Conventional and novel therapeutic options in children with familial Mediterranean fever: A rare autoinflammatory disease

Abstract

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is usually diagnosed in childhood, especially in the first decade of life. Paediatric FMF is characterized by a protean clinical expression and a variable therapeutic response, which can make its medical management very challenging. However, even if long-term complications of untreated FMF (e.g. amyloidosis and related organ damage) are less frequent in children compared to adults, they are not uncommon. Colchicine is the mainstay of the therapy in paediatric FMF; however, if children develop colchicine intolerance and/or resistance, biologics, particularly interleukin-1 antagonists, must be considered. Other conventional or biological therapeutic options do not currently have appropriate evidence-based support, except for some specific clinical presentations (e.g., arthritis). In this review, we discuss the biological basis and the clinical evidence for the current pharmacological treatment options available for paediatric FMF.

Does Switching Colchicine Preparations Have a Role in The Treatment of Familial Mediterranean Fever?

“…Since 1972, colchicine has been used to prevent attacks and renal amyloidosis in FMF. Colchicine is an alkaloid extracted from the colchicum autumnale plant [2]. It inhibits neutrophil chemotaxis and activity in response to vascular injury and in ammasome signaling, decreases active interleukin-1β production, reduces neutrophil-platelet interaction and aggregation, and ultimately suppresses in ammation [3,4].…”

Addressing the challenges of novel therapies in rare diseases with mechanistic perspectives: Missed opportunities or the way forward?

“…Poddighe et al discuss how the promising use of anti-TNF molecules for FMF Gene therapy required the utilization of a safe delivery vehicle/ vector to ensure an efficient transfer for such therapy to be successful. 5,17 Precision medicine and genetics have guided the development of novel treatments in rare epilepsies. In their review on this topic for this special issue, Marini and Giardino 18 explain how next generation techniques have led to a more precise genetic aetiology in up to 50% of paediatric genetic epilepsies and has given a better understanding of the mechanisms underlying these conditions.…”

“…The repurposing of old drugs is often the first avenue of choice in this search. In their review for this issue, Poddighe et al 5 showed how the repurposing of old drugs, such as colchicine, resulted in an effective treatment for familial Mediterranean fever, an autoinflammatory disease. However, alternatives are needed for those patients who are resistant to this type of therapy.…”

“…Indeed many failures of drug development in rare diseases may be attributed to lack of an adequate drug delivery system. Poddighe et al discuss how the promising use of anti‐TNF molecules for FMF Gene therapy required the utilization of a safe delivery vehicle/vector to ensure an efficient transfer for such therapy to be successful 5,17 …”

“…More flexible multicentre open clinical trials are needed to accommodate the unique criteria of emerging gene and cell‐based therapies and support post‐marketing surveillance and risk management of these promising therapies 24 . In fact, several of the reviews in this issue refer to how the approval of these drugs in these rare diseases often rely on observational studies and case reports, such as the effectiveness of ANK is effective in reducing frequency of attacks in patients with familial Mediterranean Fever 5 . The translation of such therapies from in silico, through animal models into human is not always successful, yet the reasons for the failure are often poorly understood (e.g., the use of Jaknibs in beta thalassaemia).…”