Pathophysiology, clinical manifestations and current management of IL-1 mediated monogenic systemic autoinflammatory diseases, a literature review

Abstract

Background Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease with early-onset, severe condition and difficult diagnosis, which seriously affects the growth and development of children. Most children need a genetic diagnosis. However, with the limitation of access to genetic testing and the detection of somatic mutations, the diagnosis of SAIDs remains challenging. IL-1 is one of the important cytokines involved in the pathogenesis of SAIDs. Here we briefly review monogenic SAIDs mediated by aberrant IL-1 production, with the aim to further understand the pathogenesis, clinical manifestations and treatments of IL-1 mediated SAIDs. Methods Literature reviews were performed using “PubMed” and “Web of Science” by searching for the terms “autoinflammatory diseases” and “IL-1”. Results Monogenic SAIDs mediated by IL-1 include MKD, FMF, TRAPS, PAAND, PAPA, CAPS, DIRA, Majeed syndrome, NAIAD, NLRC4-MAS, PFIT, APLAID. Monogenic SAIDs have early onset, various clinical manifestations and difficult diagnosis, so early recognition and early treatment can reduce the complications and enhance the quality of life. Conclusions There are many kinds of IL-1 mediated SAIDs. Pediatricians should be alert to SAIDs in the face of the patients with repeated fever, repeated rash and poor effect of routine treatment. The patients should be carried out with gene testing and treatment in time.

Efficacy of Anakinra Treatment in two Moroccan Patients With Mevalonate Kinase Deficiency

“…The clinical use of this bioagent in MKD has been approved with satisfactory results leading to a disappearance or a significant reduction in the severity of MKD features, including fever, lymphadenopathy, abdominal pain and aphthous ulcers. 13,17 Whereas Rilonacept, a soluble receptor, is more indicated in CAPS. In a placebo-controlled study, the disease activity score decreased by 84% in patients receiving Rilonacept, compared with those receiving placebo (13%).…”

The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases

“…Furthermore, as discussed below, specific missense mutations S242R and E244K, involving this region of interest, cause the AID named "pyrinassociated autoinflammation with neutrophilic dermatosis" (PAAND) (33). In the meanwhile, the homozygous pathogenic variant S208T has been observed in children with a different clinical phenotype characterized by arthralgia, lymphadenopathy, purpuric rash, and infiltrates in bone marrow (14,34,35). It has been suggested that the S208 amino acid is not so central for pyrin inactivation than S242 (14).…”

“…It has been suggested that the S208 amino acid is not so central for pyrin inactivation than S242 (14). However, both patients with PAAND and homozygous S208T variants show increased IL-1b and IL-18 serum levels (14, [34][35][36]. In summary, pathogenic variants in the region of interest between PYD and B-box prevent PKN1/2 from phosphorylating pyrin, preventing the binding of 14-3-3 and leading to pyrin hyperactivation.…”

“…In fact, the B-box domain is thought to play an autoinhibitory role by enveloping the PYD domain and thereby interfering with its binding to ASC. In addition, via B-box and CC, pyrin interacts with the regulatory protein CD2-binding protein 1 (CD-BP1), which is encoded by the PSTPIP1 gene and primarily involved in the PSTPIP1-associated inflammatory diseases (PAIDs) (14, 35,37). CD-BP1 and pyrin co-localize with the tubulin cytoskeleton and CD-BP1 triggers pyrin by binding B-box and CC, and therefore unmasking other domains, leading to its oligomerization (14, 38).…”

Osteoarthropathy of the front thorax

“…Заболевание описано в 2009 г., начинается, как правило, в раннем детском возрасте (известны отдельные случаи и более позднего начала) и проявляется хроническим рецидивирующим мультифокальным остеомиелитом, пустулезной кожной сыпью, поражением легких и центральной нервной системы. Имеется возможность генетической диагностики (выявление мутаций гена ILIRN) [28]. ХНО возможен еще при одном генетическом аутовоспалительном заболевании -синдроме PAPA (pyogenic arthritis, pyoderma gangrenosum, acne) -аутовоспалительный синдром, характеризующийся комбинацией стерильного эрозивного артрита, осложненных акне и гангренозной пиодермии, обусловленный мутациями гена белка PSTPIP1.…”