TYK2 as a novel therapeutic target in psoriasis.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease affecting approximately 60 million people worldwide. Genome-wide association studies (GWAS) have allowed identification of novel therapeutic targets in psoriasis including tyrosine kinase 2 (TYK2) where an exonic variant within the gene increases the risk of developing psoriasis. AREAS COVERED: This review discusses the role of TYK2 in psoriasis pathogenesis, how that relates to genetic variants and recently published ground-breaking clinical trials of novel TYK2 inhibitors. Keyword searches of PubMed were made until January 2023, using the terms: 'TYK2 inhibitor,' 'TYK2 inhibitor AND psoriasis' and 'TYK2 AND GWAS.' Articles and references have been thoroughly reviewed by the authors. EXPERT OPINION: The TYK2 inhibitor deucravacitinib shows promise as an effective oral agent for treating psoriasis. Longer term data are needed to know if thrombotic risk/cancer risk is distinct from other Janus kinase (JAK) inhibitors. Psoriasis is a complex genetic disease for which risk is influenced by genes and environmental factors. GWAS studies have identified several regions of DNA associated with increased risk of disease. We believe that pathway analysis by genetic and genomic means will be key to optimizing TYK2 therapy for the right person at the right time.

Biosimilars for the Treatment of Psoriasis: A Systematic Review of Clinical Trials and Observational Studies.

Importance: Biosimilars have the potential to reduce costs for the management of moderate-to-severe psoriasis compared with originators. However, the extrapolation of evidence enables the approval of a biosimilar for use in indications held by the originator without directly being studied in clinical trials. Thus, biosimilars can be approved for psoriasis based on extrapolated evidence from other diseases. The availability of evidence for the effectiveness and safety of biosimilars for the treatment of psoriasis is therefore unclear. Objective: To compare the efficacy/effectiveness and safety of biosimilars with originator biologics for the treatment of patients with psoriasis. Evidence Review: MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, and The European Union Clinical Trials Register were searched in August 2022. Eligible studies were appraised using the Cochrane Risk of Bias 2 and ROBINS-I tools. All analyses were conducted from September 2022 to November 2022. Findings: Fourteen trials (10 adalimumab, 2 etanercept, 1 infliximab, and 1 ustekinumab) and 3 cohort studies (1 adalimumab, 1 etanercept, 1 infliximab and etanercept) were included. Twelve trials compared biosimilars with originators in originator-naive patients (starters), and 11 trials compared switching from originator to biosimilar (switchers) with continuous originator treatments. There was no clinically or statistically significant difference in rates of achieving 75% improvement in Psoriasis Area and Severity Index scores and risks of adverse events (AEs) at week 16 and week 52 between the comparators. Two cohort studies showed no difference in effectiveness and safety outcomes between originators and biosimilars, whereas 1 study reported more AEs in patients who switched to biosimilars of adalimumab at 12 months. Three trials showed low risk of bias, whereas 11 trials had moderate risk of bias. All cohort studies had moderate to high risk of bias. Conclusions and Relevance: In this systematic review, there was no clinically or statistically significant difference in the efficacy and safety between biosimilars and originators for the treatment of patients with psoriasis. Most of the available evidence was based on randomized clinical trials, although high-quality real-world evidence was lacking. Future studies are needed to examine the long-term effectiveness and safety of biosimilars for the treatment of patients with psoriasis.

A Case of IgG4-Related Disease and Membranous Nephropathy Associated with Thrombospondin Type-1 Domain-Containing 7A.

Background: IgG4-related disease (IgG4-RD) is a systemic multi-organ inflammatory disorder which affects the kidney 20% of the time. Patients with intrinsic IgG4-related kidney disease (IgG4-RKD) often have tubulointerstitial nephritis (TIN) whereas glomerular lesions like membranous nephropathy (MN) are less common. Antibodies to thrombospondin type-1 domain-containing 7A (THSD7A) have been described in primary MN, but never in association with IgG4-RKD. Case Report: We report the first case of IgG4-MN associated with THSD7A antibodies in serum and positivity on glomerular staining, in a 57-year-old Caucasian male with IgG4-RD affecting the pancreas, liver, lacrimal glands, extraocular muscles, and kidneys. This patient presented initially with glomerular disease including significant proteinuria consistent with MN. Glomerular staining for THSD7A antigen and serum THSD7A antibody titres was positive. Treatment with corticosteroids and cyclophosphamide successfully induced remission with resolution of proteinuria, and improvement in renal function. However, despite maintenance azathioprine, the patient relapsed 39 months later. On relapse, there was minimal proteinuria but a significant rise in creatinine. Subsequent renal biopsy showed less glomerular disease and instead a TIN pattern. Subsequent treatment with Rituximab and corticosteroids successfully induced remission. Conclusion: The role of THSD7A autoantibodies in MN is emerging, and as both IgG4-MN and presence of THSD7A antibody are rare occurrences in themselves, we speculate that there may be an undiscovered association between THSD7A and IgG4-MN. Routine testing for THSD7A in IgG4-MN may help to identify the link.

Tailored treatment options for patients with psoriatic arthritis and psoriasis: review of established and new biologic and small molecule therapies.

The diverse clinical picture of PsA suggests the need to identify suitable therapies to address the different combinations of clinical manifestations. This review aimed to classify the available biologic agents and new small molecule inhibitors (licensed and nonlicensed) based on their proven efficacy in treating different clinical manifestations associated with psoriasis and PsA. This review presents the level of evidence of efficacy of different biologic treatments and small molecule inhibitors for certain clinical features of treatment of PsA and psoriasis, which was graded in categories I-IV. The literature searches were performed on the following classes of biologic agents and small molecules: TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab), anti-IL12/IL23 (ustekinumab), anti-IL17 (secukinumab, brodalumab, ixekizumab), anti-IL6 (tocilizumab), T cell modulators (alefacept, efalizumab, abatacept, itolizumab), B cell depletion therapy (rituximab), phosphodiesterase 4 inhibitor (apremilast) and Janus kinase inhibitor (tofacitinib). A comprehensive table including 17 different biologic agents and small molecule inhibitors previously tested in psoriasis and PsA was generated, including the level of evidence of their efficacy for each of the clinical features included in our review (axial and peripheral arthritis, enthesitis, dactylitis, and nail and skin disease). We also proposed a limited set of recommendations for a sequential biologic treatment algorithm for patients with PsA who failed the first anti-TNF therapy, based on the available literature data. There is good evidence that many of the biologic treatments initially tested in psoriasis are also effective in PsA. Further research into both prognostic biomarkers and patient stratification is required to allow clinicians the possibility to make better use of the various biologic treatment options available. This review showed that there are many potentially new treatments that are not included in the current guidelines that can be used for selected categories of patients based on their disease phenotype, clinician experience and access to new biologic therapies.