Targeted anti-TNF therapy in severe sarcoidosis: towards precision medicine

Abstract

Sarcoidosis is a multisystem, granulomatous disorder of unknown etiology. The disease has many clinical phenotypes, ranging from asymptomatic and self-limiting to severe and life threatening disease. Virtually any organ can be involved, but pulmonary involvement is seen in approximately 90% of patients. Often other organs such as lymph nodes, eyes and skin are involved. In severe cases, third-line therapy with anti-tumor necrosis factor (TNF) biologicals infliximab or adalimumab is a therapeutic option. Since sarcoidosis is a rare disease and only approximately 10% of sarcoidosis patients are eligible for treatment with these agents, guidelines are based on limited clinical data. The aim of this thesis was to study the effect of infliximab and adalimumab in severe sarcoidosis and to assess whether pharmacogenetics, inflammatory biomarkers, pharmacokinetics and exposure to infliximab can aid in more precision based anti-TNF treatment in severe sarcoidosis. In a prospective, single arm study infliximab was found to be effective in severe, refractory sarcoidosis after six months of treatment: pulmonary function test forced vital capacity (FVC) showed a clinically significant mean improvement of 6.6% predicted. A significant reduction in inflammatory parameters soluble interleukin-2 receptor (sIL-2R), angiotensin-converting enzyme (ACE) and maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose by positron emission tomography (18F-FDG PET) scan was found. Quality of life improved significantly according to patient global assessment score on a visual analogue score and physical functioning on short-from 36. SUVmax on 18F-FDG PET scan of the pulmonary parenchyma at baseline correlated with improvement in FVC: patients with a higher SUVmax on 18F-FDG PET scan showed a larger improvement in FVC. The positive effect of infliximab was maintained for at least two years when treatment was continued. In patients who had become intolerant to infliximab, adalimumab was a suitable alternative: in 72% of the patients at least a stable disease pattern was observed when they switched from infliximab to adalimumab. Patients with certain genetic variations in TNFRSF1A, TNFRSF1B and HLA had a better response to infliximab compared to patients without these genetic variations, but further research is needed to confirm these findings. A population pharmacokinetic model was designed for infliximab in severe sarcoidosis. Body surface area, body weight, serum albumin and antibodies against infliximab were found to influence infliximab pharmacokinetics. No correlation between infliximab concentration or exposure to infliximab and response was found. This suggests that the infliximab concentrations in sarcoidosis might be supratherapeutic and that the dose can be lowered. Future studies are needed to establish the minimal effective concentration in severe sarcoidosis treatment.