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Objectives: There is limited data on the incidence, prevalence, and treatments for myelofibrosis (MF) in Germany. This retrospective study examined claims data from 3.3 million insured individuals, spanning from 2010 to 2021. Methods: Four sensitivity scenarios were explored to identify cases of MF. Point prevalence and cumulative incidence of MF were determined as of December 31, 2021, and within 2021, respectively. A cross‐sectional analysis used the main scenario definition of MF to identify cases and evaluate the period prevalence of patients receiving treatment for symptoms and/or splenomegaly, including first‐line (1L) Janus kinase inhibitor (JAKi), second‐line, or further (2L+) MF‐related treatment therapies during 2021. The prevalence of anemia treatment was also reported. Results: The estimated standardized point prevalence of MF on December 31, 2021, was 9.9–12.4 cases per 100 000 persons, and cumulative incidence in 2021 was 1.2–1.8 cases per 100 000 persons. Standardized period prevalence in 2021 for MF patients receiving 1L JAKi and/or 2L+ MF‐related treatment was 4.0 cases per 100 000. Among these patients, 47.1%–53.7% required treatment for anemia, resulting in a period prevalence of 1.9–2.2 cases per 100 000 individuals. Conclusion: The data reveal gaps in MF treatments and the need to improve patient quality of life. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Design Data Sources Eligibility Criteria for Selected Trials Results Conclusion Eczema is the most burdensome skin condition worldwide and topical anti‐inflammatory treatments are commonly used to control symptoms. The relative effectiveness and safety of different topical anti‐inflammatory treatments is uncertain.Network meta‐analysis performed within a Cochrane systematic review to compare and statistically rank efficacy and safety of topical anti‐inflammatory eczema treatments.Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to June 2023.Included trials were within‐participant or between‐participant randomised controlled trials. Participants had eczema that was not clinically infected and was not contact dermatitis, seborrheic eczema or hand eczema. Interventions were topical anti‐inflammatory treatments but not complementary treatments, antibiotics alone, wet wraps, phototherapy or systemic treatments. Comparators were no treatment/vehicle or another topical anti‐inflammatory.We identified 291 trials (45,846 participants), mainly in high‐income countries. Most were industry‐funded with median 3 weeks treatment duration. Risk of bias assessed using the Cochrane Risk of Bias 2.0 tool was high in 89% of trials, mainly due to risk of selective reporting. Network meta‐analysis of binary outcomes ranked potent and/or very potent topical steroids, tacrolimus 0.1% and ruxolitinib 1.5% among the most effective treatments for improving patient‐reported symptoms (40 trials, all low confidence) and clinician‐reported signs (32 trials, all moderate confidence). For investigator global assessment, the Janus kinas inhibitors ruxolitinib 1.5%, delgocitinib 0.5% or 0.25%, very potent/potent topical steroids and tacrolimus 0.1% were ranked as most effective (140 trials, all moderate confidence). Continuous outcome data were mixed. Local application site reactions were most common with tacrolimus 0.1% (moderate confidence) and crisaborole 2% (high confidence) and least common with topical steroids (moderate confidence). Skin thinning was not increased with short‐term use of any topical steroid potency (low confidence) but skin thinning was reported in 6/2044 (0.3%) participants treated with longer‐term (6–60 months) topical steroids.Potent topical steroids, Janus kinase inhibitors and tacrolimus 0.1% were consistently ranked as among the most effective topical anti‐inflammatory treatments for eczema. [ABSTRACT FROM AUTHOR]

Background: Supplementation of polyunsaturated fatty acids (PUFA) enables dose reduction of prednisolone and ciclosporin in canine atopic dermatitis (cAD). Objective: To determine if oral administration of PUFA reduces the dose of oclacitinib in cAD. Animals: Twenty‐two client‐owned dogs with cAD receiving oclacitinib. Materials and Methods: Dogs received a fish oil product (PUFA) or paraffin oil (placebo) for 16 weeks. Owners adjusted the oclacitinib dose according to daily pruritus assessments. On Day (D)0, D56 and D112, Canine Atopic Dermatitis Extent and Severity Index, fourth iteration (CADESI‐04), pruritus Visual Analog Scale (PVAS), quality‐of‐life score (QoL), Global Assessment (GA), quality‐of‐coat (QoC) and adverse events were recorded. Results: Mean daily oclacitinib dose was significantly reduced in the PUFA group from 0.51 ± 0.20 mg/kg/24 h (D0) to 0.19 ± 0.14 mg/kg/24 h (D85–112; p < 0.00001) and not in the placebo group (D0: 0.70 ± 0.33 mg/kg/24 h; D85–112: 0.53 ± 0.35 mg/kg/24 h, p = 0.5422). CADESI‐04 did not change over time or differ between groups. PVAS was significantly lower in the PUFA group (2.8 ± 1.5) compared to placebo (4.2 ± 1.6) at D112 (p = 0.0375). QoL and QoC improved only in the PUFA group (QoL: D0: 20 ± 7, D112: 12 ± 5, p = 0.0057; QoC: D0: 0 ± 0.5, D112: 1 ± 0.5, p = 0.0410). GA on D112 was higher in the PUFA group (p = 0.008). No adverse events were observed. Conclusion: Oral supplementation of PUFA allowed dose reduction of oclacitinib and improved PVAS, QoL, QoC and GA. The use of PUFA is recommended and was safe in the atopic study dogs receiving oclacitinib. [ABSTRACT FROM AUTHOR]

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne‐related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk‐benefit profile. [ABSTRACT FROM AUTHOR]

This article provides a review of the use of Janus Kinase inhibitors (JAKi) in the treatment of various types of scarring alopecia. It discusses the potential benefits of JAKi therapy in improving symptoms and hair regrowth in patients with conditions such as lichen planopilaris, central centrifugal cicatricial alopecia, folliculitis decalvans, frontal fibrosing alopecia, and dissecting cellulitis of the scalp. The article acknowledges the need for further research to fully understand the effectiveness and potential side effects of JAKi in this context. Overall, JAKi therapy shows promise but more investigation is required. [Extracted from the article]

The article discusses the successful treatment of pyoderma gangrenosum (PG) with the Janus kinase inhibitor, baricitinib. A 44-year-old female patient with multiple site involvement of PG showed significant improvement after being treated with a daily dose of 4mg of baricitinib. The study highlights the potential of JAK inhibitors as a promising therapy for PG, although more clinical trials are needed to further evaluate their efficacy in treating this rare neutrophilic dermatosis. [Extracted from the article]

Aicardi‐Goutières syndrome (AGS) is a genetic interferonopathy classically characterized by early onset of severe neurologic injury with basal ganglia calcifications, white matter abnormalities, and progressive cerebral atrophy, along with lymphocytosis and raised interferon alpha (INFα) in the cerebrospinal fluid (CSF). Here, we report a 31/2 year‐old patient born with prenatal onset AGS, first manifesting as intra‐uterine growth retardation. Cranial ultrasonography and cerebral MRI revealed ventriculomegaly and periventricular and basal ganglia calcifications, along with cerebral atrophy. Perinatal infections and known metabolic disorders were excluded. Both CSF lymphocytosis and raised INFα were present. Molecular analysis disclosed two already described compound heterozygous pathogenic variants in TREX1 (c. 309dup, p.(Thr104Hisfs*53) and c. 506G > A, p.(Arg169His)). The evolution was marked by severe global developmental delay with progressive microcephaly. Promptly, the patient developed irritability, quadri‐paretic dyskinetic movements, and subsequently tonic seizures. Sensorineural hearing loss was detected as well as glaucoma. Initially, he was symptomatically treated with trihexyphenidyl followed by levetiracetam and topiramate. At age 22 months, baricitinib (0.4 mg/kg/day) was introduced, leading to normal serum INFα levels. Clinically, dyskinetic movements significantly decreased as well as irritability and sleep disturbance. We confirmed that baricitinib was a useful treatment with no major side effect. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association of large joint involvement (LJI) with disease activity and drug retention in patients with rheumatoid arthritis (RA) who started receiving a biological disease‐modifying antirheumatic drug or Janus kinase inhibitor. Methods: Patients with RA from a Japanese multicenter observational registry were enrolled. Our definition of large joints included the shoulder, elbow, hip, knee, and ankle joints. Linear mixed‐effects models were used to examine changes in the clinical disease activity index (CDAI) score at Week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We examined the potential effect modifications of changes in the CDAI by baseline characteristics. Results: Overall, 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in CDAI from baseline at Week 24 (difference in change in CDAI: −5.84 [−6.65 to −5.03], p <.001), CDAI was significantly higher in patients with LJI over time. Retention rates were similar in both groups. The association of LJI with changes in disease activity was more prominent in patients with a short disease duration, negative anti‐citrullinated peptide antibodies, and interleukin‐6 receptor inhibitor (IL‐6Ri) use. Conclusion: Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat‐to‐target strategy using an IL‐6Ri may be beneficial for patients with LJI. [ABSTRACT FROM AUTHOR]

Aims and objectives: The purpose of this study is to investigate the effectiveness and safety of oral and injectable systemic treatments, such as methotrexate, azathioprine, cyclosporine, tofacitinib, baricitinib, corticosteroids, statins, zinc, apremilast, etc., for treating vitiligo lesions. Method: Databases including PubMed, Scopus, and Web of Science were meticulously searched for studies spanning from 2010 to August 2023, focusing on systemic oral and injectable therapies for vitiligo, using comprehensive keywords and search syntaxes tailored to each database. Key data extracted included study design, treatment efficacy, patient outcomes, patient satisfaction, and safety profiles. Results: In a total of 42 included studies, oral mini‐pulse corticosteroid therapy (OMP) was the subject of six studies (14.2%). Minocycline was the focus of five studies (11.9%), while methotrexate, apremilast, and tofacitinib each were examined in four studies (9.5%). Antioxidants and Afamelanotide were the subjects of three studies each (7.1%). Cyclosporine, simvastatin, oral zinc, oral corticosteroids (excluding OMP) and injections, and baricitinib were each explored in two studies (4.8%). Azathioprine, mycophenolate mofetil, and Alefacept were the subjects of one study each (2.4%). Conclusion: Systemic treatments for vitiligo have been successful in controlling lesions without notable side effects. OMP, Methotrexate, Azathioprine, Cyclosporine, Mycophenolate mofetil, Simvastatin, Apremilast, Minocycline, Afamelanotide, Tofacitinib, Baricitinib, Antioxidants, and oral/injectable corticosteroids are effective treatment methods. However, oral zinc and alefacept did not show effectiveness. [ABSTRACT FROM AUTHOR]

Background and Aim: Treatment of inflammatory bowel disease (IBD), consisting of ulcerative colitis (UC) and Crohn's disease (CD), has advanced with the application of biologics or Janus kinase inhibitor (JAKi); however, some patients still need surgery. We assessed time trends of surgery and biologics or JAKi variety in Japan. Methods: Patients hospitalized due to IBD were analyzed using Diagnosis Procedure Combination data between 2015 and 2019. Longitudinal trend analysis was performed for demographics, and interrupted time‐series analysis was performed to examine the association between surgery rates and an increase in the types of biologics or JAKi. Results: Totally, 37 867 cases with UC and 35 493 cases with CD were analyzed. Over 5 years, the surgery rate decreased in both UC and CD. The proportion of biologics and JAKi usage increased in UC and stabilized in CD. Between decreasing surgery and expanding treatment options of biologic or JAKi, interrupted time‐series analysis results showed no significant correlation (level change in UC, −1.13, 95% confidence interval [CI]: −2.11 to −0.16, P = 0.0235; slope change in UC, −0.05, 95% CI: −0.26 to 0.16, P = 0.6372; level change in CD, −0.55, 95% CI: −1.82 to 0.71, P = 0.3815; slope change in CD, −0.22, 95% CI: −0.63 to 0.19, P = 0.2892). Conclusions: In Japan, from 2015 to 2019, the use of biologics or JAKi increased for UC and slightly decreased for CD, while the number of surgeries decreased in both. Our findings suggest that more widespread use of biologics or JAKi therapy could reduce surgeries in patients with IBD. [ABSTRACT FROM AUTHOR]

Recent data, indicating that inflammatory bowel disease (IBD) may be a risk factor for future chronic kidney disease, highlight the need to study the safety and clinical effectiveness of advanced IBD therapies in patients with end stage renal disease (ESRD), defined as an eGFR <15 mL/min/1.73m2. Upadacitinib, a selective oral Janus kinase (JAK) 1 inhibitor, has demonstrated efficacy in the management of moderate to severe ulcerative colitis. There is also emerging data indicating that JAK inhibition may be clinically effective in the setting of steroid‐refractory acute severe ulcerative colitis (ASUC). There is, however, a lack of "real‐world" data documenting the use of JAK inhibitors in patients with ESRD. Here, we report the use of upadacitinib in a patient with ESRD for the management of steroid‐refractory ASUC, demonstrating, for the first time, the safe and clinically effective use of upadacitinib in this population. [ABSTRACT FROM AUTHOR]

Ruxolitinib cream is a topical formulation of ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and JAK2. In two phase 3 studies in adults and adolescents (aged ≥12 years) with atopic dermatitis (AD; TRuE‐AD1/TRuE‐AD2), significantly more patients who applied ruxolitinib cream versus vehicle cream achieved Investigator's Global Assessment treatment success (IGA‐TS; IGA score of 0/1 with ≥2‐point improvement from baseline) at week 8 (primary endpoint). This post hoc analysis evaluated the efficacy, safety, and disease control of ruxolitinib cream in patients with AD who did not achieve IGA‐TS at week 8. Patients in TRuE‐AD1/TRuE‐AD2 (N = 1249) were randomized 2:2:1 to apply twice‐daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle cream for 8 weeks followed by a long‐term safety period in which patients applied ruxolitinib cream as needed. In this pooled analysis, clinically meaningful response thresholds included ≥50% improvement in the Eczema Area and Severity Index, ≥2‐point reduction in the Itch Numerical Rating Scale, ≥4‐point improvement in the Dermatology Life Quality Index (DLQI) or ≥6‐point improvement in Children's DLQI, and ≥1‐point reduction in IGA from baseline. Among patients who did not achieve IGA‐TS at week 8 (n = 584), significantly more patients who applied either strength ruxolitinib cream versus vehicle achieved each response threshold at week 8. A response in ≥1 clinically meaningful endpoint was achieved in significantly more patients who applied ruxolitinib cream (93.4%/90.9% for 0.75%/1.5% ruxolitinib cream, respectively) versus vehicle (69.0%, both P < 0.0001). Progressive improvements in disease control were observed, with many patients achieving IGA‐TS by week 52 (55.2%/56.3% for 0.75%/1.5% ruxolitinib cream, respectively). Ruxolitinib cream was well tolerated during the 52‐week study in this patient population. Taken together, these results demonstrate that most patients with AD who did not achieve IGA‐TS at week 8 have clinically meaningful responses to ruxolitinib cream, and continued therapy beyond 8 weeks could result in additional benefit. [ABSTRACT FROM AUTHOR]

This article discusses a case of tattoo granuloma with uveitis (TAGU), a condition characterized by inflammation in the skin and eyes. The patient, a 41-year-old male, had papules and nodules in his tattoos along with blurred vision and other eye symptoms. Treatment with the Janus kinase inhibitor abrocitinib resulted in the regression of skin lesions and improvement in eye symptoms. The article suggests that TAGU may be related to delayed type hypersensitivity reaction or a limited form of sarcoidosis, and that JAK inhibitors like abrocitinib could be a potential treatment option. Further research is needed to assess long-term efficacy and follow-up. [Extracted from the article]

This article discusses a rare case of a patient with Sjögren syndrome (SS) and psoriasis who was successfully treated with the Janus kinase inhibitor, tofacitinib. The patient presented with symptoms such as xerostomia, xerophthalmia, blurred vision, itching skin rash, scaly plaques, muscle weakness, and weight loss. Laboratory results showed abnormalities in potassium levels, CO2 combining power, blood urea nitrogen, creatinine, and inflammatory markers. Treatment with tofacitinib, along with other medications, resulted in significant improvement in symptoms and laboratory values without any adverse events. The article highlights the potential of targeted synthetic drugs like tofacitinib in the treatment of autoimmune diseases. [Extracted from the article]

Chronic hand and foot eczema (CHFE) is a common inflammatory disorder that generally lasts for over 3 months. If it is intractable to topical agents, systemic immunomodulators can be considered; however, they are not suitable for long‐term management because of their adverse effects. Baricitinib is an oral Janus kinase inhibitor that has been approved for the treatment of moderate‐to‐severe atopic dermatitis. However, its effect on CHFE has rarely been described. Herein, we report nine cases of recalcitrant CHFE that were treated with baricitinib after an inadequate response to low‐dose ciclosporin. All patients had more than moderate improvement within 2–8 weeks without serious adverse effects. [ABSTRACT FROM AUTHOR]

We hypothesized that ruxolitinib may inhibit the immune checkpoint protein, B7H3; and, thus, investigated its effects on this immune inhibitor using multiple myeloma (MM) cell lines, bone marrow (BM) mononuclear cells from MM patients and human MM LAGλ‐1A xenografts. Ruxolitinib reduced B7H3 gene and protein expression and increased IL‐2 and CD8 gene expression. These results suggest that ruxolitinib inhibition of B7H3 may restore exhausted T‐cell activity in the MM BM tumor microenvironment. [ABSTRACT FROM AUTHOR]

Background: In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT‐I) and COMFORT‐II clinical trials, adult patients with intermediate‐2 or high‐risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS). Methods: This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation. Results: The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p =.0610; 44.0% vs. 26.9% at Week 48, p =.0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p =.022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p =.0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT. Conclusions: These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate‐2 and high‐risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS. Plain Language Summary: Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed. A pooled analysis of the Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT‐I) and COMFORT‐II phase 3 trials suggests that earlier ruxolitinib initiation in adult patients with intermediate‐2 or high‐risk myelofibrosis is associated with improved clinical outcomes, including significantly prolonged overall survival and improved spleen and symptom responses. These data suggest that patients with myelofibrosis may benefit from earlier intervention. [ABSTRACT FROM AUTHOR]

This is the English version of guidance for the use of oral Janus kinase (JAK) inhibitors in the treatment of atopic dermatitis. Several cytokines, such as interleukin (IL)‐4, IL‐13, IL‐22, IL‐31, thymic stromal lymphopoietin, and interferon‐γ, are involved in the pathogenesis of atopic dermatitis. As oral JAK inhibitors hinder the JAK‐signal transducers and activators of transcription signal transduction routes involved in the signal transduction of these cytokines, they may be effective for the treatment of atopic dermatitis. In Japan, as oral JAK inhibitors for atopic dermatitis, a JAK1/2 inhibitor, baricitinib, expanded its authorized indications for atopic dermatitis in 2020. Consequentially, a JAK1 inhibitor, upadacitinib, also expanded its indications to atopic dermatitis in 2021, followed by new approval of another JAK1 inhibitor, abrocitinib, for the use under the Japanese health insurance system. Physicians who intend to use them should sufficiently understand and comply with contents of guidelines prepared by the Japanese Ministry of Health, Labour and Welfare to promote optimal use of these drugs. In the treatment with oral JAK inhibitors, it is important to sufficiently consider disease factors, treatment factors and patient backgrounds, and share them with patients to choose treatment options. Points to be considered for drug selection include the efficacy and safety of drugs, age of patients, and dosage and administration of the drug. This guidance was developed for board certified dermatologists, who are specialized in the treatment of atopic dermatitis, and for promoting proper use of oral JAK inhibitors, taking into account a variety of factors in individual patients. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is one of the most prevalent inflammatory skin diseases. Janus kinase (JAK) inhibitor baricitinib is a promising treatment for AD as shown in recent clinical trials. We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) reporting the efficacy and safety of baricitinib. Data analysis was carried out using Cochrane Collaboration Review Manager 5.4 software and performed as risk ratios (RR) with 95% confidence intervals. Six RCTs involving a total of 2595 patients were included in the review. The meta‐analysis revealed that patients in the baricitinib group had significantly higher rates achieving EASI75, EASI90, IGA‐Response, SCORAD75, and Itch NRS improvement. Pooled analysis also showed no significant differences in treatment of emergent adverse events (TEAEs) between baricitinib and placebo groups. In conclusion, our meta‐analysis showed that baricitinib has promising efficacy for moderate‐to‐severe AD with favourable safety files. [ABSTRACT FROM AUTHOR]

Two Janus‐associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate‐risk and high‐risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non‐JAKi agents are being actively explored (in combination with ruxolitinib in first‐line or salvage settings and/or as monotherapy in JAKi‐pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B‐cell lymphoma 2/B‐cell lymphoma 2‐xL inhibitor), parsaclisib (a phosphoinositide 3‐kinase inhibitor), navtemadlin (formerly KRT‐232; a murine double‐minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non‐JAKi treatments to modify the natural history of MF. Janus‐associated kinase inhibitor (JAKi) agents improved spleen volume and symptoms in patients who had myelofibrosis but were associated with high discontinuation rates, a lack of predictors of response, and poor outcomes after discontinuation. Non‐JAKi agents, in combination with or subsequent to JAK agents, were being actively explored in phase 3 clinical trials. [ABSTRACT FROM AUTHOR]

Topical Janus kinase (JAK) and phosphodiesterase‐4 (PDE4) inhibitors are novel treatment approaches for atopic dermatitis (AD). This study aimed to compare the efficacy and safety of JAK and PDE4 inhibitors for AD treatment. The databases of PubMed, EMBASE, Web of Science, and Cochrane Library were searched until June 2021 for eligible studies of AD patients treated with topical JAK and PDE4 inhibitors. Baseline and follow‐up data were extracted. Efficacy of JAK inhibitors was evaluated using Investigator's Global Assessment (IGA) achieving "clear" or "almost clear", with 2 points or more improvement from baseline at the end of treatment, referred to as "IGA response"). A Bayesian multiple treatment network meta‐analysis with fixed effects was performed. Odds ratio (OR) with 95% credibility interval (CrI) were used for comparing the efficacy of JAK and PDE4 inhibitors with placebo for AD. A total of 10 randomized controlled trials of topical JAK and PDE4 inhibitors with 4689 patients were included for analysis. A total of three topical JAK inhibitors and two topical PDE4 inhibitors were included. Compared with placebo, all JAK and PDE4 inhibitors had higher IGA response at 4 weeks of treatment. Notably, with similar safety profile, tofacitinib 2% b.i.d., ruxolitinib 1.5% b.i.d., and delgocitinib 3% b.i.d. showed favorable IGA response compared with topical tacrolimus and corticosteroids. Ranking analysis suggested that among all included JAK and PDE4 inhibitors, tofacitinib 2% b.i.d. had the highest probability of achieving IGA response (SUCRA = 0.880). Besides, JAK and PDE4 inhibitors showed non‐inferior safety profile with placebo. This study confirmed that topical JAK and PDE4 inhibitors had promising treatment efficacy and safety for AD patients. Tofacitinib 2% b.i.d., ruxolitinib 1.5% b.i.d. and delgocitinib 3% b.i.d. showed superior efficacy over other JAK and PDE4 inhibitors. [ABSTRACT FROM AUTHOR]

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

This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16‐day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79‐0.96) for bupropion maximum plasma concentration (Cmax), 0.92 (0.87‐0.98) for bupropion area under the plasma‐concentration time curve from time 0 to infinity (AUCinf), 0.78 (0.72‐0.85) for hydroxybupropion Cmax, and 0.72 (0.67‐0.78) for hydroxybupropion AUCinf when administered with, relative to when administered without, upadacitinib. After multiple‐dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC0‐24 was 641 ± 177 ng·h/mL, and Cmax was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6. [ABSTRACT FROM AUTHOR]

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open‐label, randomized, 2‐way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150‐mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150‐mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150‐mg tablet formulation of peficitinib was bioequivalent to the developmental 150‐mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation. [ABSTRACT FROM AUTHOR]

Itacitinib is a novel, selective, Janus kinase 1 inhibitor in development for treatment of graft‐versus‐host disease. The objective of this study was to assess pharmacokinetics and safety of 300‐mg itacitinib dosed in participants with normal renal function (n = 10), severe renal impairment (n = 8), and end‐stage renal disease (ESRD) on hemodialysis (n = 8). Serial plasma and urine samples (urine from normal and severe groups only) were collected before dosing until 72 hours after dosing. In the ESRD group, itacitinib was evaluated in 2 periods, when dosed before (period 1) and after (period 2) a hemodialysis session. Geometric mean ratios (90% confidence interval) in participants with severe renal impairment, ESRD period 1 and ESRD period 2 relative to participants with normal renal function were 1.65 (1.13‐2.39), 0.71 (0.49‐1.03), and 0.83 (0.57‐1.20) for maximum plasma drug concentration and 2.23 (1.56‐3.18), 0.81 (0.57‐1.16), and 0.95 (0.66‐1.35) for area under the plasma concentration–time curve from time zero to infinity. Itacitinib was well tolerated, and 3 grade 1 treatment‐emergent adverse events were reported over the course of the study. Given the magnitude of exposure changes in participants with severe renal impairment or ESRD and the historic risk‐benefit profile, no dose adjustment is recommended for itacitinib in patients with impaired renal function, although the final dosage recommendation will be based on cumulative pharmacokinetics and safety from this study and from the pivotal graft‐versus‐host disease trial. Additionally, itacitinib may be administered to patients undergoing dialysis regardless of the time of dialysis. [ABSTRACT FROM AUTHOR]

Peficitinib (ASP015K) is a novel Janus kinase inhibitor developed for the treatment of rheumatoid arthritis (RA). The impact of hepatic impairment on the peficitinib pharmacokinetic (PK) and safety profile was investigated in non‐RA subjects (n = 24) in an open‐label, parallel‐group, multicenter comparative study in Japan. Subjects received a single, clinically relevant, oral dose of a peficitinib 150 mg tablet under fasting conditions. Plasma PK parameters were measured for peficitinib and its metabolites H1 (sulfate and methylated metabolite), H2 (sulfate metabolite), and H4 (methylated metabolite) in subjects with normal hepatic function, mild hepatic impairment, or moderate hepatic impairment. The peficitinib area under the plasma‐concentration–time curve from time 0 to infinity (AUCinf) and maximum observed concentration (Cmax) were not markedly different in subjects with mild hepatic impairment versus normal hepatic function. In subjects with moderate hepatic impairment versus normal hepatic function, the geometric mean ratios for peficitinib AUCinf and Cmax, were 1.92 (90% CI: 1.39, 2.66) and 1.82 (90% CI: 1.24, 2.69), respectively. Five treatment‐emergent adverse events (TEAEs) were experienced by 3 subjects, 1 in each group. There were no deaths, no serious TEAEs, and no TEAEs leading to withdrawal. In summary, the PK profile was unaltered in subjects with mild hepatic impairment after a single clinically relevant dose of peficitinib, but exposure almost doubled in subjects with moderate hepatic impairment. Peficitinib dose reduction may be considered in RA patients with moderate hepatic impairment. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated that delgocitinib ointment, a novel topical Janus kinase inhibitor, rapidly improved clinical signs and symptoms of atopic dermatitis (AD) in Japanese adult patients. We sought to evaluate the long‐term safety and efficacy of delgocitinib 0.5% ointment in a 52‐week study (QBA4‐2). Japanese patients aged 16 years or older with AD received delgocitinib 0.5% ointment b.i.d. for up to 52 weeks. Topical corticosteroids for the treatment of worsening of AD could be used at the investigators' discretion during the treatment period. Safety end‐points included the incidence and severity of adverse events (AEs). Pooled safety analyses included the data from the other long‐term study (QBA4‐1). Efficacy end‐points included the percentage change from baseline in the modified Eczema Area and Severity Index (mEASI). A total of 506 patients were included in the pooled safety population. Overall, AEs were reported in 69.0% of patients; most AEs were mild and unrelated to delgocitinib ointment. The most common AE was nasopharyngitis, followed by contact dermatitis, acne, and application site folliculitis. No skin atrophy or telangiectasia was found at the application sites of delgocitinib ointment. Application site irritation symptoms were infrequent (<2%) and mild. The incidence of AEs did not increase over time, except for seasonal diseases. The improvement effects on AD as assessed by mEASI were maintained throughout the treatment period. Delgocitinib 0.5% ointment was well tolerated and effective when administrated to Japanese adult patients with AD for up to 52 weeks. [ABSTRACT FROM AUTHOR]

Several cytokines signalling via Janus Kinase (JAK) proteins have been implicated in the pathogenesis of immune‐mediated inflammatory diseases, including psoriasis and rheumatoid arthritis (RA). Tofacitinib, a small JAK inhibitor, is approved for the treatment of RA and has demonstrated good efficacy in psoriasis phase III clinical trials. In this work, we analysed the in vitro effects of tofacitinib on the functions of human dendritic cells (DCs) and macrophages. When assessing the effects of tofacitinib on monocyte‐derived DCs, we observed reduced differentiation of monocytes into immature DCs, as evidenced by a decreased transcription of CD209 and CD80. Phenotype assessment in the presence of tofacitinib suggested a switch towards a M1‐like macrophage phenotype, as evidenced by the expression of M1 markers such as iNOS, as well as cytokines typically expressed by M1 cells, including IL‐12 and IL‐23. Of note, Arginase1 and CD200R, typically expressed by M2 cells, were absent on tofacitinib‐treated DCs. Furthermore, tofacitinib affected the response of differentiated DCs to maturation stimuli such as LPS and IFNγ, resulting in a partial up‐regulation of IL‐23 and down‐regulation of IL‐12, as assessed by qPCR. When investigating macrophage development, we found that tofacitinib inhibited the ability of monocytes to differentiate and polarize into regulatory M2 macrophages, while rather enhancing the ability to develop into inflammatory M1‐like macrophages, as evidenced by decreased expression of the M2 marker CD200R and enhanced production of IL‐12 and IL‐23. In conclusion, tofacitinib impacts the differentiation of human DCs and macrophages, it particularly favours generation of M1‐like pro‐inflammatory macrophages. [ABSTRACT FROM AUTHOR]

Purpose: To assess the capability of in vivo positron emission tomography (PET) using 18F‐fluorodeoxyglucose (18F‐FDG) to quantify changes in inflammatory activity in response to tofacitinib, a Janus kinase (JAK) inhibitor, over a timeframe of a few hours to few days in a preclinical model of rheumatoid arthritis (RA). Methods: Twenty‐four mice with collagen‐induced arthritis in the following groups were assessed: Group 1, where the changes in PET measures for the extremity joints were evaluated at the peak and trough plasma drug levels after administration of a single dose of tofacitinib (4 hours apart); Group 2, where joint PET measures were assessed before treatment and after 6 days of administration of a daily dose of tofacitinib; and group 3 (controls), where joint PET measures were derived from the same mice, 6 days apart. Results: At about peak plasma levels of the drug after a single tofacitinib administration, there was a reduction in PET measures compared to pretreatment values, suggesting decreased inflammatory activity. These measures were equivalent to those obtained after 6 days of daily dosing by tofacitinib. However, PET measures at trough plasma levels of the drug from tofacitinib administration were significantly higher than those at peak plasma drug levels and equivalent to pretreatment measures. There were insignificant changes in PET measures for the control animals. Conclusion: 18F‐FDG PET can detect changes in inflammatory activity occurring in response to the JAK inhibitor tofacitinib: (a) during peak and trough plasma drug levels, that is within mere hours of treatment; and (b) over a span of days. [ABSTRACT FROM AUTHOR]

Lung cancer patients with mutations in epidermal growth factor receptor (EGFR) benefit from treatments targeting tyrosine kinase inhibitors (TKIs). However, both intrinsic and acquired resistance of tumors to TKIs are common, and EGFR variants have been identified that are resistant to multiple TKIs. In the present study, we characterized selected EGFR variants previously observed in lung cancer patients and expressed in a murine bone marrow pro‐B Ba/F3 cell model. Among these EGFR variants, we report that an exon 20 deletion/insertion mutation S768insVGH is resistant to erlotinib (a first‐generation TKI), but sensitive to osimertinib (a third‐generation TKI). We also characterized a rare exon 21 germline variant, EGFR P848L, which transformed Ba/F3 cells and conferred resistance to multiple EGFR‐targeting TKIs. Our analysis revealed that P848L (a) does not bind erlotinib; (b) is turned over less rapidly than L858R (a common tumor‐derived EGFR mutation); (c) is not autophosphorylated at Tyr 1045 [the major docking site for Cbl proto‐oncogene (c‐Cbl) binding]; and (d) does not bind c‐Cbl. Using viability assays including 300 clinically relevant targeted compounds, we observed that Ba/F3 cells transduced with EGFR P848L, S768insVGH, or L858R have very different drug‐sensitivity profiles. In particular, EGFR P848L, but not L858R or S768insVGH, was sensitive to multiple Janus kinase 1/2 inhibitors. In contrast, cells driven by L858R, but not by P848L, were sensitive to multikinase MAPK/extracellular‐signal‐regulated kinase (ERK) kinase and ERK inhibitors including EGFR‐specific TKIs. These observations suggest that continued investigation of rare TKI‐resistant EGFR variants is warranted to identify optimal treatments for cancer. [ABSTRACT FROM AUTHOR]

Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open‐label, single‐dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15‐mg dose of the upadacitinib extended‐release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child‐Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration‐versus‐time profile from time 0 to infinity (AUCinf) for subjects with mild and moderate hepatic impairment were 1.28 (0.91‐1.79) and 1.24 (0.87‐1.76), respectively. The central ratios of upadacitinib maximum observed concentration (Cmax) were 1.04 (0.77‐1.39) and 1.43 (1.05‐1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics. [ABSTRACT FROM AUTHOR]

Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15‐mg dose of upadacitinib extended‐release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06–1.32), 1.33 (90%CI, 1.11–1.59), and 1.44 (90%CI, 1.14–1.82) for area under the plasma concentration–time curve and 1.06 (90%CI, 0.92–1.23), 1.11 (90%CI, 0.88–1.40), and 1.14 (90%CI, 0.84–1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function. [ABSTRACT FROM AUTHOR]

Abstract: Tofacitinib is an oral Janus kinase (JAK) inhibitor. This study characterized the pharmacokinetics of tofacitinib in patients with psoriasis and evaluated the impact of patient factors on disposition. Pooled phase 2/3 data (2981 patients: 9735 concentrations, dose range: 2‐15 mg twice daily) up to 56 weeks were used for modeling. A one‐compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution, zero‐order absorption (duration, D), with interindividual variability and inter‐occasion variability terms, described tofacitinib pharmacokinetics. A full covariate model incorporated effects for age, sex, race, ethnicity, and baseline variables (body weight, Psoriasis Area Severity Index [PASI], C‐reactive protein [CRP], creatinine clearance [CrCl]). The parameter estimates (95%CI) for CL/F, Vd/F, and D in a typical individual (white, male, 86 kg, 46 years, CrCl 121 mL/min, PASI 19.8, and CRP 0.267 mg/dL) were 26.7 (25.9, 27.5) L/h, 125 (120.8, 128.3) liters, and 0.69 (0.646, 0.735) hours, respectively. Only CrCl led to clinically relevant changes in exposure. The analysis suggested no dosing modifications for age, body weight, sex, race, ethnicity, baseline PASI, or CRP based on the magnitude of exposure change. Dosing adjustments for renal impairment were derived from a separate phase 1 study. [ABSTRACT FROM AUTHOR]

Abstract: Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open‐label, parallel‐group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200‐mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least‐squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration–time curve from time 0 to ∞ [AUC∞] and maximum concentration) of momelotinib and M21. There was no clinically significant difference in plasma exposures of momelotinib and M21 between subjects with moderate or severe renal impairment or moderate hepatic impairment and healthy control subjects. Compared with healthy control subjects, momelotinib AUC∞ was increased (GMR, 197%; 90%CI, 129%–301%), and M21 AUC∞ was decreased (GMR, 52%; 90%CI, 34%–79%) in subjects with severe hepatic impairment. The safety profile following a single dose of momelotinib was similar between subjects with hepatic or renal dysfunction and healthy control subjects. These pharmacokinetic and safety results indicate that dose adjustment is not necessary for momelotinib in patients with renal impairment or mild to moderate hepatic impairment. In patients with severe hepatic impairment, however, the dose of momelotinib should be reduced. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor. These post-hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52-week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo-treated patients advanced to tofacitinib at week 16. Primary efficacy end-points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index ( PASI-75) and Physician's Global Assessment ( PGA) of 'clear' or 'almost clear' ( PGA response) at week 16. Other end-points included: Itch Severity Item ( ISI), Dermatology Life Quality Index ( DLQI) score and Nail Psoriasis Severity Index ( NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI-75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis. [ABSTRACT FROM AUTHOR]

Myelofibrosis is characterized by splenomegaly and debilitating constitutional symptoms that negatively impact patients' quality of life. ROBUST, a UK, open-label, phase II study, evaluated the safety and efficacy of ruxolitinib in patients with myelofibrosis ( N = 48), including intermediate-1 risk patients. The primary composite endpoint was the proportion of patients achieving treatment success [≥50% reduction in palpable spleen length and/or a ≥50% decrease in Myelofibrosis Symptom Assessment Form Total Symptom Score ( MF- SAF TSS)] at 48 weeks. This was the first time that efficacy of ruxolitinib in myelofibrosis has been evaluated based on these criteria and the first time the MF- SAF was used in a population of patients solely from the United Kingdom. Overall, 50% of patients and 57% of intermediate-1 risk patients, achieved treatment success; reductions in spleen length and symptoms were observed in all risk groups. The majority of patients (66·7%) experienced ≥50% reductions from baseline in spleen length at any time. Improvements in MF- SAF TSS were seen in 80·0%, 72·7%, and 72·2% of intermediate-1, intermediate-2, and high-risk patients, respectively. Consistent with other studies of ruxolitinib, the most common haematological adverse events were anaemia and thrombocytopenia. Results indicate that most patients with myelofibrosis, including intermediate-1 risk patients, may benefit from ruxolitinib treatment. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration-time profile from time 0 to infinity (AUCinf) and maximum observed concentration (Cmax) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment-emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment. [ABSTRACT FROM AUTHOR]

The pharmacokinetics (PK) of tofacitinib were assessed in patients with mild (Cockcroft-Gault creatinine clearance >50 and ≤80 mL/min), moderate (≥30 and ≤50 mL/min), and severe (<30 mL/min) renal impairment, and end-stage renal disease (ESRD) requiring dialysis. Six patients each with normal, mild, moderate, or severely impaired renal function, and 12 patients with ESRD, received single tofacitinib doses of 10 mg. PK data were obtained from blood and dialyzate (patients with ESRD only) samples prior and subsequent to dosing and/or hemodialysis (patients with ESRD only). Relative to patients with normal renal function, mean (90% CI) AUC(0-∞) ratios were 137% (97-195), 143% (101-202), and 223% (157-316) in patients with mild, moderate, and severe renal impairment, respectively. Maximum plasma concentrations (Cmax) were similar across the four treatment groups. Terminal phase half-life (t1/2) increased with severity of renal impairment. Mean AUC(0-∞) in patients with ESRD on a non-dialysis day was similar to that in patients with moderate renal impairment and approximately 40% greater than healthy volunteer data. Mean (SD) dialyzer efficiency (ratio of dialyzer clearance/blood flow entering the dialyzer) was 0.73 (0.15). However, due to extensive non-renal clearance, dialysis procedure is unlikely to result in significant elimination of tofacitinib. [ABSTRACT FROM AUTHOR]

We report a case of aggressive bullous pemphigoid (BP) concurrent with plaque psoriasis successfully treated with Janus kinase inhibitor Baricitinib. The 83-year-old Chinese man suffered 10 years of psoriasis and developed BP with typical intense blisters and significantly elevated serum anti-BP180 autoantibodies. Due to concerns on his poor health conditions including stage III hypertension and potential serious side effects of standard treatment with systematic steroid, he was given Baricitinib orally 4 mg/day. Significant improvement in skin lesions and pruritus was noted following treatment for 12 weeks, from which the dose of Baricitinib was halved and continued for an additional 12 weeks. He showed a complete remission of both bullous and psoriatic lesions without any adverse effects at the 24-week follow-up visit. Our observation suggests a potential of Baricitinib as a new alternative therapeutic option for concurrent plaque psoriasis and BP or either of them., (© 2022 Wiley Periodicals LLC.)

Janus kinase (JAK) inhibitors have become promising treatments for atopic dermatitis (AD), however no study directly comparing JAK inhibitors with each other has been reported. We conducted this network meta-analysis to determine the comparative efficacy and safety of three common oral JAK inhibitors including abrocitinib, baricitinib, and upadacitinib for moderate-to-severe AD. We first identified eligible studies from published meta-analyzes, then we searched PubMed to obtain additional studies published between February and July 2021. Clinical efficacy and safety were evaluated as primary and secondary outcome, respectively. After extracting data and assessing methodological quality, we utilized ADDIS 1.4 software to conduct pair-wise and network meta-analyzes. Ten eligible studies were included in the final analysis. Pooled results that abrocitinib, baricitinib, and upadacitinib obtained higher investigator global assessment (IGA), eczema area, and severity index (EASI) response, however abrocitinib and upadacitinib caused more treatment-emergent adverse events (TEAEs) regardless of doses, compared with placebo. Network meta-analyzes revealed that upadacitinib 30 mg was superior to all regimens and upadacitinib 15 mg was better than remaining regimens except for abrocitinib 200 mg in terms of IGA and EASI response. Moreover, abrocitinib 200 mg was superior to abrocitinib 100 mg, baricitinib 1 mg, 2 mg, and 4 mg for clinical efficacy. However, upadacitinib 30 mg caused more TEAEs. Abrocitinib, baricitinib, and upadacitinib were consistently effective therapies in adult and adolescent patients with AD; however, upadacitinib 30 mg may be the optimal option in short-term studies. More efforts should be done to reduce the risk of TEAEs caused by upadacitinib 30 mg., (© 2022 The Authors. Dermatologic Therapy published by Wiley Periodicals LLC.)

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. WHAT THIS STUDY ADDS • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. AIMS To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. METHODS In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). RESULTS In vitro studies demonstrated low potential for CYP inhibition (I C50 estimates tofacitinib >30 µ m), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥25 µ m) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration ( Cmax) (95.98, 108.87) was also wholly within this acceptance region. CONCLUSIONS These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole. [ABSTRACT FROM AUTHOR]

Segmental vitiligo often presents in childhood and tends to be more recalcitrant to therapy than generalized vitiligo. Recently, Janus kinase inhibitors have emerged as a promising treatment option, with some reports suggesting that concomitant ultraviolet light exposure may enhance therapeutic response. Here, we present a child with segmental vitiligo who responded rapidly and completely to treatment with tofacitinib cream plus phototherapy. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) inhibitors are novel treatment approaches for atopic dermatitis (AD). This study was aimed to compare the efficacy of JAK inhibitors for AD treatment. The database of PubMed, EMBASE, Web of Science, and Cochrane Library were searched until March 28, 2021, for randomized control trials (RCTs) of AD patients treated with JAK inhibitors. Baseline and follow-up data were extracted. Efficacy of JAK inhibitors was evaluated using 50% improvement in Eczema Area and Severity Index (EASI-50). A Bayesian multiple treatment network meta-analysis with fixed effects was performed. Odds ratio (OR) with 95% credibility interval (CrI) were used for comparing the efficacy of JAK inhibitors with placebo for AD. A total of seven RCTs of JAK inhibitors with 2530 patients were included for analysis. After excluded one study with high risk of bias, a total of six JAK inhibitors with 17 different formulations and doses were analyzed. The severity of atopic dermatitis of included patients was almost moderate to severe (93.4%). Compared with placebo, all JAK inhibitors had higher EASI-50 at 4 weeks of treatment, except for baricitinib with 1 mg once daily (QD) (OR: 1.4, 95% Crl: 0.9-2.1), ruxolitinib with 0.15% QD (OR: 2.3, 95% Crl: 0.8-11.4), and ruxolitinib with 0.5% QD (OR: 3.4, 95% Crl: 0.9-18.1). Among all included, upadacitinib had the highest probability of being the best treatment (SUCRA value of 0.936). In topical JAK inhibitors, delgocitinib 3% twice a day (BID) had the highest probability of being the best treatment (SUCRA value of 0.849). JAK inhibitors had promising treatment efficacy for AD patients. Upadacitinib with 30 mg QD had the best efficacy among all included JAK inhibitors, and delgocitinib 3% BID showed superior efficacy over other topical JAK inhibitors for AD treatment., (© 2021 Wiley Periodicals LLC.)

Most of drugs could have certain mucocutaneous reactions and COVID-19 drugs are not an exception that we focused. We systematically reviewed databases until August 15, 2020 and among initial 851 articles, 30 articles entered this study (20 case reports, 4 cohorts, and 6 controlled clinical trials). The types of reactions included AGEP, morbiliform drug eruptions, vasculitis, DRESS syndrome, urticarial vasculitis, and so on. The treatments have been used before side effects occur, included: antimalarial, anti-viral, antibiotics, tocilizumab, enoxaparin and and so on. In pandemic, we found 0.004% to 4.15% of definite drug-induced mucocutaneous reactions. The interval between drug usage and the eruption varied about few hours to 1 month; tightly dependent to the type of drug and hydroxychloroqine seems to be the drug with highest mean interval. Antivirals, antimalarials, azithromycin, and tocilizumab are most responsive drugs for adverse drug reactions, but antivirals especially in combination with antimalarial drugs are in the first step. Types of skin reactions are usually morbilliform/exanthematous maculopapular rashes or urticarial eruptions, which mostly may manage by steroids during few days. In the setting of HCQ, specific reactions like AGEP should be considered. Lopinavir/ritonavir is the most prevalent used drug among antivirals with the highest skin adverse reaction; ribarivin and remdisivir also could induce cutaneous drug reactions but favipiravir has no or less adverse effects. Logically the rate of dermatologic adverse effects among anivirals may relate to their frequency of usage. Rarely, potentially life-threatening reactions may occur. Better management strategies could achieve by knowing more about drug-induced mucocutaneous presentations of COVID-19., (© 2020 Wiley Periodicals LLC.)