Treatment of Psoriasis Patients with Latent Tuberculosis Using IL-17 and IL-23 Inhibitors: A Retrospective, Multinational, Multicentre Study.

BACKGROUND: Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation. OBJECTIVE: To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis. METHODS: This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded. RESULTS: A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0-5.43%] and 0% for all other agents and 0.46% (95% CI 0-1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant). CONCLUSIONS: The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors.

Abrocitinib for the treatment of atopic dermatitis.

Abrocitinib is an oral small molecule which selectively inhibits JAK1, modulating multiple cytokine pathways involved in atopic dermatitis. Both abrocitinib 200 mg and 100 mg reached efficacy results comparable to dupilumab and superior to placebo. Abrocitinib 200 mg was superior to dupilumab in some trials, consistently providing a faster response and itch relief from week 2 to 26. Continuous abrocitinib 200 mg is the most effective at controlling this disease, but with an induction-maintenance approach with abrocitinib 200 mg followed by 100 mg, over 55% of patients did not flare for 40 weeks. Abrocitinib common adverse effects are nonserious. A self-limited dose-related decrease in platelet counts was consistently observed, without clinical repercussion. Abrocitinib demonstrated high efficacy and a favorable safety profile.

Atopic dermatitis is the most common form of eczema, a condition that causes the skin to become itchy, dry and cracked. Abrocitinib is a medication taken orally (by mouth) that specifically targets JAK1, a protein involved in inter- (within cells) and intracellular (between cells) pathways that cause atopic dermatitis. Both the 200 mg and 100 mg doses of abrocitinib were effective compared with a placebo, a substance that looks like the treatment drug but doesn't have any of its chemical effects. Abrocitinib 200 mg was even better than dupilumab, another recently available injectable treatment option, especially by reducing itch from week 2. Using continuous abrocitinib 200 mg showed the best results for controlling the disease. However, an approach of starting with abrocitinib 200 mg and then reducing it to 100 mg also worked well, with over 55% of patients not experiencing a worsening of their condition for 40 weeks. The most common side effects of abrocitinib are not serious. There was a temporary decrease in platelet counts, tiny blood cells that help your body form clots to stop bleeding, but this did not cause any clinical issues. It has also proven effectiveness and safety in adolescents from 12 years of age. Overall, abrocitinib was highly effective and had a positive safety profile.

Deucravacitinib for the treatment of psoriatic arthritis: the evidence so far.

Psoriatic arthritis (PsA) is a heterogeneous disease that may develop in up to 30% of patients with psoriasis. PsA mainly involves peripheral joints; however, axial skeleton and entheses can also be involved. PsA is the result of a complex interplay between an individual's genotype and environmental factors that triggers an immune response and leads to the production of a cytokine cascade. Even though there are about 17 targeted therapies for PsA, a significant percentage of patients fail to respond to such treatments, have a partial response or develop side-effects. This article aims to review the current knowledge on deucravacitinib, a new oral small molecule that selectively inhibits tyrosine kinase 2 (TYK2), for the treatment of PsA. TYK2, a member of the Janus kinase (JAK) family, is responsible for mediating intracellular signalling of cytokines involved in the pathogenesis of PsA and psoriasis, namely IL-12, IL-23, and type I interferons. Recently, deucravacitinib was approved by the FDA for the treatment of moderate-to-severe plaque psoriasis and is currently being evaluated in phase III clinical trials in PsA. In a phase II clinical trial, deucravacitinib showed sustained effectiveness in several domains of PsA, namely arthritis, enthesitis and dactylitis, was well tolerated, and had a favourable safety profile. In patients with psoriasis, deucravacitinib had shown a higher efficacy than placebo and apremilast. Deucravacitinib is a promising therapy, with a unique mechanism of action. Results from the phase III programme and studies evaluating long-term response and head-to-head comparisons with other targeted agents will be important to establishing the position of deucravacitinib in the management of PsA.

Deucravacitinib in the treatment of psoriasis.

PURPOSE OF THE ARTICLE: Psoriasis is a chronic, immune-mediated, skin disease with a significantly negative impact on patients' quality of life. Moderate-to-severe disease often requires systemic therapies and currently available ones still have numerous disadvantages or limitations. Tyrosine kinase 2 (TYK2) mediates immune signaling of IL-12, IL-23, and type I interferons, without interfering with other critical systemic functions. This article aims to review the current knowledge on deucravacitinib, a new oral drug which selectively inhibits TYK2, granting it a low risk of off-target effects. MATERIALS AND METHODS: A review of the published literature was conducted using the PubMed database, published abstracts and virtual presentations from scientific meetings, data from industry press releases, and results published on ClinicalTrials.gov regarding the deucravacitinib for the treatment of psoriasis. Manuscripts with trial results, case series, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on the topic of the article were selected. RESULTS: Two phase 3, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast - POETYK PSO-1 and PSO-2, enrolling 1688 patients with moderate-to-severe psoriasis. At week 16, over 50% of patients treated with deucravacitinib reached PASI75, significantly superior to placebo and apremilast. Symptomatic improvement was also reported, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities. Persistent efficacy and consistent safety profiles were reported for up to 2 years. CONCLUSIONS: Deucravacitinib has the potential to become a safe, effective, and well-tolerated treatment for patients with moderate-to-severe disease. Future studies will be important to determine the exact role of this drug in the treatment of psoriasis.

OX40-OX40L Inhibition for the Treatment of Atopic Dermatitis-Focus on Rocatinlimab and Amlitelimab.

Despite the recent emergence of targeted therapeutic options, there are still unmet needs concerning moderate-to-severe atopic dermatitis treatment. This review aims to discuss the OX40-OX40L pathway as a therapeutic target for the treatment of atopic dermatitis. OX40 and OX40L are two checkpoint molecules that bind to potentiate pro-inflammatory T-cell responses that are pivotal to atopic dermatitis pathogenesis. Two OX40-OX40L inhibitors, rocatinlimab and amlitelimab, are being developed for the treatment of atopic dermatitis. Rocatinlimab, an anti-OX40 antibody, was evaluated in phase 2b, a randomized, placebo-controlled clinical trial. At week 16, rocatinlimab groups achieved a greater reduction in the EASI percentage change from the baseline (−48.3% to −61.1%) against the placebo (−15.0%; p < 0.001), and clinical response was maintained 20 weeks after the treatment had ceased. Amlitelimab, an anti-OX40L antibody, was studied in a 12-week treatment phase 2a clinical trial, with a significant efficacy response observed within 2 weeks. At week 16, amlitelimab groups reached the EASI mean percentage change from the baseline of −69.9% and −80.1% versus the placebo (−49.4%; p = 0.072 and p = 0.009). Among the responders, 68% of amlitelimab patients were sustained 24 weeks following the last dose. Both treatments were shown to be safe and well tolerated. Current evidence points to OX40-OX40L inhibitors as future options for atopic dermatitis treatment with potential disease-modifying effects.

Deucravacitinib for the Treatment of Psoriatic Disease.

Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is responsible for mediating immune signalling of IL-12, IL-23 and type I interferons, without interfering with other critical systemic functions as other JAK proteins do. This article aims to review the current knowledge on deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a low risk of off-target effects. After good efficacy and safety results in a phase II, placebo-controlled trial, two phase III, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast-an active comparator. POETYK PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. In POETYK PSO-1, these results improved until week 24 and were maintained through week 52, with over 65% of patients achieving PASI75 at this point. A reduction in signs and symptoms was also reported by patients, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities, which are a concern among other JAK inhibitors. Persistent efficacy and consistent safety profiles were reported for up to 2 years. Despite advances in the treatment of psoriasis, namely among biologic agents, an oral, effective and safe new drug can bring several advantages to prescribers and patients. Further investigation is required to understand where to place deucravacitinib among current psoriasis treatment options.

Generalized pustular psoriasis: the new era of treatment with IL-36 receptor inhibitors.

Generalized pustular psoriasis (GPP) is a rare yet severe variant of psoriasis, characterized by the eruption of superficial sterile pustules that appear suddenly and widely distributed, potentially life-threatening. It more commonly presents through recurrent acute flares triggered by stress, corticosteroid withdrawals, pregnancy, or infections. The pathogenesis of this disease is yet to be fully understood. Nevertheless, studies have suggested an important role of an IL-1 subfamily of cytokines, due to an imbalance of the IL-36 axis favoring of pro-inflammatory activity. The therapeutic intervention for this condition is still a challenge as its rarity and scarce available information contribute to the absence of specific treatment. Current options stand on small, open-label trials or follows standard treatment for plaque psoriasis. Spesolimab and imsidolimab are two IL-36 receptor inhibitors which completed phase 1 and 2 trials with a good efficacy and safety profile in the treatment of this disease, including in the fast control of its acute flares. The most common adverse events reported with spesolimab were mild to moderate infections, and imsidolimab was well tolerated. GPP clinical trials remain to have their small sample size as a major limitation, but IL-36 receptor inhibitors are promising therapeutic options currently under investigation.

New Topical Therapies for Psoriasis.

Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.