Duodenitis associated with ulcerative colitis and pouchitis after total colectomy successfully treated with upadacitinib: A case report.

A 27-year-old man had ulcerative colitis (UC) 1 year prior and underwent a colectomy and two-stage ileal pouch-anal anastomosis for medically refractory UC 6 months ago. He visited our department with epigastric pain and discomfort, increased stool frequency, and bloody diarrhea. Esophagogastroduodenoscopy revealed continuous diffuse friable mucosa, erosions, and edema in the duodenum, and pouchoscopy revealed multiple ulcers and purulent mucus adhesions. Based on endoscopic and pathological findings, the patient was diagnosed with duodenitis associated with UC and pouchitis, for which he received oral prednisolone (40 mg/day) and ciprofloxacin. The frequency of stools and occurrence of bloody diarrhea reduced, and epigastric pain and discomfort improved after 2 weeks. However, when prednisolone was discontinued, the symptoms worsened, albumin level decreased, and C-reactive protein level increased. Following this, we administered a 20 mg prednisolone sodium phosphate enema once daily, and the patient's symptoms improved. However, the symptoms relapsed when the enema was discontinued. Assuming that the patient had steroid-dependent duodenitis associated with UC and pouchitis, we initiated upadacitinib. His symptoms improved within a few days, and biomarkers returned to normal after 1 month. Nine months after initiating the upadacitinib treatment, endoscopic remission was achieved in the mucosa of the duodenum and pouch. The patient has been in clinical remission for 1 year without any adverse events.

Game changer: How Janus kinase inhibitors are reshaping the landscape of ulcerative colitis management.

Recent advancements in the treatment landscape of ulcerative colitis (UC) have ushered in a new era of possibilities, particularly with the introduction of Janus kinase (JAK)-signal transducer and activator of transcription inhibitors. These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes. With approved JAK inhibitors (JAKis), such as tofacitinib, filgotinib, and upadacitinib, clinicians now have powerful tools to modulate immune responses and gene expression, potentially revolutionizing the treatment algorithm for UC. Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission, presenting viable options for patients who have failed conventional therapies. Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy, particularly in patients with aggressive disease phenotypes or refractory to biologic agents. The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC, offering timely relief for patients with active disease and facilitating personalized treatment approaches. Despite safety concerns, including cardiovascular risks and infections, ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.

Rapid Remission With Upadacitinib in a Child With Refractory Crohn's Disease and ATM Mutation: A Case Report.

Managing pediatric Crohn's disease (PCD) presents challenges due to severe complications and higher biologic therapy needs. Transitioning from anti-tumor necrosis factor agents to off-label therapies adds complexity. Although upadacitinib has demonstrated efficacy and tolerability in adult inflammatory bowel disease and pediatric atopic dermatitis, there are limited data for its application in PCD. This case report delineates successful remission with upadacitinib in a child with CD refractory to infliximab, ustekinumab, adalimumab, thalidomide, and prednisone. Notably, the patient carried an ataxia telangiectasia mutated (ATM) gene mutation. These findings provide valuable evidence for PCD management and highlight the potential benefits of upadacitinib in this population.

Drug-Induced Alopecia Areata From Upadacitinib.

This case report describes an unexpected occurrence of alopecia areata (AA) in a 55-year-old woman undergoing treatment with upadacitinib for atopic dermatitis. This patient developed AA approximately one year into her upadacitinib treatment for atopic dermatitis. This case highlights possible upadacitinib-induced AA, which has not been reported in the literature. Not only does this case demonstrate the typical timeline for drug-induced alopecia, but it also raises questions about whether upadacitinib can cause drug-induced alopecia.

The Successful Use of Upadacitinib as Monotherapy for Hidradenitis Suppurativa and Ulcerative Colitis in the Setting of Refractory Disease.

Hidradenitis suppurativa (HS) and ulcerative colitis (UC) are associated chronic inflammatory conditions with complex disease courses and potential for overlapping therapeutic management. We describe a case of severe pediatric HS and UC that were poorly controlled despite several standard-of-care therapies, including infliximab and ustekinumab. Transitioning the patient to upadacitinib monotherapy resulted in clinical improvement of both her UC and HS within 3 months, and she was then able to be weaned off her other systemic therapies. While upadacitinib is not currently FDA-approved for HS or pediatric UC, this case report shows promise for upadacitinib monotherapy for both of these complex inflammatory disorders.

Upadacitinib to improve anxiety in patients with adalimumab-treated psoriatic arthritis: study protocol for a randomized controlled trial.

BACKGROUND: Patients with psoriatic arthritis (PsA) often suffer from anxiety disorders. While upadacitinib has shown effectiveness in reducing various disease activity indicators in active PsA, its impact on anxiety disorders in PsA patients needs further investigation. METHODS: In this 12-week randomized, open-label, controlled trial, PsA patients with coexisting anxiety were randomly assigned to either the upadacitinib group or the adalimumab group in a 1:1 ratio. The upadacitinib group received a daily dose of 15 mg, while the adalimumab group received 40 mg every 2 weeks. The primary outcome measured the change in Hospital Anxiety Self-Assessment Scale (HADS-A) total scores after the 12-week intervention. Secondary outcomes included changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI), the percentage of participants meeting the ACR20 criteria compared to baseline after 12 weeks, and the percentage of participants achieving a grade 0 or 1 in the psoriasis static Investigator's overall assessment (sPGA) at week 12 with an improvement of at least 2 points from baseline (sPGA 0/1). One-way analysis of variance (ANOVA) was used to compare the means of normally distributed variables between the upadacitinib and adalimumab groups. DISCUSSION: The impact of upadacitinib on anxiety in PsA patients remains uncertain. This 12-week open randomized controlled trial aims to provide insights into disease progression and underscore the importance of addressing PsA-related anxiety during treatment. TRIAL REGISTRATION: ChiCTR2400079755. Registered on January 11, 2024, with ChiCTR. https://www.chictr.org.cn/showproj.html?proj=216538.

Predictive Factors for Long-Term High Responders to Upadacitinib Treatment in Patients with Atopic Dermatitis.

Background: Upadacitinib, a Janus kinase 1 inhibitor, is an effective medicine for moderate-to-severe atopic dermatitis (AD). Identifying long-term responders to upadacitinib is crucial for optimal treatment strategies in real-world clinical practice. To identify predictive factors for long-term high responders to upadacitinib 15 mg or 30 mg, defined as achievers of investigator's global assessment (IGA) 0/1 with ≥2-point improvement from baseline IGA at week 48. Methods: A retrospective study was conducted from August 2021 to September 2023 on 63 AD patients treated with upadacitinib 15 mg and 31 patients with 30 mg. Patients of each group were categorized into long-term high responders (achievers of IGA 0/1 at week 48) and low responders (non-achievers). We compared baseline values of clinical indexes and laboratory parameters between long-term responders and nonresponders. Results: In 15 mg group, long-term high responders showed lower rate of bronchial asthma (BA), lower values of baseline eczema area and severity index (EASI) of head and neck, IgE, and systemic inflammatory response index (SIRI) compared with low responders. In 30 mg group, long-term high responders showed lower baseline levels of IgE compared with low responders. Conclusion: Patients with lower baseline EASI of head and neck, IgE, or SIRI or without BA and those with lower baseline IgE may have a higher potential to become long-term high responders to upadacitinib 15 mg and 30 mg treatment, respectively.

Separation and characterization of degradation impurities of upadacitinib by liquid chromatography and high resolution mass spectrometry.

Upadacitinib is an oral Janus Kinase inhibitor used for the treatment of rheumatoid arthritis. This research focuses on the forced degradation study of upadacitinib and the characterization of its degradation impurities. Upadacitinib was subjected to various degradation conditions such as hydrolysis (acid, base, neutral), oxidation, thermal, and photolysis according to International Council for Harmonisation guidelines. Twelve degradation impurities of upadacitinib were observed under oxidation (H2O2, AIBN, Fenton's reagent) and photolysis (UV light). Zeneth software was used to predict the in silico degradation profile. High-performance liquid chromatography was used to separate the observed degradation impurities with ammonium formate (pH 3.63) and acetonitrile as mobile phases on an Agilent Zorbax Eclipse plus C18 column (4.6 × 250 mm, 5 µm). The separated degradation impurities were characterized by using high resolution mass spectrometry. The accurate masses obtained from LC-HRMS/MS were used to determine the structures of all the degradation impurities. A suitable mechanism for the formation of degradation impurities was proposed. DEREK Nexus and SARAH Nexus were used for the in silico toxicity and mutagenicity assessments.

Effectiveness and safety of upadacitinib in acute severe ulcerative colitis patients from single Chinese IBD Center: a monocentric study.

Upadacitinib is an oral new selective JAK1 inhibitor that has been approved for treating adult patients with moderately to severely active ulcerative colitis. However, a growing number of studies are needed on the effectiveness of upadacitinib in the treatment of acute severe ulcerative colitis. This study was mainly aimed to describe the clinical and endoscopic effectiveness of upadacitinib 45 mg in Chinese acute severe ulcerative colitis patients following eight weeks of treatment. In this study, we examined all patients with acute severe ulcerative colitis from Xijing IBD Center, Xi'an, China, with acute severe ulcerative colitis. All patients were initially given oral upadacitinib 45 mg. Clinical indicators, C-reactive protein, and erythrocyte sedimentation rates were collected. Clinical response and clinical remission were assessed using modified Mayo. Endoscopic evaluation was performed carried out using the Mayo Endoscopic Score and Ulcerative colitis endoscopic index of severity score. A total of 14 patients who received upadacitinib were included in the study period. All patients exhibited a clinical response to 45 mg upadacitinib initially. All patients completed the 8-week induction. The clinical remission rate was 28.6% after eight weeks. Two patients revealed endoscopic remission at 14.3%. The pathology improved in 50.0% of patients. The 8-week surgical resection rate was 7.1%, with the 16-week surgical resection rate being 14.3%. Adverse events included herpes simplex virus infection and increased thrombin time. The results of our study support the short-term effectiveness and safety of upadacitinib in acute severe ulcerative colitis, providing new choices for patients' treatment. However, more extended investigation needs to be performed on the long-term effectiveness and safety.

Sensitive and selective determination of upadacitinib using a custom-designed electrochemical sensor based on ZnO nanoparticle-assisted molecularly imprinted polymer.

Upadacitinib (UPA) is a selective and reversible oral Janus kinase (JAK) 1 inhibitor and is of great importance in treating inflammatory bowel disease (Zheng et al., Int Immunopharmacol 126:111229, 2024; Foy et al., JAAD Case Rep 42:20-22, 2023). Although there are limitations to the effectiveness of UPA, it has received positive responses in clinical trials and is approved for the treatment of atopy dermatitis (AD) (Li et al., Int Immunopharmacol 125:111193, 2023). In this study, a nanoparticle-doped molecularly imprinted polymer (MIP)-based electrochemical sensor was developed for sensitive and selective detection of UPA. The developed sensor was designed as a thin film layer using the photopolymerization method on the surface of the prepared nanoparticle-doped polymerization solution glassy carbon electrode (GCE). Various nanoparticles, such as multi-walled carbon nanotube, titanium dioxide, oxide, and zinc oxide (ZnO) nanoparticles, were the most suitable for UPA. Surface characterization of the developed sensor was done by scanning electron microscopy (SEM), and electrochemical characterization was done by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The quantitative analysis of UPA was performed in 5.0 mM [Fe (CN)6]3-/4- solution using the differential pulse voltammetry (DPV) technique. Under optimum conditions, the calibration range was between 0.1 and 1 pM. The limit of detection (LOD) and limit of quantification (LOQ) were calculated as 0.005 pM and 0.017 pM, respectively. The sensor's accuracy was proven by performing a recovery study in serum. The sensor's selectivity was also evaluated using common interfering substances such as KNO3, CaCl2, Na2SO4, uric acid, ascorbic acid, dopamine, and paracetamol. According to the results obtained, the performance of the designed sensor was found to be quite sensitive and selective in determining UPA. The developed UPA-ZnO/3-APBA@MIP-GCE sensor showed high sensitivity and selectivity towards UPA. In addition, the selectivity, the most important feature of the MIP-based sensor, was confirmed by imprinting factor (IF) calculations using tofacitinib (TOF) and ruxolitinib (RUX). The sensor's unique selectivity is demonstrated by its successful performance even in the presence of UPA impurities.

Corrigendum: Efficacy and safety of Janus kinase inhibitors in non-infectious inflammatory ocular diseases: a prospective cohort study from the international AIDA network registries.

[This corrects the article DOI: 10.3389/fmed.2024.1439338.].

Efficacy and Safety of Upadacitinib for Perianal Fistulizing Crohn's Disease: A Post Hoc Analysis of 3 Phase 3 Trials.

BACKGROUND & AIMS: Efficacy of upadacitinib, an oral Janus kinase inhibitor, for moderate-to-severe Crohn's disease was demonstrated in phase 3 induction (U-EXCEL, U-EXCEED) and maintenance (U-ENDURE) trials; this post hoc analysis evaluated upadacitinib outcomes in patients with fistulizing disease in these studies. METHODS: Patients were randomized (2:1) to once-daily upadacitinib 45 mg (UPA45) or placebo for 12 weeks. UPA45 clinical responders were rerandomized (1:1:1) to upadacitinib 15 mg (UPA15), 30 mg (UPA30), or placebo for 52 weeks. In patients with fistulas (any and perianal), resolution of drainage, closure of external openings, clinical remission, endoscopic response, and safety were assessed. RESULTS: Of 1021 patients in U-EXCEL and U-EXCEED, 143 (14.0%) had any fistulas at baseline (66 draining); of these, most (128) had perianal fistulas (56 draining). Greater proportions of patients receiving upadacitinib vs placebo achieved resolution of drainage of perianal fistulas at the end of induction (placebo, 5.6%, n/N = 1/18; UPA45, 44.7%, n/N = 17/38; P = .003) and maintenance (placebo, 0%, n/N = 0/11; UPA15, 28.6%, n/N = 4/14; P = .105; UPA30, 23.1% n/N = 3/13; P = .223) and closure of perianal fistula external openings (induction: placebo, 4.8%, n/N = 2/42; UPA45, 22.1%, n/N = 19/86; P = .013; maintenance: placebo, 0%, n/N = 0/30; UPA15, 18.8%, n/N = 6/32; P = .024; UPA30, 16.0%, n/N = 4/25; P = .037). CONCLUSION: Patients with fistulizing disease (primarily perianal) treated with upadacitinib achieved higher rates of resolution of drainage, closure of external openings, clinical remission, and endoscopic response vs placebo. CLINICALTRIALS: gov numbers: U-EXCEL (NCT03345849), U-EXCEED (NCT03345836), U-ENDURE (NCT03345823).

Efficacy and safety of Janus kinase inhibitors in non-infectious inflammatory ocular diseases: a prospective cohort study from the international AIDA network registries.

Introduction: Non-infectious inflammatory ocular diseases pose significant challenges in diagnosis and management, often requiring systemic immunosuppressive therapy. Since Janus kinase (JAK) inhibitors may represent a novel therapeutic option for these disorders, the present study aimed to expand current knowledge about their efficacy and safety in patients with these conditions. Methods: This prospective cohort study included 12 adult patients from the international AutoInflammatory Disease Alliance (AIDA) Network registries dedicated to non-infectious ocular inflammatory conditions. We assessed ocular flares, visual acuity, disease course, and complications before and after initiating JAK inhibitor therapy. Results: Ocular inflammation was related to a systemic disease in 8 (66.7%) patients as follows: spondyloarthritis (n = 3), peripheral psoriatic arthritis (n = 1), rheumatoid arthritis (n = 1), antinuclear antibodies (ANA) positive juvenile idiopathic arthritis (n = 1), Behçet's syndrome (n = 1), Vogt-Koyanagi-Harada syndrome (n = 1). In total, 4 patients received baricitinib, 1 patient received tofacitinib, and 7 patients underwent upadacitinib treatment. The overall average duration of JAK inhibitors treatment was 8.6 ± 5.5 months (ranging from 3 to 20 months). At the last assessment, ocular disease control was complete in 12/12 patients. One patient discontinued baricitinib due to poor compliance after a 12-month relapse-free period. The incidence of ocular flares was 125 episodes/1.000 person-months prior to the initiation of JAK inhibitors and 28.6 episodes/1.000 person-months thereafter. The incidence rate ratio for experiencing a relapse before starting a JAK inhibitor compared to the following period was 4.37 (95% CI 1.3-14.7, p-value: 0.02). Conclusion: JAK inhibitors demonstrate efficacy and safety in controlling ocular inflammatory relapses, confirming that they represent a valuable treatment option for patients with non-infectious inflammatory ocular diseases resistant to conventional treatments.

Induction of Endoscopic Response, Remission, and Ulcer-Free Endoscopy With Upadacitinib Is Associated With Improved Clinical Outcomes and Quality of Life in Patients With Crohn's Disease.

BACKGROUND: We evaluated the association of achieving endoscopic outcomes at week 12 of induction with improvements in clinical outcomes and quality of life (QoL) at week 52 of maintenance in patients with moderately to severely active Crohn's disease (CD) treated with upadacitinib (UPA). METHODS: This post hoc analysis evaluated data from 2 phase 3 induction trials (NCT03345836 and NCT03345849) and 1 maintenance (NCT03345823) trial. Clinical responders to 12-week induction therapy with UPA who also received 52-week maintenance treatment with UPA were included. Endoscopic response, remission, healing, and ulcer-free endoscopy were assessed at week 12. Meaningful improvements in clinical and QoL outcomes were evaluated at week 52. RESULTS: A significantly greater proportion of patients who achieved an endoscopic response at the end of induction, compared with patients who did not, attained Crohn's Disease Activity Index (CDAI) remission (52.0% vs 34.6%; P ≤ .01), corticosteroid-free CDAI remission (50.0% vs 30.9%), Inflammatory Bowel Disease Questionnaire remission (52.6% vs 30.3%), and meaningful improvements in Functional Assessment of Chronic Illness Therapy-Fatigue response (46.7% vs 25.9%), overall work impairment (47.1% vs 26.5%), and daily activity impairment (53.3% vs 34.1%) (all P < .05) at week 52. Similar findings were observed for patients who achieved endoscopic remission, endoscopic healing, and ulcer-free endoscopy at the end of induction vs those who did not. CONCLUSIONS: Early improvement in endoscopic outcomes after UPA induction treatment was associated with long-term meaningful improvements in clinical outcomes and QoL in patients with CD. CLINICAL REGISTRATION NUMBER: U-EXCEED induction trial (NCT03345836), U-EXCEL induction trial (NCT03345849), and U-ENDURE maintenance trial (NCT03345823).

In patients with Crohn's disease treated with 12 weeks of upadacitinib, a greater proportion with early improvements in endoscopic response, remission, healing, and ulcer-free endoscopy, vs those without improvements, attained long-term meaningful improvements in clinical outcomes and quality of life.

Erosion regression in patients with rheumatoid arthritis after upadacitinib-a pilot study using high resolution peripheral quantitative computed tomography.

OBJECTIVES: To evaluate whether inhibition of Janus kinases (JAK) 1 could lead to erosion repair on high-resolution peripheral quantitative computer tomography (HR-pQCT) in patients with active rheumatoid arthritis (RA). METHODS: This was a prospective, non-randomized pilot study. We enrolled 20 adult patients with active RA with ≥1 bone erosion on HR-pQCT. They were given upadacitinib 15 mg once daily for 24 weeks. HR-pQCT of the metacarpophalangeal joint was performed at baseline and 24-week. The serum bone biomarkers level was evaluated before and after treatment. Twenty age-and-sex matched RA patients from another study treated with conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) were included as active controls. RESULTS: Nineteen patients in the upadacitinib group completed the study procedures. After 24 weeks, despite similar improvement in disease activity, a reversed trend in the mean erosion volume change on HR-pQCT was observed comparing the upadacitinib and active control group (upadacitinib group: -0.23 ± 3.26mm3 vs control group: 1.32 ± 6.05mm3, p= 0.131). A greater proportion of erosions in the upadacitinib group demonstrated regression (27% vs 12%, p= 0.085). Using general estimating equation (GEE), the use of upadacitinib was significantly associated with erosion regression (OR: 3.61, 95% CI: 1.00-13.00, p= 0.049) after adjusting for the difference in disease duration. The serum levels of bone resorption markers reduced after upadacitinib treatment. No new safety signal was noted. CONCLUSION: Despite a similar improvement in RA disease activity after upadacitinib compared with csDMARDs, a differential regression of erosion on HR-pQCT was observed in patients received upadacitinib. The potential role of JAK1 inhibition in erosion repair should be investigated.

Successful treatment of the dupilumab-induced psoriatic dermatitis/arthritis and atopic dermatitis with a JAK inhibitor: A case report and literature review.

Dupilumab-induced psoriatic dermatitis and arthritis in a patient with atopic dermatitis were effectively managed with upadacitinib, highlighting the use of Janus kinase inhibitors as a possible treatment for biologic therapy side effects.

Response to Upadacitinib in Patients with Inflammatory Bowel Disease Previously Treated with Tofacitinib.

BACKGROUND AND AIMS: Upadacitinib is an oral selective Janus kinase (JAK) inhibitor approved in the United States for ulcerative colitis (UC) and Crohn's disease (CD). However, data regarding its use following prior treatment with the JAK inhibitor tofacitinib is sparse. As such, we aimed to evaluate the effectiveness of upadacitinib therapy following tofacitinib exposure. METHODS: This is a multicenter retrospective study of patients with confirmed diagnosis of UC or CD who received upadacitinib after prior treatment with tofacitinib. The primary outcome of interest was patient-reported clinical improvement at first follow-up. Secondary outcome included discontinuation of corticosteroids, change in Mayo Endoscopic Score (MES) and change in inflammatory marker levels. RESULTS: A total of 31 patients met the inclusion criteria. Following upadacitinib initiation, 80.6% (25/31) of patients had clinical improvement, including 92.3% (24/26) of those with UC and 20% (1/5) of those with CD. Of the patients initially requiring systemic corticosteroid therapy, 80% (12/15) were able to discontinue corticosteroids. Individual mean change of fecal calprotectin was a decrease of 501.5 mcg/g ± 608.6 (P value = 0.01) while C-reactive protein decreased on average by 14.8 mg/L ± 25.3 (P value = 0.02) compared to when patients were on tofacitinib, with significant changes observed in the UC cohort. In patients with UC, individual MES after initiating upadacitinib decreased compared to prior to tofacitinib discontinuation (P value = 0.04). CONCLUSION: Our study demonstrates that upadacitinib therapy in patients with prior tofacitinib exposure is associated with clinical improvement and a decrease in objective markers of inflammation in patients with UC.

Association between myeloid disorders and adult onset-inflammatory syndromes, successful treatment with JAK-inhibitors: Case series and literature review.

Approximately one-third of patients with myeloid disorders like myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) exhibit inflammatory and autoimmune disorders (IADs). These IADs often include atypical and incomplete forms of common autoimmune conditions, and exhibit resistance to conventional immunosuppressive therapies. There is growing interest in molecular relationships between IADs and MDS/CMML to find potential targeted therapies. Recently, patients with somatic mutations in the UBA1 gene were identified as having VEXAS syndrome. Herein, we present a concise case-series illustrating concurrent elderly-onset inflammatory manifestations and myeloid disorders (MDS, CMML, and idiopathic cytopenia of undetermined significance). These patients manifested inflammatory or autoimmune symptoms, including erythema nodosum, Raynaud's phenomenon, Sjogren syndrome, and refractory pruritus, having onset after 60-years of age. The inflammatory manifestations were largely refractory to traditional immunosuppressive regimens. Remarkably, treatment with a JAK-1 inhibitor, upadacitinib, in two cases yielded marked resolution of inflammatory symptoms, facilitating the gradual tapering of corticosteroids, improvement of hemoglobin levels, and reduction in serum C-reactive protein levels. Upon loss of response to upadacitinib, JAK-2 inhibitor ruxolitinib provided clinical benefit in one of the cases, facilitating further tapering of glucocorticoids. This arena warrants further exploration through prospective studies of larger cohorts to delineate optimal management strategies.