OBJECTIVE: This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD.
METHODS: In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to <6 years and 6 to <12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment.
RESULTS: A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator\'s Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75).
CONCLUSIONS: The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD.
BACKGROUND: NCT03646604, registered 2018-08-23.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder. Topical corticosteroids are the cornerstone of therapy in mild AD, whereas the JAK inhibitor upadacitinib is approved in the United States, Europe, and other countries for treating moderate-severe AD in adults and children over 12 years old whose disease is not adequately controlled with other systemic drugs, including biologics. The objective of this meta-analysis was to assess the overall efficacy and safety of upadacitinib in moderate to severe AD. All randomized controlled trials (RCTs) evaluating the efficacy and safety of upadacitinib in moderate to severe AD were included in the meta-analysis. The pooled analysis revealed a significant proportion of patients achieving Eczema Area and Severity Index-75 (EASI 75) (R.R. = 3.86; 95% CI = 3.12 to 4.78, p < 0.00001), EASI 100 (R.R. = 13.09; 95% CI = 7.40 to 23.17, p < 0.00001), Worst Pruritus Numerical Rating Score (WP-NRS) response (R.R. = 4.44; 95% CI = 3.72 to 5.29, p< 0.00001), and validated Investigator\'s Global Assessment (v-IGA) (RR = 5.96; 95% CI = 4.79 to 7.41, p < 0. 00001) in the upadacitinib arm compared to the placebo arm. Moreover, the pooled analysis also suggested that treatment-emergent adverse events (TAEs) were relatively higher with upadacitinib than with placebo, but were mild and easily manageable (R.R. = 1.15; 95% CI = 1.09 to 1.23, p<0.00001). This meta-analysis showed that upadacitinib had a significant beneficial effect and tolerable adverse effect profile in patients with moderate and severe AD. Dose regimens of 15 mg and 30 mg seemed to have similar benefits. However, further trials are needed to assess long-term efficacy and safety profile.

In recent years Janus kinase inhibitors (JAKi) have joined tumor necrosis factor inhibitors (TNFi) and interleukin (IL)-17 inhibitors (IL-17i) as approved disease modifying anti-rheumatic drugs (DMARD) for moderate to severe forms of axial spondyloarthritis (axSpA). Drug survival in axSpA patients has not been well studied in a real-world outpatient scenario since the approval of JAKi. We aimed to analyze the three drug classes based on modes of actions (MoA) for their persistence rates among German axSpA outpatients. A retrospective analysis of the RHADAR database for axSpA patients with a new initiation of TNFi, IL-17i, or JAKi treatment between January 2015 and October 2023 was conducted. Analyses included Kaplan-Meier curves and adjusted Cox regressions for drug discontinuation. 1222 new biological DMARD (TNFi [n = 954], IL-17i [n = 190]) or JAKi (n = 78) treatments were reported. The median drug survival was 31 months for TNFi, 25 for IL-17i, and 18 for JAKi. The corresponding 2-year drug survival rate was 79.6%, 72.6%, and 62.8% for TNFi, IL-17i, and JAKi, respectively. The probability for discontinuation for JAKi was significantly higher compared with TNFi (HR 1.91 [95% CI 1.22-2.99]) as well as for IL-17i compared with TNFi (HR 1.43 [95% CI 1.02-2.01]), possibly related to more frequent use of TNFis as first-line therapy. IL-17i and JAKi discontinuation probabilities were similar. Primary non-response was the reason for drug discontinuation in most cases across all MoA. TNFi treatment might persist longer than JAKi and IL-17i in German axSpA outpatients, possibly related to more severe or refractory disease in patients with JAKi-treated or IL-17i-treated axSpA.

UNASSIGNED: Adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) are rare autoimmune diseases with characteristic skin rashes, weakness, and other systemic features. Upregulated interferon signaling has been consistently described in both adult and juvenile DM which makes janus kinase inhibitors (jakinibs) an attractive therapeutic agent that has a targeted mechanism of action.
UNASSIGNED: Herein is a review of the growing literature of jakinib use in adult and juvenile DM, including reports on specific disease features and safety of jakinibs in this population and a comparison between adult and juvenile DM. We performed a literature review using PubMed including all English-language publications before 1 February 2024 and abstracts from key recent rheumatology conferences.
UNASSIGNED: Jakinibs are an exciting and promising treatment in both adult and juvenile DM. Current Phase 2 and 3 randomized placebo-controlled trials of jakinibs in both adult and JDM will provide significant insights into the efficacy of this class of medication as a potentially more mechanistically targeted treatment of both skin and muscle disease. In fact, these results will likely inform the treatment paradigm of dermatomyositis in that it may even be considered as first or second line. The next five years in the therapeutic landscape of both juvenile and adult DM is an exciting time for both patients and medical providers.

UNASSIGNED: As new therapies for the treatment of Crohn\'s disease (CD) are approved, there is an increasing need for evidence that clarifies their positioning and sequencing.
UNASSIGNED: Comparative effectiveness research (CER) aims to inform physicians\' decisions when they choose which intervention (drug or treatment strategy) to administer to their patients. Pragmatic head-to-head trials represent the best tools for CER, but only a few have been published in the IBD field. Network meta-analyses can point toward the superiority of one drug over another, but they do not reflect everyday clinical practice. Finally, real-world evidence complements that coming from head-to-head trials and network meta-analyses, assessing the real-life effectiveness of therapeutic interventions.
UNASSIGNED: There is insufficient evidence to create a definitive therapeutic algorithm for CD, but some general considerations can be made. Anti-TNF-α agents seemingly represent the most \'sustainable\' first-line choice, considering benefit-harm ratio and costs; vedolizumab, ustekinumab, and risankizumab may be considered as first-line choice when safety issues become prominent. In the event of pharmacodynamic failure, out-of-class swap is to be preferred - possibly with anti-IL23p19 as the best option, with unclear data regarding upadacitinib positioning; a second anti-TNF-α could be considered, as a second choice, after pharmacokinetic failure.

A rectovaginalis fistula a penetráló Crohn-betegség ritka szövődménye, jelenléte esetén a gyógyszeres kezelés és a sebészeti beavatkozás együttes alkalmazása javasolt. Habár perianalis sipollyal szövődött Crohn-betegség esetén a TNFα-blokkolók hatékonyak lehetnek, rectovaginalis fistula esetén kisebb hatékonyság mutatkozik, feltehetően anatómiai okok, valamint a gyulladás talaján megváltozott szövetekbe történő csökkent penetrációs készség miatt. Az újabb biologikumok és kis molekulájú szerek hatékonyságáról és biztonságosságáról penetráló Crohn-betegségben kevés adat áll rendelkezésünkre. Esetünk egy fiatal penetráló Crohn-beteg nőről szól, aki közepesen súlyos/súlyos betegségaktivitás és kiújuló rectovaginalis fistula miatt több vonalbeli biológiai kezelésben részesült. Ultimum refugiumként deviáló ileostoma képzése történt, illetve upadacitinib indult ötödik terápiás vonalként. 12 hetes indukciót követően a rectovaginalis sipoly teljes bezáródását, valamint a vastagbél teljes szakaszán komplett nyálkahártya-gyógyulást tapasztaltunk. Az ileostoma zárását aktivitásfokozódás vagy fistulakiújulás nem követte. A szelektív JAK1-gátló upadacitinib hatékonynak mutatkozott stomaképzést követően, nehezen kezelhető, közepesen súlyos-súlyos luminalis aktivitást mutató, recidív rectovaginalis fistulával szövődött Crohn-betegségben. Orv Hetil. 2024; 165(32): 1252–1257.

BACKGROUND: Evidence on the comparative efficacy and safety of approved therapies for ulcerative colitis (UC) during induction and maintenance, including upadacitinib (UPA), vedolizumab (VEDO), ustekinumab (UST), and tofacitinib (TOFA), is limited.
METHODS: Using data from phase 3 trials, three placebo (PBO)-anchored matching-adjusted indirect comparisons of the efficacy and safety of UPA versus VEDO, UST, and TOFA (U-ACHIEVE and U-ACCOMPLISH, GEMINI-1, UNIFI, and OCTAVE induction and maintenance trials) have been conducted. Baseline characteristics from UPA trials were weighted separately to match each comparator trial. Induction responders were re-randomized to oral UPA 15 or 30 mg, VEDO 300 mg intravenously every 8 weeks (Q8W), UST 90 mg SC Q8W, or oral TOFA 5 mg, or PBO in maintenance. Treat-through efficacy outcomes at weeks 44(UST)/46(VEDO)/52(UPA/TOFA) were adjusted by the likelihood of induction response and included clinical response, clinical remission, and endoscopic improvement. Safety outcomes included adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation (except UPA vs. VEDO). Benefit-risk was assessed by numbers needed to treat (NNT)/harm, calculated as the inverse of the difference in proportions of patients achieving each efficacy/safety outcome for UPA versus comparator.
RESULTS: The proportions of patients who demonstrated clinical response or endoscopic improvement was greater with UPA 15 mg versus VEDO and TOFA (p < 0.05). The proportions of patients demonstrating all treat-through efficacy outcomes were significantly greater with UPA 30 mg versus VEDO, UST, or TOFA with NNTs 3.2-8.7. No significant differences in proportions of AEs, SAEs, and AEs leading to discontinuation were observed between the two doses of UPA and comparators.
CONCLUSIONS: In patients with active UC, greater clinical efficacy, and similar safety after 1 year of maintenance were observed with UPA versus VEDO, UST, and TOFA, suggesting a favorable benefit-risk profile for UPA. Despite matched baseline characteristics, differences in trial design and endpoints may persist.

BACKGROUND: This study compared the clinical effectiveness of switching from tumor necrosis factor inhibitor (TNFi) to upadacitinib (TNFi-UPA), another TNFi (TNFi-TNFi), or an advanced therapy with another mechanism of action (TNFi-other MOA) in patients with rheumatoid arthritis (RA).
METHODS: Data were drawn from the Adelphi RA Disease Specific Programme™, a cross-sectional survey administered to rheumatologists and their consulting patients in Germany, France, Italy, Spain, the UK, Japan, Canada, and the USA from May 2021 to January 2022. Patients who switched treatment from an initial TNFi were stratified by subsequent therapy of interest: TNFi-UPA, TNFi-TNFi, or TNFi-other MOA. Physician-reported clinical outcomes including disease activity (with formal DAS28 scoring available for 29% of patients) categorized as remission, low/moderate/high disease activity, as well as pain were recorded at initiation of current treatment and ≥ 6 months from treatment switch. Fatigue and treatment adherence were measured ≥ 6 months from treatment switch. Inverse-probability-weighted regression adjustment compared outcomes by subsequent class of therapy: TNFi-UPA versus TNFi-TNFi, or TNFi-UPA versus TNFi-other MOA.
RESULTS: Of 503 patients who switched from their first TNFi, 261 were in TNFi-UPA, 128 in TNFi-TNFi, and 114 in TNFi-other MOA groups. At the time of switch, most patients had moderate/high disease activity (TNFi-UPA: 73%; TNFi-TNFi: 52%; TNFi-other MOA: 60%). After adjustment for differences in characteristics at point of switch, patients in TNFi-UPA group (n = 261) were significantly more likely to achieve physician-reported remission (67.7% vs. 40.3%; p = 0.0015), no pain (55.7% vs. 25.4%; p = 0.0007), and complete adherence (60.0% vs. 34.2%; p = 0.0049) compared with patients in TNFi-TNFi group (n = 121). Similar findings were observed for TNFi-UPA versus TNFi-other MOA groups (n = 111).
CONCLUSIONS: Patients who switched from TNFi to UPA had significantly better clinical outcomes of remission, no pain, and complete adherence than those who cycled TNFi or switched to another MOA.

BACKGROUND: Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients\' quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD.
METHODS: This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up.
RESULTS: This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8-13.4 times as many days with an EASI 90 response and 7.0-10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab.
CONCLUSIONS: Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab.
BACKGROUND: ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).

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.