Human leucocyte antigen Cw6 predisposes to clinical response to the inlterleukin-12/23 blocker ustekinumab: results of long-term treatment

Psoriasis is a chronic disease, therefore effective therapies without significant long-term toxicity are needed. Genetic studies have repeatedly highlighted human leucocyte antigen (HLA)-C as the major determinant for psoriasis susceptibility, with the Cw*0602 allele conferring significant disease risk in a wide range of populations. Ustekinumab is a fully human IgG1j monoclonal antibody with a novel mechanism of action that targets the cytokines interleukin (IL)-12 and IL-23. These cytokines are secreted by activated antigen-presenting cells and play a role in activating natural killer cells, and in the differentiation and activation of CD4+ T cells. Ustekinumab binds with high affinity and specificity to the p40 protein subunit of IL-12 and IL-23 and prevents their contributions to immune cell activation, such as intracellular signalling and cytokine secretions, which are relevant to psoriasis pathology. We present a retrospective study on the long-term efficacy and safety of ustekinumab in the treatment of moderate-to-severe plaque psoriasis in a group of patients genotyped for the HLA-Cw6 allele. In total 109 patients were treated at dosage of 45 mg or 90 mg (weight > 100 kg) administrated at weeks 0 and 4 followed by maintenance therapy every 12 weeks. The HLACw6 allele was detected by standard polymerase chain reaction using allele-specific primers. The efficacy of treatment was evaluated at baseline and weeks 12, 24, 52, 76 and 104 (2 years) by calculating the Psoriasis Area and Severity Index (PASI). Efficacy data were analysed by an intent-to-treat lastobservation- carried-forward (ITT-LOCF) modality. Ustekinumab treatment was effective and considerably improved patients’ PASI scores. The mean PASI at baseline was 169 85; at week 4, 72% and 12% of ustekinumab-treated patients had achieved PASI50 and 75 responses, respectively. We observed that HLA-Cw6-positive patients responded faster to ustekinumab, with 83% reaching PASI50 at week 4, after a single injection (vs. 549% of HLACw6-negative patients). The superior response of HLA-Cw6-positive patients was maintained throughout the study period, reaching the highest statistical significance for PASI 75 at weeks 52 and 104. Ustekinumab was generally well tolerated and no serious adverse events were noted. Our observations confirm the role of HLA-Cw6 not only as a psoriasis susceptibility gene, but also as a pharmacogenetic marker of response to ustekinumab in psoriasis.