Oral Janus Kinase Inhibitor Research Articles

Rapid and sustained improvements in itch and quality of life with upadacitinib plus topical corticosteroids in adults and adolescents with atopic dermatitis: 52-week outcomes from the phase 3 AD Up study

Purpose: Atopic dermatitis (AD) adversely impacts quality of life (QoL). We evaluated the effect of upadacitinib, an oral selective Janus kinase inhibitor approved for moderate-to-severe AD, plus topical corticosteroids (+TCS) on patient-reported outcomes (PROs) over 52 weeks. Materials and methods: In the phase 3 AD Up study (NCT03568318), adults and adolescents with moderate-to-severe AD were randomized 1:1:1 to once-daily upadacitinib 15 mg, 30 mg, or placebo + TCS. Itch, skin pain/symptoms, sleep, QoL, daily activities, emotional state, mental health, and patient impressions of disease severity/improvement/treatment satisfaction were assessed. Results: This analysis included 901 patients. Within 1–2 weeks, PRO improvements were greater with both upadacitinib doses than with placebo (p <.05). Improvements increased through weeks 4–8; rates were generally maintained through week 52. At week 52, the proportion of patients with clinically meaningful improvements in itch (Worst Pruritus Numerical Rating Scale improvement ≥4), skin pain (AD Symptom Scale Skin Pain improvement ≥4), sleep (AD Impact Scale [ADerm-IS] Sleep improvement ≥12), daily activities (ADerm-IS Daily Activities improvement ≥14), and emotional state (ADerm-IS Emotional State improvement ≥11) ranged from 62.1%–77.7% with upadacitinib 15 mg + TCS and 71.3%–83.6% with upadacitinib 30 mg + TCS. Conclusions: Upadacitinib + TCS results in rapid, sustained improvements in burdensome AD symptoms and QoL.

Upadacitinib Rapidly Improves Patient-Reported Outcomes in Atopic Dermatitis: 16-Week Results from Phase3 Clinical Trials (Measure Up1 and 2).

Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16weeks. This integrated analysis of the double-blind, placebo-controlled periods of phase3 monotherapy clinical trials Measure Up1 (NCT03569293) and Measure Up2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). Data from 1683 patients (upadacitinib 15mg, n = 557; upadacitinib 30mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week1 (upadacitinib 15mg, 11.2%; upadacitinib 30mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week16 (upadacitinib 15mg, 47.1%; upadacitinib 30mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2weeks), increased through weeks 4-6, and were maintained through week16. Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severeAD. ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422.

Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials.

This integrated analysis of the phase 2/3 and phase 3 SELECT trials describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, for up to 5years of exposure across psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA) (including pooled axial spondyloarthritis [axSpA]). Safety data from five trials of upadacitinib in PsA (2 trials), AS (2 trials), and nr-axSpA (1 trial) were analyzed up to a data cut-off of August 15, 2022. One PsA study included adalimumab as an active comparator. Treatment-emergent adverse events (TEAEs) were summarized for PsA (pooled upadacitinib 15mg once daily and adalimumab 40mg biweekly), AS (pooled upadacitinib 15mg), nr-axSpA (upadacitinib 15mg), and pooled axSpA (pooled upadacitinib 15mg from axSpA trials). TEAEs were reported as exposure-adjusted event rates per 100 patient-years (E/100 PY). A total of 1789 patients (PsA, n = 907; AS, n = 596; nr-axSpA, n = 286) received ≥ 1 dose of upadacitinib 15mg for 3689 PY of exposure or adalimumab (n = 429) for 1147 PY of exposure. Overall TEAEs and serious TEAEs were highest in PsA and numerically higher with upadacitinib versus adalimumab; rates were similar between AS and nr-axSpA. In PsA, higher rates of serious infection, herpes zoster (HZ), lymphopenia, and nonmelanoma skin cancer (NMSC) were observed with upadacitinib versus adalimumab. Rates of malignancy excluding NMSC, adjudicated major adverse cardiovascular events, and adjudicated venous thromboembolic events were comparable between upadacitinib and adalimumab in PsA and were similar across diseases. Higher rates of serious infection, HZ, lymphopenia, and NMSC were observed with upadacitinib versus adalimumab in PsA; slightly elevated rates for most of these TEAEs were seen with upadacitinib in PsA versus axSpA. Upadacitinib 15mg demonstrated a generally consistent safety profile across disease states with no new safety signals identified. SELECT-AXIS 1: NCT03178487; SELECT-AXIS 2: NCT04169373; SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

The Real-World Effectiveness, Persistence, Adherence, and Safety of Janus Kinase Inhibitor Baricitinib in Rheumatoid Arthritis: A Long-Term Study.

Background/Aim: Baricitinib (BAR) is the first oral selective Janus kinase inhibitor approved in Europe for rheumatoid arthritis (RA). Real-world data are still needed to clarify its long-term benefits/risk profile. This study aimed to evaluate the effectiveness, persistence, adherence, and safety of BAR in a real-world setting. Methods: An ambispective study was conducted between October 2017 and December 2021 in RA patients starting BAR. The effectiveness was evaluated, assessing changes from the baseline of the Disease Activity Score using 28-joint counts-C reactive protein (DAS28CRP), and the achievement of low disease activity/remission. Drug persistence was evaluated using Kaplan-Meier analysis. Adherence was estimated using the medication possession ratio (MPR) and the 5-item Compliance Questionnaire for Rheumatology. Safety was assessed determining global incidence proportion and adverse event adjusted incidence rates. Results: In total, 61/64 recruited patients were finally analyzed, 83.6% were female, 78.7% were seropositive, the mean age was 58.1 (15.4) years, and the disease duration was 13.9 (8.3) years. A total of 32.8% of patients were naïve to biologics and 16.4% received BAR as monotherapy. The median exposure to BAR was 12.4 (6.6-31.2) months (range 3.1-51.4). A significant change in DAS28CRP was observed after treatment (difference -1.2, p = 0.000). 70.5% and 60.7% of patients achieved low disease activity or remission, respectively, and 50.8% (31/61) remained on BAR throughout the follow-up, with a median persistence of 31.2 (9.3-53.1) months. The average MPR was 0.96 (0.08) and all patients exhibited "good adherence" according to the questionnaire. In total, 21.3% of patients discontinued baricitinib due to toxicity. Conclusions: In our real-world practice, BAR demonstrated effectiveness, large persistence, high adherence to treatment, and an acceptable safety profile.

Effect of Tofacitinib on One-Year Colectomy Risk in Anti-TNF Refractory Ulcerative Colitis: A Prospective Multicenter Italian Study.

Tofacitinib is an oral Janus kinase inhibitor recently approved to induce and maintain remission in ulcerative colitis (UC). Considering the number of anti-TNF non-responders, this study aims to assess the effectiveness and safety of tofacitinib in a cohort of multi-failure patients with moderate-to-severe UC at 52weeks. From January 2021 to March 2023, we performed a prospective multicenter study observing adult patients with moderate-to-severe UC starting tofacitinib after an anti-TNF failure for a 52-week-long period. Effectiveness and safety were assessed in terms of colectomy rate, clinical remission and response, endoscopic remission, steroid-free clinical remission, and rate of adverse events. We included 58 patients with UC with an age of 42 ± 14.4years, 59% males, 96.6% left-sided or pancolitis, who were failure to a single (65.5%) or more than one anti-TNF (34.5%). Only 6 (10.3%) patients underwent colectomy. Colectomy was clinically associated with the necessity and the number of extra cycles of tofacitinib 10mg bid at W8 (p = 0.023) and W24 (p = 0.004), and with a higher partial Mayo score at W8 (p = 0.025). At W52, clinical remission, clinical response, and steroid-free clinical remission were 53.4%, 43.1%, and 48.3%, respectively. Of 22 performed colonoscopies at W52, 11 (50%) showed endoscopic remission. Adverse events occurred in 14 (24.1%) patients, but only 2 (3.4%) led to tofacitinib discontinuation. In a real-life setting of patients with anti-TNF refractory UC, tofacitinib has proved to be effective in preventing colectomy and inducing clinical and endoscopic remission at 52weeks with a good safety profile.

Early and Sustained Improvements in Symptoms and Quality of Life with Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: 52-Week Results from Two Phase III Randomized Clinical Trials (Measure Up 1 and MeasureUp2).

Atopic dermatitis is a chronic inflammatory disease characterized by increased itch, skin pain, poor sleep quality, and other symptoms that negatively affect patient quality of life. Upadacitinib, an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, is approved to treat moderate-to-severe atopic dermatitis. We aimed to evaluate the effect of upadacitinib on patient-reported outcomes over 52weeks in adults and adolescents with moderate-to-severe atopic dermatitis. Data from two phase III monotherapy trials of upadacitinib (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422) were integrated. Changes in pruritus, pain, other skin symptoms, sleep, quality of life, mental health, and patient impression were evaluated. Patient-reported outcome assessments included the Worst Pruritus Numerical Rating Scale, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Atopic Dermatitis Symptom Scale, Atopic Dermatitis Impact Scale, Hospital Anxiety and Depression Scale, SCORing Atopic Dermatitis index, Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment. Minimal clinically important differences, achievement of scores representing minimal disease burden, and the change from baseline were evaluated in patients who received upadacitinib through week 52 and in patients who received placebo through week16. This analysis included 1609 patients (upadacitinib 15 mg, N=557; upadacitinib 30 mg, N=567; placebo, N=485). Baseline demographics and disease characteristics were generally similar across all arms. The proportion of patients treated with upadacitinib reporting improvements in itch increased rapidly by week 1, increased steadily through week 8, and was sustained through week 52. Patients receiving upadacitinib also experienced improvements in pain and other skin symptoms by week 1, which continued through week 16; improvements were maintained through week 52. Patient reports of improved sleep increased rapidly from baseline to week 1, increased steadily through week 32, and were sustained through week 52. Patients experienced quality-of-life improvements through week 8, which were maintained through week 52. By week 1, patients in both upadacitinib groups experienced rapid improvements in emotional state, and by week 12, patients also achieved meaningful improvements in anxiety and depression. Improvements in mental health continued steadily through week 32 and were maintained through week 52. Patients treated with upadacitinib30mg generally experienced improvements in patient-reported outcomes earlier than those treated with upadacitinib 15 mg. Through week 16, patients receiving upadacitinib experienced greater improvements versus those receiving placebo in all assessed patient-reported outcomes. Adults and adolescents with moderate-to-severe atopic dermatitis treated with once-daily upadacitinib 15 or 30 mg experienced early improvements in itch, pain, other skin symptoms, sleep, quality of life, and mental health that were sustained through week52. ClinicalTrials.gov identifiers NCT03569293 (13 August 2018) and NCT03607422 (27 July 2018).

Characteristics and Management of Patients with Alopecia Areata and Selected Comorbid Conditions: Results from a Survey in Five European Countries.

Alopecia areata (AA) is an autoimmune condition that causes non-scarring hair loss and can impose a high psychosocial burden on patients. The presence of comorbid conditions may impact the management of AA in clinical practice. This analysis aims to describe disease characteristics and management of AA in patients with concomitant atopic, autoimmune, and psychiatric comorbid conditions. Data were collected from the Adelphi Disease Specific Programme™, a cross-sectional survey of physicians and their adult patients with AA conducted in France, Germany, Italy, Spain, and the UK between October 2021 and June 2022. Patients' disease severity was based on physician's definition. Physician-reported data on demographics, AA clinical characteristics, comorbid conditions, and information related to AA therapies were analyzed. Analyses were descriptive. Overall, 239 dermatologists provided data for 2083 patients, of which 558 patients (27%) had at least one atopic, autoimmune, or psychiatric comorbid conditions. The most common comorbid conditions were atopic dermatitis, autoimmune thyroid disease, and anxiety. The mean (standard deviation) patient age for the three comorbidity groups was 37.6years (12.1) and 56% of the patients were women (n = 313). In the three comorbidity groups, 51%, 50%, and 55% of patients with atopic, autoimmune, and psychiatric comorbidities had severe AA with disease progression reported as worsening in 30%, 28%, and 30%, respectively, whereas in the group with no comorbidities, 37% were described as having severe AA and 21% getting worse. Scalp hair loss was the primary sign reported across the three groups of comorbid conditions (atopic, 91%; autoimmune, 91%; psychiatric, 88%). Patients with preselected comorbidities presented more frequently AA-related signs and symptoms beyond scalp hair loss than patients without comorbid conditions. These patients were also more likely to receive topical calcineurin inhibitors, topical immunotherapy, conventional systemic immunosuppressants, and oral Janus kinase inhibitors for the treatment of their AA. This analysis provided insights into the burden and management of AA in patients presenting with atopic, autoimmune, and psychiatric comorbid conditions in five European countries.

Comparative Effectiveness of Tofacitinib and Adalimumab in Axial Spondyloarthritis: A Real-World Clinical Context Multicenter Study.

Tofacitinib, an oral Janus kinase inhibitor, is a putative choice in the treatment of axial spondyloarthritis (AxSpA). The objective of this study was to compare the effectiveness and tolerability of tofacitinib with adalimumab, in AxSpA, in a real-world clinical setting. In this multicentric medical records review study, adult patients with active AxSpA treated with either tofacitinib 5 mg twice daily or adalimumab 40 mg subcutaneously fortnightly were recruited. Effectiveness was measured with Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Drug-cost analysis was calculated with Incremental Cost-Effectiveness Ratio (ICER drug ). Among the 266 patients, 135 were treated with tofacitinib and 131 with adalimumab (follow-up: 6.5 ± 1.6 months). Mean improvement of BASDAI (3.39 ± 0.09 vs. 3.14 ± 1.16, respectively) and that of ASDAS (1.78 ± 0.68 vs. 2.07 ± 2.08, respectively) were comparable between the adalimumab and tofacitinib groups. A higher proportion of patients achieved BASDAI50 response in the second (49.5% vs. 31.6%) and fourth month (83.9% vs. 62.8%) and ASDAS low disease activity in the fourth month (71.6% vs. 47.9%) in the adalimumab group. All disease activity measurements were similar by the sixth month in both groups. A higher proportion of patients in the tofacitinib group than in the adalimumab group required change in therapy (14.8% vs. 7.6%, respectively). ICER drug for adalimumab compared with tofacitinib was US $188.8 per patient in the adalimumab group for each person-month with BASDAI <4. Tofacitinib showed comparable effectiveness with adalimumab in patients with AxSpA at the sixth month, despite lesser response in the initial months, with favorable ICER drug .

Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib.

Histological outcomes and JAK-STAT signaling were assessed in a prospective ulcerative colitis (UC) patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor. Forty UC patients received tofacitinib 10mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement (HEMI). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, Tyrosine kinase 2 (TYK2) and total signal transducer and activator of transcription (STAT) 1-6 were assessed using immunohistochemistry (IHC). At baseline, the median RHI was 14 (interquartile range (IQR) 10-19). Twenty-six of 40 (65%) patients had severe endoscopic disease (endoscopic Mayo score 3) and 31/40 (78%) failed prior anti-TNF treatment. At week 8, 15 patients (38%) had HEMI, 23 patients (58%) histological remission and 34 (85%) histological response. RHI decreased by a median of 14 points (IQR 9-21) in responders (p<0.001) and by 6 points (IQR 0-13) in non-responders (p=0.002). STAT1, STAT3 and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower week 8 STAT1 expression levels compared to non-responders (0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p=0.001), suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders (2.7%, IQR 0.1-7.7) compared to responders (0.4%, IQR 0.1-2.1). Tofacitinib treatment resulted in histological improvement in the majority of UC patients and a substantial decrease of STAT1, STAT3 and STAT5 expression. HEMI was associated with more profound suppression of STAT1.

Upadacitinib Reduces Crohn’s Disease Symptoms Within the First Week of Induction Therapy

Upadacitinib (UPA), an oral Janus kinase inhibitor, is approved to treat moderately to severely active Crohn's disease (CD). As symptomatic response is an important initial treatment goal for patients, we evaluated the rapidity of symptomatic improvement in patients with CD receiving UPA 45 mg once daily (UPA45) induction therapy. This post hoc analysis included pooled data from 2 phase 3, multicenter, double-blind 12-week induction trials (U-EXCEL and U-EXCEED) and 1 maintenance trial (U-ENDURE). Daily diary data for the first 15 days of UPA45 or placebo (PBO) treatment were used to analyze improvement in very soft/liquid stool frequency (SF) and abdominal pain score (APS). Clinical outcomes were evaluated at every study visit. Overall, 1021 patients (n = 674 UPA45; n = 347 PBO) were analyzed. UPA45 demonstrated greater efficacy vs PBO for SF <3 and APS ≤1, providing rapid relief by day 5 or 6, regardless of prior biologic exposure. Mean changes in SF and APS were greater with UPA45 beginning at week 2 (-2.0 and -0.5, respectively; P < .001) and were maintained through week 12 (-3.0 and -1.0, respectively; P < .001) vs PBO. First achievement of daily SF/APS clinical remission occurred earlier with UPA45 (median 13 days) vs PBO (median 32 days), and patients treated with UPA45 showed improved rates of SF/APS clinical remission (21.1% UPA45 vs 8.9% PBO) and clinical response (58.8% UPA45 vs 37.9% PBO) starting at week 2 (both P ≤ .01). UPA45 provided rapid relief of clinical symptoms within the first week of treatment in patients with CD. NCT03345849, NCT03345836, and NCT03345823.

Upadacitinib Achieves Clinical and Endoscopic Outcomes in Crohn’s Disease Regardless of Prior Biologic Exposure

Upadacitinib, an oral Janus kinase inhibitor, achieved significantly higher rates of clinical remission and endoscopic response vs placebo during induction (U-EXCEL [NCT03345849]; U-EXCEED [NCT03345836]) and maintenance (U-ENDURE [NCT03345823]) treatment in patients with moderate-to-severe Crohn's disease (CD). Prior biologic failure is often associated with reduced responses to subsequent therapies. This post hoc analysis assessed upadacitinib efficacy by prior biologic failure status. Patients were randomized to placebo or upadacitinib 45 mg (UPA45) for 12 weeks (induction). UPA45 clinical responders were enrolled in U-ENDURE and rerandomized to placebo, upadacitinib 15 mg (UPA15), or upadacitinib 30 mg (UPA30) for 52 weeks. Assessments were by prior biologic failure. Of 1021 patients, 733 (71.8%) had prior biologic failure. Across outcomes and subgroups, upadacitinib-treated patients achieved higher rates vs placebo. During induction, upadacitinib had higher rates vs placebo for clinical remission based on stool frequency/abdominal pain score (without failure: 54.0% vs 28.3%; with failure: 42.2% vs 14.1%) and endoscopic response (without failure: 52.0% vs 16.2%; with failure: 35.7% vs 5.3%). In maintenance, the greatest treatment effect (upadacitinib vs placebo) was among patients with prior biologic failure treated with UPA30 (clinical remission without failure: 58.5% vs 32.7%; with failure: 42.5% vs 8.7%; endoscopic response without failure: 43.9% vs 17.9%; with failure: 38.9% vs 4.0%). Patients without vs with prior biologic failure had fewer adverse events. Upadacitinib led to higher absolutes rates of clinical and endoscopic outcomes in patients without vs with prior biologic failure. Patients treated with upadacitinib achieved greater rates of clinical and endoscopic improvements vs placebo, regardless of prior biologic exposure. GOV: NCT03345849, NCT03345836, NCT03345823.

Pharmacokinetics and bioequivalence of tofacitinib 5 mg in healthy Korean male subjects.

Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz). A randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC0-t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for Cmax and AUC0-t were calculated to evaluate pharmacokinetic equivalence. The 90% CIs of the geometric mean ratios of Cmax and AUC0-t for tofacitinib free base to tofacitinib citrate were 0.9144-1.1230 and 1.0245-1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events. In healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent criteria. Both formulations were safe and well-tolerated.

Off-label use of Baricitinib improves moderate and severe atopic dermatitis in China through inhibiting MAPK and PI3K/Akt/mTOR pathway via targeting JAK-STAT signaling of CD4+ cells.

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD.

The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report

/SummaryBackgroundNail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA).Case presentationA 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission.ConclusionsWe have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.

Safety and Efficacy of Various Doses of Tofacitinib among Patients with Active Seronegative Spondyloarthritides – A Retrospective Observational Study

Introduction: Seronegative spondyloarthritides (SpA) are a family of various joint disorders that classically include ankylosing spondylitis (AS), psoriatic arthritis (PsA), inflammatory bowel disease (IBD) associated arthritis, reactive arthritis (formerly Reiter syndrome; ReA), and undifferentiated SpA. Treatment goals for SpA are reducing symptoms, decreasing complications associated with the disease, and reducing functional limitations. Aim of the study: The purpose of this study is to find efficacy and safety of various doses of Tofacitinib, an oral Janus kinase inhibitor, compared with placebo in different stages of the treatment in patients with active Seronegative Spondyloarthritides. Methods: This retrospective observational study was carried out in the Popular Medical College Hospital, Bangladesh. Total 203 subjects of both sexes, aged more than 18 years were selected during the period of May 2023 to November 2023. In this 6 months study duration, patients received 16 weeks treatment (12-week treatment, 4-week washout) and were under follow up session for 8 weeks. Study patients with active SpA phase II were grouped to receive (N=25, 25, 25, 25, respectively) placebo or Jakloc (Tofacitinib) 5 mg and Jakloc (Tofacitinib) XR 11 mg manufactured by Popular Phermaceuticals PLC and Tofacitinib 2 mg or 10 mg (manufactured by other phermaceuticals) twice daily. Jakloc (Tofacitinib) XR 11 mg was used for adult patients with inadequate response or intolerance to methotrexate (3 patients). The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine after follow up session for 8 weeks. Safety was monitored. Result: The Emax model analysis of the primary endpoint predicted a Jakloc (Tofacitinib) 10 mg twice daily ASAS20 response rate of 67.4%, which ........

500 - Patient-reported outcomes following 24 weeks of treatment with upadacitinib in adults with non-segmental vitiligo: results from a phase 2, randomized, double-blind, dose-ranging study

Abstract Introduction &amp; Objectives Vitiligo has a considerable negative impact on patients’ health-related quality of life (HRQoL). Patients often experience social stigma, low self-esteem, anxiety, and depression. Assessment of HRQoL is therefore recommended as part of the evaluation of disease severity and treatment benefits. Accordingly, the impacts of treatment with upadacitinib (UPA), an oral Janus kinase inhibitor, on a range of patient-reported HRQoL outcomes were evaluated as part of a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study in adults with non-segmental vitiligo. Materials &amp; Methods Adults aged 18–65 years with non-segmental vitiligo with a Facial Vitiligo Area Scoring Index score ≥0.5 and a Total Vitiligo Area Scoring Index score ≥5 at baseline were included in this 52-week study (NCT04927975). During a 24-week, double-blind, placebo-controlled treatment period (period 1), patients were randomly assigned to receive UPA 6 mg (UPA6), UPA 11 mg (UPA11), UPA 22 mg (UPA22), or placebo once daily (QD). Patient-reported HRQoL outcomes assessed at the week 24 primary analysis timepoint (ie, end of period 1) included change from baseline in vitiligo QoL (VitiQoL) total score (lower scores reflect better HRQoL), achievement of a Vitiligo Noticeability Scale (VNS) response of 4 (“a lot less noticeable”) or 5 (“no longer noticeable”), change from baseline in Dermatology Life Quality Index (DLQI; lower scores reflect better HRQoL), change from baseline in Hospital Anxiety and Depression Scale (HADS) anxiety and depression scores (where lower scores reflect less anxiety and/or depression), and achievement of a Patient’s Global Impression of Change-Vitiligo (PaGIC-V) response of 1 (“much better”) or 2 (“a little better”). Results A total of 185 patients were enrolled in the study (UPA6 n=49; UPA11, n=47; UPA22, n=43; placebo n=46). Mean reductions in VitiQoL scores from baseline to week 24 with UPA22 (−6.6) and UPA6 (−7.5) were numerically larger than with placebo (−5.5), although not statistically significant. At week 24, more patients treated with UPA22 reported a VNS response of “a lot less noticeable” or “no longer noticeable” than with placebo (11.6% vs 0%, respectively; P &amp;lt; .05). Mean reductions in DLQI scores from baseline to week 24 were significantly larger with UPA22 than with placebo (−2.2 vs −0.6; P &amp;lt; .05). HADS anxiety scores decreased from baseline to week 24 in the UPA6 and UPA22 groups, with similar reductions in HADS depression scores observed for the UPA11 and UPA22 groups; changes in HADS scores were not significantly different vs placebo. A significantly greater proportion of patients achieved a PaGIC-V response of “much better” or “a little better” with any UPA dose vs placebo: UPA6 (34.7%), UPA11 (55.3%), and UPA22 (60.5%) vs placebo (19.6%; P &amp;lt; .05 vs placebo for all UPA doses). Conclusion Among adults with non-segmental vitiligo, 24 weeks of treatment with UPA at all doses resulted in improvements compared to placebo in patient impressions of disease improvement based on PaGIC results. These initial findings suggest that UPA22 may improve patient HRQoL and perceptions of vitiligo noticeability; longer term data from the extension phase of this study will further clarify the impact of UPA treatment on QoL.

501 - Efficacy and safety of upadacitinib in a phase 2 randomized, double-blind, dose-ranging study of adults with extensive non-segmental vitiligo

Abstract Introduction &amp; Objectives Janus kinase (JAK) inhibition is a promising approach for the treatment of vitiligo. Here, we report the clinical efficacy and safety of upadacitinib (UPA), an oral JAK inhibitor, in a phase 2b multicenter, randomized, double-blind, placebo-controlled study of adults with extensive non-segmental vitiligo (NSV). Materials &amp; Methods Eligible patients were aged 18–65 years with NSV, a Facial Vitiligo Area Scoring Index (F-VASI) of ≥0.5, and a Total Vitiligo Area Scoring Index (T-VASI) of ≥5 at baseline. This 52-week study (NCT04927975) comprised 2 periods. In period 1, patients were randomly assigned to once daily UPA 22 mg (UPA22), UPA 11 mg (UPA11), UPA 6 mg (UPA6), or placebo (PBO) for 24 weeks of treatment. In a 28-week blinded extension (period 2), patients receiving UPA during period 1 continued their respective regimens; patients who received PBO in period 1 were pre-assigned to either UPA11 or UPA22. Clinical efficacy endpoints evaluated through week 36 included percent change from baseline (%CFB) in F-VASI (week 24, primary endpoint), reductions from baseline in F-VASI of ≥50% (F-VASI 50) and ≥75% (F-VASI 75), %CFB in T-VASI, and reduction from baseline in T-VASI of ≥50% (T-VASI 50). Safety data as of January 13, 2023 (data cutoff date) are presented. Results Of the 185 patients enrolled in period 1, 165 (89.2%) continued to period 2. At baseline, 68% of patients had extensive vitiligo (T-VASI &amp;gt; 10), and 71% had active vitiligo. At week 24, the %CFB in F-VASI was greater with UPA11 (−35.6%) and UPA22 (−34.0%) vs PBO (−14.4%; nominal P = .005 and P = .013, respectively). A greater proportion of patients achieved F-VASI 50 and F-VASI 75 with UPA11 (38.3%, 19.1%) and UPA22 (39.5%, 14.0%) vs PBO (10.9%, 2.2%; nominal P &amp;lt; .05 for both doses and for both endpoints). Likewise, the %CFB in T-VASI was greater with UPA11 (−17.3%) and UPA22 (−20.7%) vs PBO (−6.4%; nominal P = .026 and P = .005, respectively). A higher percentage of patients achieved T-VASI 50 with UPA22 (11.6%) than with PBO (2.2%; nominal P = .027). UPA efficacy continued to improve through week 36, with %CFB in F-VASI for UPA6, UPA11, and UPA22 of −20.8%, −44.9% and −47.7%, respectively. At week 36, F-VASI 50 was achieved with UPA6, UPA11, and UPA22 by 34.2%, 54.3% and 61.5% of patients and F-VASI 75 by 15.8%, 40.0%, and 30.8%, respectively. At week 36, %CFB in T-VASI for UPA6, UPA11 and UPA22 were −24.3%, −32.0% and −37.6%, with 10.5%, 20.0% and 19.2% of patients, respectively, achieving T-VASI 50. Treatment-emergent adverse event (TEAE) rates were generally similar with UPA and PBO in period 1 (most common TEAEs: COVID-19, acne, fatigue, and headache) and were similar across treatment arms in period 2. One death adjudicated as undetermined/unknown cause and deemed by the investigator to have no reasonable possibility of being related to study drug occurred in the UPA22 group (period 1). One adjudicated event of nonfatal ischemic stroke occurred with UPA11 (period 2). There were no adjudicated events of venous thromboembolism, gastrointestinal perforation, or events of opportunistic infection, active tuberculosis, or malignancy. Conclusion Treatment with UPA for 24 weeks resulted in greater improvements vs PBO in the clinical outcomes of adults with extensive NSV. Observed clinical efficacy continued to improve through week 36 with UPA treatment. UPA was generally well tolerated, with no new safety signals ­identified.

527 - Efficacy of upadacitinib for moderate-to-severe atopic dermatitis: analysis of time spent in skin clearance response states from the Measure Up 1, Measure Up 2, and Heads Up studies

Abstract Introduction/Background Atopic dermatitis (AD) is a debilitating chronic inflammatory skin disease with fluctuating disease severity that requires long-term control. Patients report that complete or almost complete skin clearance is highly important as a treatment goal. Upadacitinib is a selective oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 vs JAK2, JAK3, and tyrosine kinase 2. Objectives In this post-hoc analysis of the upadacitinib phase 3/3b studies, we analyzed the time patients spent in skin clearance response states over 16 weeks with upadacitinib 15 mg (UPA 15) and 30 mg (UPA 30) compared to placebo and dupilumab. Methods Data were from phase 3/3b multicenter, randomized, double-blinded studies comparing the safety and efficacy of upadacitinib to either placebo (Measure Up 1 and Measure Up 2) or dupilumab (Heads Up) in patients with moderate-to-­severe AD. In the Measure Up 1 and Measure Up 2 studies, adults and adolescents were randomized to receive UPA 15, UPA 30, or placebo once daily for 16 weeks. In the Heads Up study, adults were randomized to receive UPA 30 once daily or dupilumab 300 mg every 2 weeks beginning at week 2 following an initial loading dose of 600 mg. The days patients spent in skin clearance response states based on Eczema Area Severity Index (EASI) improvements ≥75%/90%/100% (EASI 75/90/100) from baseline were assessed. Missing data at study visits were imputed using non-responder imputation. Response states between study visits were interpolated using last observation carried forward. Results Integrated data from Measure Up 1 and Measure Up 2 included 1683 adults and adolescents randomized to UPA 15 (N=557), UPA 30 (N=567), or placebo (N=559); 44.0% were female, and 48.8% had previously received systemic therapy. In the Heads Up study, 673 adults were randomized to UPA 30 (N=342) or dupilumab (N=331); 44.3% were female, and 52.7% had previously received systemic therapy. Patients in Measure Up 1 and 2 taking UPA 15 or UPA 30 cumulatively spent a greater proportion of days in EASI 75 (UPA 15: 54.2%, UPA 30: 64.6%, Placebo: 10.2%), EASI 90 (UPA 15: 32.0%, UPA 30: 44.0%, Placebo: 3.2%), and EASI 100 (UPA 15: 7.5%, UPA 30: 13.5%, Placebo: 0.6%) response states compared to placebo over 16 weeks. In the Heads Up study, patients taking UPA 30 vs dupilumab cumulatively spent a greater proportion of days in EASI 75 (67.1% vs 44.9%), EASI 90 (47.0% vs 23.2%), and EASI 100 (12.6% vs 3.6%) response states over 16 weeks. Conclusions Treatment of moderate-to-severe AD with UPA 15 or UPA 30 resulted in a greater proportion of days spent with higher levels of skin clearance (EASI 75/90/100) compared to placebo over 16 weeks, mirroring findings from the Heads Up study comparing UPA 30 to dupilumab. Increases in time spent with high levels of skin clearance with upadacitinib treatment may reflect improved long-term disease control and translate into more time spent experiencing a better quality of life that is less burdened by AD.

525 - Real-world effectiveness of upadacitinib in moderate-to-severe atopic dermatitis (AD): Results from cross-sectional analyses of the CorEvitas AD Registry

Abstract Introduction/Background Upadacitinib is an oral Janus kinase inhibitor approved to treat moderate-to-severe atopic dermatitis (AD). While clinical trials have demonstrated its efficacy in treating the signs and symptoms of AD, less is known about its effectiveness in a real-world setting. Objectives This cross-sectional study describes the real-world clinical and patient-reported outcomes of adults with AD enrolled in the CorEvitas AD Registry and treated with upadacitinib for at least four or more weeks. Methods The CorEvitas AD Registry is a prospective, non-interventional registry of adults diagnosed with AD by a dermatologist or qualified dermatology practitioner. The current analysis included participants enrolled between July 21, 2020 through August 7, 2023 who were treated with upadacitinib for at least 4 weeks at the time of evaluation by their provider. Outcome measures included assessments of: skin clearance (Validated Investigators Global Assessment Scale for Atopic Dermatitis [vIGA-AD™], Eczema Area and Severity Index [EASI]); worst itch in the past 24 hours (Peak Pruritus Numeric Rating Scale [PP-NRS]); symptom frequency (Patient-Oriented Eczema Measure [POEM]); quality of life (Dermatologic Life Quality Index [DLQI]); and disease control (Atopic Dermatitis Control Tool [ADCT]). Outcomes were cross-sectionally summarized using data collected at the latest registry visit (Overall cohort), as well as 1 to less than 5 months (1-5 months) and 5-9 months following upadacitinib initiation (Month 1-5 cohort and Month 5-9 cohort, respectively). Subgroup analyses were also conducted based on prior use of biologics indicated for AD (bio-naïve, bio-experienced). Data were analyzed as observed with no imputation. Safety events were not assessed in this ­analysis. Results A total of 335 patients (mean age 45.6 years; 51.6% female; 64.2% White) were treated with upadacitinib (15 mg: n=221 [70.8%]; 30 mg: n=91 [29.2%]; median treatment duration: 6.9 months). Some patients reported concomitant use of topical corticosteroids (28.1%) and prior use of biologics indicated for AD (dupilumab: 45.4%; tralokinumab: 6.0%). For the Overall cohort, 57.3% had clear or almost clear skin (vIGA-AD 0/1). An EASI ≤3 was observed in 74.8% of patients and 45.3% reported no/minimal itch (PP-NRS 0/1); 40.9% had both EASI ≤3 and PP-NRS 0/1. Most patients (69.3%) reported that their AD was controlled (ADCT &amp;lt;7), 36.4% reported clear or almost clear disease (POEM 0–2), and 39.8% reported no impact of AD on their quality of life (DLQI 0/1). Similar results were observed for the Month 1-5 (n=144) and Month 5-9 (n=194) cohorts; results in bio-naïve and bio-experienced patients were comparable. Conclusions More than half of patients with ≥4 weeks of upadacitinib treatment had clear or almost clear skin and greater than two-thirds reported controlled disease, with similar results observed in both bio-naïve and bio-experienced patients. Over a third reported no/minimal symptom and disease burden. These findings suggest that low levels of disease severity are observed with real-world use of upadacitinib. Future analyses will aim to report changes in disease severity and burden due to persistent upadacitinib treatment.

P1040 Comparative effectiveness of upadacitinib versus ustekinumab in patients with moderately to severely active Crohn’s disease: a matching-adjusted indirect comparison

Abstract Background Upadacitinib (UPA), an oral Janus kinase inhibitor, and ustekinumab (UST), a parenteral IL 12/23 antagonist, are effective treatments for moderately to severely active Crohn’s Disease (CD). In the absence of head-to-head data, a placebo (PBO)-anchored matching-adjusted indirect comparison (MAIC) was conducted to indirectly compare efficacy of UPA vs UST. Methods Individual patient (pt)-level data from phase 3 UPA trials and published data from phase 3 UST trials were used. For induction, pts received UPA 45mg daily or PBO for 12 weeks or UST ~6mg/kg IV or PBO IV at week 0 with 8-week follow-up. For maintenance, UPA clinical responders were re-randomized to UPA 15mg, 30mg, or PBO daily for 52 weeks. UST clinical responders were re-randomized to 90mg SC (every 8 or 12 weeks) or PBO SC for 44 weeks. UPA pts had baseline (BL) CD Activity Index (CDAI) 220-450; those with prior UST or vedolizumab exposure were excluded. Treatment effect modifiers, including BL mean CDAI, Simple Endoscopic Score for CD (SES-CD), median C-reactive protein, prior biologic(s) failure, and disease location, from UPA data were weighted to match the UST population. Outcomes assessed were CDAI response (≥100-point decrease or CDAI &amp;lt;150), CDAI remission (CDAI &amp;lt;150), endoscopic response (SES-CD ≥50% decrease), and SES-CD ≤2. Separate MAICs were conducted for induction and maintenance; data reported for induction clinical outcomes are stratified by prior inadequate response to tumor necrosis factor inhibitors (TNFi-IR). Results A greater proportion of UPA- vs UST-treated pts achieved endoscopic response (difference 26.3%, P&amp;lt;0.001) and SES-CD ≤2 (difference 9.9%, P&amp;lt;0.05) at the end of induction. In TNF-IR patients, a greater proportion of UPA- vs UST-treated pts achieved CDAI response at the end of induction (difference 18.2%, P&amp;lt;0.05) and at the end of Week 8 (difference 26.0%, P&amp;lt;0.001). CDAI remission rates were also higher at end of Week 8 for UPA- vs UST-treated pts (difference 13.3%, P&amp;lt;0.05). Rates of achieving CDAI response and remission were similar between UPA- and UST-treated pts at the end of induction and Week 8 among bio-naïve pts. Following maintenance treatment, similar rates of SES-CD ≤2, endoscopic response, and CDAI remission were obtained in the total population of UPA and UST-treated pts. Conclusion Pts with moderately to severely active CD treated with UPA achieved higher rates of endoscopic (total population) and clinical (TNFi-IR population) outcomes during induction compared to UST-treated pts. Outcomes at the end of maintenance were similar for UPA and UST, however, results should be interpreted with caution due to low sample size.