A quantitative systems pharmacology model for certolizumab pegol treatment in moderate-to-severe psoriasis.

Background: Psoriasis is a chronic immune-mediated inflammatory systemic disease with skin manifestations characterized by erythematous, scaly, itchy and/or painful plaques resulting from hyperproliferation of keratinocytes. Certolizumab pegol [CZP], a PEGylated antigen binding fragment of a humanized monoclonal antibody against TNF-alpha, is approved for the treatment of moderate-to-severe plaque psoriasis. Patients with psoriasis present clinical and molecular variability, affecting response to treatment. Herein, we utilized an in silico approach to model the effects of CZP in a virtual population (vPop) with moderate-to-severe psoriasis. Our proof-of-concept study aims to assess the performance of our model in generating a vPop and defining CZP response variability based on patient profiles. Methods: We built a quantitative systems pharmacology (QSP) model of a clinical trial-like vPop with moderate-to-severe psoriasis treated with two dosing schemes of CZP (200 mg and 400 mg, both every two weeks for 16 weeks, starting with a loading dose of CZP 400 mg at weeks 0, 2, and 4). We applied different modelling approaches: (i) an algorithm to generate vPop according to reference population values and comorbidity frequencies in real-world populations; (ii) physiologically based pharmacokinetic (PBPK) models of CZP dosing schemes in each virtual patient; and (iii) systems biology-based models of the mechanism of action (MoA) of the drug. Results: The combination of our different modelling approaches yielded a vPop distribution and a PBPK model that aligned with existing literature. Our systems biology and QSP models reproduced known biological and clinical activity, presenting outcomes correlating with clinical efficacy measures. We identified distinct clusters of virtual patients based on their psoriasis-related protein predicted activity when treated with CZP, which could help unravel differences in drug efficacy in diverse subpopulations. Moreover, our models revealed clusters of MoA solutions irrespective of the dosing regimen employed. Conclusion: Our study provided patient specific QSP models that reproduced clinical and molecular efficacy features, supporting the use of computational methods as modelling strategy to explore drug response variability. This might shed light on the differences in drug efficacy in diverse subpopulations, especially useful in complex diseases such as psoriasis, through the generation of mechanistically based hypotheses.

Reflectance confocal microscopy as a new diagnostic tool in transformed mycosis fungoides.

Patients with mycosis fungoides typically experience an indolent disease. In some cases, the disease undergoes a process of large cell transformation which often heralds a more aggressive course with shortened overall survival. In order to rule out large cell transformation, biopsy specimens are often collected from patients with established disease who develop new papules, plaques or tumours. In some cases, multiple biopsies are needed and scar, infection and sampling error can occur. Our aim was to evaluate lesions suggestive of large cell transformation using in vivo reflectance confocal microscopy and to correlate confocal features with histopathologic findings in three patients with biopsy-proven mycosis fungoides who developed new lesions during follow-up. A total of six lesions, two lesions per patient, were examined. Reflectance confocal microscopy demonstrated large bright roundish pleomorphic cells in the epidermis, dermoepidermal junction, dermis and hair follicle in 5 of 6 lesions. The same 5 lesions were confirmed as large cell transformation by histopathology. Dermoepidermal junction obscuration, Pautrier microabscesses, epidermal disarray, spongiosis and dendritic cells were also detected by reflectance confocal microscopy and correlated to histopathology. In conclusion, reflectance confocal microscopy is useful in identifying large cell transformation within mycosis fungoides lesions. Reflectance confocal microscopy can therefore be of value in targeting the biopsy site, thereby reducing the chance of a false-negative histopathological finding.