = 54 [19.9%]), 1-year survival rates were 55.6%, 72.5%, and 82.3%, and median OS was 13.2 months, 44.4 months, and not reached, respectively. Risk of mortality was significantly lower post- versus preapproval regardless of exposure to ruxolitinib (ruxolitinib-unexposed: adjusted hazard ratio [HR], 0.67; ruxolitinib-exposed: adjusted HR, 0.36; P P = 0.002). Findings from this study complement clinical data of ruxolitinib in MF by demonstrating a survival benefit in a real-world setting.

In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population.

Osteoarthritis (OA) is a major health problem worldwide that affects the joints and causes severe disability. It is characterized by pain and low-grade inflammation. However, the exact pathogenesis remains unknown and the therapeutic options are limited. In OA articular chondrocytes undergo a phenotypic transition becoming hypertrophic, which leads to cartilage damage, aggravating the disease. Therefore, a therapeutic agent inhibiting hypertrophy would be a promising disease-modifying drug. The therapeutic use of tyrosine kinase inhibitors has been mainly focused on oncology, but the Food and Drug Administration (FDA) approval of the Janus kinase inhibitor Tofacitinib in Rheumatoid Arthritis has broadened the applicability of these compounds to other diseases. Interestingly, tyrosine kinases have been associated with chondrocyte hypertrophy. In this review, we discuss the experimental evidence that implicates specific tyrosine kinases in signaling pathways promoting chondrocyte hypertrophy, highlighting their potential as therapeutic targets for OA.

With an advance in therapy, there are increasing emerging and re-emerging opportunistic infections among patients with hematologic conditions and malignancy. Herein, we present a 56-year-old woman with primary myelofibrosis who developed combined tuberculosis (TB) and cryptococcosis with extensive pulmonary, pleural, and nodal involvement during ruxolitinib therapy. Marked clinical and radiologic improvements were undoubtedly evident after receiving anti-TB and antifungal therapies and pleural drainage. Hence, the presence of atypical clinical and radiologic manifestations and incomplete responses, despite receiving adequate antimicrobial treatment, should raise concerns regarding the combined emerging and re-emerging opportunistic infections and the possibility of unusual radiologic manifestations of cryptococcosis in a ruxolitinib-treated patient.

Background The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. Objective We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (F eno ), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. Methods We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and F eno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in F eno from baseline to day 14. Baseline was defined as the average F eno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. Results Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean F eno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in F eno was −23% (95% CI, −37.3 to −9) for 15 mg QD and −42% (95% CI, −57 to −27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater F eno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. Conclusions GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in F eno in mild asthma and was well tolerated without evidence of systemic toxicity.

Janus kinase (JAK) inhibitors are emerging treatments for atopic dermatitis (AD). Due to this novel role as a therapeutic option for patients with AD, we aimed to review current evidence on the pathophysiology and the safety and adverse effects (AEs) of oral JAK inhibitors for the treatment of AD utilizing the key terms atopic dermatitis, JAK inhibitors, and adverse effect or event. Our study indicated that oral JAK inhibitors have a moderate safety profile for use in AD in several reviews and phase II or III clinical trials. Headaches, nausea, and nasopharyngitis are the most commonly reported systemic AEs. Furthermore, acne, herpes simplex, herpes zoster, and eczema herpeticum are the most commonly recorded dermatological AEs. Current evidence indicates JAK inhibitors may also have less association with some of the serious AEs, although there is potential for increased risk of asthma, acute pancreatitis, neutropenia, and thrombocytopenia. Whereas data remain limited for the long-term safety of JAK inhibitor use in patients with AD, many ongoing clinical trials have promising preliminary results.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder. Though corticosteroids are the cornerstone of therapy, the Janus kinase inhibitor abrocitinib has shown promise in recent clinical trials for the treatment of AD.To assess the overall efficacy and safety of abrocitinib in moderate to severe AD.All randomized controlled trials (RCTs) evaluating the efficacy and safety of abrocitinib in moderate to severe AD were included in the meta-analysis.The pooled analysis revealed a significant proportion of patients achieving Investigator's Global Assessment (IGA) response (RR = 3.52, 95% CI; 2.78-4.46,This meta-analysis showed that abrocitinib had a significant beneficial effect and tolerable adverse effect profile in patients of AD. Dose regimens of 200 and 100 mg seemed to have similar benefits. However, long-term trials are needed for corroboration.Key pointsAbrocitinib is emerging as a potential treatment option for moderate to severe atopic dermatitis.The pooled analysis from 4 RCTs demonstrated significant effectiveness of abrocitinib in both physician and patient-reported outcomes like IGA, EASI, and PP-NRS. The drug was also well-tolerated across the trials.The number needed to treat (NNT) for all efficacy outcomes was low suggesting clinically desirable benefits with the use of abrocitinib.

Introduction Axial spondyloarthritis (AxSpA) is an inflammatory disorder that affects the joints, entheses, and bone tissues and is sometimes associated with psoriasis, anterior uveitis, and gut inflammation. Its pathogenesis is not wholly understood and treatment strategies require optimization. Data concerning AxSpA pathogenesis support a critical role of abnormal CD4+ T cell differentiation and exacerbated type 3 immune response. This knowledge boosted the development of interleukin (IL)-17 and Janus kinase inhibitors for AxSpA treatment beyond tumor necrosis factor-α inhibition. Areas covered Emerging drug targets in animal and cellular models and with phase-II clinical trials have been evaluated. We also reflect on key issues for preclinical and clinical research going forward. Expert opinion Some of the most promising approaches include: (i) modulation of transforming growth factor-β family that could exert a specific role on bone formation; (ii) blockade of granulocyte-macrophage colony-stimulating factor that could reduce type 3 immune responses, and (iii) rebalancing of biased immune response by cytokines such as IL-2 or IL-27 that could favor anti-inflammatory response and sustained drug-free remission. Multiomics tools and artificial intelligence could contribute to identification of optimal targets and help stratify patients for the most appropriate treatment options.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 (coronavirus disease 2019), which is associated with high morbidity and mortality, especially in elder patients. Acute respiratory distress syndrome (ARDS) is a life-threatening complication of COVID-19 and has been linked with severe hyperinflammation. Dexamethasone has emerged as standard of care for COVID-19 associated respiratory failure. In a non-randomized prospective phase II multi-center study, we asked whether targeted inhibition of Janus kinase-mediated cytokine signaling using ruxolitinib is feasible and efficacious in SARS-CoV-2- induced ARDS with hyperinflammation. Sixteen SARS-CoV-2 infected patients requiring invasive mechanical ventilation for ARDS were treated with ruxolitinib in addition to standard treatment. Ruxolitinib treatment was well tolerated and 13 patients survived at least the first 28 days on treatment, which was the primary endpoint of the trial. Immediate start of ruxolitinib after deterioration was associated with improved outcome, as was a lymphocyte-to-neutrophils ratio above 0.07. Together, treatment with the janus-kinase inhibitor ruxolitinib is feasible and might be efficacious in COVID-19 induced ARDS patients requiring invasive mechanical ventilation. The trial has been registered under EudraCT-No.: 2020-001732-10 and NCT04359290.

Background Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety in the treatment of patients with rheumatoid arthritis (RA). This study evaluated the effect of peficitinib on patient- and physician-reported outcomes in Asian patients with RA and an inadequate response to prior disease-modifying antirheumatic drugs (DMARDs). Methods Patients from two randomized, placebo-controlled, double-blind, phase 3 trials (RAJ3 and RAJ4) received once-daily peficitinib 100 mg, peficitinib 150 mg, or placebo, alone or in combination with DMARDs (RAJ3), or in combination with methotrexate (RAJ4). Mean changes in Work Productivity and Activity Impairment (WPAI) questionnaire domain scores from baseline, and percentages of patients achieving minimal clinically important differences (MCIDs) for patient- and physician-reported outcomes (WPAI, Health Assessment Questionnaire – Disability Index [HAQ-DI], and Subject’s Global Assessment of Pain [SGAP]), and Physician’s Global Assessment of disease activity (PGA) were evaluated at weeks 4, 8, 12, and 12/early termination (ET). Results Data from 1025 patients were analyzed. At week 12/ET in both studies, patients who received peficitinib 100 mg or 150 mg reported significantly improved WPAI domain scores from baseline (except for absenteeism in RAJ4) compared with placebo (both doses, pp Conclusions Peficitinib 100 mg or 150 mg administered daily over 12 weeks resulted in clinically meaningful improvements in outcomes that are important to RA patients, including pain, physical function, and work productivity and activity. These observations were reinforced through similar improvements in physicians’ rating of disease activity. Trial registration RAJ3: ClinicalTrials.gov, NCT02308163, registered 4 December 2014. RAJ4: ClinicalTrials.gov, NCT02305849, registered 3 December 2014.

Coronavirus disease-2019 (COVID-19) represents a global public health nightmare. The “cytokine storm,” the most prominent underlying pathophysiologic mechanism of this disease, can theoretically be targeted at several stages. Janus kinase (JAK) inhibitors constitute a drug class that could ameliorate the inflammatory response and enhance antibody production. Herein, we aimed to evaluate the efficacy of JAK inhibitors in patients with COVID-19, performing the most updated relevant meta-analysis. We searched two major databases for randomized controlled trials (RCTs) enrolling adult patients with documented COVID-19 in the in-hospital setting, assigned either to JAK inhibitor treatment plus standard of care or standard of care alone. We set as primary efficacy outcome the endpoint of COVID-19 death on day 28 and as secondary efficacy composite outcome that of mechanical ventilation or initiation of extracorporeal membrane oxygenation (ECMO). We finally pooled data of interest from 4 RCTs in a total of 1338 subjects with documented COVID-19 infection, utilizing the following JAK inhibitors: baricitinib, ruxolitinib, tofacitinib, and nezulcitinib. Treatment with JAK inhibitor compared to control resulted in a significant reduction in the risk for COVID-19 death by 43%, while it also led to a significant decrease in the risk for mechanical ventilation or ECMO initiation by 36%. Herein, we demonstrate a clear benefit with JAK inhibitors added to standard of care in patients with COVID-19 in terms of risk reduction concerning major outcomes. Larger RCTs will elucidate their place in treatment armamentarium against COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s10067-021-05884-4.

Elena Campione,1 Terenzio Cosio,1 Monia Di Prete,2 Caterina Lanna,1 Annunziata Dattola,1 Luca Bianchi1 1Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, 00133, Italy; 2Anatomic Pathology, University of Rome Tor Vergata, Rome, 00133, ItalyCorrespondence: Elena CampioneDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier,1, Rome, 00133, ItalyTel +39.06.20900252Email elena.campione@uniroma2.itAbstract: Psoriasis is a chronic, relapsing, immune-mediated systemic disease. Its pathogenesis is complex and not fully understood yet. Genetic and epigenetic factors interact with molecular pathways involving TNF-α, IL-23/IL-17 axis, and peculiar cytokines, as IL-36 or phosphodiesterase 4. This review discusses the mechanisms involved in the development of the disease, as well as the therapeutic options proposed following the investigation of the inflammatory psoriatic pathways. We performed a comprehensive search using the words “psoriasis” and the newest molecules currently under investigation and approval. From these data, a new scenario in psoriasis is occurring to personalize the therapies - especially systemic ones and those using small molecules – and avoid topical and injectable drugs. We reported the newest therapeutic opportunities, including the inhibitors of Janus kinase/tyrosine kinase 2, phosphodiesterase-4 and IL-36 receptor. Today, more than 20 molecules are under investigation for the treatment of cutaneous psoriasis. Most of them are constituted by small molecules or biologic therapies. This underlines how psoriasis needs systemic therapies, due to its complex pathogenesis and multisystemic involvement.Keywords: psoriasis, janus kinase inhibitors, tyrosine kinase 2 inhibitors, phosphodiesterase 4 inhibitors, IL-36 receptors inhibitors

BACKGROUND Obesity may affect efficacy and safety of biologic treatments for ulcerative colitis (UC). Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. AIMS To assess efficacy and safety of tofacitinib in patients with UC, by baseline body mass index (BMI). METHODS This post hoc analysis evaluated patients with UC receiving placebo or tofacitinib from the 8-week OCTAVE Induction 1 and 2 (NCT01465763, NCT01458951) and 52-week OCTAVE Sustain (NCT01458574) studies. Patients were stratified by BMI at OCTAVE Induction 1 and 2 baseline (

The last decade has seen considerable advancement in the treatment options available to patients with rheumatoid arthritis (RA) through the development of oral, small molecules that target and inhibit Janus kinases (JAKi). These drugs have a rapid onset of action, disrupting the Janus kinase/signal transducer and activator of transcription pathway and preventing the production of cytokines involved in inflammatory processes. They have the potential to provide immunomodulatory benefits across a broad range of diseases. This narrative review focuses on the safety profile of tofacitinib, baricitinib, upadacitinib, and filgotinib. Although JAKi have been shown to be effective in the treatment of RA, it is posited that they have different selectivities, which are likely to affect their safety profiles in RA patients. Currently, there are limited long-term safety data available, with most data coming from randomized controlled trials. However, the data that are available show that upadacitinib and filgotinib may have improved safety profiles. This is particularly true in relation to herpes zoster, venous thromboembolism, and gastrointestinal perforation. Future research is needed to investigate the safety and efficacy of switching between JAKi when a previous JAKi has not been tolerated or has been ineffective.

Tofacitinib is a JAK1/3 inhibitor used off-label to treat alopecia areata (AA). Oral tofacitinib undergoes extensive hepatic metabolism and has numerous drug interactions and a half-life of 3 hours necessitating twice daily dosing. Sublingual delivery bypasses hepatic first-pass metabolism, which may provide pharmacokinetic benefits and reduce gastrointestinal side effects. We investigate sublingual tofacitinib as a novel form of administration in a cohort of treatment-resistant patients. The objective of this work is to assess the efficacy and pharmacokinetics of sublingual tofacitinib in moderate-to-severe AA patients. An open-label, roll-over pilot clinical trial was conducted. Participants were recruited from a preceding trial. All responders (≥50% reduction in Severity of Alopecia Tool [SALT] score, SALT50) in the preceding trial continued on the same treatment (cyclosporine/placebo), whereas nonresponders rolled over to receive open-label sublingual tofacitinib 5 mg twice daily for 12 weeks. Treatment response as reduction in SALT score after 12 weeks (low: 15-29%, medium: 30-49%, good: 50-75%, and high grade: 75-100%) was measured. Pharmacokinetics was analyzed using liquid chromatography tandem mass spectrometry. Eighteen participants completed the trial. Total treatment response to tofacitinib was 37.5%. SALT50 was achieved in 12.5%. The mean improvement in SALT score was 15.57%. Mean maximum plasma concentration was 43.18 ng/ml occurring after 1 hour. Elimination half-life is estimated to be up to 11 hours. An estimated half-life of up to 11 hours may be achieved with sublingual tofacitinib, which is significantly longer than the oral form and may facilitate daily dosing. Larger clinical trials are required to further characterize its pharmacokinetics and efficacy.

Axial involvement in psoriatic arthritis is quite common. There is no data on the use of tofacitinib, an oral Janus kinase inhibitor, in psoriatic arthritis patients with axial involvement, nor is there any data on its effect on active MRI sacroiliitis.The aim of the study was to assess the effect of tofacitinib therapy on the dynamics of active MRI sacroiliitis in psoriatic arthritis patients.Materials and methods. 41 patients with active psoriatic arthritis fulfilling the CASPAR criteria were included. Median age was 41.0 [34; 50] years old, median disease duration was 6.0 [3; 10] years. Apart from a standard clinical examination, 40 patients underwent sacroiliac joint MRI on scanner Siemens General Electric 1.5 TESLA. Bone marrow edema on MRI (STIR) with one lesion on two consecutive slices or at least two lesions on a single slice, was considered active MRI sacroiliitis. Tofacitinib was given in 5 mg tablets twice a day with a possible dose increase up to 10 mg twice a day after 12 weeks of therapy. At the end of study, over a period of 24 weeks, sacroiliac joint MRI examination was repeated in 35 patients.Results. Prior to tofacitinib therapy, active MRI sacroiliitis was detected in 14 of 40 (35%) patients: bilateral – in 9 patients, unilateral – in 5 patients. At the end of 24 weeks therapy, active MRI sacroiliitis was detected in 4 of 35 (11.4%) patients observed: in 1 patient with baseline bilateral MRI sacroiliitis and in 2 patients with unilateral MRI sacroiliitis. 1 patient showed negative dynamics, that is, development of active MRI sacroiliitis (absent at baseline). The decrease in number of active MRI sacroiliitis patients is statistically significant (p=0.017). At baseline, inflammatory changes were detected in 23 of 80 (28.8%) sacroiliac joints, after 24 weeks of therapy they were found in 5 of 70 (7.1%; p=0.001) sacroiliac joints observed. During the treatment period, there was a significant decrease in the initially high activity of spondylitis. After 24 weeks of treatment, median BASDAI decreased from 6.0 [4.2; 7.0] to 1.4 [0.6; 3.2], median ASDAS-CRP from 3.8 [2.8; 4.4] to 1.5 [1.0; 2.1] (p=0.001 for both comparisons). Prior to tofacitinib therapy, high activity according to BASDAI was observed in 90.2% of patients, low activity – in 9.8%; at the end of study – in 13.5% and 86.5% of patients, respectively (p=0.001). At baseline, very high activity by ASDAS-CRP was detected in 61% of patients, high activity – in 29.2%, low activity – in 9.8% of patients. At the end of study there weren’t any patients with very high activity by ASDAS-CRP (p=0.001), high activity remained in 23.1%, moderate and low activity – in 30.7% and 46.2% of patients, respectively (p=0.001 for both comparisons). Significant differences between baseline symptoms in patients with MRI sacroiliitis and without it were defined by number of digits with dactylitis – 2 [0; 4] and 0 [0; 2] (p=0.04) and by ESR values – 47 [26; 76] and 20 [6; 37] mm/h (p=0.02). These parameters were higher in MRI sacroiliitis subgroup. By the end of study, these differences leveled out: the number of digits with dactylitis decreased to 0 [0; 0] and 0 [0; 0] (р=0.48), ESR – to 12 [6; 16] and 8 [6; 16] mm/h, respectively (p=0.78).Conclusion. Tofacitinib therapy shows high efficacy in reducing active MRI sacroiliitis and decreasing activity of axial involvement in psoriatic arthritis patients. The use of tofacitinib in patients with active MRI sacroiliitis as well as dactylitis and increased ESR levels demonstrated its high efficacy.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs), which are uncontrolled lymphoid proliferation or lymphoma induced by immunosuppressive medication, arise mainly in patients with rheumatoid arthritis (RA). The vast majority of OIIA-LPDs are caused by methotrexate (MTX), and the reported incidence rates in the oral and maxillofacial regions are similar to those in other organs. In addition, tofacitinib (TFC), which is a Janus kinase inhibitor, has been clinically applied for the immunosuppressive treatment of RA in recent years. Herein, we present a case of OIIA-LPD of the oral floor in a patient with RA who had been treated with TFC and MTX. Clinical and pathological findings suggested that inflammatory stomatitis and/or infective response by oral bacteria promoted lymphoid activation in the oral mucosa, which could potentially become malignant. This case report indicates that OIIA-LPD might result from the combined usage of MTX and TFC, and a synergistic influence between MTX and TFC on immunosuppression may lead to diversification of OIIA-LPDs. The findings suggest the difficulty in controlling complications of RA and the importance of understanding the mechanisms of immunosuppressive treatments.

Introduction Upadacitinib is a Janus kinase inhibitor under investigation in patients with psoriatic arthritis (PsA). This study assessed the 56-week efficacy and safety of upadacitinib in patients with PsA and an inadequate response or intolerance to biologic therapy. Methods In the phase 3 SELECT-PsA 2 study, patients were randomized to 56 weeks of blinded treatment with oral upadacitinib 15 or 30 mg once daily, or placebo switched to upadacitinib 15 or 30 mg once daily at week 24. Efficacy endpoints included the proportion of patients achieving 20/50/70% improvement in American College of Rheumatology criteria (ACR20/50/70), 75/90/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), and minimal disease activity. Safety was assessed throughout the study. Results Of 641 patients who received ≥ 1 dose of study drug, 479 (74.7%) completed 56 weeks of treatment. Improvements in the proportion of patients achieving ACR20/50/70, PASI75/90/100, and minimal disease activity were maintained with both doses of upadacitinib through 56 weeks. Week 56 results for patients who switched from placebo to upadacitinib at week 24 were similar to those for patients originally randomized to the upadacitinib groups. The exposure-adjusted event rate for serious infections was 2.6 and 6.1 events/100 patient-years in the upadacitinib 15 and 30 mg groups, respectively. Herpes zoster occurred more frequently with upadacitinib 30 versus 15 mg; most cases were non-serious. Conclusion In patients with PsA who had an inadequate response or intolerance to biologic therapy, the efficacy of upadacitinib was maintained over 56 weeks with no new significant safety signals observed. Trial registration NCT03104374. Electronic supplementary material The online version of this article (10.1007/s40744-021-00305-z) contains supplementary material, which is available to authorized users.

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.

Background This study aimed to analyze the effects of ruxolitinib on children with secondary hemophagocytic lymphohistiocytosis (HLH). Methods Eleven pediatric patients diagnosed with HLH and treated with ruxolitinib (ruxolitinib group: group R) between November 2017 and August 2018 were retrospectively analyzed. Eleven age-matched pediatric patients with HLH undergoing conventional treatment (control group: group C) during the same period were also analyzed. Results In group R, three patients who did not respond to methylprednisolone (MP) pulse and intravenous immunoglobulin (IVIG) therapies were treated with Ruxolitinib and their temperature decreased to normal levels. Four patients had normal temperature after conventional treatment (dexamethasone and etoposide, with or without cyclosporine A), but they had severe organ involvement, including obvious yellowing of the skin, increased liver enzyme levels and neuropsychiatric symptoms, and they were all ameliorated with ruxolitinib treatment. Four patients were relieved with ruxolitinib therapy alone. In group C, the body temperatures of eleven patients decreased to normal levels after conventional treatment. The body temperature of group R patients decreased to normal levels more rapidly than that of group C patients. The glucocorticoid dosage in group R was significantly lower than that in group C. Both groups were followed-up for 2–2.5 years. No obvious adverse drug reactions to ruxolitinib were observed during treatment and follow-up. Conclusion Ruxolitinib might be an effective drug in controlling body temperature and reducing inflammation indicators. It might be a potential replacement for glucocorticoid therapy for HLH treatment in children, thereby reducing or avoiding glucocorticoid-related adverse reactions.

Background The Janus kinase inhibitor upadacitinib is a potential treatment for psoriatic arthritis. The efficacy and safety of upadacitinib as compared with adalimumab, a tumor necrosis factor a inhibitor, in patients who have an inadequate response to nonbiologic disease-modifying antirheumatic drugs are unclear. Methods In a 24-week, phase 3 trial, we randomly assigned patients in a 1:1:1:1 ratio to receive oral upadacitinib at a dose of 15 mg or 30 mg once daily, placebo, or subcutaneous adalimumab (40 mg every other week). The primary end point was an American College of Rheumatology 20 (ACR20) response (>20% decrease in the number of tender and swollen joints and >20% improvement in at least three of five other domains) at week 12 with upadacitinib as compared with placebo. Secondary end points included comparisons of upadacitinib with adalimumab. Results A total of 1704 patients received an active drug or placebo. The percentage of patients who had an ACR20 response at week 12 was 70.6% with 15-mg upadacitinib, 78.5% with 30-mg upadacitinib, 36.2% with placebo (P

Aicardi-Goutieres Syndrome (AGS) is a monogenic leukodystrophy with pediatric onset, clinically characterized by a variable degree of neurologic impairment. It belongs to a group of condition called type I interferonopathies that are characterized by abnormal overproduction of interferon alpha, an inflammatory cytokine which action is mediated by the activation of two of the four human Janus Kinases. Thanks to an ever-increasing knowledge of the molecular basis and pathogenetic mechanisms of the disease, Janus Kinase inhibitors (JAKIs) have been proposed as a treatment option for selected interferonopathies. Here we reported the 24 months follow-up of the fifth AGS patient treated with ruxolitinib described so far in literature. The treatment was globally well tolerated; clinical examinations and radiological images demonstrated a progressively improving course. It is however to note that patients presenting with mild and spontaneously improving course have been reported. Large natural history studies on AGS spectrum are strongly required in order to get a better understanding of the results emerging from ongoing therapeutic trials on such rare disease.

ObjectivesThis integrated analysis presents the safety profile of upadacitinib, a Janus kinase inhibitor, at 15 mg and 30 mg once daily in patients with moderately to severely active rheumatoid arthritis (RA).MethodsTreatment-emergent adverse events (TEAEs) and laboratory data from five randomised, placebo- or active-controlled phase III trials of upadacitinib for patients with RA were analysed and summarised. Exposure-adjusted event rates are shown for placebo (three trials; 12/14 weeks), methotrexate (two trials; mean exposure: 36 weeks), adalimumab (one trial; mean exposure: 42 weeks), upadacitinib 15 mg (five trials; mean exposure: 53 weeks) and upadacitinib 30 mg (four trials; mean exposure: 59 weeks).Results3834 patients received one or more doses of upadacitinib 15 mg (n=2630) or 30 mg (n=1204), for a total of 4020.1 patient-years of exposure. Upper respiratory tract infection, nasopharyngitis and urinary tract infection were the most commonly reported TEAEs with upadacitinib. Rates of serious infection were similar between upadacitinib 15 mg and adalimumab but higher compared with methotrexate. Rates of herpes zoster and creatine phosphokinase (CPK) elevations were higher in both upadacitinib groups versus methotrexate and adalimumab, and rates of gastrointestinal perforations were higher with upadacitinib 30 mg. Rates of deaths, malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) were similar across treatment groups.ConclusionIn the phase III clinical programme for RA, patients receiving upadacitinib had an increased risk of herpes zoster and CPK elevation versus adalimumab. Rates of malignancies, MACEs and VTEs were similar among patients receiving upadacitinib, methotrexate or adalimumab.Trial registration numbersSELECT-EARLY:NCT02706873; SELECT-NEXT:NCT02675426; SELECT-COMPARE:NCT02629159; SELECT-MONOTHERAPY:NCT02706951; SELECT-BEYOND:NCT02706847.

Introduction Peficitinib, a Janus kinase (JAK) inhibitor, is approved for clinical use in Japan, Korea, and Taiwan, but head-to-head comparisons versus other JAK inhibitors are lacking. We indirectly compared peficitinib, tofacitinib, and baricitinib for rheumatoid arthritis treatment. Methods We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and congress archives up until February 12, 2019, for randomized controlled trials of peficitinib, tofacitinib, and baricitinib. Efficacy (American College of Rheumatology responses, disease activity scores, modified total Sharp score, Simplified Disease Activity Index [SDAI]) and safety outcomes were compared using a Bayesian network meta-analysis. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results. A network meta-regression assessed the impact on outcomes of proportions of patients receiving concomitant methotrexate or of Asian ethnicity. Results The network meta-analysis included 21 randomized controlled trials. At 12 weeks, all evaluable efficacy outcomes were comparable or improved with peficitinib 150 mg and 100 mg once daily, versus baricitinib 2 and 4 mg once daily and tofacitinib 5 mg twice daily. At 24 weeks, efficacy outcomes were comparable or improved for each peficitinib dose versus baricitinib and tofacitinib. Risk of adverse events and serious adverse events at 12 weeks were similar with peficitinib 100 and 150 mg versus baricitinib and tofacitinib. The proportion of patients receiving concomitant methotrexate had no effect on any outcome analyzed, but Asian ethnicity had a positive effect on multiple efficacy outcomes. Conclusions Peficitinib had comparable efficacy versus tofacitinib and baricitinib for reduction in disease activity as measured by SDAI, and for reduction in progression of joint damage as measured radiographically. No notable differences in safety outcomes were observed. Further studies are required to better characterize the impact of ethnicity on the efficacy of JAK inhibitors. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00284-1.

Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program. Methods Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. Results Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years’ treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors. Conclusions For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

This study aimed to evaluate the impact of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) on lipid profile and atherogenic index of plasma (AIP) in rheumatoid arthritis (RA) patients and to compare the occurrence of dyslipidemia between patients using bDMARDs, tsDMARDs, or conventional DMARDs (cDMARDs).Data on lipid profile, AIP, and occurrence of dyslipidemia were collected from the Korean College of Rheumatology BIOlogics registry. A comparison was conducted between patients using bDMARDs (tumor necrosis factor (TNF)-α inhibitor, tocilizumab, abatacept), Janus kinase inhibitors (JAKis), and cDMARDs. The Kaplan-Meier method was used to compare the occurrence of dyslipidemia between groups, and hazard ratios (HR) were calculated using the cox proportional hazard method.The data of 917, 826, 789, 691, and 520 RA patients were eligible for analysis at the baseline, 1-year, 2-year, 3-year, and 4-year follow-ups, respectively. Baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were higher in the cDMARDs group, whereas AIP was comparable. During the 4-year follow-up, AIP was comparable between the groups. The occurrence of dyslipidemia did not show a significant difference when comparing the bDMARDs/tsDMARDs and cDMARDs groups (P=0.06) or the TNF-α inhibitor, tocilizumab, abatacept, JAKi, and cDMARD user groups (P=0.3). In the multivariate cox proportional hazard model, older age (HR=1.03, P=0.005) and concomitant hypertension (HR=2.21, P=0.013) were significantly associated with dyslipidemia occurrence.Long-term use of bDMARDs and tsDMARDs is relatively safe with regard to lipid profile, AIP, and the occurrence of dyslipidemia in RA patients. Key Points • The use of bDMARDs and tsDMARDs did not increase the risk of dyslipidemia than cDMARDs use in patients with RA. • AIP was comparable between bDMARDs user, tsDMARDs user, and cDMARDs user group in 4-year follow-up data. • Based on the present study, the long-term use of bDMARDs or tsDMARDs did not significantly deteriorate atherogenic lipid profile nor an increased risk of dyslipidemia in patients with RA.

Ulcerative colitis (UC) is a relapsing and remitting inflammatory disease of the colon with a variable course. Despite advances in treatment, only approximately 40% of patients achieve clinical remission at the end of a year, prompting the exploration of new treatment modalities. This review explores novel therapeutic approaches to UC, including promising drugs in various stages of development, efforts to maximize the efficacy of currently available treatment options, and non-medication-based modalities. Treatment approaches which show promise in impacting the future of UC management are highlighted.

Extramedullary hematopoiesis is widely known to occur in patients with primary myelofibrosis (PMF). Autopsy studies on individuals with PMF revealed that extramedullary hematopoiesis occurred in the kidneys in 35% of the cases, but there is little awareness regarding such lesions. A 63-year-old man was diagnosed with PMF based on a detailed examination of persistent high white blood cells. An examination of the patient’s medical records revealed an increased white blood cell count, deterioration of kidney function, and urinary protein excretion developed simultaneously. Thus, a kidney biopsy was performed. Advanced lymphocyte invasion was recognized in the interstitial tissue, and the tubular structure was highly disrupted. Based on these findings, he was diagnosed with interstitial nephritis. However, because of the large number of cells with nuclear atypia in the stroma, additional immunohistochemical staining was also performed, such as glycophorin A, naphthol AS-D, myeloperoxidase, and CD42b. As a result, invasion of three lineages of immature cells, erythroblasts, megakaryocytes, and granulocytes, was identified. Renal dysfunction resulting from interstitial cellular infiltration due to extramedullary hematopoiesis was therefore diagnosed. Treatment with ruxolitinib was initiated after a renal biopsy and the rate of decline in renal function was slightly reduced. Although, in myeloproliferative disorders, proliferative glomerular lesions are widely considered to be renal disorders, there is little awareness regarding interstitial lesions. Extramedullary hematopoiesis of the kidney in PMF is not uncommon, but 40% of cases are reportedly misdiagnosed as interstitial nephritis. Because extramedullary hematopoiesis can be controlled by ruxolitinib, early detection is important.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. This study evaluated the efficacy and safety of tofacitinib 5 mg twice daily monotherapy after methotrexate withdrawal. Methods: OPAL Balance was an open-label, long-term extension study of tofacitinib in patients with psoriatic arthritis who participated in the OPAL Broaden and OPAL Beyond phase 3 studies. This 12-month, randomised, double-blind, placebo-controlled, methotrexate withdrawal substudy (50 centres, 14 countries) included patients from OPAL Balance who completed tofacitinib treatment for 24 months or more (≥3 months' stable tofacitinib 5 mg twice daily) and were receiving methotrexate (7·5–20 mg/week). Patients were blindly randomised (1:1) using interactive response technology and received open-label tofacitinib 5 mg twice daily with either placebo (tofacitinib 5 mg twice daily plus placebo group) or continued methotrexate (tofacitinib 5 mg twice daily plus methotrexate group). Patients were masked to placebo or methotrexate, with identical capsules used. Coprimary endpoints were changes from substudy baseline in psoriatic arthritis disease activity score (PASDAS) and health assessment questionnaire-disability index (HAQ-DI) at month 6 in all randomised patients with one or more substudy drug dose. Safety was assessed throughout. No specific statistical hypothesis (either superiority or non-inferiority) was tested. The study (OPAL Balance) is registered with ClinicalTrials.gov ( NCT01976364) and is complete. Findings: Between Oct 30, 2017, and May 20, 2019, 180 patients from OPAL Balance who were eligible for the substudy were randomly assigned to treatment (90 patients received tofacitinib 5 mg twice daily plus placebo and 89 patients assigned to tofacitinib plus methotrexate; one patient was not treated because of randomisation error). At month 6, least squares mean (LSM) changes in PASDAS were 0·23 (SE 0·08) for tofacitinib 5 mg twice daily plus placebo and 0·14 (0·08) for tofacitinib 5 mg twice daily plus methotrexate (treatment difference LSM 0·09 [95% CI –0·13 to 0·31]), and changes in HAQ-DI were 0·04 (0·03) and 0·02 (0·03), respectively (treatment difference 0·03 [–0·05 to 0·10]). Rates of adverse events, discontinuations because of adverse events, adverse events of special interest, and laboratory changes were generally similar between treatment groups, although liver enzyme elevations were more common with tofacitinib 5 mg twice daily plus methotrexate than tofacitinib 5 mg twice daily plus placebo. Flares of worsening symptoms was reported in one (1%) of 90 patients in the tofacitinib 5 mg twice daily plus placebo group (recorded as psoriatic arthropathy). Interpretation: Some patients with psoriatic arthritis who are stable on tofacitinib 5 mg twice daily with background methotrexate might be able to discontinue methotrexate without clinically meaningful changes in disease activity and safety.

Objectives To evaluate real-world efficacy of approved JAK inhibitors (JAKi) tofacitinib and baricitinib in a large, single-centre cohort of RA patients across the treatment pathway, including those refractory to multiple biologic drugs. Methods All RA patients, treated with tofacitinib (from time of compassionate access scheme) or baricitinib since approval in 2017 had DAS28-CRP scores and components recorded at baseline, 3 and 6 months (with retrospective data for compassionate access scheme). Efficacy was evaluated in the total cohort, each treatment group, and subgroups of number of prior biologic classes failed. Results One hundred and fifteen patients were treated with a JAKi (tofacitinib 54, baricitinib 69, 8 both); 76.4% female; mean (s.d.) age 57.3 (14.3) years. On average patients had received three previous bDMARDs; 11 (9.6%) were bDMARD naïve. Combined group baseline DAS28-CRP (s.d.) 5.62(1.14) improved by 1.49(1.44) and 1.67(1.61) at 3 and 6 months, respectively, comparable in individual JAKi groups; with 24% in at least low disease activity at 3 months. The biggest improvement was observed in the biologic-naïve group (mean DAS28-CRP improved from 5.16–2.14 after 6 months); while those with prior exposure to minimum three bDMARD classes had DAS28-CRP improvement of >1.2. Five out of 8 patients treated with both JAKi sequentially responded. Twelve patients previously unresponsive to IL-6 blockade responded to JAKi. No unexpected safety events were recorded. Two cases of venous thromboembolism were observed. Conclusion JAK inhibition is effective in a real-world population of RA patients, including in a subset of patients refractory to multiple previous bDMARDs.

BACKGROUND Concomitant ulcerative colitis (UC) and idiopathic thrombocytopenic purpura (ITP) is a rare phenomenon. The management of UC with ITP can be challenging, since a decreased platelet count augments UC. CASE SUMMARY A 24-year-old man with UC and steroid-resistant ITP experienced UC flare. Although continuous infusion of cyclosporine was initiated, UC did not improve. The administration of tofacitinib subsequently led to the induction of remission. The patient has maintained remission of UC and ITP for over one year on tofacitinib treatment. Whole transcriptomic sequencing was performed for inflamed rectal mucosae obtained before and after the initiation of Janus kinase (JAK) inhibitor, suggesting that distinct molecular signatures seemed to be regulated by JAK inhibitors and other conventional therapies including tumor necrosis factor lockers. CONCLUSION Tofacitinib should be considered in refractory cases of UC with ITP.

Alopecia areata (AA) is a common autoimmune disorder causing nonscarring patchy hair loss. Alopecia totalis (AT) is a severe variant of AA. Although there are several available treatment modalities for AA, efficacy of most of them is not satisfactory in case of AT. Recently, several case reports and series and small open-label studies have shown efficacy of oral Janus kinase (JAK) inhibitors as treatment for AT. Tofacitinib is one of the JAK inhibitors, which is an approved drug for treatment of rheumatoid and psoriatic arthritis. In this case report, we have treated a 24-year-old girl who had juvenile chronic arthritis and developed AT. She was treated for 3 years with different modalities without satisfactorily results. We treated her with tofacitinib 5 mg orally twice a day and assessed its efficacy and adverse effects if any. We monitored scalp hair regrowth of the patient using the score of severity of alopecia tool. The patient tolerated the treatment well; hair regrowth started from the 4th week and full regrowth attained by the 9th month of the treatment. No serious adverse effects were noticed. Tofacitinib can potentially be considered as an effective and well-tolerated treatment for AT; however, larger studies are needed to address its long-term efficacy.

ObjectivesTo evaluate efficacy and safety of immediate switch from upadacitinib to adalimumab, or vice versa, in patients with rheumatoid arthritis with non-response or incomplete-response to the initial therapy.MethodsSELECT-COMPARE randomised patients to upadacitinib 15 mg once daily (n=651), placebo (n=651) or adalimumab 40 mg every other week (n=327). A treat-to-target study design was implemented, with blinded rescue occurring prior to week 26 for patients who did not achieve at least 20% improvement in both tender and swollen joint counts (‘non-responders’) and at week 26 based on Clinical Disease Activity Index (CDAI) >10 (‘incomplete-responders’) without washout.ResultsA total of 39% (252/651) and 49% (159/327) of patients originally randomised to upadacitinib and adalimumab were rescued to the alternate therapy. In both switch groups (adalimumab to upadacitinib and vice versa) and in non-responders and incomplete-responders, improvements in disease activity were observed at 3 and 6 months following rescue. CDAI low disease activity was achieved by 36% and 47% of non-responders and 45% and 58% of incomplete-responders switched to adalimumab and upadacitinib, respectively, 6 months following switch. Overall, approximately 5% of rescued patients experienced worsening in disease activity at 6 months postswitch. The frequency of adverse events was similar between switch groups.ConclusionsThese observations support a treat-to-target strategy, in which patients who fail to respond initially (or do not achieve sufficient response) are switched to a therapy with an alternate mechanism of action and experience improved outcomes. No new safety findings were observed despite immediate switch without washout.

Background Atopic dermatitis (AD) is a common chronic, inflammatory skin condition. The pathogenesis of AD involves many cytokines that utilize the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling cascade; therefore, JAK inhibitors may be used in the treatment of AD. This review aims to evaluate the pathophysiology, efficacy, and safety of JAK inhibitors and their emerging role as a therapeutic option for patients with AD. Methods A PubMed search of Phase I, II, and III clinical trials was conducted for relevant literature published between January 2015 and June 2020 utilizing the key terms: JAK inhibitors, atopic dermatitis, efficacy, safety, and treatment. The search was subsequently expanded to include additional terms. Results In multiple Phase II and III clinical trials, JAK inhibitors were more efficacious than placebo or vehicle controls and slightly more efficacious in direct comparisons to corticosteroids. Overall, JAK inhibitors have a moderate safety profile for use in AD. Some of the more severe theoretical adverse events included thrombosis and reactivation of viral infections. While data remain limited for the long-term efficacy and safety of JAK inhibitor use in patients with AD, many ongoing clinical trials have promising preliminary results. Discussion Short-term data suggest that both topical and oral JAK inhibitors are efficacious and safe for use in patients with AD, although cases of thrombosis and viral disease have been reported. While the current standard treatments for AD are likely preferred, failed therapy with these agents or corticosteroid phobia may be indications for the use of JAK inhibitors in patients with AD.

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. We evaluated radiographic progression in tofacitinib-treated patients with RA for up to 3 years in two pooled long-term extension (LTE) studies (ORAL Sequel; A3921041) (primary analysis), and for up to 5 years using data integrated from one phase (P)2 (A3921068), two P3 (ORAL Start; ORAL Scan) and two LTE studies (exploratory analysis). Methods In LTE studies, patients received tofacitinib 5 mg twice daily (BID) or 10 mg BID as monotherapy or with conventional synthetic (cs)DMARDs. Radiographic outcomes up to 3 years: least squares mean (LSM) change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS), erosion score (ΔES) and joint space narrowing (ΔJSN) score; proportion of patients with no radiographic progression (ΔmTSS ≤0.5); proportion of patients with no new erosions (ΔES ≤0.5). ΔmTSS was evaluated for up to 5 years in an exploratory analysis. Results For all tofacitinib-treated patients with radiographic data available at LTE month 36 (n = 414), LSM ΔmTSS was 1.14, LSM ΔES was 0.66, LSM ΔJSN was 0.74, and 74.3% and 86.2% of patients showed no radiographic progression and no new erosions, respectively. Similar values were observed regardless of tofacitinib dose, or whether patients received tofacitinib as monotherapy or with csDMARDs. In an exploratory analysis of integrated P2/P3/LTE studies, LSM ΔmTSS was 3.34 at month 60 (n = 269). Conclusion Limited progression of structural damage was observed in tofacitinib-treated patients up to 5 years, with similar results for tofacitinib used as monotherapy or combination therapy up to 3 years. Trial registration ClinicalTrials.gov (http://clinicaltrials.gov): NCT01164579; NCT01039688; NCT00847613; NCT00413699; NCT00661661.

Background Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulatio...