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Abstract Background Sarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways. Despite having a list of drugs capable of treating RA inflammation, their effect on muscle is unclear. Our objective was to evaluate the tofacitinib effect on the muscle mass of collagen-induced arthritis (CIA) mice. Methods CIA was induced in male DBA/1J mice by subcutaneous injection of Type 2 Collagen plus Freund Adjuvant. Animals were randomized into 3 groups: CIA + tofacitinib; CIA + vehicle; and healthy controls. Treatment was administered twice a day, between days 18 and 45 after induction. Clinical score, edema, and body weight were evaluated during the experimental period. After euthanasia, tibiotarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Protein expression was evaluated by western blot using GA homogenates. Serum inflammatory markers were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey’s or with Kruskal-Wallis. The statistical difference was assumed for p

Background: Janus kinase (JAK) inhibitors are promising for inflammatory bowel diseases (IBDs), but their long-term safety, including risks of nonmelanoma skin cancer (NMSC), is uncertain. Objectives: The objective of the study was to conduct a systematic review and meta-analysis to examine the risk of NMSC in patients taking JAK inhibitors for IBDs during the induction trial, maintenance trial, and long-term extension (LTE) of treatment. Methods: We searched the PubMed, Embase, and Cochrane databases to identify studies reporting NMSC with the use of JAK inhibitors. Results: In total, we retained 22 references that included 31 trials for a qualitative systematic review and 28 trials for a quantitative meta-analysis. Average risk differences were < 0.0001 (P = 0.980) in induction trials, 0.002 (P = 0.546) in maintenance trials, and 0.019 (P = 0.012) in LTE trials. Subgroup analyses showed that there were no significant differences between generic drugs, trial phases, ages, or genders. Conclusion: In patients with an IBD, there was no statistically significant difference in the risk probability of NMSC occurrence whether or not JAK inhibitors were used, regardless of the follow-up period during induction and maintenance studies. Furthermore, the overall estimated NMSC incidence rate was significantly higher than the reference incidence. Although large heterogeneity among trials, both gastroenterologists and dermatologists still should be cautious of appropriate skin screening for IBD patients using JAK inhibitors.

Background/Aims The aim of this study was to compare the short- and long-term retention rates of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in Korean patients with seropositive rheumatoid arthritis. Methods This study was conducted with 1,538 treatment courses of 1,063 patients, including adalimumab (n = 332), etanercept (n = 369), infliximab (n = 146), abatacept (n = 152), tocilizumab (n = 299), tofacitinib (n = 136), and baricitinib (n = 104), in patients with seropositive rheumatoid arthritis who started b/tsDMARD treatment between 2008 and 2020 at Seoul St. Mary’s Hospital. Discontinuation 1 and 3 years after the first prescription of each drug was investigated. Kaplan– Meier estimates of time to discontinuation were calculated to compare the difference in drug retention rate for each drug. Patient-level predictors of drug discontinuation were evaluated using a Cox proportional hazards model. Results The overall 1-year drug retention rate was from 60.1% for adalimumab to 90.0% for tofacitinib in the b/tsDMARD-naïve group, and from 55.2% for infliximab to 84.8% for tofacitinib in the b/tsDMARD-experienced group. The 3-year drug retention rate was from 36.9% for infliximab to 86.5% for tofacitinib in the b/tsDMARD-naïve group, and from 31.0% for infliximab to 65.4% for tocilizumab in the b/tsDMARD-experienced group. Drug discontinuation appeared to be affected by specific types of b/tsDMARDs. Conclusions Tocilizumab and tofacitinib are less commonly discontinued compared to tumor necrosis factor-α inhibitors at 1 and 3 years. Specifically, tofacitinib in the b/tsDMARD-naïve group and tocilizumab in the b/tsDMARD-experienced group showed the highest 3-year retention rates.

Background: Chronic spontaneous urticaria (CSU) is a distressing skin condition characterized by the recurrent appearance of itchy hives. A subset of CSU patients remains resistant to conventional treatment with high-dose antihistamines. Tofacitinib, a Janus kinase inhibitor, has shown promise in various inflammatory skin diseases. We aimed to evaluate the efficacy of oral tofacitinib in patients with CSU resistant to antihistamines. Methods: This study examined data retrospectively from seven patients who were diagnosed with CSU and were treated with tofacitinib for at least six months. These patients initially exhibited resistance to treatment with four-fold up-dosed antihistamines. One of the patients was already on omalizumab, and another was tried on cyclosporine. The patients were administered oral tofacitinib at a dosage of 5 mg twice daily for six months. Patients were followed up monthly for disease control and side effects. The response to treatment was evaluated using the urticaria activity score over 7 days (UAS7) and urticaria control test (UCT). Paired t-tests were conducted to determine the statistical significance of the results using SPSS version 25 software. Results: Six out of the seven patients demonstrated a significant improvement in both UAS7 and UCT scores after six months of treatment with oral tofacitinib. The mean UAS7 score decreased from 24.86 at baseline to 3.83 at the study endpoint (P < 0.0001). Similarly, the mean UCT score increased from 0.57 at baseline to 14 at the study endpoint (P < 0.0001). The standard deviations for both measures were 4.85 and 0.98 at baseline and 3.1 and 3.1 at the study endpoint for UAS7 and UCT, respectively. Conclusion: In this six-month follow-up study, oral tofacitinib demonstrated significant efficacy in treating CSU patients’ resistant to high-dose antihistamines. Most patients experienced a remarkable reduction in urticaria activity and an improvement in disease control. These findings suggest that tofacitinib holds promise as a potential therapeutic option for this challenging subset of CSU patients. However, larger, randomized controlled trials are warranted to further investigate the long-term safety and effectiveness of tofacitinib in this population.

Abstract Background Patients with rheumatoid arthritis (RA) have an increased risk of developing serious infections (SIs) vs. individuals without RA; efforts to predict SIs in this patient group are ongoing. We assessed the ability of different machine learning modeling approaches to predict SIs using baseline data from the tofacitinib RA clinical trials program. Methods This analysis included data from 19 clinical trials (phase 2, n = 10; phase 3, n = 6; phase 3b/4, n = 3). Patients with RA receiving tofacitinib 5 or 10 mg twice daily (BID) were included in the analysis; patients receiving tofacitinib 11 mg once daily were considered as tofacitinib 5 mg BID. All available patient-level baseline variables were extracted. Statistical and machine learning methods (logistic regression, support vector machines with linear kernel, random forest, extreme gradient boosting trees, and boosted trees) were implemented to assess the association of baseline variables with SI (logistic regression only), and to predict SI using selected baseline variables using 5-fold cross-validation. Missing values were handled individually per prediction model. Results A total of 8404 patients with RA treated with tofacitinib were eligible for inclusion (15,310 patient-years of total follow-up) of which 473 patients reported SIs. Amongst other baseline factors, age, previous infection, and corticosteroid use were significantly associated with SI. When applying prediction modeling for SI across data from all studies, the area under the receiver operating characteristic (AUROC) curve ranged from 0.656 to 0.739. AUROC values ranged from 0.599 to 0.730 in data from phase 3 and 3b/4 studies, and from 0.563 to 0.643 in data from ORAL Surveillance only. Conclusions Baseline factors associated with SIs in the tofacitinib RA clinical trial program were similar to established SI risk factors associated with advanced treatments for RA. Furthermore, while model performance in predicting SI was similar to other published models, this did not meet the threshold for accurate prediction (AUROC > 0.85). Thus, predicting the occurrence of SIs at baseline remains challenging and may be complicated by the changing disease course of RA over time. Inclusion of other patient-associated and healthcare delivery-related factors and harmonization of the duration of studies included in the models may be required to improve prediction. Trial registration ClinicalTrials.gov: NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT02831855; NCT02092467.

Although Janus kinase inhibitor (JAKi) therapy is used for patients with autoimmune diseases (AD), one safety concern, interstitial lung disease (ILD), is life-threatening. We evaluated actual usage of JAKi and safety upon JAKi treatment, in an epidemiological retrospective cohort study utilizing the electronic medical record database in Japan. Among 391,565 AD patients, we analyzed data of new-users receiving JAKi or tumor necrosis factor alpha inhibitor (TNFi)/biologics during the period July 2013–May 2022. ILD (ICD10: J70.2, J70.3, J70.4 and J84) criteria were defined: new-ILD (1) and new-ILD (2) which differed in the latter’s prompter therapeutics cessation upon ILD development. We analyzed ILD occurrence and death, ILD cumulative incidence by the Kaplan–Meier method, and hazard ratio (HR) by the Cox model, for 957 JAKi and 3931 TNFi users. JAKi use has become widespread amidst additional drug-development. Among JAKi users, two-year new-ILD (2) incidence, at 1.4%, was higher than for TNFi users (risk ratio: new-ILD (2) 1.75, death 2.31). Cumulative incidence (2.9% in 20.48 days) was also significantly higher (log-rank test p = .013, HR 2.23 (95% CI 1.16–4.27)); risk factors estimated by HR included JAKi (2.14), rheumatoid arthritis (4.94), diabetes mellitus (2.67) and cerebrovascular disease (2.86). ILD screening is essential.

Abstract Background Current strategies that target cytokines (e.g., tumor necrosis factor (TNF)-α), or signaling molecules (e.g., Janus kinase (JAK)) have advanced the management for allergies and autoimmune diseases. Nevertheless, the molecular mechanism that underpins its clinical efficacy have largely remained elusive, especially in the local tissue environment. Here, we aimed to identify the genetic, epigenetic, and immunological targets of JAK inhibitors (JAKis), focusing on their effects on synovial fibroblasts (SFs), the major local effectors associated with destructive joint inflammation in rheumatoid arthritis (RA). Methods SFs were activated by cytokines related to inflammation in RA, and were treated with three types of JAKis or a TNF-α inhibitor (TNFi). Dynamic changes in transcriptome and chromatin accessibility were profiled across samples to identify drug targets. Furthermore, the putative targets were validated using luciferase assays and clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. Results We found that both JAKis and the TNFi targeted the inflammatory module including IL6. Conversely, specific gene signatures that were preferentially inhibited by either of the drug classes were identified. Strikingly, RA risk enhancers for CD40 and TRAF1 were distinctively regulated by JAKis and the TNFi. We performed luciferase assays and CRISPR-based genome editing, and successfully fine-mapped the single causal variants in these loci, rs6074022-CD40 and rs7021049-TRAF1. Conclusions JAKis and the TNFi had a direct impact on different RA risk enhancers, and we identified nucleotide-resolution targets for both drugs. Distinctive targets of clinically effective drugs could be useful for tailoring the application of these drugs and future design of more efficient treatment strategies.

Background. Clinical guidelines for the treatment of rheumatoid arthritis (RA) recommend reducing the use of glucocorticoids (GCs) due to the high risk of associated complications. Aim. To determine the frequency of GC cancellations and dose reductions in real clinical practice, while taking into account active RA therapy. Materials and methods. The study group consisted of 303 patients with RA reliable according to ACR/EULAR criteria (women 79.9%, age 52.8±13.3, disease duration 9 [4; 16] years, DAS-28-CRP 4.9±1.0, RF seropositivity 77.4%, ACPA seropositivity 70.3%), who were prescribed or changed therapy with disease-modifying antirheumatic drugs (DMARDs), biologic disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (iJAK) due to disease exacerbation and ineffectiveness of previous treatment. All patients initially received GC (7.7±3.8 mg/day equivalent of prednisolone). After adjustment of therapy, 42.9% of patients received methotrexate, 27.6% leflunomide, 2.5% sulfasalazine, hydroxychloroquine, or a combination with an Non-steroidal anti-inflammatory drugs, 63.7% bDMARDs, and 7.2% iJAK. The need for GC intake was assessed by a telephone survey conducted 6 months after the start of follow-up. Results. Telephone survey was possible in 274 (90.4%) persons. There was a significant decrease in pain intensity (numerical rating scale, NRS 0–10) from 6.3±1.4 to 4.3±2.4 (p0.001), fatigue (NRS) from 6.7±2.3 to 5.2±2.1 (p0.001), and functional impairment (NRS) from 5.4±2.1 to 3.9±2.0 (p0.001). A positive PASS index (symptom status acceptable to patients) was noted in 139 (50.7%) patients. GC cancellation was noted in 19.7%, dose reduction in 25.9%, maintaining the same dose in 42.7%, and dose increase in 11.7%. Conclusion. Against the background of intensive RA therapy, including combination of DMARDs with bDMARDs or iJAK, complete withdrawal or reduction of GC dose was achieved in less than half (45.6%) of patients after 6 months.

Background: The risk of cardiovascular disease in atopic dermatitis (AD) is not well established. Objectives: Our aims were to evaluate the incidence rate (IR) of venous thromboembolism (VTE) in patients with AD in a population-based cohort study and to assess atherosclerotic cardiovascular disease (ASCVD) risk factors and incidence of malignancies, major adverse cardiovascular events (MACE), and VTE in patients with AD and rheumatoid arthritis (RA) in a nested cohort analysis. Methods: Data from individuals age 12 years or older (nested cohort age ≥ 18 years) from January 1, 2000, to December 31, 2018, were extracted from the Danish National Patient Registry. Patients with AD were age- and sex-matched with 10 healthy controls. ASCVD risk factors included age 65 years or older and history of smoking, coronary artery disease, stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and malignancy. Results: The population-based cohort comprised 190,751 patients (17,341 patients with AD and 173,410 healthy controls). The IRs per 100 patient-years were comparable between the AD cohort and healthy controls for VTE (0.14 [95% CI = 0.12-0.16] vs 0.11 [95% CI = 0.11-0.12]), DVT (0.08 [95% CI = 0.06-0.09] vs 0.06 [95% CI = 0.06-0.07]), and PE (0.06 [95% CI = 0.05-0.08] vs 0.05 [95% CI = 0.05-0.05]). The IR for VTE was higher in the AD cohort age 65 years or older (0.71 [95% CI = 0.56-0.90]) than in the age-matched controls (0.50 [95% CI = 0.46-0.54]). ASCVD risk factors were more frequent in the patients with RA than in the patients with AD. The IRs for malignancies and MACE were higher with specific ASCVD risk factors. Conclusions: The IRs of cardiovascular events were comparable between the AD cohort and general population. The risk of VTE, malignancy, or MACE was higher with specific ASCVD risk factors, underscoring the need for patient monitoring.

The use of drugs off-label for managing COVID-19 offers a potential approach. Among these potential drugs, tofacitinib, a JAK inhibitor, is strongly implicated in its ability to mitigate mortality by attenuating the cytokine storm syndrome. This study systematically reviewed and quantitatively assessed the effectiveness and safety profile of tofacitinib use through meta-analysis. Through searches of the PubMed, Scopus, and the Cochrane Library databases up to May 31, 2024, six articles meeting inclusion criteria were identified, encompassing 669 patients diagnosed with COVID-19. The review findings indicate that tofacitinib use demonstrates significant clinical efficacy, as evidenced by a reduced risk of mortality (P = 0.003), and a decreased need for invasive mechanical ventilation (P = 0.0002). Furthermore, tofacitinib use is not correlated with an increased risk of adverse drug reactions (P = 0.98), indicating a favorable safety profile. In conclusion, the evidence supports the clinical efficacy of tofacitinib for COVID-19 patients without concomitant risks of adverse effects. Further clinical studies, especially larger-scale randomized controlled trials, are necessary to validate the findings of this study.

Background and purpose: Outcomes for cancer patients with steroid-resistant immune checkpoint inhibitor-associated myocarditis (srICIAM) are poor. Intensified immunosuppressive therapies, including tofacitinib, a novel Janus kinase (JAK) inhibitor, may have some therapeutic benefits. However, due to the lack of sufficient clinical data, the effectiveness of such treatments and their impact on cardiovascular outcomes remain unclear. This study aimed to investigate the therapeutic effect of tofacitinib on srICIAM. Methods: This retrospective case-control study included 36 malignant tumor patients who received immune checkpoint inhibitor treatment at Zhongshan Hospital affiliated to Fudan University from July 2019 to May 2022 and developed srICIAM. Patients receiving corticosteroids in combination with tofacitinib were assigned to the tofacitinib group (n=19), while those not treated with tofacitinib were allocated to the control group (n=17). The study compared clinical characteristics, laboratory findings, and imaging results between the two groups. Additionally, follow-up was conducted to monitor the incidence of cardiovascular endpoints in these patients. The research plan was approved by the Ethics Committee of Zhongshan Hospital Affiliated to Fudan University (Approval Number: B2021-275R). This study was conducted in accordance with the ethical guidelines of the Helsinki Declaration. Results: Compared to the control group, and with no significant difference in the cumulative dose and duration of corticosteroids (P

Abstract Introduction Upadacitinib (UPA), a selective, reversible, oral Janus kinase (JAK)-1 inhibitor, was approved in 2019 in Canada for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). This phase 4 prospective study aimed to characterise the effectiveness of UPA in the real-world population of patients with RA. Methods Adults with RA who initiated treatment with once daily UPA (15 mg) and enrolled in the Canadian Real-Life post-marketing Observational Study assessing the Effectiveness of UPadacitinib for treating rheumatoid arthritis (CLOSE-UP) and who completed a 6-month assessment as of 28 February 2023 were included. The primary endpoint of the CLOSE-UP study is the proportion of patients achieving a Disease Activity Score-28 Joint Count C-reactive protein (DAS28-CRP)

AbstractBackground Previous clinical trials presented efficacy and safety of Janus kinase 1 inhibitor upadacitinib through 52 weeks for moderate-to-severe atopic dermatitis (AD).Objectives To assess the effectiveness and safety of upadacitinib through 48 weeks in real-world clinical practice for Japanese AD patients (aged ≥12 years).Methods This retrospective study included 287 patients with moderate-to severe AD treated with 15 mg (n = 216) or 30 mg (n = 71) of upadacitinib daily. Effectiveness was assessed using eczema area severity index (EASI) scores, atopic dermatitis control tool (ADCT), peak pruritus-numerical rating scale (PP-NRS), and investigator’s global assessment (IGA). Safety was evaluated through the incidence of treatment-emergent adverse events.Results From baseline, EASI, ADCT, PP-NRS, and IGA rapidly reduced at week 4, and the reduction was maintained until week 48 of treatment with upadacitinib at both doses. Achievement rates of EASI 75, EASI 90, and EASI 100 at week 48 were 63.5, 30.2, and 7.9 in 15 mg group, and 77.4, 54.8, and 3.2% in 30 mg group, respectively. Acne and herpes zoster were frequent, but no serious adverse events occurred.Conclusions Upadacitinib was therapeutically effective and tolerable for moderate-to-severe AD through 48 weeks in real-world clinical practice.

AbstractPurpose: For individuals with atopic dermatitis (AD), interpreting scientific papers that present clinical outcomes including the Eczema Area and Severity Index (EASI) and Investigators Global Assessment may be difficult. When compared to tabulated data and graphs, images from before and after treatment are often far more meaningful to these patients that ultimately will be candidates for the treatment. This systematic review focused on determining the frequency of clinical image sharing in AD research.Materials and methods: Conducted in accordance with PRISMA guidelines, the review concentrated on randomized controlled trials that investigated predefined and available systemic treatments for AD. The search was performed in the MEDLINE database for studies published from the inception until 21 December 2023.Results: The review included 60 studies, encompassing 17,799 randomized patients. Across these studies, 16 images representing 6 patients were shared in the manuscripts, leading to a sharing rate of 0.3‰.Conclusions: The almost missing inclusion of patient images in clinical trial publications hinders patient understanding. Adding images to scientific manuscripts could significantly improve patients’ comprehension of potential treatment outcomes. This review highlights the need for authors, the pharmaceutical industry, study sponsors, and publishers to enhance and promote patient information through increased use of visual data.

AbstractIn this report, we describe the case of a 28-year-old female with bilateral breast cancer in the setting of a BRCA1 mutation, who presented to dermatology with an eczematous reaction, ultimately diagnosed as a cutaneous immune-related adverse event (cirAE) secondary to an immune checkpoint inhibitor (ICI), pembrolizumab. Our case report highlights a novel therapeutic option for an eczematous cirAE: the topical JAK 1/2 inhibitor, ruxolitinib. CirAEs can occur in up to 55% of patients on ICIs, a class of medications seeing rapidly increasing use in cancer therapy, and prior research has demonstrated that ICI-induced dermatitis may involve different pathways than traditionally observed in their spontaneous counterparts. Specifically, marked Th1 skewing is noted in ICI-induced dermatitis, as opposed to a predominant Th2 response which typically characterizes spontaneous atopic dermatitis. To our knowledge, this is the first case report in the literature discussing use of a topical JAK inhibitor, ruxolitinib, in the treatment of topical steroid-refractory cirAEs. Furthermore, as topical JAK inhibitors are thought to not carry the risks of systemic JAK inhibitors, including malignancy, ruxolitinib cream is a promising therapeutic option for this challenging patient population.

AbstractBackground Janus kinase 1 inhibitor upadacitinib is therapeutically effective for atopic dermatitis (AD). However, predictive factors for high responders to upadacitinib have not been established in real-world clinical practice.Objectives To identify predictive factors for responders to upadacitinib 15 mg or 30 mg, defined as achievers of investigator’s global assessment (IGA) 0/1 with ≥ 2-point improvement from basal IGA.Methods A retrospective study was conducted from August 2021 to July 2023 on 159 AD patients treated with upadacitinib 15 mg and 52 patients with 30 mg. Patients in each group were categorized into responders (achievers of IGA 0/1 at week 12) and non-responders (non-achievers). We compared baseline values of clinical and laboratory parameters between responders and non-responders. Logistic regression analysis was used to detect variables predicting responders. Receiver-operating characteristic curves were used for evaluating prediction capabilities of the variables.Results In logistic regression analysis, responders to 15 mg upadacitinib were associated with lower total EASI and higher age whereas responders to 30 mg were associated with lower LDH and lower IgE.Conclusions Lower total EASI and higher age may predict responders to upadacitinib 15 mg while lower IgE and lower LDH may predict responders to 30 mg.

AbstractBackground Though Janus kinase inhibitors such as upadacitinib rapidly relieve itch in atopic dermatitis (AD) patients, how early itch relief impacts later skin clearance is not examined.Objectives This study aims to determine if early itch relief by upadacitinib could predict complete skin clearance in later phases.Methods This retrospective study involved 105 patients with moderate-to-severe AD treated with upadacitinib 15 mg/day. Eczema area and severity index (EASI), atopic dermatitis control tool, and achievement rate of EASI 100 were evaluated at weeks 4, 12, and 24. The threshold of early peak pruritus-numerical rating scale (PP-NRS) predicting later skin clearance was assessed by area under the receiver-operating characteristic curve, and predictors for EASI 100 achievement were determined by logistic regression analysis.Results The rate of achieving EASI 100 at week 24 was extremely higher in patients who achieved week 2 PP-NRS ≤ 1 (42.9%) than in non-achievers (1.4%). The logistic regression analysis showed that the achievement of week 2 PP-NRS ≤ 1 and low body mass index were associated with achievement of EASI 100 at weeks 12 and 24.Conclusions The achievement of week 2 PP-NRS ≤ 1 may predict later skin clearance in upadacitinib treatment.

Atopic dermatitis (AD) is a chronic, recurrent dermatosis that affects an increasing percentage of the population. It usually affects children and resolves spontaneously, however, symptoms can persist into adulthood and even appear de novo later in life. The skin lesions that appear in this disease significantly reduce patients quality of life. Visual skin symptoms are exacerbated during stress, and pruritus leads to sleep problems. The effect of an inadequately controlled disease can even be a reduction in social activities and a reluctance to leave the house. The basis of treatment is skin care using emollients and avoiding triggers and aggravating factors. In the next stage, the doctor may prescribe topical or systemic treatment for the patient, depending on the severity of the disease. Such measures may not be enough, so more and more new drugs are being registered for the treatment of atopic dermatitis. One of them is upadacitinib, which appears to be extremely effective compared to other medications used to treat moderate to severe ad. It is a selective JAK inhibitor that reduces the inflammatory response by inhibiting migration, proliferation and cytokine secretion by granulocytes. It brings rapid and sustained effects in reducing skin lesions and reducing one of the most bothersome symptoms, pruritus.It may serve as a good alternative to the existing methods for treating moderate to severe atopic dermatitis The purpose of our study is to describe this new drug, its mechanism of action and discuss its possible benefits versus side effects.

Abstract Recent data, indicating that inflammatory bowel disease (IBD) may be a risk factor for future chronic kidney disease, highlight the need to study the safety and clinical effectiveness of advanced IBD therapies in patients with end stage renal disease (ESRD), defined as an eGFR

Chrong-Reen Wang,1 Wei-Chieh Lin,2 Tak-Wah Wong3 1Division of Rheumatology and Immunology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 2Division of Critical Care Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 3Department of Dermatology, National Cheng Kung University Hospital, Tainan, TaiwanCorrespondence: Chrong-Reen Wang, Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan, 70403, Taiwan, Email wangcr@mail.ncku.edu.twIntroduction: In East Asia, more than half of patients with amyopathic dermatomyositis (ADM) have interstitial lung disease (ILD). There is up to 50% 6-month mortality in MDA5-positive ILD refractory to corticosteroid (CS) combined with immunosuppressant therapy.Patient Details: A 39-year-old local woman had a 1-month history of reddish-purple discoloration around the eyelids (heliotrope rash), and erythematous areas on the upper back and posterior neck (shawl sign) as well as on the front of her chest (V sign), followed by dry cough and mild dyspnea for 1 week. She had normal muscle strength, muscle-enzyme concentrations, and muscular magnetic resonance images. Laboratory tests showed hypoxemia, increased ferritin and CRP levels, and positive MDA5 antibodies. High-resolution chest computed tomography revealed bilateral ground-glass opacity. She received a diagnosis of anti-MDA5-positive ADM with early-stage ILD.Intervention: Pulse methylprednisolone and cyclophosphamide therapies were initiated, followed by high-dose CS treatment. Immediate-release twice-daily 5 mg tofacitinib (Tof) has been demonstrated to be effective induction therapy for early-stage ILD in anti-MDA5-positive ADM. Owing to the patient’s preference for once-daily therapy, 11 mg extended-release Tof was prescribed 4 weeks after starting the initial pulse CS treatment for ILD.Outcomes: Respiratory symptoms and cutaneous manifestations were absent and the use of CS spared 5 months after initiating Tof therapy. Laboratory examinations exhibited normalized ferritin/oxygen levels, and chest images displayed completely resolved pulmonary infiltration. ILD remains under adequate control with Tof monotherapy without recurrence at 5 months.Lessons: Owing to a rapid decline in higher mortality in anti-MDA5-positive ADM patients with ILD, early detection with prompt initiation of extended-release Tof induction therapy might achieve a beneficial outcome.Keywords: amyopathic dermatomyositis, positive MDA5 antibody, interstitial lung disease, extended-release tofacitinib, Janus kinase inhibitor

A treat-to-target approach was recently developed to guide systemic treatment for adults with atopic dermatitis (AD). Recommendations outlined criteria for a 3-month initial acceptable treatment target and a 6-month optimal target, evaluated using global assessment of patient-reported disease severity, as well as Eczema Area and Severity Index, itch assessed on an 11-point numerical rating scale, Dermatology Life Quality Index, or Patient-Oriented Eczema Measure. Achievement of these targets with once-daily upadacitinib (15 mg and 30 mg) monotherapy was evaluated using integrated adult data from the Measure Up 1 and 2 phase 3 studies. Among the 852 patients treated with upadacitinib 15 mg or 30 mg, the 3-month initial acceptable target was achieved by >80%, >78%, and ≥87% of patients, and the 6-month optimal target was achieved by ≥53%, >61%, and >73% of patients at weeks 2, 16, and 52, respectively. Achievement of all 6 individual criteria for each of the target goals also increased over time. These findings suggest that upadacitinib 15 mg and 30 mg may help improve standards of care in patients with moderate-to-severe AD by achieving 6-month target goals at 16 weeks and as early as 2 weeks for most patients.

BackgroundAtopic dermatitis (AD) is a chronic skin disease characterized by type 2-skewed immune responses, and significantly influenced by cytokines dependent on Janus kinases (JAKs). Upadacitinib, a JAK1 inhibitor, is effective for moderate-to-severe AD. This study aims to identify biomarkers that reflect long-term therapeutic effects of upadacitinib 15 mg or 30 mg.MethodsA retrospective study from August 2021 to July 2023 included 213 AD patients treated with upadacitinib 15 mg and 70 AD patients with 30 mg. We analyzed eczema area and severity index (EASI), peak pruritus-numerical rating scale (PP-NRS), serum immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), and total eosinophil count (TEC) at weeks 0, 4, 12, 24, 36, and 48 of treatment.ResultsBoth treatments with upadacitinib 15 mg and 30 mg significantly reduced EASI and PP-NRS scores over week 4 to 48 compared to baseline. Upadacitinib 15 mg or 30 mg treatment significantly decreased TEC compared to baseline through week 4 to 36 or week 4 to 48, respectively. The percent reduction of TEC correlated with those of EASI and PP-NRS through week 4 to 48 of treatment with upadacitinib 15 mg, or through week 12 to 48 with 30 mg, respectively. After adjusting for % reductions of other laboratory markers, the significance of correlations was preserved at weeks 36 and 48 of 15 mg treatment, while at weeks 4 and 36 of 30 mg treatment.ConclusionThe % reduction of TEC correlated with those of EASI and PP-NRS during upadacitinib treatment, indicating its potential as a biomarker reflecting treatment responses to upadacitinib in AD patients. However, the variability of significant correlation during treatment indicates that further inspection is needed for its usefulness in monitoring responses to upadacitinib treatment for AD.

Psoriasis and atopic dermatitis (AD) are prevalent inflammatory skin disorders, each stemming from diverse factors, and characterized by recurring episodes. In certain complex cases, the clinical and pathological features exhibit overlapping and atypical characteristics, making accurate clinical diagnosis and targeted treatment a challenge. Psoriasiform dermatitis is the term used to describe such cases. Moreover, when patients have a history of malignancy, the situation becomes even more intricate, resulting in limited treatment options. Biologic therapies have transformed the management of immune-mediated inflammatory diseases, including psoriasis and AD. Meanwhile, the safety of biologics in special populations, especially among patients with a history of malignancy, should be underlined. The selective Janus kinase 1 (JAK1) inhibitor abrocitinib has been approved for the treatment of AD and has showed satisfying efficacy and safety in the treatment of psoriasis in clinical trials. Although unreported, JAK1 inhibitors are thought to have the potential to increase the risk of potential tumors. Apremilast, an oral phosphodiesterase (PDE)-4 inhibitor, is approved for moderate to severe plaque psoriasis. It has been investigated for its efficacy in AD, and is not contraindicated in malignancy. This report presents three cases of psoriasiform dermatitis in patients with a history of malignancy, showcasing significant improvement following treatment with systemic glucocorticoid, abrocitinib, or apremilast.

Abstract Objectives Juvenile dermatomyositis (JDM) is a chronic autoimmune disease. Some patients remain in an active state even though they were administrated with a combination of corticosteroid and methotrexate. Existing research has suggested that interferon and Janus kinase played an important role in pathogenesis. Existing research has suggested the efficacy of JAK inhibitors (JAKi). Our retrospective study aimed to investigate the efficacy of tofacitinib in refractory JDM patients. Methods A total of eighty-eight patients in China who had been diagnosed with JDM and subjected to tofacitinib therapy for over 3 months were retrospectively analyzed. Skin and muscle manifestations were assessed using the Cutaneous Assessment Tool-binary method (CAT-BM), Childhood Myositis Assessment Scale (CMAS), and kinase. Pulmonary function was assessed using a high-resolution CT (computerized tomography) scan and pulmonary symptoms. All patients were subjected to regular follow-up, and core measures were assessed every 3 months after initiation. Furthermore, the data were analyzed using the Wilcoxon single test, Mann–Whitney U test, and chi-square test. Results Compared with the baseline data, skin and muscle manifestations were found significantly improved during the respective follow-up visit. At the most recent follow-up, nearly 50% of patients achieved a clinical complete response and six patients received tofacitinib monotherapy. Sixty percent of patients suffering from interstitial lung disease well recovered on high-resolution CT. Seventy-five percent of patients showed a reduction in the size or number of calcinosis, and 25% of patients showed completely resolved calcinosis. Conclusion In this study, the result suggested that tofacitinib therapy exerted a certain effect on skin manifestations, muscle manifestations, interstitial lung disease (ILD), calcinosis, as well as downgrade of medication. In-depth research should be conducted to focus on the correlation between the pathogenesis of JDM and JAKi.

Abstract Background Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study. Methods Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported. Results Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population. Conclusions Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure. Trial registration NCT02049138.

Background/Aims We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease-modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. Methods A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)–28– erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). Results Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. Conclusions Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

AbstractJanus kinase inhibitors (JAKis) are a group of drugs with a different mechanism of action from biologics and are most rapidly uptaken in the rheumatology field. JAK is a protein kinase activated in the cytoplasm by multiple cytokines and hormones involved in inflammatory pathology. The expression of JAK has been observed in various diseases, indicating the utility of JAK inhibitors in a wide variety of immune-mediated inflammatory diseases. Clinical trials are underway for a number of different rheumatic diseases based on the therapeutic efficacy of JAKis, which is comparable to that of biologics. This article will review the current status of JAKis for rheumatic diseases in terms of efficacy and safety and extend to future clinical applications for rare diseases.

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Abstract Introduction Upadacitinib (UPA) is an oral, selective Janus kinase inhibitor that has demonstrated favorable efficacy with an acceptable safety profile across a global, phase 3 program in rheumatoid arthritis (RA). This phase 2 open-label extension investigated the efficacy and safety of UPA through 6 years of treatment. Methods Patients from two phase 2b trials (BALANCE-1 and -2) enrolled in BALANCE-EXTEND (NCT02049138) and received open-label UPA 6 mg twice daily (BID). Dose increases to 12 mg BID were required for patients with

Systemic sarcoidosis is a granulomatous disease involving multiple organs and systems. A 36-year-old woman was admitted due to multiple nodules of the trunk for 4 months. Upon admission， laboratory and auxiliary examinations were performed. A biopsy specimen revealed multiple nodules in the superficial dermis， which were composed of cells with abundant cytoplasm， large cell body and round or oval nuclei. PET/CT revealed systemic multiple lymph node enlargement complicated with active metabolism. She was eventually diagnosed with systemic sarcoidosis. After combined treatment of methylprednisolone， hydroxychloroquine and tofacitinib for 4 months， the skin lesions were significantly mitigated and no new skin lesions were found. This case prompts that Janus kinase inhibitors can be used to replace conventional immunosuppressants with reproductive toxicity for systemic sarcoidosis patients of reproductive age.

Nan Luo, Lingyuan Zhong, Nana Luo, Qiuyue Wang, Tianhao Li, Pingsheng Hao Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of ChinaCorrespondence: Pingsheng Hao; Tianhao Li, Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan, 610075, People’s Republic of China, Tel +86-13881965024 ; +86-13880986337, Fax +86-28-87732407, Email hpswl@126.com; litianhao_doctor@163.comAbstract: Psoriasis is a recurring systemic disease that can be treated with biologics to some effect. However, precisely targeting inflammatory mediators may disrupt immune system homeostasis and lead to new conditions. Here, we report a case of psoriasiform dermatitis (PsoD) caused by IL-17 inhibitors (IL-17i) namely secukinumab treatment for psoriasis. This case proposes an effective use of Janus kinase inhibitor (JAKi) tofacitinib to confront lesions induced by IL-17i. This is the first case report of PsoD caused by secukinumab treated with tofacitinib.Keywords: tofacitinib, Janus kinase inhibitor, psoriasiform dermatitis, Th1-Th2 balance, IL-17 inhibitors

Xinxin Li, Yifang Sun, Juan Du, Fang Wang, Xiaolan Ding Department of Dermatology, Peking University People’s Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xiaolan Ding, Department of Dermatology, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People’s Republic of China, Tel +8613522658992, Fax +861088325474, Email Lancyding@126.comAbstract: Vitiligo is an acquired autoimmune skin disorder, clinically characterized by distinct white macules and patches resulting from progressive melanocyte destruction. JAK-STAT pathway plays an important role in the loss of epidermal melanocytes. Baricitinib can block the JAK-STAT pathway and the downstream chemokines as a new JAK1/2 inhibitor. In this report, we describe the successful treatment of 2 patients with oral baricitinib combined with NB-UVB phototherapy, which provides a good alternative and supplementary to treat refractory vitiligo.Keywords: IFN-γ signaling pathway, Janus kinase inhibitor, baricitinib, vitiligo

Primary Sjögren’s syndrome (pSS, Sjögren’s disease) is a systemic autoimmune disease which develops in previously healthy individuals and characterized by damage to exocrine glands, mainly lacrimal and salivary glands, with gradual formation of their secretory insufficiency and various systemic manifestations. According to EULAR recommendation (2019) therapeutic management of pSS bases on symptomatic treatment of sicca syndrome and broad-spectrum immunosuppression for systemic manifestations. The perspective group for the treatment of autoimmune disease is Janus kinase inhibitors, which can block the signals from biologically active molecules (interferons, erythropoietins and cytokines) and providing a response to these target cell signals. Therefore, the use of JAK inhibitors in patients with pSS requires clinical confirmation of effectiveness. The article described the clinical case of the positive effect of tofacitinib with methotrexate combination in the treatment of patient with pSS. A 55-year-old female with sicca syndrome (confirmed by Schirmer’s test), arthralgia, low-grade fever, weight loss and a positive test for the detection of specific antibodies (SS-A/Ro > 240 units/ml, SS-B/La 94 units/ml) was diagnosed with pSS. The total score of EULAR Sjögren’s syndrome disease activity index (ESSDAI) was 9 (activity grade II). The treatment included symptomatic methods of sicca syndrome correcting (replacement therapy with artificial tear preparations and chewing gums with xylitol) in combination with immunosuppressive therapy. The addition of tofacitinib 5 mg twice daily to methotrexate (10 mg weekly) has been shown to significantly reduce disease activity after 6 months of treatment (ESSDAI = 0).

Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib.

Ruxolitinib, a selective inhibitor of Janus kinases, is a standard treatment for intermediate/high-risk myelofibrosis (MF) but is associated with a predisposition to opportunistic infections, especially herpes zoster. However, the incidence and characteristics of invasive fungal infections (IFIs) in these patients remain uncertain. In this report, we present the case of a 59-year-old woman with MF who developed disseminated histoplasmosis after seven months of ruxolitinib use. The patient clinically improved after ten weeks of combined amphotericin B and azole therapy, and ruxolitinib was discontinued. Later, the patient received fedratinib, a relatively JAK2-selective inhibitor, without relapse of histoplasmosis. We also reviewed the literature on published cases of proven IFIs in patients with MF who received ruxolitinib. Including ours, we identified 28 such cases, most commonly due to Cryptococcus species (46%). IFIs were most commonly disseminated (39%), followed by localized lung (21%) infections. Although uncommon, a high index of suspicion for opportunistic IFIs is needed in patients receiving JAK inhibitors. Furthermore, the paucity of data regarding the optimal management of IFIs in patients treated with JAK inhibitors underscore the need for well-designed studies to evaluate the epidemiology, pathobiology, early diagnosis, and multimodal therapy of IFIs in patients with hematological malignancies receiving targeted therapies.

A woman diagnosed with rheumatoid arthritis and treated with Janus kinase (JAK) inhibitors presented with a gradually enlarging bilateral submandibular lymph nodes swelling that had lasted several weeks. A lymph node biopsy showed epithelioid granulomatous lymphadenitis with caseous necrosis. Mycobacteria grew in acid-fast bacteria culture and were identified as Mycobacterium avium by polymerase chain reaction. The patient was diagnosed with cervical lymphadenitis caused by M. avium. A computed tomography scan showed no evidence of a mass or infection at other sites, including the lungs; therefore, the mass was excised without any antimicrobial treatments. Her neck mass had not recurred at 9 months after the excision. JAK inhibitors have emerged as an important new class of oral therapy for rheumatoid arthritis and other diseases. Physicians should be aware of the relatively rare complications, such as cervical lymphadenitis caused by nontuberculous mycobacteria, when using JAK inhibitors.