The Protean Visage of Systemic Autoinflammatory Syndromes: a Challenge for Inter-Professional Collaboration

European Review for Medical and Pharmacological Sciences 2010; 14: 1-18 The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration

D. RIGANTE

Department of Pediatric Sciences, Catholic University of the Sacred Heart, Rome (Italy)

Abstract. – Systemic autoinflammatory CAPS: cryopyrin-associated periodic syndromes syndromes are a group of inherited and ac- CINCA syndrome: chronic infantile neurolog- quired disorders of the innate immunity characterized by recurrence of seemingly unprovoked ical cutaneous articular febrile attacks of variable duration and multi- syndrome district inflammation of different severity. The So-JIA: systemic-onset juvenile idiopathic vast majority of these conditions when ob- arthritis served in pediatrics is caused by mutations in PFAPA syndrome: periodic fever/aphthous genetic systems involved in the orchestration of stomatitis/pharyngitis/cer- inflammation and apoptosis. The group in- vical adenitis syndrome cludes hereditary recurrent fevers, idiopathic febrile syndromes, hereditary pyogenic disor- CRMO syndrome: chronic recurrent multifo- ders, bone autoinflammatory diseases, immune- cal osteomyelitis syndrome mediated granulomatous diseases, complement disorders, hemophagocytic and vasculitic syndromes. Diagnostic identification derives from the combination of genotype studies and clini- Introduction cal/bioumoral data showing the spontaneous activation of cells of the innate immunity in the absence of specific ligands, although diagnosis re- Systemic autoinflammatory syndromes (AIS) mains only clinical for idiopathic febrile syn- are rare inherited and acquired errors of the in- dromes such as systemic-onset juvenile idio- nate immunity, which are depicting an emerging pathic arthritis and PFAPA syndrome. Meeting chapter of the postgenomic medicine. Though the needs of patients with complex chronic dis- clinically similar to various infectious and eases as systemic autoinflammatory syndromes rheumatologic diseases, neither distinct requires the provision of collaborative multidisciplinary care and the expertise of a number of pathogens, nor specific autoantibodies can be health care providers across varied health care identified in AIS: this group of disorders is main- settings. ly characterized by fluctuating topical signs of inflammation affecting skin, gastrointestinal Key Words: tube, joints, serosal surfaces and central nervous Autoinflammatory syndrome, Recurrent fever. system, with a variable modality of recurrence, alternating with periods of full well-being. By definition a “rare” disease affects less than 5 per 10,000 inhabitants: currently over 6000 rare diseases are known, which means that several million people are affected all over the world and about 30 million in Europe alone. Treatment ex- Abbreviatons ists for about 200 of these conditions and for most AIS there are now many therapeutical op- AIS: systemic autoinflammatory syndromes tions. Despite their rather recent nosological FMF: familial mediterranean fever characterization, AIS have existed throughout the HIDS: hyperIgD/periodic fever syndrome past centuries, although confined to small groups TRAPS: tumour necrosis factor receptor-asso- of populations living around the Mediterranean ciated periodic syndrome basin and in the North-West Europe. The high

Corresponding Author: Donato Rigante, MD; e-mail: [email protected] 1 D. Rigante frequency of mutations related to AIS in limited Sheppard Siegal in 1945, although the first case geographical areas (Mediterranean basin for fa- compatible with FMF was observed in 1908 and milial Mediterranean fever, the Netherlands for the term “FMF” was coined in 1958. This is a re- mevalonate kinase deficiency syndrome and Ire- cessive disorder characterized by acute episodes land for tumour necrosis factor receptor-associat- of fever and neutrophil-mediated recurrent in- ed periodic fever syndrome) suggests that het- flammatory signs localized to serosal and syn- erozygotes may have some selective advantage, ovial membranes. The gene responsible for FMF, for instance an increased resistance to unidenti- called MEFV (from MEditerranean FeVer), is lo- fied agents. Actually all AIS cannot be over- cated on the short arm of chromosome 16 and looked in the differential diagnosis of recurrent codes for pyrin (named also “marenostrin”, refer- fevers for patients of whatever origin and age, ring to the Latin name for the Mediterranean sea, since molecular diagnosis and effective therapies once called “mare nostrum”), a protein with 781 are now becoming largely available1-3. Despite amino acids involved in the caspase-1 activation some similarities in symptoms, there are major and mainly expressed in the cytoplasm of neu- distinctions in the etiology, duration and frequen- trophil granulocytes and cytokine-activated cy of inflammatory attacks and the overall clini- monocytes. Caspase 1 can cleave the 31-kDa pre- cal pictures. The first subgroup of AIS encom- cursor form of interleukin-1β, the evolutionary passes “hereditary recurrent fevers”, which in- most ancient cytokine, into its biologically active clude the main diseases characterized by autoin- 17-kDa fragment, a potent mediator of innate im- flammation, i.e. familiar Mediterranean fever, munity, leading to fever and local/systemic in- mevalonate kinase deficiency syndrome, tumour flammation. In particular, pyrin regulates the in- necrosis factor receptor-associated periodic syn- tensity of inflammatory reactions through the in- drome and cryopyrinopathies. Genetic details of hibition of interleukin-1β production in individu- inherited AIS are listed in Table I; the notewor- als with the wild-type MEFV. Most MEFV muta- thy features of each hereditary recurrent fever are tions encode amino acid changes proximal to the described in Table II. site which controls the binding to caspase-1 and this leads to interleukin-1β upregulation. To date Familial Mediterranean Fever more than 70 MEFV mutations have been record- Familial Mediterranean fever (FMF, OMIM ed. Current listings of all mutations can be easily 249100) was first described in New York by read by visiting INFEVERS, a mutational data-

Table I. Genetic characterization of the inherited systemic autoinflammatory syndromes with their pattern of inheritance.

Disease Gene Locus Protein encoded Inheritance

Familial Mediterranean fever MEFV 16p13.3 Pyrin Recessive Mevalonate kinase deficiency MVK 12q24 Mevalonate-kinase Recessive syndrome Tumour necrosis factor TNFRSF1A 12p13 p55 receptor of tumour Dominant receptor-associated periodic necrosis factor syndrome Cryopyrinopathies CIAS1 1q44 Cryopyrin (NALP3 or Dominant (NLRP3) PYPAF1) Interleukin-1 receptor IL1RN 2q Interleukin-1 Recessive antagonist deficiency receptor antagonist

PAPA syndrome PSTPIP1 15q24-25 CD2 antigen-binding Dominant protein 1 Majeed syndrome LPIN2 18p11.31 Lipin 2 Recessive Blau syndrome CARD15/ NOD2 16q12.1-13 NOD2/CARD15 Dominant

Hereditary angioedema C1NH 11q11-q13.1 C1-esterase inhibitor Dominant CRMO syndrome Undefined 18q21.3-22 Unknown Recessive

Cherubism SH3BP2 4p16.3 SH3 domain-binding protein 2 Recessive Recurrent hydatidiform mole NALP7 19q13.4 PYPAF3 (NLRP7) Recessive (NLRP7)

2 The protean visage of systemic autoinflammatory syndromes

Table II. Specific clinical clues for the diagnosis of hereditary recurrent fevers.

Disease Clinical peculiarity

Familial Mediterranean fever Erysipelas-like erythema on foot/ankle Mevalonate kinase deficiency syndrome Onset in the first year of life with febrile attacks characterized by recurring lymphadenopathy and splenomegaly Tumour necrosis factor receptor-associated Long duration of febrile attacks (more than 1 week) periodic syndrome with periorbital edema and conjunctivitis Cryopyrinopathies Urticaria-like rash (mainly induced by cold-expostion or fixed), neurosensorial hypoacusia, osteo-articular involvement of variable severity base at http://fmf.igh.cnrs.fr/infevers/. Four Erysipelas-like lesions, in the form of painful ery- founder mutations, M694V, M680I, M694I and thema on the shins, around the ankles or on the V726A in exon 10 predominate in patients living feet might appear in 20-40% of cases and are con- in the Mediterranean basin (the mutation V726A sidered to be FMF-specific findings. Several new- leads to a milder form of the disease). It is still ly described manifestations such as severe pro- ambiguous whether E148Q in exon 2 is a true tracted febrile myalgia, orchitis and vasculitis FMF mutation or a functional polymorphism, ob- have enriched the clinical spectrum of FMF. served in 4-12% of several ethnic groups with a Bouts of incapacitating myalgia that precludes low FMF prevalence. As widely recognized, the palpation of the muscles, accompanied with a disease has a peculiar ethnic distribution as it oc- high-grade fever, may last for several weeks and curs predominantly in Sephardic Jews (the ratio usually respond to glucocorticoids. A self-limited of persons with the mutated gene to those without acute scrotal swelling and tenderness might ap- is 1:5 to 1:16), Armenians (1:7), Turks, Arabs, pear in 3% of young male patients. Increased in- North-Africans, though it has been reported even flammatory markers (erythrosedimentation rate, among Ashkenazi Jews. Attacks of FMF occur ir- C-reactive protein, serum amyloid-A and fibrino- regularly and apparently in a spontaneous fash- gen) are typically observed in the acute attack, ion: their frequency varies considerably from whilst serum IgA and IgD can be high respective- weekly bouts to once every 3 to 4 months. In 50% ly in 25 and 15% of cases. The most severe com- of cases the disease appears in the first decade plication affecting prognosis of FMF is the onset with self-limiting bouts of fever and painful mani- of AA amyloidosis (its precursor protein is serum festations in one or more body sites. Each attack amyloid-A), partly related to specific MEFV mu- is characterized by the massive influx of poly- tations and partly to patient’s origin country: it morphonuclear cells into the affected anatomic can be found in kidneys, but also in the gastroin- compartments: a typical attack consists of fever testinal tract, giving rise to malabsorption, liver, and serositis or arthritis lasting from 12 hours to 4 spleen, heart, lungs, thyroid and testes. Renal days, while patients are symptom-free between amyloidosis might be the first FMF manifestation attacks. Table III lists the most frequent clinical (the so-called “phenotype II” of FMF). Several signs of FMF and their percentages in children with a confirmed FMF. Abdominal pain (due to sterile peritonitis) is found in 95% of cases and Table III. Clinical signs of acute attacks of familiar Medite- many patients might have undergone exploratory rranean fever and their overall percentage in the pediatric surgery or even appendectomy in the emergency population. room (with the appendix being normal in most Fever (lasting 1-4 days) 96% cases). A characteristic unilateral pleurisy with Peritonitis 91% chest pain can be demonstrated in 15-30% of pa- Pleurisy 57% tients, whilst pericardial involvement is observed Arthralgias or arthritides 45% only in 1%. About 50-75% of patients with FMF Erysipelas-like erythema on foot/ankle 13% experience arthritis during the inflammatory at- Recurrent pericarditis 1-2.5% tacks: arthritides with effusions of large joints Amyloidosis 2% might be the sole manifestations of FMF.

3 D. Rigante studies comparing phenotype manifestations and Table V. Distribution of MEFV mutations (in the exon 10) genotype analysis have disclosed that FMF pa- according to different ethnicity of patients with familiar tients homozygous for the M694V mutation have Mediterranean fever. a more severe disease with an early onset, more Populations mostly involved frequent attacks, severe joint involvement, require higher doses of colchicine and are more prone to M694V Jews, Turks and Armenians develop amyloidosis. Diagnosis of FMF remains M680I Armenians and Egyptians clinical and strictly combined with ethnicity, fam- M694I Arabs ily history and response to colchicine, since a spe- V726A – cific laboratory test is not yet available. Several sets of criteria have been proposed through the years, though few were based on statistical evalu- agement of these patients and the response to ation studies. Table IV describes the diagnostic colchicine can be used to help validating the diag- criteria established at the Heller Institute of Med- nosis of FMF. Colchicine in a dose ranging from ical Research (Sheba Medical Center, Tel- 0.5 to 2 mg/day in one daily administration is the Hashomer, Israel) which are currently used: a def- mainstay of treatment of FMF, as it reduces attack inite diagnosis requires two major or one major frequency and duration in 60% of patients or at and two minor criteria satisfied; diagnosis is least reduces the number of attacks in 30% (in probable when only one major and one minor cri- children aged 1-2 years the dosage is 0.25 terium are satisfied. Table V shows the distribu- mg/day, for those aged 3-6 years 0.5 mg/day and tion of MEFV mutations depending on ethnic for those over 7 years 1 mg/day, which can result groups. Most of patients with a clinical overt effective until adulthood). This low daily dose re- FMF who are MEFV heterozygotes might have quired for FMF treatment is generally well toler- rare mutations in the coding region. The diagnos- ated. Colchicine is also effective in preventing or tic value of one only MEFV mutation in patients halting the development of amyloidosis in pa- with atypical or mild FMF signs, especially in tients with FMF, although 12% of patients regu- those who do not satisfy clinical criteria, is still larly taking colchicine can even develop amyloi- unknown. In populations where the carrier fre- dosis. Children given colchicine have a normal quency is lower as Italians, Greeks or Portugueses growth, whilst pregnant women or nursing moth- the discovery of only one mutation might proba- ers can keep on receiving safely colchicine. The bly have a higher diagnostic value, whereas other drug is a purely prophylactic treatment in FMF mutations remain to be discovered in the MEFV and dose escalation during an acute FMF attack is promoter or in other modifying genes leading to not effective, while diclofenac (administered in- the expression of the disease even in heterozy- tramuscularly), other non-steroidal antinflamma- gotes. The serendipitous discovery of colchicine tory drugs and interferon-α (at a dose of 5 million as an effective drug for FMF by Stephen Goldfin- IU by subcutaneous injection) might be used to ger in 1972 was a major breakthrough in the man- relieve pain and suppress the acute inflammation if administered at the earliest phase. Interleukin-1 inhibitors as anakinra have been proposed as pos- Table IV. Tel-Hashomer criteria for the diagnosis of famil- sible alternative drugs in colchicine-resistant FMF iar Mediterranean fever. (Diagnosis is definite if 2 major cri- 4-9 teria or 1 major and 2 minor criteria are satisfied; diagnosis patients . is probable if 1 major and 1 minor criteria are satisfied). Mevalonate Kinase Deficiency Major criteria (or HyperIgD/Periodic Fever) Syndrome • Recurrent febrile episodes associated with peritonitis, Mevalonate kinase deficiency syndrome pleuritis or synovitis (OMIM 260920, also named hyperIgD/periodic • Amyloidosis of AA-type without a predisposing disease fever syndrome, HIDS) is caused by mutations in • Favorable response to continuous colchicine the MVK gene, identified in 1984, which give administration rise to abnormal mevalonate kinase function, Minor criteria transmitted with an autosomal recessive inheri- • Recurrent febrile episodes tance. This peroxysomal enzyme is involved in • Erysipelas-like erythema cholesterol and non-sterol isoprene biosynthesis, • Positive history of familiar Mediterranean fever in a but the exact pathogenesis of the syndrome is first-degree relative still enigmatic. In fact, the enzymatic abnormali-

4 The protean visage of systemic autoinflammatory syndromes ty is not directly involved in the biologic process the syndrome is the constantly increased level of of the disease: it has been suggested that the pri- serum IgD (with values higher than 100 IU/ml) mary defect might lie in a decreased flux through both during fever episodes and on basal condi- the isoprenoid metabolism leading to the short- tions. The IgD was first described in 1965 and age of end-products, which is compensated by later determined on the lymphocyte surface: its increased mevalonic acid. In addition, the de- role in the immune system is still mysterious, crease of the last metabolic products in the though a participation in the immunological mevalonic acid pathway as dolichols, coenzyme memory has been suggested. No relationship ex- Q10 and prenylated proteins might be critical to ists between disease activity and serum IgD con- evoke intracellular signal transduction, cell-cycle centrations. The polyclonal elevation of serum regulation, apoptosis and inflammation control. IgD is found mostly in patients older than Due to the high frequency in the Netherlands 3 years, but can be observed secondarily in many (where heterozygous frequency is 1:65) and in other acute inflammatory diseases and even in North-West Europe this syndrome was also de- other hereditary recurrent fevers, as FMF and fined “Dutch-type periodic fever”, albeit various others. Table VII shows the reference values of patients have been reported in different ethnic serum IgD according to different ages. Serum to- groups. More than 100 MVK mutations have tal IgA may be also increased in 85% of patients. been reported: the most frequent is V377I which High serum IgD level is characteristic, but not- is associated with a mild phenotype and a resid- specific for HIDS; on the contrary, the increase ual mevalonate kinase activity. HIDS usually in urinary excretion of mevalonic acid can be starts in early childhood: typical flares are irregu- demonstrated only during HIDS febrile attacks lar, usually last for 3-7 days, have an abrupt on- and is of outstanding priority for the diagnostic set, are interrupted by asymptomatic intervals of confirmation. A constant increased urinary ex- several weeks and can be induced by vaccina- cretion of mevalonic acid can be found in chil- tions, infections, emotional stress and menstrual dren with mevalonic aciduria, an inborn error of cycle. In each attack children present high-grade cholesterol and non-sterol isoprene biosynthesis, fever (>39°C), often accompanied with chills, which is caused by the absolute deficiency of firm and painful lymph node enlargement (in mevalonate kinase and is characterized by psy- 90% of cases), splenomegaly, gastrointestinal chomotor retardation, microcephaly, cerebellar symptoms (as severe abdominal pain, diarrhoea atrophy, ataxia, cataract, retinal dystrophy, pro- and vomiting), cephalalgia, arthralgias, oral or gressive myopathy, dysmorphic features, failure vaginal ulcers and generalized rash of varying in- to thrive and periodic fever. HIDS and mevalonic tensity and features, from erythematous to nodu- aciduria can be merely considered different ex- lar and even purpuric. Table VI lists the most fre- pressions of an identical genetic defect. Thera- quent HIDS clinical features during acute flares. peutical benefits in HIDS have been described In the majority of cases all these recurring symp- with corticosteroids, naproxen, simvastatine (80 toms tend to decrease over time. The risk of renal mg/day, according to the hypothesis that hydrox- amyiloidosis has been recently confirmed in pa- ymethylglutaryil CoA reductase inhibition might tients with HIDS, though it is lower than in other exert antinflammatory effects and prevent cy- AIS. Typical of HIDS and justifying the name of tokine release in febrile attacks), etanercept (0,8 mg/kg/week by subcutaneous injection) and interleukin-1 receptor antagonists as anakinra (at Table VI. Clinical signs appreciated during flares of meval- the dosage of 1 mg/kg/day subcutaneously ad- onate kinase deficiency syndrome (hyperIgD/periodic fever syndrome). Table VII. Reference values for serum immunoglobulin D Periodic fever (lasting 3-7 days), often exerted by levels. vaccinations, infections, emotional stress or menstrual cycle Age Geometrical mean 95° centile Latero-cervical lymph node enlargement Splenomegaly 1-3 years 4.5 IU/ml 33.5 IU/ml Arthralgia or non erosive arthritis 3-5 years 12 IU/ml 78 IU/ml Maculo-papular, nodular or vasculitic rash 6 years – 25.5 IU/ml 105.5 IU/ml Oral aphthosis adulthood

5 D. Rigante ministered), though no evidence-based guidelines might display fever alone. Central nervous system exist and though any therapy has been somewhat involvement has been reported with a demyelinat- disappointing in the long run. Drugs aimed at ing picture in a few cases. The main features of promoting the synthesis of nonsterol isoprenoids this disorder are depicted in Table VIII. The most might provide an interesting therapeutic option in discriminatory laboratory finding is a low serum future for the treatment of HIDS10-18. level of the soluble type 1 TNFR (< 1 ng/ml) during quiescent periods in patients with decreased Tumour Necrosis Factor Receptor- receptor shedding. Serum IgD levels may result Associated Periodic Fever Syndrome elevated (but less than 100 IU/ml) in 10% of these First described in 1982 in a family of Irish and patients. Nevertheless genetic testing is central to Scottish descent and known also as “familial Hi- the diagnosis of TRAPS. Prognosis is determined bernian fever” (the ancient Roman name of Ire- mainly by the risk of amyloidosis, which can be land was “Hibernia”), tumour necrosis factor re- observed in 10-25% of patients. Treatment with ceptor-associated periodic syndrome (TRAPS, oral prednisone or high-dose corticosteroids for OMIM 142680) has subsequently been reported in the time of duration of fever can mitigate inflam- many ethnic groups, including Jews, Arabs and matory symptoms, though some patients become Central Americans. This autosomal dominantly steroid-dependent. Anti-tumour necrosis factor transmitted disease is caused by mutations in the therapy has been proposed due to the observation TNFRSF1A gene, a 10-exon gene encoding for the that TRAPS molecular defect is sometimes associ- 55kD tumour necrosis factor receptor (TNFR). ated with an impaired TFNR shedding from cell The disease is mainly characterized by febrile membranes: etanercept, a dimeric recombinant fu- episodes lasting more than 1 week, which recur at sion protein consisting of two copies of the solu- least 2-4 times a year. The kind of inheritance and ble extracellular ligand-binding domain of TNFR, clinical response to corticosteroids can differenti- linked by the Fc fragment of IgG1, at the dosage of ate TRAPS from FMF. The interpretation of TN- 0.8 mg/kg/week subcutaneously injected, can be FRSF1A mutations (almost 70 have been reported) useful in some patients (infliximab seems unhelp- is challenging: the defective shedding of the mu- ful, whilst the eventual efficacy of new tumour tant TNFR from the cell surface, causing persis- necrosis factor inhibitors as certolizumab and goli- tent pro-inflammatory cellular signaling and rela- mumab has never been tested). Table IX lists the tive lack of the antinflammatory soluble TNFR in most significant side-effects of etanercept. serum, might be a potential pathogenic mecha- Anakinra (1 mg/kg/day by daily subcutaneous in- nism, albeit this has not been demonstrated for all jection) has showed efficacy in a subgroup of mutations. Two TNFRSF1A variants, P46L and TRAPS patients19-24. R92Q, are present in approximately 10% of healthy West Africans and 1% of healthy Cau- Cryopyrinopathies casians, showing poor correlation with the TRAPS The cryopyrin-associated periodic syndromes phenotype. The disease is generally manifested in (CAPS), also abbreviated with the name “cryopy- the pre-adolescence, but onset age is variable be- rinopathies”, have an incidence of 1-2 per million tween 3 and 20 years. In addition to fever, “local- in the USA and Western Europe, with an equal ized” manifestations of TRAPS involve skin, gas- distribution between male and female individuals, trointestinal tube, muscle, joints and eye. The but are mostly observed in Caucasian ethnic most frequently observed are erythematous migra- groups. The first systematic description referred tory painful lesions or cellulitis-like plaques, pan- niculitis of the limbs, chronic fasciitis, muscular pain, tenosynovitis, arthritis (in about 2/3 of pa- Table VIII. Clinical signs appreciated during flares of tumour tients), severe colicky abdominal pain, diarrhea or necrosis factor receptor associated periodic fever syndrome. even constipation and characteristic ocular mani- Periodic fever (lasting many days or even weeks) festations, such as periorbital edema and painful Abdominal pain conjunctivitis (in 8-10% of patients). Myalgia lo- Arthromyalgia, tenosynovitis and fasciitis calized in legs or calves is extremely common and Lymph node enlargement may dominate the clinical picture. All these clini- Erythematous migratory rash and cellulitis-like plaques cal signs can be sometimes surprisingly vague: Periorbital edema and conjunctivitis some patients might notice only periodic localized Scrotal pain myalgia or recurrent conjunctivitis and others

6 The protean visage of systemic autoinflammatory syndromes

Table IX. Side-effects of etanercept (subdivided per or- to this group of diseases dates back to 1982, but gan/district involved). the genotypical characterization of CAPS was performed in the period 2001-2002. The group Infections encompasses three distinct autosomal-dominantly Very common: rhinopharingitis, bronchitis, inherited diseases which share mutations of the cysto-urethritis, pyodermitis Not common: pneumonia, septic arthritis, sepsis same cold-induced autoinflammatory syndrome 1 gene (CIAS1, now named NLRP3), consisting of Allergic reactions 9 exons and encoding for the cryopyrin protein, Common: hives β Rare: angioedema, anaphylaxis which is a part of an intracellular interleukin-1 - converting multi-protein complex, called “inflam- Hematologic abnormalities masome”. More than 80 disease-associated Not common: thrombocytopenia CIAS1 mutations have been reported to date for Rare: anemia, leukopenia, neutropenia, pancytopenia Very rare: aplastic anemia CAPS, nearly all of them located in exon 3. Cry- opyrin (also known as NALP3 or PYPAF1) con- Cardiologic abnormalities tains a domain which is a member of the NOD- Rare: Worsening of a pre-existing congestive heart failure like receptor family, that is thought to be an intra- Neurologic abnormalities cellular pathogen recognition receptor, leading to Rare: paroxysms, demyelinizing encephalopathy, optic pro-caspase 1 activation and pro-interleukin-1 neuritis, transverse myelitis processing. Numerous data suggest that cryopyrin Skin abnormalities is required for the detection of “danger”, includ- Common: itch ing bacteria, toxins, monosodium urate crystals, Rare: discoid lupus erythematosus and confirm that it plays a crucial role in the in- Local abnormalities in the injection-site nate immunity. Mutant cryopyrin forms result in β Very common: infiltrative reactions the persistent release of active interleukin-1 . The clinical entities belonging to this group are not Systemic abnormalities separate, but represent a continuum of sub-pheno- Rare: Neoplasms (mammary carcinoma, lung tumors and lymphomas) types sharing CIAS1 mutations as a common molecular basis. Table X lists the most relevant fea-

Table X. Summary of the general clinical signs of cryopyrin-associated periodic syndromes.

Familial cold urticarial Muckle-Wells CINCA syndrome syndrome syndrome (or NOMID)

Onset age Infancy Infancy-adolescence Neonatal period Skin manifestations Cold-induced urticaria Evanescent urticaria Widespread polymorphous urticaria-like rash Audiologic study Normal Sensorineural hypoacusia Sensorineural deafness (for high-pitched sounds) Ocular signs Conjunctivitis Conjunctivitis Chronic papilledema, optic nerve atrophy, visual loss Musculo-skeletal Arthralgias or Lifelong arthralgias, Deforming osteo-arthropathy symptoms joint stiffness non-erosive polyarthritis of large joints (with premature kneecap ossification and protrusion), digital clubbing Systemic signs Fever spikes of short Fever, drowsiness Recurrent fever with shivers, duration (after cold chronic aseptic meningitis exposure), thirst, profuses weating (after cold exposure) Dysmorphic features – – Frontal bossing, saddle nose, midface hypoplasia Long-term consequences Fatigue, amyloidosis Amyloidosis Bone and joint deformities, (in 2-4% of cases) central nervous system damage, amyloidosis

7 D. Rigante tures and the most typical clinical scenarios referred to the three cryopyrinopathies. Familial cold autoinflammatory syndrome (OMIM 120100), formerly known as “familial cold urticaria”, is typical of childhood and characterized by fever lasting for 1-2 days, intermit- tent non-itching urticarial rash evoked by cold exposition or environmental temperature variations, recurrent arthralgias, conjunctivitis and headache, which can disappear within 24 hours. These patients usually do not display deafness, but sometimes can develop amyloidosis (in 2-4% of cases). Muckle-Wells syndrome (OMIM 191900) was historically reported for the first time by doctors T.J. Muckle and M. Wells in 1962, who described a new familial syndrome characterized by recurrent urticarial rash, usually unrelated to cold exposition, progressive neurosensorial deafness and potential development of renal amyloidosis (in 25% of cases). In addition these patients displayed lifelong arthralgias and episodic fever of short duration with attacks elicited by stress, infections or low temperature, recurring at variable intervals and resolving spontaneously after 12 to 36 hours. CINCA syndrome (chronic infantile neurolog- Figure 1. Typical knee osteo-arthropathy of CINCA syn- ical cutaneous articular syndrome, also named drome in a 12-year-old child, showing kneecap protrusion “neonatal-onset multisystem inflammatory dis- and a mass-producing process in the femoral epiphysis, ease” or NOMID in the U.S.A., OMIM 607115) leading to flexion contractures and severe disability in the deambulation. is the most severe expression of CIAS1 mutations, firstly described in 1987. This syndrome is at the most severe end of CAPS clinical spectrum and is due to de novo-CIAS1 mutations, though only show other day-by-day signs as conjunctivitis, fa- 60% of CINCA patients carry mutations in the tigue or headache, with following deep psycho- CIAS1 gene. The classical manifestations can be social impact on relationships with families and observed immediately after birth, especially peers, education, high-school graduation and job. chronic urticaria-like rash without pruritus. This The onset of amyloidosis has been reported in rash is present in 75% of CINCA patients at birth 20% of patients with CINCA syndrome. and develops within the first few months of life in For many years treatment of CAPS has been the others. Sometimes the onset might be prena- only supportive and many patients were disheart- tal. Pathological studies have demonstrated cuta- ened and progressively disconnected from health neous neutrophilic/lymphocytic infiltrates and the professionals. Recently the hypothesis that CAPS relative absence of mast cells, which differentiate manifestations are mediated by interleukin-1 has the rash from a true urticaria. The knee is nearly been the rationale for interleukin-1 blocking ther- always affected with a severe typical osteopathy, apy with anakinra, the recombinant form of inter- leading to kneecap protrusion, femoral distal epi- leukin-1 receptor antagonist. Anakinra has a short physeal deformity, flexion contractures and se- plasma half life and has been successfully used in vere disability, but other large joints might be in- patients with rheumatoid arthritis at the dose of 1- volved without any sign of synovial proliferation 2 mg/kg/day by subcutaneous injection: the drug (Figure 1). Chronic meningitis with papilledema, has produced a great success in Muckle-Wells hydrocephalus, cerebral atrophy, progressive cog- syndrome and CINCA syndrome, but it has the nitive impairment (in some patients) and neu- disadvantage to be daily administered (only some rosensorial deafness have been reported to date. patients with Muckle-Wells syndrome might tol- Usually there is also a stunted growth and patients erate anakinra administrations at least every 2

8 The protean visage of systemic autoinflammatory syndromes days, remaining in ongoing remission). Table XI tween urticaria, systemic symptoms, hyperostosis lists the most frequent side-effects of anakinra. and the monoclonal B-cell proliferation is still Unfortunately bony overgrowth deriving from de- unknown. Corticosteroids represent the only ranged endochondral bone formation in CINCA treatment influencing the course of systemic and syndrome is usually not controlled by any cy- osteoarticular symptoms. Fluoroquinolones have tokine-targeted treatment. Among more recent been shown to modify immune and inflammatory interleukin-1 antagonists we have to consider responses implicating various proinflammatory rilonacept, a dimeric fusion molecule consisting cytokines and their receptors: in particular, pe- of the interleukin-1 receptor attached to a human floxacin appears the most effective fluoro- immunoglobulin, designed for subcutaneous ad- quinolone in reducing the urticarial flares of ministration at weekly intervals, and canakinum- Schnitzler syndrome. A pivotal role of inter- ab (used at the dose of 150 mg aut 2 mg/kg once leukin-1 in its pathogenesis has been lately sug- every 8 weeks), a fully human monoclonal anti- gested and consistent clinical improvement has interleukin-1 antibody, functioning as a long- been observed with anakinra in some patients lasting interleukin-1 inhibitor with a highly with a refractory disease30. favourable safety profile, which has recently re- vealed to induce the rapid remission of symptoms Deficiency of Interleukin-1 in most patients with CAPS25-29. Receptor Antagonist (DIRA) A recently discovered disease is caused by the Schnitzler Syndrome deficiency of the interleukin-1 receptor antago- An acquired autoinflammatory disorder, still nist (DIRA, OMIM 612852) and is characterized not known in its pathogenetic mechanisms and by neonatal onset of pustular skin eruption and called Schnitzler syndrome, requires to be differ- sterile multifocal osteomyelitis in association entiated from cryopyrinopathies, Still’s disease, with increased inflammatory markers, neu- hereditary angioedema and lymphoma. It was trophilia and thrombocytosis, leading to sepsis- firstly described in 1972 by the French dermatol- like multiorgan failure. The deficiency of this an- ogist Liliane Schnitzler and about 100 adult pa- tagonist is not observed in children with CINCA tients have been reported to date: the disease is syndrome. In particular, DIRA is an autosomal characterized by chronic urticarial rash recurring recessive autoinflammatory syndrome, due to ho- with frequency ranging from daily to twice a mozygous mutations in the IL1RN gene on chro- year and monoclonal immunoglobulin M gam- mosome 2q, stopping interleukin-1 receptor an- mopathy, in association with at least two signs tagonist secretion, which in normal conditions among fever of apparently undetermined origin, inhibits the proinflammatory cytokines inter- arthralgia/bone pain, lymphadenopathy, he- leukin-1α and β. DIRA and CINCA syndrome patosplenomegaly and raised inflammatory might be considered the extremes of an imbal- markers. There is frequently the radiologic evi- ance between interleukin-1β and its receptor an- dence of osteosclerosis and the risk of evolution tagonist: the absence of the interleukin-1 receptor towards a lymphoplasmacytic neoplasm as antagonist causes an unopposed interleukin-1 ac- Waldenstrom’s macroglobulinemia. The link be- tivity, thereby allowing for uncontrolled over-inflammatory responses31.

Table XI. Side-effects of anakinra. Idiopathic Febrile Syndromes A specific variant of juvenile idiopathic Transient local erythematous reactions (in the arthritis, called systemic-onset juvenile idio- injection-site) pathic arthritis (So-JIA, OMIM 604302), cor- Skin, subcutaneous, articular, bony infections (related responds to 10-20% of all forms of childhood to site-administration) arthritides and has recently been inserted in the Flu-like syndrome group of AIS due to its similarity with many pe- Cephalalgia, nervous system disorders riodic fever syndromes, especially with CINCA Respiratory way infections (pneumococcal infections) syndrome, though no mutations have been found Infestations in the proteins constituting the “inflamma- Blood and lymphatic system disorders (lymphoma), neutropenia some”. SoJIA has an unknown etiology and is Increased risk of malignancies basically characterized by spiking fever accompanied or followed by arthritis (even occurring

9 D. Rigante after months or years) and at least one among drome, best known as PFAPA syndrome, char- evanescent salmon-pink erythematous rash, dif- acterized by periodic fever with abrupt onset at fuse lymph node enlargement, serositis and he- a nearly predictable rhythm every 4-6 weeks, patosplenomegaly. Unfortunately no laboratory firstly reported by Gary Marshall in 12 children test is available to ascertain this diagnosis and during the late 1980s. The disease recurs myste- the specific clinical sign (i.e. arthritis) may de- riously in association with at least one sign velop later in the course of the disease. Table among aphthous stomatitis, pharyngitis and lat- XII shows the clinical features of So-JIA. These ero-cervical lymph node enlargement, but with- patients typically show a marked elevation of out clinical signs of upper airways infections. acute-phase reactants and a clinical course re- Pharyngitis and cervical adenitis are the least sembling sepsis: a time-consuming diagnostic distinctive manifestations of PFAPA syndrome, work-up often prevents the early initiation of ap- which is largely underdiagnosed among the propriate antinflammatory treatment. Evidence- non-hereditary causes of AIS, often confused based medicine guidelines for So-JIA manage- with FMF, HIDS or TRAPS. PFAPA syndrome ment are lacking and this disease still represents usually begins before the age of 5 years without a huge therapeutic challenge: a significant num- any elucidated etiology and in most cases re- ber of patients have ongoing disease activity de- solves spontaneously before age 10. Flares of spite aggressive treatment. Recent advances in PFAPA syndrome may “abort” with corticos- the study of its pathogenesis advocate a Th1- teroid administration in the day of fever onset predominance and a key-role for inflammatory (prednisone: 1-2 mg/kg/dose or betamethasone: cytokines as interleukin-1, interleukin-6 and in- 0.1 mg/kg/dose), eventually followed by half terleukin-18, suggesting that de novo mutations dose the day after, though steroids do not pre- or polymorphisms of genes within the inter- vent further episodes, and are mitigated for fre- lukin-1 pathway may contribute to its pathogen- quency and intensity by the tonsillectomy34. The esis. Response to anakinra has been notable in a clinical definition of PFAPA syndrome is speci- subset of patients with So-JIA resistant to con- fied in Table XIII. Differential diagnosis for ventional treatment with non-steroidal antin- PFAPA syndrome must include primary or ac- flammatory drugs, corticosteroids, methotrexate quired immunodeficiency disorders such as de- and intravenous immunoglobulins32. ficiency of total immunoglobulins and its sub- Similarly to So-JIA, adult-onset Still’s dis- classes and T lymphocyte dysfunctions, but also ease is an uncommon systemic autoinflammato- HIDS, human immunodeficiency virus infection ry disorder of unknown etiology, characterized and cyclic neutropenia. by high-spiking fever, rash, polyserositis, lym- Cyclic neutropenia (OMIM 162800) is dom- phadenopathy, splenomegaly, hepatic dysfunc- inantly inherited and caused by ELA-2 mutations tion, arthralgias or arthritides33. encoding neutrophil elastase: this can be easily In the group of idiopathic febrile syndromes recognized by the reduction of neutrophil granu- we need to consider the periodic fever/aphthous locyte number every 3 weeks, when infections of stomatitis/pharyngitis/cervical adenitis syn- variable severity (pharyngitis, otitis, oral aphthae

Table XII. Clinical definition of systemic-onset juvenile idiopathic arthritis (according to the Edmonton 2001 revised classification criteria drafted by the International League of Associations for Rheumatology).

Cardinal signs Systemic signs Exclusion criteria

Fever (of at least 2 weeks’ a) Non-fixed evanescent erythematous Psoriasis or history of psoriasis in the duration) in association skin rash patient or in a first-degree relative with arthritis in one or b) Generalized lymph node enlargement Arthritis in a HLA-B27 positive male more joints with one or c) Hepatomegaly and/or splenomegaly beginning over 6 years of age, more systemic signs d) Serositis Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, acute anterior uveitis or history of one of these disorders in a first-degree relative, Rheumatoid factor positivity on at least 2 occasions at least 3 months apart

10 The protean visage of systemic autoinflammatory syndromes

Table XIII. Cardinal systemic signs of periodic fever/aphthous stomatitis/pharyngitis/cervical adenitis (PFAPA) syndrome.

Cardinal signs Systemic signs Exclusion criteria

Periodically recurring high fever a) Aphthous stomatitis Signs of upper respiratory (with “clockwork” periodicity b) Pharyngitis yairwa infection at intervals of 4-6 weeks) c) Cervical lymph node enlargement Child’s complete wellness between febrile episodes (with good growth and no sequelae) Association with at least one systemic sign or pimples) might occur. Its diagnosis requires gested as macrophages isolated from patients with the white blood cell count 2 times a week for an PAPA syndrome have shown increased inter- overall period of 6-8 weeks35. leukin-1 release after various stimuli36. Majeed syndrome (OMIM 609628) has been Hereditary Pyogenic Disorders observed in Jordan since 1989 and is character- Two pyogenic diseases, recently defined at a ized by early-onset recurrent multifocal os- genetic level and probably related to a prominent teomyelitis, often with a lifelong course, con- role of interleukin-1 pathway, have been en- genital dyserythropoietic anemia, starting dur- closed in the family of AIS. ing the first year of life, and transient inflamma- PAPA syndrome (OMIM 614416), firstly de- tory dermatosis, often manifesting as Sweet scribed by Noralane Lindor in 1997, is caused by syndrome (with neutrophilic skin infiltration). mutations in the PTSTPIP1 gene, localized on Diagnosis of Majeed syndrome is based on clin- chromosome 15q24-25, but was historically re- ical findings and molecular genetic testing of ported as “streaking leucocyte factor disease”. The LPIN2, though the function of lipin 2 and its condition is characterized by autosomal dominant role in the inflammation remains obscure. Non- inheritance and recurrence of self-limiting pyo- steroidal antinflammatory drugs are moderately genic sterile arthritis, after minor trauma or also helpful for treating most manifestations of the spontaneously occurring, severe cutaneous ulcers syndrome, in combination with corticosteroids resembling “pyoderma gangrenosum” and cystic or interferon-α37. The general details of heredi- acne with disfiguring outcome. The involved gene tary pyogenic disorders are listed in Table XIV. encodes the proline/serine/threonine phosphatase- interacting protein 1 (PSTPIP1), also named CD2 Bone Autoinflammatory Diseases antigen-binding protein 1 (CD2BP1), highly ex- AIS can involve electively bone tissue in two pressed in neutrophil granulocytes, which acts as a peculiar syndromes. cytoskeletal protein and interacts with pyrin, lead- CRMO syndrome (OMIM 259680) was origi- ing to dysregulated apoptosis with a final effect of nally described in 1972 by Andreas Giedion as a inhibiting pyrin-mediated inflammatory signals. “chronic recurrent multifocal osteomyelitis” affect- The molecular mechanism by which PTSTPIP1 ing the metaphyses of long bones without a known mutations cause the syndrome is still elusive, but etiology and with unpredictable course: the disease many treatments have been attempted as corticos- is characterized by osteolytic/sclerotic lesions of teroids and anti-tumour necrosis factor inhibitors. non-infectious nature, which give rise to self-limit- A potential treatment with anakinra has been sug- ing bone swelling, severe localized pain, particular-

Table XIV. General details of hereditary pyogenic disorders.

Gene Inheritance Clinical signs

PAPA syndrome PSTPIP1 Autosomal dominant Sterile pyogenic oligoarthritis, pyoderma gangrenosum, cystic acne Majeed syndrome LPIN2 Autosomal recessive Multifocal osteomyelitis, dyserythropoietic anemia, rash (diffuse neutrophilic dermatosis, Sweet syndrome)

11 D. Rigante ly deep at night, and recurrent fever. The disease Blau syndrome (OMIM 186580), also known was thought to be the pediatric variant of SAPHO as “juvenile systemic granulomatosis”, is a rare syndrome, which is a combination of “synovitis, autosomal dominant disease characterized by re- acne, pustulosis, hyperostosis and osteitis”, adopt- current non-caseating granulomatous polyarthri- ed as an umbrella term to describe a spectrum of tis, uveitis and brown-coloured scaly rash: it is clinical presentations which need to be differentiat- related to the CARD15/NOD2 gene localized on ed from Ewing’s sarcoma and X-histiocytosis. CR- chromosome 16q12, discovered in 2001, which MO syndrome affects typically the anterior tho- causes abnormal function of CARD15/NOD-2, a racic cage (especially the clavicle) and axial skele- member of the NOD-like receptor family of in- ton, but can also involve pelvic or peripheral long tracellular proteins, expressed in monocytes and bones. Its final diagnosis can be attained by a mul- chondrocytes. This disease does not involve air- tidisciplinary approach consisting of imaging and ways and this differentiates it from early-onset histopathologic findings. There is no specific treat- sarcoidosis (OMIM 609464), a multiorganic in- ment for this syndrome and pivotal therapies are flammatory disease with unknown etiology, char- symptomatic with non-steroidal antinflammatory acterized histologically by non-caseating epithe- drugs (as indomethacin), corticosteroids and more lioid granulomata and by the clinical triad of recently tumour necrosis factor antagonists (as in- lung, lymph node and eye involvement. Treat- fliximab) or bisphosphonates (as pamidronate)38,390. ment of Blau syndrome is based on corticos- Cherubism (OMIM 118400) is an autosomal teroids, immunosuppressant drugs (as methotrex- dominant inherited disease of the jaws: the specific ate and cyclosporine), infliximab or anakinra. lesion was first described in 1933 as a hereditary Three major CARD15/NOD2 polymorphisms non-neoplastic multilocular cystic disease of the have been associated with Crohn’s disease, a ge- jaws, leading to symmetrically swollen cheeks, netically complex disease, first reported by Bur- particularly over the angles of the mandible, and an rill Crohn in 1925, characterized by recurrent upward turning of the eyes. The term “cherubism” granulomatous inflammatory lesions of the intes- was justified because of the typical face appear- tine, which can also be accompanied by inflam- ance of patients, resembling cherubs of the Renais- mation of skin, joints and eyes. Recurrent and sance art. The affected mandible and maxilla begin excessive Th1/Th17-dominant immune responses to swell in early childhood and are gradually in- mainly involving the gastrointestinal tract have creased until the age of puberty. The characteristic opened an intense debate about the possibility of dysplasia of cherubism can be distinguished histo- categorizing Crohn’s disease as an autoinflam- logically from other giant cell-rich lesions and is matory disorder. In particular, mutations involv- strictly limited to the jaws. The gene responsible ing CARD15/NOD2 C-terminal domain generate for cherubism has been mapped to the region of a decreased NFκB activity, perturbing the func- chromosome 4p16.3 and codes for SH3 domain- tional part of the protein involved in detecting binding protein 240. muramyldipeptide, a core component of the bac- terial cell wall, and give rise to Crohn’s disease, Immune-Mediated Granulomatous Diseases while those mutations involving NACHT portion Two non-infectious diseases dominated by generate an elevated NF-κB activity and cause granulomatous inflammation can be enclosed in Blau syndrome41,42. The general details of these the heading of AIS. granulomatous diseases are listed in Table XV.

Table XV. General details of immune-mediated granulomatous diseases.

Gene Inheritance Clinical signs

Blau syndrome CARD15 /NOD2 Autosomal dominant Symmetrical granulomatous polyarthritis, uveitis (with risk of cataract and secondary glaucoma), ichthyosiform rash Crohn’s disease CARD15 /NOD2, Complex non-Mendelian Chronic intestinal inflammation with MDR1, PXR/NRII2, epithelioid granulomata and multiple DLG5, OCT1-2, etc. extra-intestinal manifestations involving joints, eye and skin, risk of colorectal cancer

12 The protean visage of systemic autoinflammatory syndromes

Complement Disorders Hemophagocytic Syndromes Complement is part of the innate immune de- The clinical pictures of hemophagocytic lym- fence and not only recognizes microbes, but also phohistiocytosis and macrophage activation syn- unwanted host molecules to enhance phagocytosis drome are both characterized by dysregulated in- and clearance: this process must be tightly regulat- flammation with prolonged fever, he- ed to prevent pathologic consequences. Endoge- patosplenomegaly, cytopenia, coagulopathy, evi- nous ligands such as dying cells, extracellular ma- dence of hemophagocytosis in the bone marrow trix proteins, amyloid deposits and prions bind the or liver and can be considered extremely severe complement activator C1q, but also interact with expressions of AIS. complement inhibitors. Recent advances have Hemophagocytic lymphohistiocytosis is a shown that diseases caused by complement dysreg- rare, highly fatal disorder of uncontrolled inflam- ulation may be enclosed in the family of AIS. Dis- mation, usually affecting infants, caused by unar- turbances to the complement regulation on endoge- rested proliferation of activated lymphocytes and nous ligands can lead to hereditary angioedema histiocytes secreting high amounts of inflammato- and atypical hemolytic uremic syndrome. ry cytokines and occurring in familial forms (all Hereditary angioedema (OMIM 106100) is a showing an impaired function of natural killer rare, but potentially life-threatening autosomal cells and cytotoxic T-cells, due to defects of cyto- dominant disease, caused by the lack of C1-es- toxic granule exocytosis involving either perforin terase inhibitor, characterized by recurrent and or MUNC 13-4 protein in at least 40-50% of cas- self-limiting episodes of swelling which may affect es) or on the basis of rheumatologic disorders, in- skin, gastrointestinal tract and upper airways, po- fectious diseases, malignancies and various inher- tentially leading to laryngeal edema that might be- ited/acquired immune deficiencies as Chediak- come fatal. The local increase in vascular perme- Higashi syndrome, Griscelli syndrome and X- ability in the subcutaneous and submucosal layers, linked lymphoproliferative syndrome. Characteris- identified as angioedema, is mediated by increased tic biochemical markers include elevated serum levels of bradykinin. Acute episodes of hereditary triglycerides, elevated serum ferritin, low serum angioedema can be treated with fresh frozen plas- fibrinogen and elevated serum levels of inter- ma and human derived C1-esterase inhibitor con- leukin-2 receptor. Although multi-agent immuno- centrates or averted by androgens and anti-fibri- suppressive/immunomodulatary agents and cyto- nolytics. Advances in understanding the complex static drugs have been attempted, allogeneic effects of C1-esterase inhibitor deficiency at the hematopoietic cell transplantation remains the on- molecular level have led to new molecular-targeted ly curative therapy for patients with familial approaches as inhibitors of kallikrein (to prevent forms of lymphohistiocytosis45,46. bradykinin release), antagonists of the bradykinin receptor (to prevent its action) and recombinant hu- Vasculitic Syndromes man C1-esterase inhibitors43. Many immune-mediated inflammatory dis- Hemolytic uremic syndrome consists of ac- eases involve blood vessels and among these we quired microangiopathic hemolytic anemia, throm- must consider Behçet’s disease (OMIM bocytopenia and acute renal failure that occur 109650), which usually occurs in the third acutely in otherwise healthy individuals. The dis- decade of life with an equal sex predilection, re- ease can be divided into two broad categories: typi- sulting rather rare in pediatrics. Classified as a cal, preceded by a diarrheal prodrome, and atypi- systemic vasculitis, Behçet’s disease can involve cal, when associated with defective complement both the arteries or veins of almost any organ de- control. Atypical hemolytic uremic syndrome can pending on the combination of genetic, environ- be considered a genetic disease and gene mutations mental and immunological factors. This is a mul- have been reported for factor H, membrane cofac- tisystem autoinflammatory disorder of unknown tor protein/CD46 and factor I, all acting to control etiopathogenesis, characterized by recurring oral the activity of the complement convertase C3bBb, and genital ulcers associated with relapsing which initiates the alternative pathway and amplifi- uveitis, skin signs (mainly erythema nodosum), cation of the complement system. Factor H defi- joint, gastrointestinal and central nervous system ciency-associated atypical hemolytic uremic syn- manifestations. The disease has a worldwide dis- drome usually occurs in middle-aged adults to in- tribution, but its prevalence is highest in Central fants, even in neonates, and can be reversed by the Asia and the Far East (along the ancient “silk repetitive infusion of fresh frozen plasma44. road” from Turkey to Japan, corresponding to the

13 D. Rigante

30th and 45th degree Northern latitudes). Table 4-6 mg/dl; “hyperuricemia” is defined as a XVI depicts the diagnostic criteria according to serum urate concentration exceeding 7 mg/dl in the 1990 International Study Group for Behçet’s men and 6 mg/dl in women, resulting from ei- disease. Genetically the haplotype HLA-B51 has ther excess uric acid production or reduced ex- received attention as a risk factor to this disease, cretion) and has been long recognized as the though the essential diagnostic features are recur- cause of gouty arthritis. There are at least three rent oral ulcerations and ocular abnormalities, different inherited defects that might lead to an which are the most important clues influencing early development of severe hyperuricemia and prognosis. Diagnosis can be sometimes problem- gout: glucose-6-phosphatase deficiency (which atical, especially if the typical oral ulcers are not is the cause of von Gierke glycogenosis type I, evident at the presentation. Treatment of Behçet OMIM 232200), hypoxanthine-guanine phos- patients is largely symptomatic and challenging, phoribosyltransferase deficiency (its complete but must be tailored to the pattern of organ in- deficiency is called Lesch-Nyhan syndrome, volvement for each patient by the use of topical OMIM 300322, an X-linked recessive inborn er- steroids, non-steroidal antinflammatory agents, ror of purine metabolism; the partial deficiency colchicine, immunosuppressant/cytotoxic agents, of the same enzyme leads to Kelley-Seegmiller thalidomide, interferon or tumour necrosis factor syndrome, OMIM 300323, with the only effect antagonists47. of excessive uric acid synthesis), and elevated 5- phosphoribosyl-1-pyrophosphate synthetase ac- Crystal Deposition Diseases tivity. Gout is the most common type of inflam- Crystal deposition arthritides have found a matory arthritis in adult men, deriving from the place in the umbrella of AIS, as recently sug- deposition of monosodium urate crystals in syn- gested by the observation that monosodium ovial fluid leukocytes and in different body tis- urate and calcium pyrophosphate dihydrate crys- sues, including skin and soft tissues. The forma- tals can activate the “inflammasome”, resulting tion of urate crystals leads to the formation of in the production of proinflammatory cytokines. “tophi”, particularly in the joints, and uric acid The role of uric acid and calcium crystals as me- urolithiasis appears after many years of hyper- diators of vascular damage is not a new concept, uricemia. Numerous circumstances can precipi- but has recently gained widespread acceptance tate gouty attacks such as trauma, surgery, ex- as a contributor to the worsening of osteoarticu- cessive alcohol consumption, administration of lar diseases. Uric acid is the product of purine certain drugs and the ingestion of purine-rich nucleotide catabolism (the mid-normal range is foods. Allopurinol and probenecid remain the drugs of choice to diminish uric acid overpro- duction. However, tophi and tissue stores of Table XVI. Diagnostic criteria for Behçet’s disease according monosodium urate crystals resolve slowly, par- to the 1990 International Study Group. ticularly in patients with longstanding disease. The uptake of monosodium urate crystals by Recurrent oral ulcerations monocytes involve interactions with toll-like re- (Aphthous or herpetiform ulcers recurring at least 3 times in 1 year – observed by a physician) plus 2 ceptors and other components of the innate im- among: mune system: at an intra-cellular level crystals Recurrent genital ulcerations activate the “inflammasome” to process pro-in- Eye lesions terleukin-1 into mature interleukin-1. This is the (Anterior or posterior uveitis, cells in vitreous by slit- antefact which strongly suggests that the inflam- lamp examination, retinal vasculitis – observed by an matory effects of monosodium urate crystals can ophthalmologist) be blocked by interleukin-1 inhibitors48. Calcium Skin lesions pyrophosphate dihydrate and calcium phosphate (Erythema nodosum, pseudofolliculitis, papulopustular nodules, acne-like lesions in the post-adolescental age crystals are the two most common calcium-con- with no history of corticosteroid treatment) taining crystals involved in the pseudo-gout, al- Positive pathergy test so known as idiopathic calcium pyrophosphate (Performed by puncturing the forearm skin with sterile deposition disease. Recent studies suggest the needles: the early reaction must be read by the physi- implication of the “inflammasome” complex and cian, appears within 24 hours, maximizes in 48 hours a pivotal role for interleukin-1 also in pseudo- and is a 1-2 mm elevated lesion surrounded by a red- dish area) gout attacks and calcium pyrophosphate crystal- related arthropathy49.

14 The protean visage of systemic autoinflammatory syndromes

Reproduction Disorders Obtaining a family history is an essential part of Familial recurrent hydatidiform mole evaluating patients with chronic febrile diseases (OMIM 231090) is an autosomal recessive con- or suspected to have AIS and priority is to exam- dition consisting of anembryoic pregnancy with ine child’s clinical and laboratory data both in trophoblast hyperproliferation, cystic degenera- the acute inflammatory phase and in the inter- tion of placental villi and no fetal development, critical phase, in order to exclude a host of recently inserted in the chapter of AIS. The inci- chronic diseases of infectious, autoimmune or dence of hydatidiform mole varies among ethnic even neoplastic nature. Box 1 shows modalities groups and reaches 1 in every 250 pregnancies in of approaching the child with the suspicion of Eastern Asia. Recurrent moles with recurrent AIS. A substantial contribute to the diagnosis pregnancy failure account for 2% of all moles might derive from the consideration of ethnicity and a few of them occur in more than one family and from genotype analysis. The discovery of member. A recessive maternal locus responsible genes underlying AIS constitutes a matter of for this condition was mapped to 19q13.4 and growing dimensions for many clinicians and pe- causative mutations in the gene NALP7 (or NL- diatricians too: a host of experimental studies RP7), involved in the synthesis of intracellular are beginning to reveal the central role of the pattern recognition receptors, have been identi- “inflammasome” in other multifactorial disor- fied by studying a family with recurrent moles50. ders, such as type 2 diabetes, hypertension or neovascular age-related macular degeneration. Concluding Remarks The provision of collaborative multidisciplinary The most typical characteristic of AIS can be care to persons with complex illnesses such as limited in a few words to a wrongly tuned in- AIS can be challenging in today’s health care flammatory response, arising from undue activa- environment where the demand for quality tion of pattern recognition molecules of the in- health services is coping with dwindling re- nate immune system, manifesting with febrile sources and fragmented health delivery systems. flares and inflammation localized to various or- The diagnostic path for many of these patients gans. The onset of AIS manifestations is usually remains often long and requires lots of investiga- early, ranging from the first hours to the first tions as well as high-level expertise: the creation decade of life, but a delay in diagnosis is gener- of international registries is therefore desirable, ally the rule for most AIS. Undoubtly AIS rela- expediting the definition of best treatment proto- tive rarity and poor physicians’ awareness of cols and standardizing guidelines about the role AIS existence contribute to this diagnostic delay. of genetics to the diagnosis.

Box I. Diagnostic pathway in the patient with the suspicion of systemic autoinflammatory syndromes.

Fever and/or recurrent inflammation in the proband ↓ Evaluation of the proband → To exclude factitious fever, in an acute febrile/inflammatory attack viral infection, focal diseases (number of neutrophil granulocytes, or autonomic dysregulation erythrosedimentation rate, C-reactive protein, serum amyloid-A, plasmatic globulins, complement, cultural tests if needed according to the localizing signs) ↓ Evaluation of the proband → If the clinical and laboratory picture in an afebrile period of well-being is not normal it is mandatory to verify (number of neutrophil granulocytes, the hypothesis of chronic infection, erythrosedimentation rate, autoimmune disease or malignancy C-reactive protein, serum amyloid-A) ↓ Genotype study (MEFV, MVK, TNFRSF1A, etc.)

15 D. Rigante

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