Terapia biológica en la psoriasis moderada y grave. Estudios en práctica real de tratamientos a largo plazo y utilidad de la monitorización farmacocinética

Abstract

Plaque psoriasis is a chronic skin disease that causes well-defined erythematous plaques with silvery scales. Although any part of the skin can be affected, they predominate on the scalp, the area behind the ears, the elbows, the knees, the trunk, the face, the palms of the hands, and the soles of the feet. These lesions can cause itching, stinging, and pain. The existence of nail alterations is also very frequent. It has been postulated that psoriasis is a systemic entity rather than an exclusively dermatological disease as numerous associated comorbidities have been described. The etiology of psoriasis is unknown. The role of the immune system is being investigated, as well as the possible genetic predisposition. Immunological and genetic studies have identified the cytokines IL-23 and Th17 as key drivers of its pathogenesis. Patients with moderate to severe psoriasis are candidates to systemic treatment, including biologics. Biologics target specific therapeutic targets implicated in the pathogenesis of psoriasis, such as tumour necrosis factor or interleukins (IL). The availability of biologics therapies for psoriasis treatment has meant a revolution in the therapeutics of this pathology. In clinical trials it is shown that biological drugs are very effective, however, most of these studies are carried out to assess the response to these drugs in a short term. The loss of response to these treatments over time is well known. In addition, clinical trial populations sometimes do not represent real patient populations. Experience in the treatment of psoriasis has shown relevant variations between the results of clinical trials and those obtained in clinical practice. Immunogenicity is one of the known causes of loss of response or safety problems of biologic drugs. The therapeutic drug monitoring of biological therapies consists on blood concentrations of biological drugs and anti-drug antibodies quantification The evidence on the benefit of therapeutic drug monitoring of biological therapies in psoriatic patients is increasing, but still limited, especially for some of the drugs. Therefore, it is important to know the efficacy and safety of biological therapy in the long- term treatment of psoriasis in real practice, as well as the usefulness of its therapeutic drug monitoring. In this thesis, three studies have been developed: - Study I: The objective of this study was to evaluate response and drug survival of biologics therapies in patients with moderate to severe plaque-type psoriasis, who initiated biologic therapy at least 10 years ago, in a real-world setting. The duration of biologic therapy was 140.4 (47.6-175.4) months. The number of treatment lines was 2 (range 1-8) per patient. 62.1% of treatment lines were changed. The main reasons for change were 24.3% secondary failure, 20.7% primary failure, 3.6% side-effects. No patient treated with anti-IL had to discontinue treatment due to side effects. Ustekinumab had the highest drug survival. - Study II: The objective of this study was to evaluate the efficacy of long-term ustekinumab therapy in patients with moderate to severe plaque-type psoriasis based on sequential Psoriasis Area and Severity Index (PASI) measures, in a real-world setting. The duration of treatment was 43.4 (3.4-104.8) months. Of the patients who continued on treatment, the percentage who maintained PASI 0 response was 68.9%, 73.9%, 67.50%, 80.6%, 96.2%, 91.7%, and 100.0% at 3, 12, 24, 36, 60, 84 and 96 months respectively. Ustekinumab was discontinued in 26.2% of patients, the main discontinuation reasons were primary failure (37.5%) and secondary failure (25.0%) to treatment. No patients were withdrawn because of adverse events. - Study III: The objective of this study was to evaluate correlations among ustekinumab trough concentrations, anti-ustekinumab antibodies (AUA) and clinical response in moderate-to-severe plaque psoriasis patients, in a clinical practice setting. Significant difference between ustekinumab concentrations in optimal responders (PASI≤3) and suboptimal responders (PASI>3) groups were detected: 0.7 μg/mL (range <0.1-1.8) vs. 0.4 μg/ml (range <0.1-0.8) respectively (p=0.007). Positive correlation between ustekinumab concentration and clinical response (PASI values ≤3) was detected (p=0.009). AUA were detected in 3.4% of the samples, all in suboptimal responders. In summary, the results obtained during the development of this thesis have allowed a detailed knowledge of the long-term efficacy and safety of biologic therapy for moderate to severe psoriasis in a real-world setting, as well as ustekinumab and AUA therapeutic drug monitoring application. Among the main findings, we must highlight the maintenance of efficacy and safety of biologic therapy treatment in long term in patients with moderate to severe plaque-type psoriasis, the ustekinumab highest drug survival, treatment failure (primary and secondary) as main discontinuation reason, low rate of side effects observed and correlation between ustekinumab blood concentrations with clinical response (PASI≤3) in blood samples performed before drug administration.