ABSTRACT

Autoinflammatory disorders are immune-mediated diseases with increased production of inflammatory cytokines and absence of detectable autoantibodies. They course with recurrent episodes of systemic inflammation and fever is the most common symptom. Cutaneous manifestations are prevalent and important to diagnosis and early treatment of the syndromes. The purpose of this review is to emphasize to dermatologists the skin symptoms present in these syndromes in order to provide their early diagnosis.

Keywords:
Acquired hyperostosis syndrome; Behçet syndrome; Cryopyrin-associated periodic syndromes; Familial mediterranean fever; Mevalonate kinase deficiency; Still's disease, adult-onset; Schnitzler syndrome; Sweet syndrome; Hereditary autoinflammatory diseases; Tumor necrosis factor receptor-associated peptides and proteins

INTRODUCTION

Autoinflammatory disorders are a group of diseases characterized by recurrent episodes of systemic inflammation, with an increased production of inflammatory cytokines that can occur without detectable autoantibodies or auto-reactive T cells.¹1 Kallinich T, Gattorno M, Grattan CE, de Koning HD, Traidl-Hoffmann C, Feist E, et al. Unexplained recurrent fever: when is autoinflammation the explanation? Allergy. 2013;68:285-96.

2 Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-9.

3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.

4 Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229-65.^-55 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80. Cutaneous manifestations can be the dominant symptoms in some of the patients and can even be the initial manifestation of the disease.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80. According to their characteristics, the main cutaneous manifestations of autoinflammatory diseases are grouped into: urticarial exanthema, dermo-hypodermitis, neutrophilic dermatosis, granulomatous dermatitis and bipolar aphthosis.

The identification of genetic polymorphisms and their association with proteins of the inflammasome complex and other regulatory proteins were decisive for a better understating of autoinflammatory diseases. Their spectrum covers monogenic, polygenic and multifactorial diseases.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,66 McGonagle D, Aziz A, Dickie LJ, McDermott MF. An integrated classification of pediatric inflammatory diseases, based on the concepts of autoinflammation and the immunological disease continuum. Pediatr Res. 2009;65:38R-45R. Within the monogenic diseases, we will describe Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD), Majeed Syndrome, PAPA Syndrome (acronym for pyogenic arthritis, pyoderma gangrenosum and acne), TNF Receptor Associated Periodic Syndrome (TRAPS), Cryopyrin-associated Periodic Syndromes (CAPS), Familial Cold Autoinflammatory Syndrome type 2 (FCAS 2), Familial Blau Syndrome and Deficiency of the Interleukin-1-receptor Antagonist (DIRA). Among polygenic and multifactorial diseases, we will focus on SAPHO Syndrome (acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Systemic Juvenile Idiopathic Arthritis (SJIA), Adult-onset Still's Disease (AOSD), Schnitzler Syndrome, Behçet's Disease, Crohn's Disease and Periodic Fever Aphthous Pharyngitis and cervical Adenopathy (PFAPA).

It is still a matter of discussion whether some of these diseases, such as Behçet's disease, SAPHO, CRMO, AOSD and Schnitzler Syndrome, are genuine autoinflammatory diseases. Innate immune-mediated diseases, which are associated with significant tissue destruction without evident adaptive immune responses, are designated as autoinflammatory (mostly due to distinct immunopathologic features).⁶6 McGonagle D, Aziz A, Dickie LJ, McDermott MF. An integrated classification of pediatric inflammatory diseases, based on the concepts of autoinflammation and the immunological disease continuum. Pediatr Res. 2009;65:38R-45R. This is highly relevant, because innate immune-mediated disorders may respond to cytokine antagonism whereas autoimmune-mediated diseases respond better to anti-T and B cell therapies.

The purpose of this review is to systematically characterize autoinflammatory disorders and to cluster the cutaneous manifestations of these diseases. This may lead to earlier diagnosis and better prevention of severe complications. This review aims to highlight the role of the dermatologist in the early diagnosis of auto-inflammatory diseases.

URTICARIAL EXANTHEMA

Cryopyrin-associated periodic syndromes (CAPS)

These autoinflammatory syndromes are rare and comprise three phenotypes with increasing severity: Familial Cold-induced Auto-inflammatory Syndrome (FCAS), Muckle-Wells Syndrome and Neonatal Multisystem Inflammatory Disease (NOMID).⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.

8 Shinkai K, McCalmont TH, Leslie KS. Cryopyrin-associated periodic syndromes and autoinflammation. Clin Exp Dermatol. 2008;33:1-9.^-99 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12-20. They are caused by gain of function mutations in NLRP3, the gene encoding cryopyrin or NALP3 (a protein of the inflammasome), leading to activation of caspase 1, with the subsequent increase of IL-1β and IL-18 secretion.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1010 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.

11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.

12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.

13 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.

14 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^-1515 Dinarello CA. A clinical perspective of IL-1ß as the gatekeeper of inflammation. Eur J Immunol. 2011;41:1203-17. In about 40% of patients with cryopyrinopathy there are no known mutations.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.

The cryopyrinopathies are characterized by cutaneous, articular, neurological and ophthalmic events.⁹9 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12-20.^,1616 Kolivras A, Theunis A, Ferster A, Lipsker D, Sass U, Dussart A, et al. Cryopyrinassociated periodic syndrome: an autoinflammatory disease manifested as neutrophilic urticarial dermatosis with additional perieccrine involvement. J Cutan Pathol. 2011;38:202-8. Cutaneous manifestations are the key symptom and are often the first manifestation of the disease. They usually appear after birth, in the form of an atypical, migratory rash or less frequently as a maculopapular urticaria-like rash.²2 Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-9.^,55 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,99 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12-20.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. Histologic examination confirms the diagnosis at an early stage, with perivascular neutrophilic infiltrate in the dermis, in contrast to lymphocytic and eosinophilic infiltrates of classical urticaria.²2 Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-9.^,99 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12-20. Blood neutrophilia and an increase in acute phase proteins during exacerbations are common.¹⁶16 Kolivras A, Theunis A, Ferster A, Lipsker D, Sass U, Dussart A, et al. Cryopyrinassociated periodic syndrome: an autoinflammatory disease manifested as neutrophilic urticarial dermatosis with additional perieccrine involvement. J Cutan Pathol. 2011;38:202-8.^,1717 Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141-9.

FCAS is the mildest of all CAPS.¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501.^,1919 Giat E, Lidar M. Cryopyrin-associated periodic syndrome. Isr Med Assoc J. 2014;16:659-61. Clinical manifestations usually appear within the first six months of life and are characterized by an atypical urticarial rash with painful and non-pruritic maculopapular lesions, associated with fever peaks.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. Attacks usually occur following exposures to cold or decreases in temperature including air conditioning and cool damp conditions.²⁰20 Waynberger M, Dorra M, Tibi P, Slama R, Bouvrain Y. Valvular prostheses during the acute stage of bacterial endocarditis. Sem Hop. 1971;47:95-100. They last less than 24 hours and patients have other associated symptoms, like arthralgias, conjunctivitis, headache, myalgias and extreme thirst.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. Amyloidosis is a rare long-term complication (Chart 1).¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501.^,2121 Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol. 2001;108:615-20.

The Muckle Well Syndrome manifests during childhood and adolescence by recurrent febrile episodes associated with vanishing non-pruritic urticarial rash, arthralgia, myalgia and conjunctivitis.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,2222 Pereira AF, Pereira LB, Vale EC, Tanure LA. Four cases of Muckle-Wells syndrome within the same family. An Bras Dermatol. 2010;85:907-11. Fever may not be present.²2 Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-9. Symptoms tend to last longer than in FCAS (12 to 36 hours). In general, cutaneous eruption is the first symptom to be noticed and might be a burning sensation.²2 Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008;4:481-9. A progressive sensorineural hearing loss begins in childhood and often results in complete deafness by adolescence. Secondary amyloidosis affects 25% of patients and can result in chronic renal insufficiency.²³23 Mathur AN, Mathes EF. Urticaria mimickers in children. Dermatol Ther. 2013;26:467-75.

NOMID is a clinical expression of the most severe form of mutation in NLRP3, which can be sporadic or autosomal-dominant.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. The triad of skin rash, severe arthropathy, and central nervous system disorders characterize NOMID.¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501. It appears immediately after birth and manifestations are chronic with periods of exacerbations.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. The patients have severe fever outbreaks associated with persistent cutaneous manifestations initially in the form of polymorphic urticarial rash or a migratory and non-pruriginous maculopapular rash.³⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. Patients also show abnormal facial features, such as flattening of the nasal bridge, macrocephaly, frontal bossing, and protruding eyes.¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501. There can also coexist musculoskeletal symptoms and impairment of the central nervous system, as well as longterm complications that modify the prognosis of this disease (Chart 1). The mortality is high in untreated patients, 20% of patients die before reaching adulthood.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,2121 Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol. 2001;108:615-20.

Familial cold autoinflammatory syndrome type 2 (FCAS 2) or NLRP12-associated hereditary periodic fever syndrome

This is a rare autosomal dominant disease, due to mutations in NLRP2, gene responsible for the synthesis of NLRP12 protein, which acts as a regulator of the immunity against pathogenic agents.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602. It has a clinical phenotype between FCAS and MWS.²⁴24 Hashkes PJ, Toker O. Autoinflammatory syndromes. Pediatr Clin North Am. 2012; 59:447-70. Patients have recurrent febrile episodes from the first years of life, triggered by exposure to cold, lasting five to ten days, associated with headache, arthralgia, urticaria, thrush, sensorineural hearing loss, lymphadenopathy, and abdominalgia with rise of acute phase proteins (Chart 1).³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.

Schnitzler syndrome

Schnitzler syndrome is a rare condition that usually arises in the fourth decade of life.²⁶26 Tinazzi E, Puccetti A, Patuzzo G, Sorleto M, Barbieri A, Lunardi C. Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: report of two new cases and review of the literature. Autoimmun Rev. 2011;10:404-9. It is characterized by the major diagnostic criteria of non-pruriginous urticarial rash (Figure 1) and monoclonal gammopathy IgM or IgG. At least two minor criteria must be present.¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,2626 Tinazzi E, Puccetti A, Patuzzo G, Sorleto M, Barbieri A, Lunardi C. Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: report of two new cases and review of the literature. Autoimmun Rev. 2011;10:404-9. It includes intermittent episodes of fever, arthralgia or arthritis, bone pain, bone densification, lymphadenopathy, hepatosplenomegaly, leukocytosis, and acute phase protein elevation.¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,2626 Tinazzi E, Puccetti A, Patuzzo G, Sorleto M, Barbieri A, Lunardi C. Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: report of two new cases and review of the literature. Autoimmun Rev. 2011;10:404-9. The frequency of exacerbations is variable, and symptoms can be daily or annual. It presents with clinical similarities to CAPS, particularly to Muckle Wells syndrome, which is also associated with monoclonal gammopathy IgM.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1010 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. Later the patients may develop secondary amyloidosis and lymphoproliferative disorders (Chart 1). Wheals usually do not vanish within 2 hours and often persist over 24 hours.

The pathophysiology of Schnitzler syndrome remains unclear, but mechanisms of autoimmunity and autoinflammation seem to play an important role, due to the presence of autoantibodies of the IgG3 class against the alpha chain (α) of cellular proteins, high affinity autoantibodies IgG2 for the IgE receptor (FceRI) and autoantibodies against IL-1α. Interferon alpha (IFN-α), which increases the expression of the IL-1 receptor antagonist, and the IL-1 antagonist anakinra induce symptomatic improvement in the patients, highlighting the importance of IL-1 in the pathogenesis of the disease.²⁶26 Tinazzi E, Puccetti A, Patuzzo G, Sorleto M, Barbieri A, Lunardi C. Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: report of two new cases and review of the literature. Autoimmun Rev. 2011;10:404-9. Recently a mutation in NLRP3 has been detected in some of the patients suggesting a role of the inflammasome in the pathogenesis of the disease, which might lead to the inclusion of this disease in CAPS group despite the absence of mutations in other patients.¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46. To date, no treatment is specifically approved for Schnitzler syndrome and spontaneous remissions are extremely rare.¹⁴14 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.

DERMO-HYPODERMITIS

Familial Mediterranean fever (FMF)

The Familial Mediterranean Fever is a rare autosomal recessive disease.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,2727 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33. Mutations in the MEFV gene (MEditerranean FeVer ), located on chromosome 16 (16p13), encoding pyrin, lead to an insufficient inhibitory regulation of the NLRP3 inflammasome, increased production of interleukin-1β (IL -1β), IL-18, IL-33 and stimulated apoptosis.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,2727 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33.^,2828 Aróstegui JI. Hereditary systemic autoinflammatory diseases. Reumatol Clin. 2011;7:45-50. Incomplete penetrance and variable clinical expression is seen among FMF patients, even in those who have the same mutation.¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501.

The disease usually appears before the age of 20 and can even, in two-thirds of the patients, appear before they are 5.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46. There are three main phenotypes: Type 1, with classical symptoms and starting at early ages; Type 2, characterized by reactive AA amyloidosis as a first manifestation; and Type 3, in which mutations in the MEFV gene are detected in the absence of signs and symptoms of the disease.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.^,2929 Doria A, Dayer JM, Punzi L. Autoinflammatory diseases: how to put the fire inside the body out? Autoimmun Rev. 2012;12:1-4.

The disorder is characterized by recurrent episodes of fever, associated with abdominal pain and arthritis that last from 1 to 3 days.²⁷27 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33.^,3030 Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147:155-74.^,3131 Bhat A, Naguwa SM, Gershwin ME. Genetics and new treatment modalities for familial Mediterranean fever. Ann N Y Acad Sci. 2007;1110:201-8. Articular involvement is present in up to 75% of patients. Most of the patients have also constitutional and emotional symptoms.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,2727 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33.

Cutaneous manifestations usually manifest in the form of dermo-hypodermitis (Chart 2).⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.^,3232 Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301-9.^,3333 Yao Q, Furst DE. Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology (Oxford). 2008;47:946-51. The most common cutaneous presentation is erysipelas-like erythema, reported in 7% to 40% and characterized by lower limb erythematous and rash that are frequently misdiagnosed as cellulitis.²⁷27 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33. It comprises erythematous plaques with 10 to 15 cm in diameter in the pre-tibial region and around the medial malleolus of the foot.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,2727 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33. Diffuse palmoplantar erythema can also be present. Other manifestations such as vasculitis, similar to polyarteritis nodosa - Henoch-Schoenlein purpura and angioedema can also occur.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.

Proteinuria is suggestive of secondary systemic amyloidosis, which is a severe and potentially lethal complication.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.^,2727 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33. In the laboratory, an increase of inflammatory parameters is found, with neutrophilic leukocytosis, increased C-reactive protein, fibrinogen and serum amyloid protein.¹³13 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,3434 Gomes JM, Gomes SM, Conde M. Autoinflammatory syndromes. Acta Reumatol Port. 2010;35:146-54.

TNF receptor associated periodic syndrome (TRAPS)

This is a rare autosomal dominant autoinflammatory syndrome.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,3535 Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38-43. It is associated with mutations in the receptor TNFRS-F1A, which encodes the p55 tumor necrosis factor (TNF), leading to the absence of the anti-inflammatory signals and to a persistent pro-inflammatory state with secretion of IL1, IL8 and IL12.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,3535 Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38-43. It usually appears after childhood, but before 20 years of age.¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.

It is characterized by recurrent episodes of fever lasting up to three weeks, accompanied by periorbital edema, conjunctivitis, abdominal pain, arthralgia, myalgia and dermo-hypodermitis.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,55 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,3535 Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38-43.

The cutaneous manifestations occur in approximately 80% of patients in the acute phase of the disease.¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,3636 Yao Q, Englund KA, Hayden SP, Tomecki KJ. Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: case report and literature review. Semin Arthritis Rheum. 2012;41:611-7. The most frequent skin lesion, seen in 40% of the cases, is a centrifugal migratory erythematous rash, warm and painful, in an area of overlapping myalgia.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,1818 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501.^,3636 Yao Q, Englund KA, Hayden SP, Tomecki KJ. Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: case report and literature review. Semin Arthritis Rheum. 2012;41:611-7. Other presentations include erysipelas-like erythema, edematous plaques, similar to cellulitis, panniculitis and urticarial lesions on the limbs and trunk. Reticulated discrete spots or serpiginous and annular plaques may also occur.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,3232 Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301-9.^,3636 Yao Q, Englund KA, Hayden SP, Tomecki KJ. Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: case report and literature review. Semin Arthritis Rheum. 2012;41:611-7.^,3737 Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601-18. The histopathology of skin lesions is characterized by perivascular lymphocytic and monocytic dermal infiltrate.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,3535 Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38-43.

Approximately one-fourth of the patients develop secondary systemic amyloidosis, the most serious complication of TRAPS, which determines the prognosis.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46. Stress and trauma can act as triggers, and other TNF receptor antagonists, beyond those used in the treatment, like infliximab and adalimumab, may cause paradoxical aggravation of inflammatory response signals (Chart 2).⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,66 McGonagle D, Aziz A, Dickie LJ, McDermott MF. An integrated classification of pediatric inflammatory diseases, based on the concepts of autoinflammation and the immunological disease continuum. Pediatr Res. 2009;65:38R-45R.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,3535 Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38-43.

Mevalonate kinase deficiency (MKD)

MKD is an autosomal recessive disease that results from insufficient activity of mevalonate kinase, involved in the biosynthesis of cholesterol and isoprenoids due to mutations in the MVK gene.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,3333 Yao Q, Furst DE. Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology (Oxford). 2008;47:946-51.^,3838 Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 201;128:e152-9. In hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), the milder form of the disease, MVK activity is reduced to 1 to 10% of normal, whereas in mevalonic aciduria, the most severe form, this activity is below 1%.³⁹39 Mandey SH, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat. 2006;27:796-802.^,4040 Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde Visser S, van der Meer JW, et al. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur J Hum Genet. 2001;9:260-6. Both are considered different spectrum of the same disease.³⁸38 Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 201;128:e152-9.

It is characterized by recurrent high fever associated with abdominal pain, diarrhea, nausea, arthritis, arthralgia, headache and dermo-hypodermitis (Chart 2).³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,55 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,3232 Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301-9.^,3939 Mandey SH, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat. 2006;27:796-802.^,4141 Bodar EJ, Drenth JP, van der Meer JW, Simon A. Dysregulation of innate immunity: hereditary periodic fever syndromes. Br J Haematol. 2009;144:279-302. Fever episodes last 3 to 7 days and typically recur every 4 to 6 weeks and can be induced by emotional and physical stress, vaccines, infections and menses.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.^,4242 Simon A, van der Meer JW. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol. 2007;292:R86-98. Clinical manifestations begin usually during the first year of life and the symptoms usually become less pronounced in adulthood.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.

Cutaneous manifestations typically arise as maculopapular or morbilliform rash, or less usually as urticarial rash and erythema nodosum.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.^,4141 Bodar EJ, Drenth JP, van der Meer JW, Simon A. Dysregulation of innate immunity: hereditary periodic fever syndromes. Br J Haematol. 2009;144:279-302.^,4343 Touitou I, Koné-Paut I. Autoinflammatory diseases. Best Pract Res Clin Rheumatol. 2008;22:811-29. In 50% of patients oral or bipolar aphthosis coexist.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,4141 Bodar EJ, Drenth JP, van der Meer JW, Simon A. Dysregulation of innate immunity: hereditary periodic fever syndromes. Br J Haematol. 2009;144:279-302. Small erythematous patches, papules, nodules or plaques clinically similar inflammatory cellulitis, petechiae or purpura may occur, resembling Henoch-Schoenlein purpura, erythema elevatum diutinum or Sweet syndrome.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.^,3737 Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601-18.^,4343 Touitou I, Koné-Paut I. Autoinflammatory diseases. Best Pract Res Clin Rheumatol. 2008;22:811-29. Patients with mevalonic aciduria also exhibit developmental delay, severe mental retardation, ataxia, hypotonia, cerebellar atrophy, dysmorphic facies, myopathy and cataracts.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,2525 Grateau G, Duruöz MT. Autoinflammatory conditions: when to suspect? How to treat? Best Pract Res Clin Rheumatol. 2010;24:401-11.^,4444 Nevyjel M, Pontillo A, Calligaris L, Tommasini A, D'Osualdo A, Waterham HR, et al. Diagnostics and therapeutic insights in a severe case of mevalonate kinase deficiency. Pediatrics. 2007;119:e523-7. Secondary systemic amyloidosis is found in less than 3% of the cases.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.

In laboratory analyses leukocytosis, neutrophilia, increase in acute phase proteins can be found as well as increased polyclonal immunoglobulin D (IgD) and A (IgA).⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,2828 Aróstegui JI. Hereditary systemic autoinflammatory diseases. Reumatol Clin. 2011;7:45-50.^,3232 Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301-9.^,4545 Stankovic K, Grateau G. Auto inflammatory syndromes: Diagnosis and treatment. Joint Bone Spine. 2007;74:544-50. However, as IgD is not always elevated in serum, a normal IgD does not exclude MKD.⁴⁶46 Ammouri W, Cuisset L, Rouaghe S, Rolland MO, Delpech M, Grateau G, et al. Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatology (Oxford). 2007;46:1597-600. The increased urinary excretion of mevalonic acid during crises is the key to diagnosis.

Systemic juvenile idiopathic arthritis (SJIA) and Adult-onset Still's disease (AOSD)

SJIA and AOSD are rare inflammatory diseases, which are distinguished by the age of onset. The first one appears in children under 16 years whereas Still's disease usually appears until 35 years of age. There is growing evidence that these may be considered autoinflammatory diseases, in which the final common pathway is triggered by persistent activation of innate immunity, verifying increased secretion of IL-1β by monocytes.¹⁵15 Dinarello CA. A clinical perspective of IL-1ß as the gatekeeper of inflammation. Eur J Immunol. 2011;41:1203-17.^,2929 Doria A, Dayer JM, Punzi L. Autoinflammatory diseases: how to put the fire inside the body out? Autoimmun Rev. 2012;12:1-4. There is an increase in acute phase proteins and in ferritin levels, with lack of positive autoantibodies or autoantigen specific T cells.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,1515 Dinarello CA. A clinical perspective of IL-1ß as the gatekeeper of inflammation. Eur J Immunol. 2011;41:1203-17.^,3434 Gomes JM, Gomes SM, Conde M. Autoinflammatory syndromes. Acta Reumatol Port. 2010;35:146-54.^,3737 Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601-18.

The classic triad includes daily spiking fevers (≥39°C), juvenile idiopathic arthritis or rheumatoid rash, and polyarthritis.⁴⁸48 Cush JJ. Autoinflammatory syndromes. Dermatol Clin. 2013;31:471-80. The fever and arthritis are followed by a not fixed, evanescent salmon-colored, maculopapular rash, generalized lymphadenopathy, hepatosplenomegaly and polyserositis (Chart 2).¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1414 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74.^,1515 Dinarello CA. A clinical perspective of IL-1ß as the gatekeeper of inflammation. Eur J Immunol. 2011;41:1203-17. Other cutaneous manifestations include urticarial rash and persistent pruritic papules and plaques.¹⁴14 Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, et al. How not to miss autoinflammatory diseases masquerading as urticaria. Allergy. 2012;67:1465-74. Although the neutrophilic urticarial dermatosis may be present in Still's disease with onset in adulthood, in SJIA this has not been identified, despite the clinical description of a characteristic evanescent rash of juvenile idiopathic arthritis mimicking neutrophil urticarial dermatosis.¹⁶16 Kolivras A, Theunis A, Ferster A, Lipsker D, Sass U, Dussart A, et al. Cryopyrinassociated periodic syndrome: an autoinflammatory disease manifested as neutrophilic urticarial dermatosis with additional perieccrine involvement. J Cutan Pathol. 2011;38:202-8. They respond favorably to inhibition of interleukins and steroid use, but there may be increased mortality from medical complications.¹⁵15 Dinarello CA. A clinical perspective of IL-1ß as the gatekeeper of inflammation. Eur J Immunol. 2011;41:1203-17.

NEUTROPHILIC DERMATOSIS

PAPA syndrome

This autosomal dominant hereditary autoinflammatory syndrome is caused by a mutation on the PSTPI1P gene, which encodes CD2BP1 (1-binding protein CD2) also known as PSTPI1P.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,4949 Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501-6.

50 Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-15.^-5151 Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol. 2010;22:567-78. This protein binds to pyrin, the mutated protein in FMF. Both of them are part of the inflammasome NLRP3 on granulocytes and monocytes. The mutated PSTPI1P suffers hyperphosphorylation, increasing the binding affinity to pyrin. This leads to the lost of the inhibitory effect on the inflammasome and on the signaling pathway proinflammatory caspase 1, predisposing to a dependent inflammatory response of IL-1β.⁵⁰50 Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-15.^,5151 Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol. 2010;22:567-78. It usually appears before the age of 5 with recurrent episodes of erosive sterile arthritis, especially of the knees, elbows and ankles, leading to joint destruction.¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.

11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.

12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^-1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,1818 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501.^,2828 Aróstegui JI. Hereditary systemic autoinflammatory diseases. Reumatol Clin. 2011;7:45-50.^,4949 Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501-6. Other less frequent clinical manifestations are recurrent otitis, pharyngeal papillomatosis, lymphadenopathy, splenomegaly, hypergammaglobulinemia, hemolytic anemia and T cell large granular lymphocytosis.⁵²52 Demidowich AP, Freeman AF, Kuhns DB, Aksentijevich I, Gallin JI, Turner ML, et al. Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne). Arthritis Rheum. 2012;64:2022-7.

Cutaneous manifestations are episodic and recurrent, appear at puberty and, contrary to arthritis symptoms, which tends to regress, they persist into adulthood (Chart 3).¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,5050 Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-15. They include nodular cystic acne with scar formation, pyoderma gangrenosum, sterile abscesses at injection sites and pathergy (Figure 2).⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1010 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.

11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^-1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,4949 Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501-6.^,5151 Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol. 2010;22:567-78. There is a localized form, with ulcers on the lower extremities and a multifocal form, with diffuse cutaneous involvement.¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.^,1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57. Histologically, the lesions consist of sterile neutrophilic infiltrate. The choice of treatment depends on the predominant clinical manifestation (Chart 3).

Deficiency of the interleukin-1-receptor antagonist (DIRA)

DIRA is an autosomal recessive, autoinflammatory disease caused by deletion of the IL1RN gene located on chromosome 2 that leads to the complete absence of the interleukin-1-receptor antagonist (IL-1RA) and consequently to the increase of pro-inflammatory cytokines IL-1α and IL-1b.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,99 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12-20.

10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.

11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^-1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,1717 Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141-9. It resembles NOMID: begins in the perinatal period with arthralgia and joint swelling, neutrophilic infiltrate in the dermis and increased acute phase proteins.⁹9 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12-20.^,1717 Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141-9.

It is characterized by plaques with overlying pustules, simulating generalized pustular psoriasis, with neutrophils infiltrating the epidermis.⁹9 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12-20.^,1717 Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141-9. It appears at birth or during the first 2 months of age.¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501. Nail changes are common. Association with pyoderma gangrenosum has been described.¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46. The cutaneous pustulosis affects all children with the disease and ranges from localized to severe diffuse pustulosis or ichthyosiform lesions.¹⁷17 Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141-9. It is also associated with multifocal periostitis and osteomyelitis.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1010 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.

11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^-1212 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.

SAPHO syndrome and Chronic Recurrent Multifocal Osteomyelitis (CRMO)

SAPHO syndrome is characterized by synovitis, acne, pustulosis, hyperostosis and osteitis and CRMO, which affects the long bones, has been considered its pediatric variant (Figure 3).⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,5353 Tlougan BE, Podjasek JO, O'Haver J, Cordova KB, Nguyen XH, Tee R, et al. Chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome with associated neutrophilic dermatoses: a report of seven cases and review of the literature. Pediatr Dermatol. 2009;26:497-505 The characteristic cutaneous manifestations of SAPHO syndrome are severe acne (conglobata and fulminans) and pustulosis palmoplantaris (PPP).¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,5454 Carneiro S, Sampaio-Barros PD. SAPHO syndrome. Rheum Dis Clin North Am. 2013;39:401-18. Severe acne can affect around one-fourth of patients, and PPP 50-75% of patients.⁵⁴54 Carneiro S, Sampaio-Barros PD. SAPHO syndrome. Rheum Dis Clin North Am. 2013;39:401-18. In CRMO, skin manifestations are less common. It manifests as recurrent multifocal sterile inflammatory bone lesions with or without fever, associated with pustulosis, severe acne and psoriasiform lesions (Chart 3).³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,5151 Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol. 2010;22:567-78.^,5555 Walsh P, Manners PJ, Vercoe J, Burgner D, Murray KJ. Chronic recurrent multifocal osteomyelitis in children: nine years' experience at a statewide tertiary paediatric rheumatology referral centre. Rheumatology (Oxford). 2015;54:1688-91.^,5656 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ. A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum. 2007;56:960-4.

Its etiology remains unknown and shares some etiopathogenic mechanisms with other autoinflammatory diseases like Receptor Antagonist Deficiency of IL-1 and Majeed syndrome.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,5151 Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol. 2010;22:567-78. There have been recent hints at a participation of a proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in the pathogenesis of CRMO. Missense mutation (L98P) of Pstpip2 in mice leads to a disease that is phenotypically similar to CRMO. Studies about these conditions have revealed an inflammasome-independent role for IL-1β in disease progression, which provides a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO.⁵⁷57 Cassel SL, Janczy JR, Bing X, Wilson SP, Olivier AK, Otero JE, et al. Inflammasome-independent IL-1b mediates autoinflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci U S A. 2014;111:1072-7. Nevertheless, SAPHO syndrome is associated with high serum levels of proinflammatory cytokines, such as IL-8, IL-18 and TNF-α, and these cytokines can be responsible for the maintenance of the clinical manifestations.⁵⁸58 Hurtado-Nedelec M, Chollet-Martin S, Nicaise-Roland P, Grootenboer-Mignot S, Ruimy R, Meyer O,et al. Characterization of the immune response in the synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology (Oxford). 2008;47:1160-7.

Diagnostic criteria include: two or more typical bone lesions as osteolysis with surrounding sclerosis in conventional radiography, lasting less than six months, typical histological features in bone biopsy and less than 18 years of age at diagnosis.¹³13 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.

Majeed syndrome

Majeed syndrome is a rare, autosomal recessive autoinflammatory disease, associated with a homozygous mutation in LPIN2 gene.³⁴34 Gomes JM, Gomes SM, Conde M. Autoinflammatory syndromes. Acta Reumatol Port. 2010;35:146-54.^,5656 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ. A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum. 2007;56:960-4. Usually it appears before the age of two and is characterized by a triad of chronic multifocal recurring osteomyelitis, congenital dyserythropoietic anemia and neutrophilic dermatosis (Chart 3).¹³13 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,5656 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ. A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum. 2007;56:960-4.

Phenotypically it is more severe than the CRMO: the recurrence rate of bone inflammation is higher, the remissions are less frequent and the disease persists in the adult age.⁵⁶56 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ. A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum. 2007;56:960-4. Congenital dyserythropoietic anemia with hypochromia and microcytosis is present, in contrast to the macrocytic or normocytic anemia that usually characterizes the congenital dyserythropoietic anemia.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,5656 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ. A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum. 2007;56:960-4. Individuals with Majeed syndrome have also growth retardation with short stature.⁵⁹59 Majeed HA, Al-Tarawna M, El-Shanti H, Kamel B, Al-Khalaileh F. The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr. 2001;160:705-10. Cutaneous manifestations include psoriasiform lesions, palmoplantar pustulosis, acne and pyoderma gangrenosum.¹³13 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,5050 Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409-15. Sweet's syndrome with typical neutrophilic infiltrates and pustulosis can be similar to Majeed syndrome.⁵5 Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375-80.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,2626 Tinazzi E, Puccetti A, Patuzzo G, Sorleto M, Barbieri A, Lunardi C. Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: report of two new cases and review of the literature. Autoimmun Rev. 2011;10:404-9.

Sweet's syndrome (SS)

SS was initially described as an acute febrile neutrophilic dermatosis. The pathogenesis of the disease is not fully understood. The association with infections, autoimmune diseases, neoplasms and drugs suggests a hypersensitivity reaction. Cytokines appear to play an etiologic role in the development of lesions and symptoms.⁶⁰60 Bonamigo RR, Razera F, Olm GS. Neutrophilic dermatoses: part I. An Bras Dermatol. 2011;86:11-25. There are no detectable autoantibodies or specific T cells.¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.

Fever is the most common sign. Eye involvement can be the initial presentation. Arthritis or arthralgia occurs in up two-thirds of the patients.⁶⁰60 Bonamigo RR, Razera F, Olm GS. Neutrophilic dermatoses: part I. An Bras Dermatol. 2011;86:11-25. Cutaneous manifestations occur in the form of painful nodules or erythematous cutaneous plaques, which are characterized histologically by neutrophil infiltrate in the upper dermis.¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590. It can also presents as a pustular dermatosis or with ulcerated and bullous lesions.⁶⁰60 Bonamigo RR, Razera F, Olm GS. Neutrophilic dermatoses: part I. An Bras Dermatol. 2011;86:11-25. It arises often associated with hematologic malignancies, rheumatoid arthritis and inflammatory bowel disease (Chart 3). Laboratory findings suggestive of SS include peripheral leukocytosis with neutrophilia and elevated erythrocyte sedimentation rate or C-reactive protein.⁶⁰60 Bonamigo RR, Razera F, Olm GS. Neutrophilic dermatoses: part I. An Bras Dermatol. 2011;86:11-25.

GRANULOMATOUS DERMATITIS

Familial Blau Syndrome and Sporadic Early-onset Sarcoidosis

The Blau Syndrome is a granulomatous, autosomal dominant disease associated with a mutation in the NATCH domain of the NOD2 / CARD15 gene.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,3232 Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301-9. Early-onset sarcoidosis shares the clinical manifestations, but happens as a sporadic condition.¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501. The two disorders were initially described as different clinical entities, however the association of mutations in the NOD2 / CARD15 gene in some patients with early-onset sarcoidosis have led some authors to consider the Blau syndrome as the familiar form of sarcoidosis and early-onset sarcoidosis as the sporadic form of the same disease.⁶¹61 Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L. Blau syndrome, clinical and genetic aspects. Autoimmun Rev. 2012;12:44-51.^,6262 Stoevesandt J, Morbach H, Martin TM, Zierhut M, Girschick H, Hamm H. Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. Pediatr Dermatol. 2010;27:69-73. Different from sarcoidosis, hilar lymph nodes and lungs are not affected.⁷7 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,3737 Kanazawa N, Furukawa F. Autoinflammatory syndromes with a dermatological perspective. J Dermatol. 2007;34:601-18.^,6262 Stoevesandt J, Morbach H, Martin TM, Zierhut M, Girschick H, Hamm H. Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. Pediatr Dermatol. 2010;27:69-73.

The onset is usually before 4 years of age and is characterized by the triad of early-onset of polyarticular synovitis, skin rash and eye involvement with recurrent anterior uveitis.¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,3232 Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301-9.^,4141 Bodar EJ, Drenth JP, van der Meer JW, Simon A. Dysregulation of innate immunity: hereditary periodic fever syndromes. Br J Haematol. 2009;144:279-302.^,6161 Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L. Blau syndrome, clinical and genetic aspects. Autoimmun Rev. 2012;12:44-51.^,6262 Stoevesandt J, Morbach H, Martin TM, Zierhut M, Girschick H, Hamm H. Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. Pediatr Dermatol. 2010;27:69-73. Skin manifestations are usually the first symptom of the disease and appear as maculopapular rash or multiple subcutaneous nodules, with symmetrical presentation located mainly on the trunk and extremities.²⁷27 Fonnesu C, Cerquaglia C, Giovinale M, Curigliano V, Verrecchia E, de Socio G, et al. Familial Mediterranean Fever: a review for clinical management. Joint Bone Spine. 2009;76:227-33.^,4141 Bodar EJ, Drenth JP, van der Meer JW, Simon A. Dysregulation of innate immunity: hereditary periodic fever syndromes. Br J Haematol. 2009;144:279-302.^,4545 Stankovic K, Grateau G. Auto inflammatory syndromes: Diagnosis and treatment. Joint Bone Spine. 2007;74:544-50.^,6161 Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L. Blau syndrome, clinical and genetic aspects. Autoimmun Rev. 2012;12:44-51. The papules, small and with variable color (from yellow to brownish red), typically are grouped and may converge. The papular rash occurs intermittently and can resolve spontaneously leaving a scar.⁶¹61 Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L. Blau syndrome, clinical and genetic aspects. Autoimmun Rev. 2012;12:44-51.^,6262 Stoevesandt J, Morbach H, Martin TM, Zierhut M, Girschick H, Hamm H. Sporadic Blau syndrome with onset of widespread granulomatous dermatitis in the newborn period. Pediatr Dermatol. 2010;27:69-73. Other cutaneous findings described are panniculitis resembling erythema nodosum and leukocytoclastic vasculitis.⁶³63 Rosé CD, Aróstegui JI, Martin TM, Espada G, Scalzi L, Yagüe J, et al. NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain. Arthritis Rheum. 2009;60:1797-803. Systemic impairment may still occur (Chart 4).

BIPOLAR APHTHOSIS

Behçet's disease

Behçet's disease is a recurring systemic inflammatory disease, with unknown etiology characterized by the triad: oral aphthous ulcers, genital ulcers and uveitis (Chart 5). The disease usually appears in the third decade of life and affects both genders equally. The most serious manifestations tend to occur more often in men, particularly amaurosis, large vessel vasculitis, cerebrovascular, lung and gastrointestinal impairment.⁶⁴64 Yazici H, Ugurlu S, Seyahi E. Behçet syndrome: is it one condition? Clin Rev Allergy Immunol. 2012;43:275-80. The disease progresses during exacerbation and remission periods.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,6464 Yazici H, Ugurlu S, Seyahi E. Behçet syndrome: is it one condition? Clin Rev Allergy Immunol. 2012;43:275-80.

Bipolar aphthosis with oral aphthous ulcers and genital lesions are the major symptoms of the disease (Figure 4).¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46.^,6464 Yazici H, Ugurlu S, Seyahi E. Behçet syndrome: is it one condition? Clin Rev Allergy Immunol. 2012;43:275-80. In adults, the classification criteria include the presence of recurrent oral ulcers, associated with at least one of the following symptoms: recurrent genital ulcers, uveitis with ocular and cutaneous impairment or positive pathergy tests.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,6565 van Daele PL, Kappen JH, van Hagen PM, van Laar JA. Managing Behçet's disease: An update on current and emerging treatment options. Ther Clin Risk Manag. 2009;5:385-90. Other cutaneous manifestations include pseudofolliculitis, papulopustular lesions, similar to acneiform nodules and erythema nodosum lesions. Systemic involvement (Chart 5) is characterized by vasculitic lesions associated with tissue infiltration by neutrophils and T lymphocytes.¹⁰10 Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590.

Periodic fever Aphthous pharyngitis and cervical adenopathy (PFAPA)

This is a chronic disease of unknown etiology, characterized by recurrent episodes of high fever accompanied by pharyngitis, cervical lymphadenopathy and aphthous stomatitis (Chart 5).³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,6666 Berkun Y, Levy R, Hurwitz A, Meir-Harel M, Lidar M, Livneh A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum. 2011;40:467-72. Other symptoms include: headache, abdominal pain, nausea, vomiting, myalgia, arthritis, arthralgia, splenomegaly (Chart 5).¹³13 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57.^,6666 Berkun Y, Levy R, Hurwitz A, Meir-Harel M, Lidar M, Livneh A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum. 2011;40:467-72. During fever periods, leukocytosis and increased acute phase proteins may occur.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57. A slight increase of IgM, IgD and IgA can be noticed. PFAPA usually appears before the age of five as the most common cause of periodic fever in childhood.²⁹29 Doria A, Dayer JM, Punzi L. Autoinflammatory diseases: how to put the fire inside the body out? Autoimmun Rev. 2012;12:1-4. However, it is not an exclusive disease of childhood. The episodes recur every four to six weeks with complete resolution of symptoms between attacks.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,3232 Lachmann HJ. Clinical immunology review series: An approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301-9.^,6666 Berkun Y, Levy R, Hurwitz A, Meir-Harel M, Lidar M, Livneh A, et al. The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. Semin Arthritis Rheum. 2011;40:467-72.

Pharyngitis is the most common symptom associated with fever and presents itself like an erythematous or exudative form, self-limited and with negative cultures. The aphthous stomatitis is characterized by small lesions, not keratinized, mainly located in the labial gingiva, is self-limited and appears a few days prior to the fever.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,1313 De Sanctis S, Nozzi M, Del Torto M, Scardapane A, Gaspari S, de Michele G, et al. Autoinflammatory syndromes: diagnosis and management. Ital J Pediatr. 2010;36:57. Occur in 40-70% of PFAPA patients.¹⁸18 Dávila-Seijo P, Hernández-Martín A, Torrelo A. Autoinflammatory syndromes for the dermatologist. Clin Dermatol. 2014;32:488-501. These lesions may have bipolar distribution with oral and genital involvement. Less commonly, it may present as erythema predominantly on the trunk and palmoplantar macules or purpura.¹²12 Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232-46. The disease usually has a benign evolution and resolves spontaneously in a high proportion of patients.¹¹11 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602.^,2929 Doria A, Dayer JM, Punzi L. Autoinflammatory diseases: how to put the fire inside the body out? Autoimmun Rev. 2012;12:1-4.

The diagnosis is clinical and involves at least one of the three symptoms: aphthous stomatitis, pharyngitis and cervical lymphadenopathy.³3 Ozen S, Frenkel J, Ruperto N, Gattorno M; Eurofever Project. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445-52.^,77 Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348-56.^,1111 Federici S, Caorsi R, Gattorno M. The autoinflammatory diseases. Swiss Med Wkly. 2012;142:w13602. The diagnostic exclusion criteria include the presence of upper respiratory tract infection, cyclic neutropenia, primary immunodeficiency and hereditary autoinflammatory disease.^7s

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