Since the late 1990s, tumor necrosis factor alpha (TNF-α) inhibitors (anti-TNFs) have revolutionized the therapy of immune-mediated inflammatory diseases (IMIDs) affecting the gut, joints, skin and eyes. Although the therapeutic armamentarium in IMIDs is being constantly expanded, anti-TNFs remain the cornerstone of their treatment. During the second decade of their application in clinical practice, a large body of additional knowledge has accumulated regarding various aspects of anti-TNF-α therapy, whereas new indications have been added. Recent experimental studies have shown that anti-TNFs exert their beneficial effects not only by restoring aberrant TNF-mediated immune mechanisms, but also by de-activating pathogenic fibroblast-like mesenchymal cells. Real-world data on millions of patients further confirmed the remarkable efficacy of anti-TNFs. It is now clear that anti-TNFs alter the physical course of inflammatory arthritis and inflammatory bowel disease, leading to inhibition of local and systemic bone loss and to a decline in the number of surgeries for disease-related complications, while anti-TNFs improve morbidity and mortality, acting beneficially also on cardiovascular comorbidities. On the other hand, no new safety signals emerged, whereas anti-TNF-α safety in pregnancy and amid the COVID-19 pandemic was confirmed. The use of biosimilars was associated with cost reductions making anti-TNFs more widely available. Moreover, the current implementation of the “treat-to-target” approach and treatment de-escalation strategies of IMIDs were based on anti-TNFs. An intensive search to discover biomarkers to optimize response to anti-TNF-α treatment is currently ongoing. Finally, selective targeting of TNF-α receptors, new forms of anti-TNFs and combinations with other agents, are being tested in clinical trials and will probably expand the spectrum of TNF-α inhibition as a therapeutic strategy for IMIDs. 

/pdf/the-second-decade-of-anti-tnf-a-therapy-in-clinical-practice-2psi11ke.pdf

The second decade of anti-TNF-a therapy in clinical practice: new lessons and future directions in the COVID-19 era

Moderate‐to‐severe atopic dermatitis (AD) in the adolescence is a high burden disease, and its treatment can be very challenging due to paucity of approved systemic drugs for this age and their side‐effects. Dupilumab was recently approved for treatment of adolescent AD.

Moderate‐to‐severe atopic dermatitis in adolescents treated with dupilumab: A multicentre Italian real‐world experience

Adverse drug reactions (ADRs) are common and influence negatively the patient's therapeutic options. They recognize multiple pathogenic mechanisms, some of immunological origin, and the clinical manifestations involve several organs and systems, including skin and/or mucous membranes in 25-30% of patients. The identification of the trigger drug remains a medical challenge, mainly in poly-medicated patients. Anamnesis and clinical approach are crucial, but allergy work-up is the essential tool to confirm or exclude the causative role of the culprit drug. Besides in-vitro tests and drug provocation test, skin tests (ST) represent the cornerstone: patch test in delayed ADR, prick test in immediate ADR, and intradermal test in both. Nevertheless, ST are in continuous evolution and characterized by technical difficulties (concentration and vehicle) that can influence their value and specificity. In this article we review the indications and the rules in performing patch test, prick test, and intradermal test with the most commonly used drugs in Italy to determine the cause of a cutaneous and/or mucous ADR, precise the involved pathogenic mechanism, and provide a valid therapeutic alternative to the patient.

/pdf/skin-tests-in-the-diagnosis-of-adverse-drug-reactions-57vrpi8ej5.pdf

Skin tests in the diagnosis of adverse drug reactions

Due to its anti-hyperglycemic effect, metformin is the first-line medication for the treatment of type 2 diabetes, particularly in people who are obese. However, metformin is a drug with a very wide range of pharmacological properties and reports of its therapeutic effect on diseases including inflammation and cancer are increasing. Numerous research groups have reported that metformin has beneficial effects on a variety of inflammatory skin disorders including psoriasis, acanthosis nigricans, acne, hidradenitis suppurativa, and allergic contact dermatitis. According to these reports, in addition to the well-known action of metformin, that is, its anti-hyperglycemic effect, NF-kB inhibition and the resulting alteration to the cytokine network may be the potential targets of metformin. Its anti-hyperandrogenism effect has also been confirmed as the major action of metformin in some inflammatory skin diseases. Moreover, novel regulatory mechanisms, including autophagy and antioxidant processes, have been suggested as promising mechanisms of action for metformin in inflammatory skin disorders.

A Molecular Perspective on the Potential Benefits of Metformin for the Treatment of Inflammatory Skin Disorders.

Biologics serve as a cornerstone in psoriasis treatment, with low disease activity or sometimes even clinical remission as a realistic treatment outcome. So far, it is unclear whether biologics should be tapered when this target is achieved. Dose tapering could offer potential benefits by decreasing side effects, the burden of repetitive injections and costs of biological therapy. However, clinical guidelines on dose tapering of biologicals in psoriasis patients are lacking. This scoping review was conducted to provide an overview of the current literature on dose tapering and offer guidance for clinicians in daily clinical practice. Dose tapering is defined as the administration of a lower dose per administration, or the prolongation of the regular dose interval, after initial treatment according to the standard dosing. Four electronic databases (PubMed, EMBASE, Cochrane, and Web of Science) were systematically searched for literature on tapering of biologics in adult patients with psoriasis from 1 January 2000. We included 19 original articles on biologic tapering in psoriasis patients: four randomized controlled trials and 15 observational studies. Tapering eligibility criteria, tapering strategies, tapering outcomes, and recapture of response after relapse were assessed. Furthermore, the available evidence on possible predictors for successful tapering, and the effect of tapering on safety, quality of life and costs is summarized. The definition of low disease activity as a measure for tapering eligibility varied widely. Beside tapering criteria, tapering strategies were also heterogeneous. Of note, quality-of-life measurements were barely integrated in the evaluation of tapering outcomes. Literature on regaining response after relapse due to tapering was limited, but restored remission has been described. The included studies did not proclaim a significant effect of tapering on the occurrence of (severe) adverse events. Even though cost savings have been reported, no proper cost-effectiveness analysis has been conducted yet. Biologic tapering seems to be effective and safe in psoriasis patients with stable low disease activity or clinical remission. Available data on biologic dose tapering in patients with psoriasis are promising, but more research is warranted to fill the current gaps in knowledge. Biologics are effective in treating psoriasis amongst other diseases, such as rheumatoid arthritis and Crohn’s disease. However, biologics are costly, and can cause side effects, such as an increased risk of infection. In patients with rheumatoid arthritis, it is not uncommon to lower the dose of these biologics (also called “dose tapering”), once stable low disease activity, or even remission, is reached. However, in psoriasis patients, dose tapering of biologics is not common practice. In this “scoping review,” we provide an overview of the available literature on dose tapering of biologics in adult patients with plaque psoriasis in order to address the current gaps in literature. We found 19 studies that addressed dose tapering. These studies used different criteria to determine which patients were eligible for tapering, which led to various interpretations of tapering success. This made it difficult for us to draw general conclusions on which tapering criteria and strategies should be further investigated. Dose tapering seems to be effective and safe in patients with a stable low disease activity, although more (high-quality) research is needed. Future studies should focus on generating more data on long-term safety, finding predictors for successful tapering, calculating the cost-effectiveness of dose tapering, and evaluating dose tapering in the newest generation of biologics.

/pdf/dose-tapering-of-biologics-in-patients-with-psoriasis-a-bs9q1efejm.pdf

Dose Tapering of Biologics in Patients with Psoriasis: A Scoping Review

References 1 Chessa MA, Sechi A, Baraldi C, et al. Zoon’s plasma cell balanitis: clinical and dermoscopic features in pediatric patients. Int J Dermatol 2018; 57: e142–e144. 2 Davis DA, Cohen PR. Balanitis circumscripta plasmacellularis. J Urol 1995; 153: 424–426. 3 Bardazzi F, Antonucci A, Savoia F, et al. Two cases of Zoon’s balanitis treated with pimecrolimus 1% cream. Int J Dermatol 2008; 47: 198–201. 4 Chander R, Garg T, Kakkar S, et al. Treatment of balanitis of Zoon’s with tacrolimus 0.03% ointment. Indian J Sex Transm Dis 2009; 30: 56–57. 5 Daga SO, Wagaskar VG, Jumnake SF, et al. Zoon’s balanitis treated with topical tacrolimus. Urol Ann 2017; 9: 211–213. 6 Lee MA, Cohen PR. Zoon balanitis revisited: report of balanitis circumscripta plasmacellularis resolving with topical mupirocin ointment monotherapy. J Drugs Dermatol 2017; 16: 285–287. 7 Bari O, Cohen PR. Successful management of Zoon’s balanitis with topical mupirocin ointment: a case report and literature review of mupirocin-responsive balanitis circumscripta plasmacellularis. Dermatol Ther (Heidelb) 2017; 7: 203–210.

Occupational human infestation due to "Martin bug" (Oeciacus hirundinis, Hemiptera: Cimicidae).

Psoriasis can be managed successfully with long-term biologics. Real-life clinical practice may require dose tapering as a therapeutic option to reduce the risk of drug-exposure and to increase cost-effectiveness. The responsiveness to extended intervals between adalimumab doses and the possible predictive factors of maintenance of complete clearance were studied in a retrospective 7-year single-centre analysis. Thirty patients who achieved complete clearance with adalimumab underwent dose tapering, progressively extending between-dose intervals (to 21-28 days). Sixty percent of subjects (group A) maintained complete clearance, whereas 40.0% (group B) relapsed and were switched back to the standard dosage to re-achieve complete clearance. Body mass index (BMI) and time to achieve Psoriasis Area Severity Index (PASI-100) with adalimumab standard treatment before dose tapering were significantly lower in group A than in group B (multi-variate Cox regression: p < 0.05, Kaplan-Meier analysis: p < 0.001, respectively). This study suggests that patients with lower BMI and shorter time to achieve PASI-100 with adalimumab standard dose were significantly more likely to be candidates for dose tapering.

/pdf/adalimumab-dose-tapering-in-psoriasis-predictive-factors-for-1it8ruvw30.pdf

Adalimumab Dose Tapering in Psoriasis: Predictive Factors for Maintenance of Complete Clearance.

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Occupational human infestation due to "Martin bug" (Oeciacus hirundinis, Hemiptera: Cimicidae).

Adalimumab Dose Tapering in Psoriasis: Predictive Factors for Maintenance of Complete Clearance.