Janus Kinase Inhibitor Research Articles

Long-term sustainability of response to upadacitinib among patients with active rheumatoid arthritis refractory to biological treatments: results up to 5 years from SELECT-BEYOND

ObjectiveTo evaluate the long-term sustainability of response to the Janus kinase inhibitor upadacitinib among patients with rheumatoid arthritis and an inadequate response or intolerance to biological disease-modifying antirheumatic drugs (bDMARD-IR)...

Treating Chronic Pruritus: Are We at the Threshold of a Breakthrough?

Chronic pruritis, characterized by persistent itchiness lasting more than six weeks, affects up to 15% of the population, significantly impairing quality of life. Despite its prevalence and impact, there is an absence of FDA-approved medications specifically for the treatment of chronic pruritus, highlighting a significant unmet need in dermatology. Advancements in dermatologic medications, however, including the development of biologics and Janus kinase (JAK) inhibitors, signal potential breakthroughs in pruritus management through a radically different mechanism of action that focuses on their effect on the nervous system. Currently, the most commonly utilized treatments for pruritis are sedating antihistamines, which have been largely ineffective for non-histamine-induced itch, underscoring the necessity for novel approaches. This editorial reviews key studies and clinical trials with a particular focus on cases of prurigo nodularis, where itch serves as the primary pathology rather than just a symptom. The effectiveness of dupilumab in phase III trials for treating prurigo nodularis, independent of its effects on dermatitis or atopic background, alongside the success of JAK inhibitors in managing chronic idiopathic pruritus, indicates a shift towards therapies that directly and specifically target itch nerve pathways instead of indirectly via immune system modulation or sedation. These developments suggest that significant progress may be on the horizon for treating chronic itch, providing hope for those suffering from pruritis, the number one cause of misery in dermatology.

Off-Label Uses of Upadacitinib

Background: Janus Kinase (JAK) inhibitors interfere with the JAK-STAT signaling pathway, which is vital in regulating inflammation and immune function. Notably, upadacitinib, a JAK inhibitor, has been increasingly used as a treatment modality for refractory inflammatory diseases. Methods: A literature review was conducted on Pubmed and Clinical Trials.gov using the keywords “upadacitinib” combined with “off-label”, “dermatology”, “skin”, or “cutaneous” from October 1st, 2021, to October 1st, 2023. 941 articles were reviewed, and 50 articles were included. Results: The systematic search revealed 20 different dermatology conditions treated with off-label use of upadacitinib. Most of these conditions showed drastic improvement by actively decreasing the inflammatory response involved in the pathogenesis of that condition. The most common side effects reported for the medication were elevated creatine kinase, headaches, urinary tract infections, and acne. Patients should also be advised to consider the shingles vaccines prior to upadacitinib treatment. Conclusion: Upadacitinib shows potential utility in the treatment of refractory inflammatory dermatologic conditions, treatment-resistant pruritus, and medication-induced skin reactions. Further large-scale, controlled clinical trials are needed to evaluate the further indications of upadacitinib and its safety profile.

Breakthrough Opportunities of Nanotheranostics in Psoriasis: From Pathogenesis to Management Strategy.

In this paper, we have discussed recent advances in our understanding of the aetiology of psoriasis, particularly as they relate to aryl hydrocarbon receptors in DCs, Langerhans cells, macrophages, signal transducer and activator of transcription 3 pathways, and dermal vascular endothelial cells. Here, we have shown that the ability to target specific cellular and molecular components of psoriasis pathogenesis with nanoscale precision using phos-phodiesterase 4 inhibitors represents a transformative opportunity to address the complex nature of this dermatological condition. In this review, we have examined the molecular mechanisms behind the pathogenic features of psoriasis and new treatments being tested in clinical settings. There is research being done on new treatments created in the last ten years. This field highlights the advantages of nan-otechnological technologies as cutting-edge candidates for drug delivery systems in psoriasis and other inflammatory chronic skin disorders. Future Developments: Nanotechnology-based treatments currently under study show good effi-cacy and low side effect profiles. However, long-term prospective trials are required to demon-strate long-term safety and effectiveness. Phosphodiesterase inhibitors, Janus kinase inhibitors, nonsteroidal anti-inflammatory drugs, combinations of vitamin D3 derivatives and corticoster-oids, and coal tar formulations are some of the newer topical treatments for psoriasis. The psoriasis treatment continues to involve conventional medications (i.e., medi-cines that are generally acknowledged as either normal therapy or outdated remedies), whether used topically or orally. Nonetheless, we are starting to see initiatives to create pharmaceuticals and biosimilars with better therapeutic results, fewer side effects, and greater efficacy.

Successful Treatment of Refractory Discoid Lupus Erythematosus with Deucravacitinib

Discoid lupus erythematosus (DLE) is the most common subtype of chronic cutaneous lupus erythematosus (CLE) that may present with or without systemic lupus erythematosus (SLE). Treatment for DLE remains limited, as there are no medications specifically approved to treat DLE. Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, is currently being studied for adults with moderate-to-severe discoid and/or subacute CLE. We report a case of successful treatment of refractory DLE with deucravacitinib. A 65-year-old female with a longstanding history of systemic lupus erythematosus presented with prominent discoid lesions involving the nose, cheeks, and mid upper cutaneous lip. Having tried topical medications, multiple courses of systemic steroids were attempted, but the patient flared shortly after the tapers. Despite the patient experiencing some improvement on mycophenolate mofetil and prednisone, the decision to switch to deucravacitinib was made due to the patient developing multiple infections while on the former regimen. Three months after starting deucravacitinib, the patient returned with their skin completely clear. A better understanding of the molecular pathogenesis of CLE is informing the development of more targeted therapeutic strategies. TYK2 and Janus Kinases (JAKs) both mediate the signaling of cytokines, some of which play a role in the pathogenesis of SLE. Deucravacitinib binds to TYK2 at the regulatory domain, which is unique to its respective kinase unlike conventional Janus Kinase (JAK) inhibitors that bind to the active domain conserved across all JAKs. Deucravacitinib offers more targeted inhibition with a potentially improved safety profile compared to conventional JAK inhibitors.

The Association Between Deep Vein Thrombosis, Pulmonary Embolism, and Janus Kinase Inhibitors: Reporting Status and Signal Detection in the Japanese Adverse Drug Event Report Database.

Although Janus kinase (JAK) inhibitors have expanding indications, deep vein thrombosis (DVT) and pulmonary embolism (PE) are serious adverse events associated with their use. Moreover, their analysis using the Japanese database of spontaneous adverse drug reaction reports has not yet been conducted. The objective of this study was to analyze the Japanese Adverse Drug Event Report database (JADER) to evaluate the association between JAK inhibitors and DVT and PE. JADER reports from April 2004 to October 2023 were analyzed. A classification of reports for the period covered was performed by drug, and an imbalance analysis was performed with oral JAK inhibitors as the target drug and DVT, PE, and "embolic and thrombotic events, venous" (Standardised MedDRA Query; SMQ) as the target adverse events. Reported odds ratios (ROR) and information components (IC) were calculated for signal detection. Overall, 6631 JAK inhibitor-related adverse events were reported, including 60 and 41 cases of DVT and PE, respectively. The ROR and IC of the JAK inhibitors for DVT were 2.52 (1.95-3.25) and 1.27 (0.41-2.13), while those of baricitinib for DVT were 4.37 (2.83-6.73) and 1.90 (0.47-3.33), respectively. ROR signals were detected for JAK inhibitors for PE and "embolic and thrombotic events, venous (SMQ)," overall and for several JAK inhibitors but none for IC. Several JAK inhibitors are under postmarketing phase vigilance, and the number of reported adverse events is low. However, when administering these drugs, care should be taken to avoid the development of thromboembolism, considering the patient's background.

Re-evaluating Methods for Assessing Differences in Response in Ileal vs. Colonic Crohn's Disease: A Post-hoc Analysis of the FITZROY Trial.

The ileum is the most commonly affected segment of the gastrointestinal tract in Crohn's disease (CD). We aimed to determine whether disease location affects response to filgotinib, a Janus kinase (JAK) inhibitor, in patients with moderate-to-severely active Crohn's disease (CD) and applying appropriate methods to account for differences in measuring disease activity in the ileum compared to the colon. This post-hoc analysis of data from the FITZROY phase 2 trial (NCT02048618) compared changes in the Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) amongst patients with ileal-dominant and isolated colonic CD treated with 10 weeks of filgotinib 200mg daily or placebo. A mixed effects model for repeated measures was used to test whether ileal disease responded differently than colonic disease, by evaluating for effect modification using the interaction term of treatment assignment-by-disease location. Numerically greater proportions of patients with isolated colonic disease compared to ileal-dominant CD achieved clinical remission (CDAI <150, 75.9% vs. 41.6%) and endoscopic response (SES-CD reduction by 50%, 52.5% vs. 15.5%) at Week 10. However, after adjusting for baseline disease activity by disease location and within-patient clustering effects, there was no significant difference in treatment response by disease location (mean difference in ΔCDAI between ileal-dominant vs. isolated colonic disease +9.24 [95% CI: -87.19, +105.67], p=0.85; mean difference in ΔSES-CD -1.93 [95% CI: -7.03, +3.44], p=0.48). Filgotinib demonstrated similar efficacy in ileal-dominant and isolated colonic CD when controlling for baseline disease activity and clustering effects.

Review of modern methods of treating vitiligo

Vitiligo is an autoimmune disease that causes skin depigmentation. The article is a review of the literature with a detailed description of the pathogenesis and the main combinations of therapeutic approaches. The issue of the use of oral and topical janus kinase inhibitors for the treatment of vitiligo was raised.

Successful treatment of infantile refractory bullous pemphigoid with baricitinib.

Infantile bullous pemphigoid (BP) is a rare autoantibody-mediated skin disorder. We report the effective treatment of a 6-month-old infant with BP using baricitinib, a Janus kinase (JAK) inhibitor, after failure with steroids and intravenous immunoglobulin. The patient achieved full remission and discontinued all medications without any relapses. To our knowledge, this is the first case of baricitinib used in an infant with BP.

Evolution of dupilumab-associated conjunctivitis in patients with atopic dermatitis after switching dupilumab to tralokinumab or Janus kinase inhibitors (RESO-ADOC study).

Clinical trials and real-life data have reported an increased incidence of conjunctivitis in patients treated with dupilumab for their atopic dermatitis (AD). Although mostly mild in severity, in some cases conjunctivitis will appear or increase after dupilumab initiation, which can lead to dupilumab discontinuation. (1) To describe the characteristics of patients developing conjunctivitis requiring discontinuation of dupilumab; and (2) to analyse the factors associated with a complete conjunctivitis improvement after dupilumab discontinuation and a switch to tralokinumab or Janus kinase inhibitors. This was a multicentre retrospective cohort study that included all patients with AD treated with dupilumab who developed conjunctivitis leading to dupilumab discontinuation and switching to tralokinumab or Janus kinase inhibitors in daily practice. Data on patients, their AD and conjunctivitis were analysed at the inclusion visit (corresponding to discontinuation of dupilumab and the institution of new AD treatment), at visit 2 (3-6 months after inclusion) and at visit 3 (corresponding to the last medical visit). After multivariate analysis, the only factors associated with a complete resolution of dupilumab-associated conjunctivitis at visit 2 and/or visit 3 were conjunctivitis duration (OR 8.98, 95% CI 1.47-55) (p = 0.018), personal history of asthma (OR 10.66, 95% CI 1.82-62.63) (p = 0.009) and switching from dupilumab to Janus kinase inhibitors (OR 17.11, 95% CI 2.94-99.66) (p = 0.002). Although uncommon, severe dupilumab-associated conjunctivitis is more frequent in daily life compared to its incidence in the dupilumab pivotal trials. In these cases, our study suggests that a rapid switch to another molecule, particularly a Janus kinase inhibitor, should be considered.

JAK inhibitors attenuate hyperactivation of nonswitched memory B cells in rheumatoid arthritis patients in remission

ObjectiveTo investigate the distribution and activation of B-cell subpopulations in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) and to analyze their correlation with disease remission.MethodsPeripheral blood samples were collected from 23 adult healthy controls and 58 RA patients, 31 of whom were treated with JAKis and assessed during a 24-month follow-up. The number of peripheral B-cell subpopulations (including naive B cells, nonswitched memory B (NSMB) cells, switched memory B cells, and double-negative B cells), their activation, and phosphorylation of SYK and AKT upon B-cell receptor (BCR) stimulation in each population were analyzed by flow cytometry.ResultsCompared with that in healthy controls, the frequency of NSMB cells was significantly lower in new-onset untreated RA patients. However, expression of CD40, CD80, CD95, CD21low and pAKT significantly increased in these NSMB cells. Additionally, the number of NSMB cells correlated negatively with DAS28-ESR and IgG and IgA levels in these patients; expression of CD80, CD95 and CD21low on NSMB cells correlated positively with DAS28-ESR and IgG and IgA levels. After treatment with JAKis, the serum IgG concentration significantly decreased in RA patients in remission, but CD40, CD95 and pAKT levels in NSMB cells significantly decreased.ConclusionRA patients present different B-cell subpopulations, in which the frequency of NSMB cells is negatively associated with disease activity. However, treatment with JAKis can inhibit activation of NSMB cells, restore the balance of kinase phosphorylation, and facilitate disease remission in RA patients.

Biologics Versus JAK Inhibitors. Part II: Risk of Infections. A Narrative Review.

The risk of infections associated with biological drugs (BD) and Janus kinase inhibitors (JAKi) has been extensively explored in the literature. However, there is a dearth of studies that evaluate both pharmacological groups together and, furthermore, compare them. Here, we review the risk of infections associated with BD and JAKi used in dermatology. A narrative review was performed. All relevant articles evaluating the risk of infection and opportunistic infections with BD and JAKi between January 2010 and February 2024 were selected. Overall, the incidence of infections, serious infections, and opportunistic infections associated with BD and JAKi is low, but higher than in the general population. JAKi approved for dermatological disorders (abrocitinib, baricitinib, deucravacitinib, upadacitinib, ritlecitinib, and topical ruxolitinib) have been shown to be safe, and present a low rate of infections. We found an elevated risk, especially with anti-tumor necrosis factor (anti-TNF) agents, rituximab, and JAKi (particularly tofacitinib at high doses). Specific associations with infections include tuberculosis and tuberculosis reactivation with anti-TNF agents and tocilizumab; candidiasis with anti-interleukin (IL) 17 agents; hepatitisB virus reactivation with rituximab, anti-TNF, and JAKi; and herpes simplex and herpes zoster infections with JAKi (especially tofacitinib and upadacitinib at high doses). The incidence of infections with ustekinumab and anti-IL-23 was very low. Anti-IL-1, nemolizumab, tralokinumab, and omalizumab were not associated with an increased risk of infections. Dupilumab could decrease the incidence of cutaneous infections. Anti-TNF agents, rituximab, and JAKi (particularly tofacitinib) can increase the risk of infections. Close monitoring of patients undergoing these therapies is recommended. Prospective studies with long-term follow-up are needed to comparatively evaluate the risks of infection deriving from treatment with BD and JAKi.

A Systematic Overview of Contraindications and Special Warnings for Biologic and Targeted Synthetic Disease Modifying Antirheumatic Drugs: Establishing a Framework to Create a "Safety Checklist".

The purpose of this review is to provide an overview of the contraindications, special warnings, and boxed warnings with the aim to establish a framework to create a prescription safety checklist for a class of drugs or disease indication. This study covers biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). We identified contraindications, boxed warnings, and special warnings provided by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The study included b/tsDMARDs approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (SpA), and juvenile idiopathic arthritis (JIA) within the drug-classes anti-CD20, tumor necrosis factor inhibitors (TNFi), interleukin-1 inhibitors (IL-1i), cytotoxic T-lymphocyte-associated protein (CTLA) 4, interleukin-12/23 inhibitors (IL-12/23i), interleukin 6 receptor inhibitors (IL-6Ri), Janus kinase inhibitors (JAKi), phosphodiesterase 4 inhibitors (PDE4i), interleukin-17 inhibitors (IL-17i), and interleukin-23 inhibitors (IL-23i). All drug classes, except PDE4i, had contraindications and/or warnings related to infections, including tuberculosis. A warning about herpes zoster was listed for anti-CD20, IL-1i, IL-6Ri, and JAKi, while a warning about hepatitis reactivation was listed for anti-CD20, TNFi, IL-1i, CTLA4-Ig, IL-6Ri, and JAKi. Malignancy risk was mentioned for all drug classes except PDE4i, IL-17i, and IL-23i. Other warnings included demyelinating disease (TNFi, CTLA4-Ig, and IL-6Ri), heart failure (anti-CD20 and TNFi), major adverse cardiac events (JAKi and IL-12/23) and venous thromboembolism (JAKi), hyperlipidemia (IL-6Ri and JAKi), liver impairment (TNFi, IL-1i, IL-6Ri, and JAKi), kidney impairment (IL-1i, JAKi, and PDE4i), inflammatory bowel disease (IL-17i), gastrointestinal perforation (IL-6Ri, JAKi), cytopenia (anti-CD20, TNFi, IL-1i, IL-6Ri, JAKi), and depression (PDE4i). Contraindications and warnings appeared to increase with the passage of time since the drug's approval. This review provides an overview to establish the framework to create an easily accessible and actionable prescription safety checklist from individual medical product prescription information provided by regulatory medical authorities.

Identification of novel covalent JAK3 inhibitors through consensus scoring virtual screening: integration of common feature pharmacophore and covalent docking.

Accumulated research strongly indicates that Janus kinase 3 (JAK3) is intricately involved in the initiation and advancement of a diverse range of human diseases, underscoring JAK3 as a promising target for therapeutic intervention. However, JAK3 shows significant homology with other JAK family isoforms, posing substantial challenges in the development of JAK3 inhibitors. To address these limitations, one strategy is to design selective covalent JAK3 inhibitors. Therefore, this study introduces a virtual screening approach that combines common feature pharmacophore modeling, covalent docking, and consensus scoring to identify novel inhibitors for JAK3. First, common feature pharmacophore models were constructed based on a selection of representative covalent JAK3 inhibitors. The optimal qualitative pharmacophore model proved highly effective in distinguishing active and inactive compounds. Second, 14 crystal structures of the JAK3-covalent inhibitor complex were chosen for the covalent docking studies. Following validation of the screening performance, 5TTU was identified as the most suitable candidate for screening potential JAK3 inhibitors due to its higher predictive accuracy. Finally, a virtual screening protocol based on consensus scoring was conducted, integrating pharmacophore mapping and covalent docking. This approach resulted in the discovery of multiple compounds with notable potential as effective JAK3 inhibitors. We hope that the developed virtual screening strategy will provide valuable guidance in the discovery of novel covalent JAK3 inhibitors.

Tofacitinib: A paradigm shift in rheumatoid arthritis management

Tofacitinib, a Janus kinase (JAK) inhibitor, represents a significant advancement in the treatment of rheumatoid arthritis (RA), a chronic inflammatory disorder. This manuscript provides an in-depth review of the efficacy, safety, and clinical application of tofacitinib in RA management. Through a comprehensive analysis of clinical trials, real-world studies, and comparative assessments with other RA therapies, we aim to elucidate the role of tofacitinib in improving patient outcomes. The review highlights the mechanisms of action, clinical efficacy, safety profile, and practical considerations for incorporating tofacitinib into RA treatment regimens.

Cost-Effectiveness of Dupilumab and Oral Janus Kinase Inhibitors for the Treatment of Moderate-to-Severe Atopic Dermatitis in Singapore.

Atopic dermatitis (AD) affects both adults and children, impacting their quality of life and productivity; however, traditional systemic treatments such as cyclosporine have limitations. Emerging novel systemic interventions, including monoclonal antibodies and Janus kinase (JAK) inhibitors, have been shown to improve patient outcomes. This study evaluates the cost-effectiveness of novel systemic interventions for moderate-to-severe AD in adults compared with the best supportive care (BSC) in Singapore. The economic evaluation used a hybrid model consisting of a decision tree and Markov model. Treatment responses at 16 weeks were based on a network meta-analysis that was developed specifically for this study. Long-term response, discontinuation rates, episodes of flares and treatment-emergent adverse events were obtained from key dupilumab, abrocitinib, baricitinib and upadacitinib trials. The study had a 5-year time horizon and considered the healthcare payer's perspective. Sensitivity and scenario analyses were performed as well. Baricitinib 4mg and 2mg have the lowest incremental cost-effectiveness ratios, at Singapore dollars (S$)60,730/quality-adjusted life-year (QALY) and S$66,842/QALY, respectively. Upadacitinib 30mg offers the highest incremental QALY gain, while baricitinib 2mg offers the least. The cost of the intervention drugs accounted for the highest proportion of the overall expenses (68-93%) for those in the maintenance state. Other influential factors within the model included (1) the incremental utility derived from intervention response; (2) the probability of achieving Eczema Area and Severity Index 75 (EASI-75) with BSC; and (3) the relative risk of achieving EASI-75 with the interventions. In a scenario where the cost of all drugs is matched to the lowest-priced drug, the top three cost-effectiveness interventions are dupilumab, upadacitinib 30mg and abrocitinib 200mg, respectively. The interventions are not found to be cost-effective at their existing prices when compared with BSC. Ideally, a composite score of treatment success and quality-of-life scores ought to be included, but such data were unavailable. Future research should consider conditional discontinuation data and long-term outcomes when such data become accessible.

Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease

The involvement of chronic inflammation in the pathogenesis of age-related macular degeneration (AMD) opens therapeutic possibilities to AMD management. To determine whether Janus kinase inhibitors (JAKis) are associated with a reduced risk of AMD development in patients with autoimmune diseases. This retrospective observational cohort study used administrative claims data from Merative MarketScan research databases (Commercial and Medicare Supplemental) and Optum Clinformatics Data Mart databases between January 1, 2010, and January 31, 2022. Patients with autoimmune diseases satisfying study eligibility criteria and who received JAKi treatment (9126 in MarketScan and 5667 in Optum) were propensity score matched (1:1) to identical numbers of study-eligible patients who received non-JAKi-based immunotherapy. Treatment duration of 6 months or longer. Incidence rates of AMD (exudative and nonexudative) over the first 6 to 18 months of treatment were determined, and bayesian Poisson regression models were used to estimate incidence rate ratios, 95% CIs, and posterior probabilities of AMD. After matching, female sex represented the majority of the patient population in both MarketScan and Optum (14 019/18 252 [76.6%] and 8563/3364 [75.2%], respectively in the JAKi patient population). More than 60% of the patient population was older than 55 years of age in both cohorts. Over the specified treatment period, a 49% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (10/9126 events; adjusted incidence rate ratio [AIRR], 0.51; 95% CI, 0.19-0.90) vs those who received non-JAKi therapy (43/9126 events; AIRR, 1 [reference]) in MarketScan, and a 73% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (3/5667 events; AIRR, 0.27; 95% CI, 0.03-0.74) vs those who received non-JAKi therapy (21/5667 events; AIRR, 1 [reference]) in Optum. The absolute percentage reductions were 0.36% (MarketScan) and 0.32% (Optum), favoring patients who received JAKi therapy. Posterior probabilities of the adjusted risk being less than unity were 97.6% (MarketScan) and 98.9% (Optum) for those who received JAKi therapy vs those who received non-JAKi therapy in MarketScan and Optum, respectively. JAKi use may be associated with a reduced risk of incident AMD in US adults with major autoimmune diseases. The absolute percentage reduction is consistent with a potential role for JAKi in this population. Future studies with long-term follow-up are recommended to investigate the association between JAKi use and incident AMD in other disease indications. Investigation into the role of systemic inflammation and JAK-signal transducers and activators of transcription signaling in AMD may improve understanding of the pathophysiology of AMD and lead to new treatment options.

Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2.

Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n=156). Patient subgroups (n=105 each) were defined by either baseline (1) hemoglobin (Hb) of<100g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of<80g/L for the previous 12weeks); outcomes have been summarized descriptively. In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of<100g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemiasupportive therapies. ClinicalTrials.gov: NCT02101268.

Pemphigoid diseases in patients with end-stage kidney diseases: pathogenesis and treatment.

Pemphigoid diseases constitute a group of autoimmune blistering disorders characterized by subepithelial blistering. The association between pemphigoid diseases and both end-stage kidney disease (ESKD) and its treatment is notable. However, there is limited evidence about the management of pemphigoid diseases in patients with ESKD. This systematic review compiled case reports and relevant studies, summarized the underlying mechanisms of pemphigoid diseases in patients with ESKD, and summarized the efficacy of various therapies. A systematic search of PubMed and Embase was performed for articles published between 1982 to June 2, 2024. Fifty-three case reports and eight relevant studies were included. Triggers for pemphigoids in patients with ESKD included materials used to treat ESKD, immune dysregulation of patients with ESKD, and rejection of renal allograft. Treatment for these patients included removing triggers, as well as administering of corticosteroids, mycophenolate mofetil (MMF), tetracyclines, rituximab, methotrexate, dapsone, azathioprine, cyclosporine, intravenous immunoglobin (IVIG), plasmapheresis, and Janus kinase inhibitors. Removing triggers is the most effective strategy. Despite their suboptimal efficacy, corticosteroids remain the most commonly used agents in this patient population. MMF, tetracyclines, and rituximab are less used but with benefits. There are significant adverse effects associated with methotrexate treatment. Other treatment may also be beneficial and require further investigation. These findings may enable clinicians to optimize the therapeutic approach for these patients.

Lichen Planus: What is New in Diagnosis and Treatment?

Lichen planus (LP), an idiopathic, multifaceted chronic inflammatory disease with a heterogeneous clinical presentation, affects approximately 0.5-1% of the population. The various clinical manifestations of LP fall into three broad categories, namely cutaneous, appendageal, and mucosal, with further subclassification depending on the morphology and distribution patterns of individual lesions. There is mounting evidence that LP has systemic associations, including autoimmune conditions, glucose intolerance, dyslipidemia, and cardiovascular disorders. Cutaneous hypertrophic and mucosal forms of LP are at a heightened risk for malignant transformation. Familiarity with these potential associations in conjunction with long-term follow-up and regular screening could lead to a timely diagnosis and management of concomitant conditions. In addition, the frequent quality of life (QoL) impairment in LP underscores the need for a comprehensive approach including psychological evaluation and support. Several treatment strategies have been attempted, though most of them have not been adopted in clinical practice because of suboptimal benefit-to-risk ratios or lack of evidence. More recent studies toward pathogenesis-driven treatments have identified Janus kinase inhibitors such as tofacitinib, phosphodiesterase-4 inhibitors such as apremilast, and biologics targeting the interleukin-23/interleukin-17 pathway as novel therapeutic options, resulting in a dramatic change of the treatment landscape of LP. This contemporary review focuses on the diagnosis and management of LP, and places emphasis on more recently described targeted treatment options.