Different AIDs can be encountered in a dermatological setting, and several syndromes display a combination of recurrent early-onset fevers, multisystem inflammation, and cutaneous lesions, for which a skin biopsy might provide diagnostic insight [41
]. lists these conditions. Among pyogenic disorders, PAPA syndrome is defined by the triad of “pyogenic arthritis, pyoderma gangrenosum, and cystic acne”, arising from mutations in the PSTPIP1
gene encoding a protein called “CD2 binding protein 1” and leading to disrupted interaction with pyrin and the inflammasome [42
]: the first description of PAPA syndrome dates back to the 1997 report of an extended family with 10 affected members in three generations, although no geographical restriction was noted in the following reports. Potential treatment methods for patients with PAPA syndrome are corticosteroids, IL-1 antagonists, and tumor necrosis factor blocking agents, with varying results in terms of clinical effectiveness [43
Dermal pathology of skin autoinflammatory disorders.
The deficiency of the interleukin-1 receptor antagonist, caused by loss-of-function mutations in the IL1RN
gene, leads to unopposed proinflammatory IL-1 signaling and is revealed by pustular skin eruption and multifocal osteomyelitis, which occur in the neonatal period and respond excellently to anakinra. The first report describing this condition concerned 9 cases from the Netherlands, Canada, Lebanon, and Puerto Rico [44
In 1985, Blau described the presence of a peculiar phenotype in 11 family members spanning four generations, characterized by asymptomatic ichthyosiform rash, deforming polyarthritides with boggy synovial effusions or cysts, and severe recurrent panuveitis: the disease was then called Blau syndrome and related to gain-of-function mutations in the NOD2
gene, inherited in an autosomal dominant manner [45
]. Systemic corticosteroids are the mainstay of therapy, but steroid-sparing agents such as methotrexate, tumor necrosis factor-inhibitors, or IL-1 antagonists have frequently been used [46
Despite demonstration of the great efficacy of IL-1 blocking therapy in many AIDs, revealing innate immune system workings and the key role of IL-1 in autoinflammatory attacks, new AIDs have recently been recognized as unresponsive to IL-1 antagonists, including the proteasome-related “chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature” syndrome, or CANDLE syndrome, which was initially described in different areas of Japan and named Nakajo-Nishimura syndrome [47
]. The disease starts in the first year of life
with a skin eruption evolving to lipomuscular atrophy in the upper body, associated with periodic high fevers and has been recognized in different countries around the world, not only in the area of Japan. Joint contractures, muscle atrophy, and panniculitis-induced lipodystrophy have also been listed as crucial signs, and the disease is now included in the group of proteasome disability syndromes, a new category of AID caused by mutations in the PSMB8
gene, encoding the β
5i subunit of the immunoproteasome, the protease complex specialized for the degradation of polyubiquitinated proteins [48
]. Interferon-gamma and interleukin-6 are the basic mediators of systemic inflammation observed in these patients, urging the continuation of research to characterize alternative subverted innate immune pathways in clinical medicine.
The up-to-date enhancement of genetic tools has led to the recognition of an increasing number of patients with AIDs and to a better description of multiple disease phenotypes. Genes involved in the regulation of the inflammatory response may also participate to the pathogenesis of different rare diseases with no precise etiology, which cannot be defined as AIDs, characterized by relapsing attacks: that is, intermittent hydrarthrosis, characterized by periodic episodes of painless joint swelling, unexpectedly associated with high frequency of heterozygous mutations in the MEFV
], systemic capillary leak syndrome, in which spontaneous capillary leakage and shift of plasma from the intravascular to the extravascular space occur [50
], and palindromic rheumatism, with idiopathic sudden-onset episodes of recurrent arthritis [51
Recently, a European AID registry, the “Eurofever registry”, has shown that a considerable number of patients with AIDs are of European ancestry [52
], and many mutation profiles show differences when analyzed for distinct populations; that is, the MEFV
E148Q mutation is frequently found in Europe, while the double heterozygosis E148Q/M694I is mainly observed in Japan [53
]. FMF can provide an example of historical positive selection pressure, favouring heterozygosity of MEFV
mutations: their extensive spread in an ideal “odyssey” through Arab conquests, the dispersal of the Armenian nation, the Jewish Diaspora, and the East-to-West European migration of recent years might reflect a better response to intracellular pathogens or a potential protection against still unknown diseases (). A number of questions remain regarding the biologic basis of the heterozygote advantage for recessively inherited AID-related genes or the natural selection of mutated genes related to dominantly-inherited AID. Nevertheless, our final impression is that AIDs can be recognized across multiple ethnicities without any geographical restriction, and therefore, clinicians' awareness of AIDs must be reinforced across various medical specialties. Further research is ongoing with the aim of strengthening our comprehension of the genetics behind these heterogeneous conditions, personalizing therapies with anti-inflammatory cytokines or at least mitigating the intensity of the inflammatory cascade, and improving the destiny of children and adults with AIDs.
The migration of M694V, V726A, E148Q, and M694I MEFV mutations from Eastern Mediterranean areas may ideally explain some ethnically restricted prevalence data for familial Mediterranean fever.