Editorial Adult-onset autoinflammatory disorders: a still debated entity? L. Cantarini1, D. Rigante2

1Research Center of Systemic in regulating the ho- episodes of fever, serositis, joint symp- Autoinflammatory Diseases and Behçet’s meostasis of innate immunity lead to toms, and erysipelas-like erythema in Disease, Rheumatology Unit, Policlinico oversecretion of many proinflammatory the lower limbs. Febrile attacks are Le Scotte, University of Siena, Siena, Italy; cytokines, including interleukin (IL)- typically prevented by long-term col- 2Institute of Paediatrics, Università Cattolica Sacro Cuore, Fondazione 1β, and cause the so-called autoinflam- chicine administration, which is also Policlinico Universitario A. Gemelli, matory disorders (AIDs), characterised the mainstay for preven- Rome, Italy. by seemingly unprovoked inflamma- tion in these patients (6). Meeting Tel Luca Cantarini, MD, PhD tion recurring with variable rhythmicity Hashomer diagnostic criteria and being Donato Rigante, MD, PhD and involving skin, serosal membranes, of Mediterranean origin should be con- Please address correspondence to: synovial membranes, or gastrointesti- sidered clues for recommending MEFV Luca Cantarini, MD, PhD, nal tube, with reactive amyloidosis as a genetic testing (7). Rheumatology Unit, potential severe long-term consequence FMF onset age is reported between 30 Policlinico Le Scotte, (1, 2). Recent findings have greatly and 50 years in only 2% of probands Università di Siena, modified our knowledge regarding the (8). In our centre we have tested 414 pa- viale Bracci 1, MEFV 53100 Siena, Italy. pathophysiology of hereditary mono- tients for mutations and 49 were E-mail: [email protected] genic AIDs, and showed that protean genetically positive. We also found 17 Received on February 28, 2015; accepted inflammatory symptoms can be -vari genetically-negative FMF patients, and in revised form on March 9, 2015. ably associated with periodic fevers, 15 were adults (9). Thirthy out of 49 ge- Clin Exp Rheumatol 2015; 33: 137-140. depicting multiple specific conditions, netically-positive patients were adults which usually start in childhood (3). and they mostly carried low-penetrance © Copyright Clinical and Experimental Rheumatology 2015. However, different case reports have MEFV mutations; their phenotype was provided insights into the principle that similar to that of younger patients. Ac- Key words: autoinflammation, some patients may experience a delayed cordingly, it is known that adult onset- interleukin-1β, anakinra, canakinumab, disease onset and receive a definite di- FMF might display clinical features amyloidosis agnosis during adulthood (4). Renal similar to those presented by younger AA amyloidosis represents the ominous patients, except for a lower rate of ar- complication of misdiagnosed and ne- thritis and erysipelas-like eruption: glected AIDs, with a prevalence ranging these subjects with oligosymptomatic from 2 to 25% for the different clinical disease should not be overlooked, and syndromes: in particular, renal amyloi- genetic testing may be contributive to dosis might lead to severe deterioration ascertain FMF diagnosis (10). of kidney function, resulting from the Tumour necrosis factor (TNF) receptor- extracellular deposition of proteolytic associated periodic syndrome (TRAPS) cleavage products of the acute phase re- is related to mutations in the soluble actant serum amyloid-A, synthetised in TNF receptor super family 1A the liver under the effect of IL-1β and (TNFRSF1A), and is the most common other biologic mediators (5). autosomal dominantly-inherited among The most frequent monogenic disease AIDs, as well as the most heterogene- among AIDs is familial Mediterranean ous in terms of clinical features (11). fever (FMF), caused by homozygo- The disease starts with long-lasting in- sity or compound heterozigosity in the flammatory attacks which comprise mi- MEditerranean FeVer (MEFV) gene gratory erythematous plaques, myalgia, encoding the pyrin , which is joint and ocular signs, following a wide mainly expressed in inflammatory spectrum of TNFRSF1A mutations: mu- cells: the incidence of this pyrin-related tated TNFRS1A variants induce cyto- autoinflammatory disease is higher in plasmic retention of the TNF receptor, populations living around the Medi- defective TNF-induced apoptosis, pro- terranean basin, and main clinical fea- duction of reactive oxygen species, and Competing interests: none declared. tures are represented by recurrent brief dysregulation in the secretion of IL-1

137 EDITORIAL Autoinflammatory disorders during adulthood / L. Cantarini & D. Rigante

Table I. Summary of the monogenic autoinflammatory disorders observed in childhood and adulthood.

FMF TRAPS FCAS MWS CINCAs NLRP12-AD BS

Gene MEFV TNFRSF1A NLRP3 NLRP12 CARD15/NOD2 Locus 16p13.3 12p13 1q44 19q13 16q12.1-13 Protein involved Pyrin TNFR Cryopyrin Monarch-1 NOD2 Inheritance AR AD AD AD AD Main clinical features Fever + + + + + + + Pleuritis + + – – – – – Pericarditis + + – – – – – Peritonitis + + – – – – – Skin rash erysipelas-like migratory cold-induced evanescent neonatal onset urticaria-like granulomatous eruption erythematous urticaria-like urticaria-like urticaria-like rash dermatitis rash rash rash rash

Eye involvement – conjunctivitis, – – uveitis, - recurrent periorbital edema retinopathy, granulomatous papilledema panuveitis

Joint involvement monoarthritis arthralgia or arthralgia lifelong arthralgia deforming arthritis; + symmetrical chronic arthritis premature abnormal granulomatous patella ossification polyarthritis

Central nervous demyelinating inflammatory – – aseptic chronic – – system involvement lesions, demyelinating meningitis reversible disease leukoencephalo- pathy syndrome

Hearing – – – sensorineural ensorineural – – hearing loss s hearing loss

Amyloidosis + + – + + – +

FMF: familial Mediterranean fever; TRAPS: tumour necrosis factor receptor-associated periodic syndrome; FCAS: familial cold autoinflammatory syndrome; MWS: Muckle-Wells syndrome; CINCAs: chronic infantile neurologic cutaneous articular syndrome; NLRP12-AD: NLRP12-associated autoinflammatory disorder; BS: Blau syndrome; AR: autosomal recessive; AD: autosomal dominant.

(12). Adult onset-TRAPS patients may carditis should also raise the diagnostic (23). In particular, FCAS is character- display a clinical picture mimicking suspicion of TRAPS in the absence of ised by episodic fevers, skin rashes and FMF and challenging a coherent differ- a positive family history (21). In ad- arthralgias, mostly triggered by expo- ential diagnosis. We identified variables dition, we observed that R92Q, P46L, sure to cold, MWS consists of similar related to the probability of detecting D12E, V95M, and R104Q variants are symptoms associated with progressive MEFV and TNFRSF1A mutations in low-penetrance mutations, rather than neuro-sensorial deafness, while CIN- patients with thoracic or abdominal benign polymorphisms, disclosed in CAs is marked by neonatal onset-skin pain and positive family history for re- adults with febrile episodes lacking the rash, severe deforming arthropathy, and current fevers (13-15). At our Centre most typical TRAPS signs and showing chronic meningeal involvement (24). the majority of TRAPS patients had a a milder disease course. These subjects When the diagnosis of CINCAs is for- clinical onset in adulthood, even in the seem to have a lower risk of developing mulated in childhood the use of IL-1 an- sixth decade (16). Late onset-TRAPS amyloidosis (22). tagonists can induce positive therapeu- was mostly related to low-penetrance The group of cryopyrin associated pe- tic effects even at a neurological level mutations and frequently started with riodic syndrome (CAPS), caused by (25). At our Centre we tested 113 adults atypical clinical sceneries, such as re- mutations in the NLRP3 gene, encoding for NLRP3 mutations, and recently de- current pericarditis, myocarditis, or the cryopyrin protein, which directly scribed a case series of patients with sacroiliitis, no less than unique isolated commands the release of bioactive FCAS-like symptoms, all carrying the manifestations (17-19). Accordingly, IL-1β, includes familial cold urticaria low-penetrance Q703K (26). we also suggested that difficult-to-treat syndrome (FCAS), Muckle-Wells syn- The NLRP12-associated autoinflam- pericarditis and lack of spontaneous drome (MWS) and chronic infantile matory disorder (NLRP12-AD) is very amelioration after the first year from the neurological cutaneous articular syn- similar to CAPS, but rarer, and caused first attack of pericarditis may represent drome (CINCAs), respectively ranging by mutations in the NLRP12 gene, further clues to investigate TNFRSF1A from the least to the most severe, and which encodes the monarch-1 protein: genotype (20). The presence of peri- starting prevalently in paediatric age the disease is characterised by recurrent

138 Autoinflammatory disorders during adulthood / L. Cantarini & D. Rigante EDITORIAL bouts of fever, skin rash, mouth ulcers, ical presentation: we have commonly ogy and management of tumour necrosis and abdominal pain (27). We analysed encountered adult onset-AIDs with in- factor receptor-associated periodic syndrome (TRAPS): personal experience and literature 61 patients for NLRP12-AD at our Cen- complete and atypical disease patterns review. Clin Exp Rheumatol 2013; 31 (Suppl. tre, and 44 of probands (11 positive) in the clinical practice. However, we 77): 141-9. had a disease onset in adulthood. We suggest caution in the interpretation of 12. RIGANTE D, LOPALCO G, VITALE A et al.: also reported 5 patients carrying a hete- low-penetrance mutations in probands Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome. rozygous F402L mutation and 1 patient with suspected AIDs, given the high Clin Rheumatol 2014; 33: 1197-207. carrying a heterozygous G448A muta- frequency of healthy carriers and the 13. CANTARINI L, LUCHERINI OM, IACOPONI tion in the NLRP12 gene, all showing a unknown influence of additional ge- F et al.: Development and preliminary vali- dation of a diagnostic score for identifying late disease onset (28). netic and/or environmental modifying patients affected with adult-onset autoinflam- Blau syndrome (BS), an autosomal factors (34, 35). The increasing reports matory disorders. Int J Immunopathol Phar- dominant granulomatous disease start- of adults with AIDs will help clarify the macol 2010; 23: 1133-41. ing within the first 4 years of life with connection between innate immunity 14. CANTARINI L, IACOPONI F, LUCHERINI OM et al.: Validation of a diagnostic score for the symmetrical polyarthritis, papular-nod- and environment, though a specific di- diagnosis of autoinflammatory diseases in ular rash with tendency to lichenoid- agnosis will still require the integration adults. Int J Immunopathol Pharmacol 2011; like lesions, and panuveitis, is caused of multiple information, both clinical 24: 695-702. by mutations in the nucleotide-binding and laboratory data, family history, eth- 15. 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