Background/Objectives: Patients with a clinical diagnosis of severe psoriasis complicated by comorbidities such as cardiovascular disease, obesity, metabolic syndrome and/or with the involvement of high-impact areas constitute a clinical challenge. Tildrakizumab is a monoclonal antibody targeting the IL-23/Th17 axis with a proven record of efficacy and safety in these patients. Methods: Here we present four cases of patients with severe psoriasis and comorbidities including cardiovascular disease (Case 1), obesity (Cases 2 and 3), metabolic syndrome (Case 3), and/or high-impact areas (Cases 2–4). Three patients (Cases 1–3) had previously received biologics but developed secondary failure or loss of efficacy; one patient was bio-naïve (Case 4). Results: The treatment with tildrakizumab in all four patients led to a quick onset (by Week 4 in all cases) of complete and lasting (1 year in Case 1, 4 years in Case 2 and 2 years in Cases 3 and 4) remission with no adverse events reported. Conclusions: Tildrakizumab is a valuable therapeutic option for patients with psoriasis and complex clinical situations, and in particular, in cases with obesity and difficult-to-treat lesion locations such as hands, scalp and genitals. Therapeutic success is often linked to an improvement in patients’ quality of life.
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