Autoinflammation: from monogenic to complex diseases

This thesis describes insights in disease mechanisms and therapeutic strategies for monogenic and complex autoinflammatory diseases. These diseases are caused by abnormal activation of the innate immune system, leading to recurrent or chronic episodes of fever and various inflammatory symptoms, like arthritis, skin rash and lymphadenopathy. They can arise from single gene mutations, which is the case in the hereditary periodic fever syndromes, or have a complex, multifactorial, origin, like systemic juvenile idiopathic arthritis (sJIA). Most of the diseases are very rare, hence little is known about the disease mechanisms, characteristics and optimal therapy.

The first part of this thesis is focused on sJIA. In peripheral blood of sJIA patients with active disease, neutrophils are primed for enhanced inflammatory responses, while monocytes are reprogrammed towards decreased responsiveness. Historically, sJIA had a poor prognosis, due to chronic refractory arthritis, severe articular damage and the need for long-term high-dose prednisone to suppress inflammation. Also with newer drugs like interleukin-1 (IL-1) blockade, which is often used as last resource, still less than half of the patients have inactive disease after one year of therapy. We employed a treat-to-target strategy, using IL-1 blockade with anakinra as first-line therapy, in new-onset sJIA patients. Using this strategy, more than 3/4 of patients has inactive disease after one year and basically no patient develops articular or extra-articular damage.

The second part of the thesis is focused on monogenic autoinflammatory diseases, primarily on the following periodic fever syndromes: cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD) and TNF-receptor associated periodic syndrome (TRAPS). Using data from the international Eurofever registry, we describe the phenotype and genotype of MKD patients, as well as the efficacy of different therapies for several autoinflammatory diseases. As high-grade evidence is lacking in most of the cases, physicians have to rely on their (sometimes limited) experience. To optimize and unify the care for these rare diseases, we provide recommendations for the management of CAPS, MKD and TRAPS patients, based on a systematic literature review and subsequent online surveys and a consensus meeting. The recurrent or chronic inflammation in these patients can cause damage in practically any organ, including joints, eyes, ears and kidneys. To enable a structured assessment of potential damage of CAPS, FMF, MKD and TRAPS, we provide an autoinflammatory disease damage index (ADDI). The ADDI is developed by a systematic literature review, interviews and surveys with patients and disease experts, and a consensus meeting with experts and a patient representative. In silico validation, using altered patient cases, shows that the ADDI is a reliable and valid index.

In summary, this thesis provides steps towards better understanding of disease mechanisms, improvement of therapy responses and optimization of clinical care for monogenic and complex autoinflammatory diseases. It demonstrates the importance of international collaboration with clinicians, basic scientists and patients.