GENETICALLY DEFINED AUTOINFLAMMATORY DISEASES

Abstract

Autoinflammatory diseases are hyperinflammatory, immune-dysregulatory conditions that typically present in early childhood with fever and rashes and disease-specific patterns of organ inflammation. This review provides a historic background of autoinflammatory disease research, an overview of the currently genetically defined autoinflammatory diseases, and insights into treatment strategies derived from understanding of the disease pathogenesis. The integrative assessment of autoinflammatory conditions led to the identification of innate pro-inflammatory cytokine “amplification loops” as the cause of the systemic and organ-specific disease manifestations, which initially centered around increased IL-1 production and signaling. More recently additional innate proinflammatory cytokine amplification loops resulting in increased Type I IFN, IL-17, IL-18 or IL-36 signaling or production have led to the successful use of targeted therapies in some of these conditions. Clinical findings such as fever patterns, type of skin lesions, genetic mutation testing, and the prevalent cytokine abnormalities can be used to group autoinflammatory diseases.

Introduction

History

The concept of “autoinflammatory diseases” was introduced by Dr. Daniel Kastner after the discoveries of the genetic causes of the most prevalent periodic fever syndrome worldwide, familial Mediterranean fever (FMF), in 1997, and of the TNF receptor associated periodic syndrome (TRAPS) in 1999 (Consortium, 1997a, Consortium, 1997b, McDermott et al., 1999). This concept aimed to distinguish autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) that were thought to be caused by adaptive immune dysregulation, from the two hereditary fever syndromes, FMF and TRAPS that lack features of adaptive immune dysregulation such as high-titer autoantibodies and auto-reactive lymphocytes in affected tissues.

In 2000/2001, the discovery that gain-of-function (GOF) mutations in the first recognized human intracellular sensor of microbial danger signals, NLRP3, causes the disease spectrum of cryopyrin associated autoinflammatory syndromes (CAPS), led to a paradigm shift in thinking about autoinflammatory disease (Hoffman et al., 2001). Upon activation, NLRP3 sensors nucleate an IL-1 activating platform, the inflammasome, a discovery that provided the molecular link between innate immune sensing and the production of the pro-inflammatory cytokine IL-1 (Broderick et al., 2015, Martinon et al., 2002) and led to the use of IL-1 inhibiting therapies that changed many patients’ lives. The periodic fever syndromes, the cryopyrinopathies (CAPS) and the deficiency of interleukin-1 receptor antagonist syndrome (DIRA) are “prototypic” autoinflammatory diseases that illustrate a key role of IL-1 in autoinflammation. Early proof of concept studies with the IL-1 blocking agent anakinra (Kineret®) in patients with cryopyrinopathies/CAPS showed impressive clinical responses, and led to the FDA approval of three IL-1 blocking agents for the treatment of CAPS (rilonacept (Arcalyst, canakinumab (Ilaris®), and anakinra (Kineret®) (Jesus and Goldbach-Mansky, 2014). More recently mutations in pathways that affect Type I IFN production, and IL-18 and IL-36 signaling have led to the recognition of other proinflammatory cytokine amplification loops in causing autoinflammatory disease phenotypes.

The genetic “mutations” leading to autoinflammatory phenotypes affect components of the innate immune responses as depicted in Figure 1 (de Jesus et al., 2015)

Figure 1. Principles of immune dysregulation in Autoinflammatory Diseases.

The innate immune system relies on danger recognition by germ line-encoded pattern recognition receptors (PRRs) such as membrane bound receptors (i.e. TLRs), and intracellular sensors (NLRs and RLRs). Genes that are mutated and lead to autoinflammatory phenotypes contribute to the innate immune dysregulation in specific ways as outlined below. (see accompanying text)

1. Gain-of function (GOF) mutations in genes encoding pattern recognition receptors (PRRs) referred to as “sensors” that recognize microbial or intracellular danger signals, or mutations in their adaptors lead to increased production of inflammatory mediators. GOF-mutations in the intracellular sensors (component 1, Figure 1): NLRP3, MEFV and NLRC4 that are linked to increased IL-1 production or in the viral RIG-Like receptors/sensors (RLR), IFIH1/MDA5 and DDX58/RIG-I, or the adaptor molecule, TMEM173/STING that are linked to increased Type I IFN production cause autoinflammatory diseases.

2. Loss-of-function (LOF) mutations in molecules that control cellular pathways result in cell maladaptation and stress (component 2, Figure 1) that cause autoinflammatory phenotypes. LOF mutations in enzymes or molecules that affect protein homeostasis (i.e. protein misfolding, endoplasmic reticulum transport, protein degradation and clearance); mitochondrial function and oxidative stress production; the cell migration; intracellular trafficking; autophagy; cell differentiation; and nucleotide metabolism/degradation cause autoinflammatory diseases.

3. LOF mutations resulting in loss of negative regulators of an immune response can also lead to autoinflammatory phenotypes (component 3, Figure 1).

4. Increased signaling through receptors that control innate immune cell function lead to hyper-responsiveness to immune signals (component 4, Figure 1). As the signaling abnormalities affect innate and adaptive immune cells, patients with these latter mutations often present with overlapping clinical features of autoinflammation, mild immunodeficiencies, and/or autoimmunity (McGonagle et al., 2009).

Clinical classification of autoinflammatory diseases

Although the genetic analyses provide the ultimate diagnosis of the monogenic diseases described below, it can take weeks to months to obtain the genetic results. However, a number of clinical characteristics distinguish the different autoinflammatory diseases and can be used to group them based on the fever pattern, skin rashes and the inflammatory organ manifestations and can provide early clues to the underlying cytokine dysregulation. Table 1 is an expansion of a previously proposed grouping now including additional novel diseases (Almeida de Jesus and Goldbach-Mansky, 2013).

Table 1.

Clinical Features of Mendelian Autoinflammatory Diseases

Clinical and laboratory findings
Cytokine Mediator		Gene affected/Inheritance	Systemic inflammation	Mucocutaneous	Musculoskeletal	Gastrointestinal	Liver, spleen and lymph nodes	Other/Specific features
IL-1 mediated autoinflammatory diseases
IL-1β	1. The classic hereditary “periodic fever syndromes”
	FMF	MEFV/AR or AD	Fever, increased inflammatory markers	Erysipellas-like erythema (FMF and TRAPS); maculopapular or purpuric exanthema (HIDS); recurrent oral ulcers may occur (HIDS)	Large joints episodic arthritis (FMF); arthralgia, non-erosive acute polyarthritis (HIDS and TRAPS); migratory myalgia (TRAPS)	Abdominal pain, diarrhea, constipation (FMF, HIDS, TRAPS); acute peritonitis (FMF and TRAPS); vomiting (HIDS)	Hepatosplenomegaly and painful cervical adenopathy (HIDS)	Pleuritis, pericarditis, epididymitis (FMF and TRAPS); periorbital edema, conjunctivitis (TRAPS); recurrent or severe infections (HIDS)
	HIDS	MVK/AR
	TRAPS	TNFRSF1A/AD
	2. The neutrophilic urticaria of the cryopyrin associated periodic syndromes (CAPS)
	FCAS	NLRP3/AD	Fever, increased inflammatory markers	Neutrophilic urticaria (NOMID, MWS, FCAS); recurrent oral ulcers (MWS)	Myalgia, arthralgia, oligoarticular arthritis (FCAS and MWS); epiphyseal and patella enlargement, periostitis, chronic arthropathy (NOMID)	Abdominal pain (NOMID and MWS)	Occasional lymphadenopathy (NOMID and MWS); hepatomegaly during disease exacerbations (NOMID)	Headache, conjunctivitis (FCAS, MWS, NOMID); sensorineural hearing loss, episcleritis, optic disk edema (MWS and NOMID); delayed mental development, chronic aseptic meningitis, progressive amurosis (NOMID)
	MWS
	NOMID/CINCA
	3a. Pustular skin dermatoses, IL-1-mediated
	DIRA	IL1RN/AR	Occasional fever, increased inflammatory markers	Pustular dermatitis	Recurrent multifocal aseptic osteomyelitis	Uncommon	Uncommon	Deformity of clavicles and ribs, absence of odontoid process, venous thrombosis, CNS vasculitis (DIRA); dyserythropoietic anemia (Majeed)
	Majeed	LPIN2/AR
	3b. Pustular skin dermatoses, partially IL-1 mediated
	PAPA	PSTPIP1/AD	Occasional fever, increased inflammatory markers	Pyoderma gangrenosum, severe acne	Deforming aseptic pyogenic arthritis	Uncommon	Uncommon	Aseptic pyogenic arthritis responsive to IL-1 inhibition; skin disease partially responsive to TNF-α inhibition
	HA20	TNFAIP3/AD	Fever, increased inflammatory markers	Folliculitis, pathergy, frequent episodes of oral and genital ulcers	Non-deforming polyarthritis	Colitis	Not reported	Anterior uveitis, retinal vasculitis, CNS vasculitis,
	3c. Pustular skin dermatoses, non- IL-1 mediated
IL-36	DITRA	IL36RN/AR	Fever, increased inflammatory markers	Generalized pustular psoriasis; oral mucosa pustulas may occur	Uncommon	Uncommon	Uncommon	Fever of elevated temperature, secondary skin infections
IL-17/IL23	CAMPS	CARD14/AD	Fever with skin secondary infections	Plaque or pustular psoriasis	Arthritis	Uncommon	Uncommon	Rare systemic manifestations
Lack of IL-10	EO-IBD	IL10RA/AR	Fever, increased inflammatory markers	Folliculitis; oral aphtous lesions	Arthritis	Severe colitis with bloody diarrhea, abscesses, perianal fistula	Occasional lymphadenopathy	Recurrent infections
		IL10RB/AR
		IL10/AR
IL-18/IL-1 mediated Diseases
	4. Diseases with the propensity to develop macrophage activation syndrome
IL-18/IL-1/(late in disease IFNγ)	NLRC4-MAS	NLRC4/AD	Fever, increased inflammatory markers	Rare dermographism, urticarial rash	Arthralgia	Early-onset non-specific enterocolitis with variable severity	Hepatosplenomegaly and occasional lymphadenopathy	Coagulopathy, pancytopenia, hyperferritinemia, hypertriglyceridemia
Type-I IFN mediated autoinflammatory diseases
	5a. Vasculopathy and panniculitis
Type I interferon	CANDLE/PRAAS	PSMB8, PSMA3, PSMB4, PSMB9/AR or digenic, POMP/AD	Fever, increased inflammatory markers	Nodular exanthema, panniculitis, lipodystrophy	Myositis, arthralgia, arthritis, joint contractures	Increased intra-abdominal fat	Hepatosplenomegaly	Basal ganglion calcifications, dyslipidemia, pancreatic abnormalities, microcytic anemia, cytopenias, eyelids edema and erythema
	5b. Vasculitis/vasculopathy and/or livedo reticularis
	SAVI	TMEM173/AD	Fever, increased inflammatory markers	Erythemato-purpuric lesions, ishemic ulcerative skin disease, necrosis of extremities, loss of tissue. Recurrent oral ulcers may occur	Arthralgia, myositis	Uncommon	Occasional lymphadenopathy	Interstitial lung disease, lung fibrosis, emphysema, paratracheal adenopathy; basal ganglia calcifications (rare); typical involvement of cheeks, ear lobes and tip of nose; flares triggered by cold; nasal septum, perforation; anemia; lymphopenia; hypergammaglobulinemia
	TREX1-associated AGS (AGS1)	TREX1/AR or AD	Occasional fever	Chilblain lesions, livedo reticularis	Uncommon	Uncommon	Hepatosplenomegaly (rare)	Basal ganglia calfications, variable degrees of white matter abnormalities and cerebral atrophy.
	TREX1-associated Familial Chilblain Lupus (FCL), or TREX1-associated SLE	TREX1/AD	Occasional fever, increased inflammatory markers	Chilblain lesions, livedo reticularis, malar rash, photosensitivity, oral and nasal ulcers, livedo reticularis	Arthralgia, acute and chronic (rare) arthritis	Uncommon	Uncommon (FCL), or hepatosplenomegaly and lymphadenopathy	Cold-induced, bluish-red lesions on the hands, feet and ears that may ulcerate and result in tissue loss (FCL). About 0.5% of SLE patients have TREX1 mutations and fulfill ACR classification criteria for SLE; their clinical manifestations do not differ from non-monogenic SLE.
	TREX1-mediated retinal vasculopathy with cerebral leukodystrophy (RVCL)	TREX1/AD (caused by specific C-terminal frameshift mutations)	Not reported	Not reported	Not reported	Not reported	Not reported	Adult-onset; retinal vasculopathy leading to blindness in middle age; cerebral white matter and mass lesions.
	AGS2, AGS3, AGS4	RNASEH2B, RNASEH2C, RNASEH2A/AR	Occasional fever	Chilblain lesions, livedo reticularis	Uncommon	Uncommon	Hepatosplenomegaly (rare, in AGS3 and AGS4)	AGS3 and AGS4 have an earlier disease onset and higher mortality than AGS2
	SAMHD1-associated AGS (AGS5)	SAMHD1/AR	Occasional fever	Chilblain lesions, livedo reticularis, peripheral calcinosis (rare), partial lipodystrophy	Arthritis, joint contractures	Uncommon	Uncommon	Cerebral vasculopathy, early-onset stroke, basal ganglion calcifications; glaucoma, cataract, cortical blindness
	ADAR-associated AGS (AGS6)	ADAR/AR or AD	Occasional fever	Chilblain lesions, livedo reticularis	Uncommon	Uncommon	Hepatosplenomegaly (rare)	Later onset, lower morbidity and mortality, variable CNS manifestations
	IFIH1-assocated AGS (AGS7)	IFIH1/AD	Occasional fever	Chilblain lesions, livedo reticularis	Arthritis (rare)	Uncommon	Hepatosplenomegaly (rare)	Variable severity of CNS disease; thrombocytopenia; asymptomatic carriers reported
	IFIH1 (MDA5)- associated Singleton- Merten disease	IFIH1/AD	Not reported	Delayed primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, severe root and alveolar bone resorption associated with dysregulated mineralization, and tooth loss; psoriasiform skin lesions (only in IFIH-SMS) Not reported in DDX58-SMS.	Arthritis, joint contractures, calcific tendinitis, erosive changes in the terminal tufts of the distal phalanges; hypotonia; osteoporosis	Not reported	Not reported	Aortic and valvular calcification; glaucoma
	DDX58 (RIG-I)-associated Singleton-Merten disease	DDX58/AD
	SPENCDI	ACP5/AR	Uncommon	Uncommon	Radiolucent and irregular spondylar and metaphyseal lesions representing islands of chondroid tissue within bone	Colitis	Uncommon	Sinopulmonary infections, opportunistic viral infections, ITP, thyroiditis, spasticity, developmental delay, late-onset cerebral calcifications
IFN +?	DADA2	CECR1/AR	Fever, increased inflammatory markers	Livedo reticularis, purpuric lesions and ischemic an necrotic skin disease	Myalgia, arthralgia	Abdominal pain, diarrhea, ascites (rare)	Hepatosplenomegaly and occasional lymphadenopathy	Ischemic or hemorrhagic stroke, testicular pain, portal hypertension, lymphopenia, low IgM, recurrent infections, amaurosis
Other
	6. Granulomatous skin diseases
IL-1+ other	PGA/Blau	NOD2 (CARD15)/AD	Rare fever, increased inflammatory markers	Ichthyosis-like exanthema	Polyarthritis, hypertrophic tenosynovitis	Uncommon	Hepatospleneomegaly and lymphadenopathy may be observed	Chronic uveitis, cataract, glaucoma, amaurosis; interstitial lung disease (rare); transient neuropathy; parotitis; pericarditis; arterial hypertension
IL-1+ other	PLAID	PLCG2/AD	Variable, fever due to infections	Cold-induced urticaria and/or granulomatous skin rash	Uncommon	Uncommon	Uncommon	Positive autoantibodies and autoimmune manifestations, recurrent and/or severe infections, allergic disease
	APLAID			Erythematous plaques and vesicopustular lesions, cellulitis	Arthralgia	Abdominal pain and bloody diarrhea	Uncommon	Interstitial lung disease; corneal erosions, ulcerations, intraocular hypertension, cataracts; mild immunodeficiency
	7. Miscellaneous
?	Cherubism	SH3BP2/AD	No fever reported	Dental impact includes disruption of primary or secondary dentition, absent teeth, rudimentary development of teeth, abnormally shaped teeth, delayed or ectopically erupting teeth.	Multilocular radioluscent expansive lesions of mandible and maxila. Involvement of zygomatic arches, condyles and ribs are rarely observed.	Not reported	Enlarged submandibular and cervical lymph nodes	Fibro-osseous tissue extension into the orbital walls with displacement of the globe and retraction of eyelids and invasion of retrobulbar spaces of the orbits causing displacement of optic nerves and proptosis may occur in more severe forms. Upper airway obstruction due to tongue displacement or obliteration of the nasal airway may rarely occur.
?	Monogenic sJIA	LACC1/AR	Characteristic quotidian fever and increased inflammatory markers	Erythematous maculopapular rash	Chronic polyarthritis	Not reported	Hepatosplenomegaly and lymphadenopathy was observed in the minority of the patients.	Patients reported fulfilled classification criteria for systemic JIA
?	SIFD	TRNT1/AR	Recurrent fever and increased inflammatory markers	Icthyotic skin lesions in one patient	Not reported	Colitis	Splenomegaly	Congenital sideroblastic anemia, developmental delay, cardiomyopathy, B-cell immunodeficiency, sensorineural hearing loss, seizures, ataxia, cerebral atrophy, retinitis pigmentosa, aminoaciduria

Abbreviations used: FMF- familial Mediterranean fever; HIDS- hyperimmunoglobulinemia D with periodic fever syndrome; TRAPS- TNF receptor-associated periodic syndrome; FCAS- familial cold autoinflammatory syndrome; MWS- Muckle-Wells syndrome; NOMID- neonatal-onset mutlisystem inflammatory disease; CINCA- chronic infantile neurological cutaneous and articular syndrome; DIRA- deficiency of interleukin-1 receptor antagonist; PAPA- pyogenic arthritis, pyoderma gangrenosum and acne syndrome; HA20- haploinsufficiency of A20; DITRA- deficiency of IL-36 receptor antagonist; CAMPS- CARD14-mediated psoriasis; EO-IBD- early-onset inflammatory bowel disease; CANDLE- chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; PRAAS- proteasome-associated autoinflammatory syndrome; SAVI- STING-associated vasculopathy with onset in infancy; AGS- Aicardi-Goutières syndrome; SLE- systemic lupus erythematosus; SPENCDI- spondyloenchondrodysplasia with immune dysregulation; DADA2- deficiency of adenosine deaminase 2; MAS- macrophage activation syndrome; PGA- pediatric granulomatous arthritis; PLAID- PLCG2-associated antibody deficiency and immune dysregulation; APLAID- PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation; sJIA- systemic juvenile idiopathic arthritis; SIFD- Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; AR- autosomal recessive; AD- autosomal dominant; CNS- central nervous system; ACR- American College of Rheumatology; ITP- immune thrombocytopenic purpura; AIHA- autoimmune hemolytic anemia.

IL-1 mediated diseases (Figure 2A)

Figure 2.

Figure 2A and B. IL-1 mediated (2A) and IFN Type I (2B) mediated autoinflammatory diseases and their genetic causes. A and B. IL-1 or Type I IFN mediated diseases caused by GOF mutations in sensors are highlighted in yellow and LOF mutations in cellular/metabolic pathways that result in stress are highlighted in green. The diseases caused by LOF mutation in a negative regulator are highlighted in red.

Abbreviations used: IL-1 mediated diseases: CAPS- cryopyrin associated periodic syndrome (FCAS- familial cold autoinflammatory syndrome, MWS- Muckle-Wells syndrome, NOMID- neonatal-onset multisystem inflammatory disease); FMF- familial Mediterranean fever; DIRA- deficiency of interleukin-1 receptor antagonist; NLRC4-MAS (macrophage activation syndrome) (also IL-18 mediated) or SCAN- syndrome of enterocolitis and autoinflammation associated with mutation in NLRC4; HIDS- hyperimmunoglobulinemia D and periodic fever syndrome; TRAPS-,TNF receptor associated periodic syndrome

Type I IFN mediated: SMS- Singleton-Merten syndrome; SAVI- STING-associated vasculopathy with onset in infancy; CANDLE- chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/PRAAS- proteasome-associated autoinflammatory syndrome; AGS- Aicardi-Goutières syndrome 1–7; SPENCDI- spondyloenchondrodysplasia with immune dysregulation

1. The classic “periodic fever syndromes” and 2. The cryopyrin associated periodic syndromes

Among the periodic fever syndromes, Familial Mediterranean fever (FMF) and Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) present with recurrent fever attacks of short duration of 3–4 days in FMF, and 3–7 days in HIDS, that recur every 4 to 6 weeks (Simon and van der Meer, 2007, Drenth et al., 1994). The fever attacks in TNF receptor associated periodic syndrome (TRAPS) are longer, lasting a week up to several weeks. FMF is the most prevalent monogenic autoinflammatory disease with more than 100,000 affected persons worldwide. It is caused by autosomal recessive, mostly missense mutations in the MEFV gene which encodes an IL-1 forming inflammasome (Consortium, 1997a, Consortium, 1997b) however autosomal dominant forms of FMF are also recognized. The prevalence of FMF is high in eastern Mediterranean populations including Sephardic Jews, Armenian, Turkish and Arabian descendants (Onen, 2006, Chae et al., 2009), hence the name “Mediterranean Fever”. HIDS is caused by recessive loss-of-function (LOF) mutations in MVK gene (Houten et al., 1999) and TRAPS by LOF mutations in the TNFRSF1A gene, which encodes the p55 TNF receptor (McDermott et al., 1999).

The 3 cryopyrinopathies or cryopyrin-associated periodic syndromes (CAPS): Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and Neonatal-onset multisystem inflammatory disease (NOMID) also called chronic infantile, neurological, cutaneous and articular (CINCA) syndrome (Aksentijevich et al., 2002) comprise a clinical disease continuum and were the first disease group to be treated with IL-1 blocking therapies. CAPS is caused by autosomal dominant gain-of-function (GOF) mutations in NLRP3/CIAS1 (Hoffman et al., 2001). While the milder diseases, FCAS and MWS are mostly familial, most severe cases of NOMID are sporadic. Of patients with “clinical NOMID”, over 70% of patients who are “mutation-negative” by Sanger sequencing have somatic mosaicism (Tanaka et al., 2011, Saito et al., 2005).

Most patients develop disease in childhood but adult onset is seen in FMF and TRAPS. Disease flares present with fever, and elevation of acute phase reactants that correlate with disease activity. In FMF the disease flares are associated with sterile peritonitis presenting as acute abdominal pain and with large joint arthritis. More variable symptoms include myalgia and other forms of serositis including pleuritis and pericarditis. The most common cutaneous manifestation in FMF is erysipelas-like erythema, which is only present in 7 to 40% of patients in various cohorts; the rash is frequently misdiagnosed as cellulitis (Fonnesu et al., 2009). In contrast HIDS patients present with tender, cervical lymphadenopathy (Bader-Meunier et al., 2011), abdominal pain and diarrhea, vomiting, polyarthralgia and non-erosive large joint arthritis. Skin lesions including papular, urticarial, nodular or purpuric rashes (Bader-Meunier et al., 2011) while serositis, myalgia, and oral and genital ulcers are rarely observed. HIDS flares can be triggered by immunizations, trauma, surgery or stress and are characterized by high-grade fever with chills (Drenth et al., 1994). In most instances, HIDS has a benign evolution (van der Hilst et al., 2008). TRAPS fever attacks present with abdominal pain that similar to FMF can mimic an acute abdomen, and migratory pain that is associated with an overlying tender erythematous macular, edematous or urticarial skin rash that is caused by an underlying monocytic fasciitis (Hull et al., 2002b). Half of TRAPS patients have ocular manifestations (periorbital edema, recurrent conjunctivitis or anterior uveitis). Arthritis and pleuritis are seen in 30–50% of the patients. Neurological manifestations are rare.

The classic presentation in the CAPS spectrum includes fever and neutrophilic urticaria, conjunctivitis, arthralgia, and a marked increase of acute phase reactants during disease activity. The inflammatory attacks in FCAS are cold induced and subside within several hours, while in MWS and NOMID, low-grade inflammation and fever are continuous in between disease exacerbations (Hoffman et al., 2004). During disease flares, patients may complain of headaches, MWS patients develop sensorineural hearing loss in the 2–3^rd decade and NOMID patients in the 1^st decade of their lives. Severe neurological involvement is a diagnostic feature of NOMID and includes chronic aseptic neutrophilic meningitis with increased intracranial pressures (Neven et al., 2008, Goldbach-Mansky et al., 2006). Untreated, organ damage develops starting in childhood (Sibley et al., 2012) including sensorineural hearing loss (Hawkins et al., 2004), hydrocephalus, brain atrophy, and optic nerve atrophy with progressive vision loss (Goldbach-Mansky et al., 2006). Many NOMID patients present with a deforming arthropathy.

Abnormal laboratory findings of the IL-1 mediated autoinflammatory diseases include marked leukocytosis with neutrophilia and thrombocytosis, and increased acute phase reactants, (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)). Chronic anemia develops in patients with persistent inflammation, and secondary amyloidosis occurs in up to 13% of Turkish patients with FMF (Tunca et al., 2005), in up to 64% of TRAPS patients (McDermott et al., 1999) with mutations in cysteine residues (Hull et al., 2002a), and in 25 to 33% of untreated MWS patients living in Europe (Aganna et al., 2002) who are not appropriately treated. It is rarely observed in HIDS.

IL-1 inhibition is standard treatment for patients with CAPS (Jesus and Goldbach-Mansky, 2014, Levy et al., 2015) and needs to be initiated early to prevent the development and progression of organ damage (Sibley et al., 2012). Colchicine remains the treatment of choice for FMF, but is ineffective in HIDS and TRAPS. However, the empiric use of IL-1 blocking agents in the treatment of the 3 classic periodic fever syndromes (FMF, HIDS, TRAPS) (Jacobelli et al., 2007), and a subset of conditions presenting with pustular dermatosis and aseptic osteomyelitis (DIRA and Majeed) see below, confirmed an important role of IL-1 in these diseases. Patients typically experience dramatic improvement of inflammatory symptoms, fever, skin rash, and acute phase reactants (Goldbach-Mansky et al., 2006), however some differences in CNS penetration of the drugs exist (Sibley et al., 2014).

3. Syndromes presenting with pustular skin rashes and episodic or continuous fever episodes

These conditions comprise a pathogenically heterogeneous group.

3a. IL-1 mediated

Deficiency of interleukin 1 receptor antagonist (DIRA) is caused by autosomal recessive LOF mutations in the IL1RN gene, which encodes the IL-1 receptor antagonist (IL-1Ra) (Aksentijevich et al., 2009, Reddy et al., 2009) and Majeed syndrome by autosomal recessive LOF mutations in LPIN2 gene, which encodes a phosphatase that catalyzes the conversion of phosphatidic acid to diacylglycerol in the endoplasmic reticulum membrane (Ferguson et al., 2005). DIRA patients present with pustular dermatitis in isolated crops or generalized with multifocal periosteitis and osteomyelitis resulting in vertebral block formation, and marked elevations of acute phase reactants. Other features include onychomadesis, widened ribs and clavicles (Aksentijevich et al., 2009, Reddy et al., 2009). A potential complication includes atlantoaxial subluxation due to odontoid destruction. Majeed syndrome presents with neonatal-onset recurrent osteitis and multifocal osteomyelitis, and congenital dyserythropoietic anemia. Skin involvement is more variable (El-Shanti and Ferguson, 2007). Both conditions rapidly and completely resolve on IL-1 inhibition (Aksentijevich et al., 2009, Reddy et al., 2009)^,(Herlin et al., 2012).

3b. Partially IL-1 mediated

Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is caused by autosomal dominant mutations in PSTPIP1 gene (Wise et al., 2002) and presents with painful cutaneous ulcers (pyoderma gangrenosum) and a sterile pyogenic arthritis. Cystic acne and pathergic pustules or skin abscesses can develop at trauma or needle injection site (Wise et al., 2002). Fever is rarely present. HA20 is caused by autosomal dominant LOF mutations in TNFAIP3, which causes haploinsufficiency in the NF-κB regulatory protein A20 leading to prolonged signaling after TNF stimulation. Patients present with oral and genital ulcers between infancy and adolescence. Other disease manifestations include folliculitis, pathergy, polyarthritis, anterior uveitis, fever, colitis, circulating autoantibodies, such as ANA, lupus anticoagulant, anti-dsDNA and anti-RNP are seen.

Laboratory findings include leukocytosis and increased ESR and CRP during flares (Wise et al., 2002). Treatment of PAPA and HA20 is challenging and optimal therapies have not been developed (Demidowich et al., 2012). Anti-TNF antibodies (infliximab and adalimumab) are often necessary to treat skin manifestations of PAPA syndrome (Demidowich et al., 2012). The joint manifestations respond to IL-1 inhibition. Treatment of HA20 includes colchicine, anti-TNF agents and anti-IL-1 therapy in a patient refractory to anti-TNF (Zhou et al., 2015).

3c. Not IL-1 mediated

Deficiency of interleukin-36 receptor antagonist (DITRA) is caused by homozygous LOF mutations in IL36RN, encoding the IL-36 receptor antagonist (Marrakchi et al., 2011). Most patients develop a generalized erythematous and pustular skin rash, associated with fever up to 40–42°C during childhood that are often triggered by viral or bacterial infections (Marrakchi et al., 2011). Increased CRP and white blood cell count are seen (Marrakchi et al., 2011) and secondary skin infections and sepsis are complications (Marrakchi et al., 2011). The mutation suggests a causative role of IL-36 in the skin disease but drugs targeting IL-36 signaling do not exist. Acitretin, oral steroids, methotrexate, cyclosporin, and TNF inhibitors have been reported with partial responses (Marrakchi et al., 2011).

CARD14 mediated psoriasis (CAMPS) is caused by autosomal dominant GOF mutations in CARD14 gene causing a monogenic form of plaque and pustular psoriasis. It is also the cause of familial pityriasis rubra pilaris, once thought to be an early-onset “psoriasis mimic” with resistance to many psoriasis treatments (Jordan et al., 2012b, Jordan et al., 2012a, Fuchs-Telem et al., 2012). Patients present with typical plaque psoriasis with variable severities and with generalized pustular psoriasis. Fever and other systemic manifestations are generally not present but can occur with superinfections (Jordan et al., 2012a, Jordan et al., 2012b). Treatment of CAMPS includes drugs used for the treatment of moderate-to-severe psoriasis, such as, methotrexate, cyclosporine and anti-TNF agents, and biologics targeting IL17 and IL23.

Early onset inflammatory bowel disease (EO-IBD) is caused by autosomal recessive LOF mutations in IL-10R and IL-10 encoding genes (Glocker et al., 2009). Patients present before 3 months of age with severe enterocolitis (bloody diarrhea, colonic abscesses, perianal fistula and oral ulcers) associated with recurrent fever and failure to thrive (Kotlarz et al., 2012). Musculoskeletal manifestations include acute recurrent arthritis of large joints(Kotlarz et al., 2012) and recurrent folliculitis (Kotlarz et al., 2012). Recurrent infections may indicate a defect in the immune responses in patients with EO-IBD (Glocker et al., 2009, Kotlarz et al., 2012). EO-IBD is refractory to standard immunosuppressants, and hematopoietic stem cell transplantation (HSCT) has resulted in complete clinical remission in most transplanted patients (Kotlarz et al., 2012, Engelhardt et al., 2012).

IL-18/IL-1 mediated Diseases

4. Diseases with the propensity to develop macrophage activation syndrome (NRLC4-MAS)

NLRC4-MAS is caused by activating heterozygous GOF mutations in the innate immune sensor NLRC4, which assembles a caspase-1 activating inflammasome (Canna et al., 2014)^,(Romberg et al., 2014). Patients have variable, early-onset enterocolitis followed by recurrent febrile episodes. Macrophage activation syndrome (MAS) attacks can be triggered by infections or physical stress. MAS presentations include pancytopenia, hepatitis, splenomegaly, and hyperferritinemia. In contrast to the CAPS patients with NLRP3 mutations, extraordinary elevation of serum IL-18 levels (10- to 100-fold higher than in CAPS) are detected even during clinical quiescence, a finding also seen in sJIA/Still’s disease patients at risk for MAS (Ichida et al., 2014, Shimizu et al., 2015). The role of IL-18 in the development of MAS and as a therapeutic target is being evaluated. The fever flares are responsive to corticosteroids and IL-1 inhibition.

Type-I IFN mediated autoinflammatory diseases (Figure 2B)

5a. Vasculopathy and Panniculitis/lipoatrophy

Proteasome associated autoinflammatory syndromes (PRAAS) or Chronic Atypical Neutrophilic Dermatitis with Lipodystrophy and Elevated temperatures (CANDLE) also called Nakajo-Nishimura syndrome is caused by recessive or digenic mutations in proteasome subunits, PSMB8 (Agarwal et al., 2010)_,(Arima et al., 2011)_,(Kitamura et al., 2011)_,(Liu et al., 2012) PSMB9, PSMA3, PSMB4 and the proteasome assembly molecule, POMP (Brehm et al., 2015). Patients present with early-onset recurrent fever, violaceous cutaneous rashes, periorbital edema and erythema, lipodystrophy, arthritis or arthralgia, myositis and with increased acute phase reactants (Torrelo et al., 2010). Marked finger swelling, in early infancy with conjunctivitis or episcleritis, lymphocytic aseptic meningitis, basal ganglia calcifications, lymphadenopathy, hepatomegaly, prominent abdomen and low weight and height are additional features (Liu et al., 2012). Laboratory abnormalities include thrombocytosis, neutropenia, lymphopenia, thrombocytopenia and hypertriglyceridemia with flares (Liu et al., 2012). Long-term organ damage from untreated patients who survive into adulthood includes the development of muscle atrophy, cardiac arrhythmias and dilated cardiomyopathy (Arima et al., 2011, Kitamura et al., 2011). Partial responses to high doses of steroids (Liu et al., 2012), NSAIDs, colchicine, dapsone, methotrexate, tacrolimus and azathioprine and biologics including anti-TNF, anti–IL-1 and anti-IL-6 agents are seen (Liu et al., 2012) but lipodystrophy progresses despite therapies(Liu et al., 2012). Laboratory data suggesting increased IFN signaling led to the development of a compassionate use protocol with the JAK1/JAK2 inhibitor baricitinib (clinicaltrials.gov/NCT01683409).

5b. Vasculitis and/or livedo retiularis

A number of syndromes presenting with vasculopathies, vasculitis and severe livido reticularis are caused by dysregulation of viral sensing pathways and are linked to Type-I IFN production marked by the presence of a strong IFN response gene signature (IRS) in the blood. STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by de-novo GOF mutations in adaptor protein in the cytosolic DNA-sensing pathway, TMEM173, which encodes the stimulator of interferon (IFN) genes (STING) (Liu et al., 2014) and pointed to the important role of IFN in these diseases. Patients with SAVI present with early-onset vasculitis that affects small dermal vessels in cold sensitive acral areas including fingers, toes, ears, kneecaps that lead to vasoocclusion and gangrene. Most patients develop progressive interstitial lung disease (ILD) with variable severity (Liu et al., 2014)_,(Jeremiah et al., 2014). Elevated autoantibody levels are variably seen in patients; however, titers do not correlate with the presence or severity of the disease. SAVI patients present with a strong IRS in whole-blood suggesting a critical role of chronic IFN stimulation in the disease pathogenesis (Liu et al., 2014)_,(Jeremiah et al., 2014). Aicardi-Goutières Syndromes (AGS) 1–7 are a rare group of diseases caused by autosomal recessive LOF mutations in genes encoding enzymes in the nucleotide metabolism, the exonuclease TREX1, the ribonucleases RNASEH2A, RNASEH2B, and RNASEH2C; a nuclease, SAMHD1, and the dsRNA-specific adenosine deaminase ADAR1. More recently, autosomal dominant GOF mutations in the viral sensors, IFIH1, encoding MDA5, and DDX58 encoding RIG-I, have been found to cause AGS (Crow and Manel, 2015). Patients who develop disease in early infancy present with subacute encephalomyelitis mimicking viral infections that rapidly lead to demyelination, spastic paraplegia and neurological decline which dominate the clinical picture. Most patients follow a non-progressive, chronic course after the initial acute phase. On MRI patients have basal ganglion calcifications and severe white matter disease, up to 40% continue to have vascular rashes, including “chilblain lesions” on hands and feet. Many patients have low-titer autoantibodies (Crow and Manel, 2015). When the disease manifests later in life or presents as autosomal dominant form, the devastating CNS manifestations do not develop and the clinical phenotype is more variable with prominent vascular manifestations (see Table 1). Later-onset conditions include a syndrome referred to in the literature as Singleton-Merten Syndrome (SMS) characterized by abnormalities of blood vessels, teeth, and bone that is caused by autosomal dominant mutations in IFIH1 or DDX58. Calcifications of the aorta, and the aortic and mitral valves, glaucoma and acro-osteolysis are typical features. Delayed primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, severe root and alveolar bone resorption associated with dysregulated mineralization leading to tooth loss are frequently observed in IFIH1-associated SMS (Rutsch et al., 2015, Jang et al., 2015). AGS-causing mutations affect enzymes that regulate nucleotide metabolism and cause accumulation of immunogenic nucleic acids. It is hypothesized that these self nucleic acids trigger chronic Type I IFN production through the viral DNA and RNA sensors. Strategies that are based on the understanding of the disease mechanism are currently being explored as treatment options and include reduction in transcription of retroviral sequences inhibition of chronic Type I IFN signaling (Crow and Manel, 2015). SPENCDI, Spondyloenchondrodysplasia with immune dysregulation is a syndrome of bone dysplasia; central nervous system involvement (cerebral calcifications); and immune dysregulation that is caused by LOF mutations in tartrate-resistant phosphatase (TRAP; encoded by ACP5) (Lausch et al., 2011, Briggs et al., 2011). Patients present with a prominent IRS features of immunodeficiency, including upper respiratory and pulmonary infections and interstitial fibrosis, fulminant hemorrhagic chickenpox; and autoimmunity including idiopathic thrombocytopenic purpura (ITP), thyroid disease (Briggs et al., 2011). DADA2, Deficiency of adenosine deaminase 2 is caused by autosomal recessive mutations in CECR1, encoding the enzyme adenosine deaminase 2 (ADA2), cause an early-onset vasculopathy resembling polyarteritis nodosa (Zhou et al., 2014, Navon Elkan et al., 2014). Patients can present with early-onset stroke, livedo reticularis, recurrent fever, hepatosplenomegaly, arterial hypertension, ophthalmologic manifestations and myalgia. CECR1 is essential for vascular integrity and neutrophil development consistent with observations that DADA2 patients have a defect in small vessel endothelial integrity and impaired of M2-like macrophage differentiation and polarization towards inflammatory M1-like macrophages and monocytes (Navon Elkan et al., 2014, Zhou et al., 2014). Therapeutic interventions include anti-TNF agents, fresh-frozen plasma and hematopoietic stem cell transplantation (HSCT) (Van Eyck et al., 2015, Zhou et al., 2014, Navon Elkan et al., 2014).

6. Syndromes presenting with granulomatous skin lesions and minimal or low-grade fever attacks also represent a heterogeneous group of diseases

Blau syndrome/early-onset sarcoidosis (pediatric granulomatous arthritis, PGA) is caused by autosomal dominant GOF mutations in NOD2/CARD15 (Alonso et al., 2003). PGA can be inherited in an autosomal dominant pattern (Blau syndrome) or occur sporadically (referred to as early-onset Sarcoidosis) (Rose et al., 2009, Rose et al., 2011). PGA patients present with granulomatous inflammation of eyes, joints and skin leading to the classical triad of chronic uveitis, arthritis and dermatitis. Uveitis is often the most recalcitrant disease manifestation, presenting as panuveitis (Arostegui et al., 2007). Cataract, glaucoma and irreversible blindness are frequent complications of untreated disease. Most patients with PGA develop an ichthyosis-like exanthema (Rose et al., 2009, Rose et al., 2011). Laboratory exams demonstrate persistent leukocytosis, thrombocytosis and increased ESR and CRP. Synovial, skin and liver biopsies may show non-caseating granulomata(Arostegui et al., 2007). Optimal therapy is not well defined. Systemic corticosteroids are used for severe disease biologics targeting TNF and IL-1 are beneficial especially in patients with refractory uveitis (Rose et al., 2011). PLAID and APLAID are caused by autosomal dominant mutations in different positions in PLCG2. PLAID is clinically characterized by a cold-induced urticarial and/or a granulomatous skin rashes atopic manifestations, positive autoantibodies, and recurrent opportunistic infections while APLAID presents with recurrent erythematous plaques and vesicopustular skin lesions, granulomas on skin biopsy, arthralgia, uveitis, and recurrent sinopulmonary infections. Treatment of PLAID includes cold avoidance, anti-histamines and IVIG. APLAID patients partially respond to anakinra and high-dose corticosteroids (Ombrello et al., 2012)_,(Zhou et al., 2012).

7. Miscellaneous

Cherubism is caused by autosomal dominant mutations in SH3BP2 and approximately 50% of the cases occur de novo. SH3BP2 is a cytoplasmic adaptor protein that interacts with TNFAIP3/A20 and with protein tyrosine kinases such as ABL1 and SYK that regulate transcriptional activity in immune cells. Patients develop symmetrical multilocular and radioluscent lesions in the mandible and the maxilla that expand and first appear in childhood in the presence of submandibular and cervical lymphadenopathy. Patients can present with significant dental problems. The majority of cherubism cases regress spontaneously after puberty (Papadaki et al., 2012, Meng et al., 2005). Monogenic Still’s disease is caused by homozygous LOF mutations in LACC1, which encodes the enzyme laccase (multicopper oxidoreductase) domain-containing 1. Patients present clinically with features of systemic juvenile idiopathic arthritis (JIA) including fever, erythematous maculopapular rashes, chronic polyarthritis, leukocytosis, thrombocytosis, and elevated markers of inflammation (Wakil et al., 2015). All patients reported were unresponsive to treatment with NSAIDs, systemic corticosteroids, methotrexate, biologics targeting TNF, IL-6 or rituximab (Wakil et al., 2015). Congenital Sideroblastic anemia, B-cell Immunodeficiency, periodic Fevers, and Developmental delay (SIFD) is a mitochondrial disease caused by autosomal recessive LOF mutations in TRNT1 (Chakraborty et al., 2014). Patients present in infancy with transfusion-dependent sideroblastic anemia, recurrent noninfectious fever episodes, B-cell lymphopenia with hypogammaglobulinemia causing recurrent sinopulmonary bacterial infections, and with progressive developmental delay (Wiseman et al., 2013). Occult multiorgan failure and/or cardiomyopathy are seen; early allogenic bone marrow transplant was curative in one patient (Wiseman et al., 2013). TRNT1 encodes an enzyme that adds two cytosine- and one adenosine-(CCA) residues to the 3′ end mitochondrial and cytosolic tRNA molecules, which is necessary for tRNA aminoacylation (Sasarman et al., 2015, Chakraborty et al., 2014). The disease-causing mutations lead to a reduction in CCA enzyme activity, defective mitochondrial translation, and the inability to detect tRNAs with backbone damage (Sasarman et al., 2015). This defect is thought to result in a ‘loss of quality-control-mechanisms’ that recognize and prevent damaged tRNA from CCA maturation and from entering the ribosome machinery of protein synthesis, thus suggesting a role of CCA addition in intracellular stress responses (Sasarman et al., 2015).

Conclusion

In the past 15 years the pathogenesis of a number of immune dysregulatory disorders that present with fever, systemic and organ-specific inflammation were clinically and genetically defined which provided insights into their pathogenesis and gave rise to novel targeted agents in the treatment of these conditions and the important role of IL-1 in causing the disease spectrum. But unresponsiveness to IL-1 blocking agents in a growing group of autoinflammatory diseases/phenotypes led to the search for additional dysregulated cytokine pathways and resulted in the discovery of dysregulation in Type I IFN production, IL-18 over-secretion, lack of IL-10 signaling and unopposed IL-36 signaling. In a number of diseases oral ulcers and other oral cavity and tooth abnormalities are present and may provide clues to these disorders (Figure 3). It is thus necessary that caring clinicians who see young infants and children be familiar with the clinical aspects of these diseases in order to recognize them, to initiate appropriate referrals to tertiary care centers so that early therapy can be started to prevent physical sequela, mortality from untreated diseases and guarantee a better quality of life for these patients.

Figure 3. Features of oral disease manifestations.

(A) “Chubby cheek” appearance due to mandibular enlargement in a boy with cherubism (From Meng et al. (2005). Reprinted with permission from Elsevier). (B) Expansion of the mandible in cherubism with resultant dental abnormalities (From Meng et al. (2005). Reprinted with permission from Elsevier). (C) This plain film reveals multiple large radiolucent lesions with surrounding sclerosis in the mandible of a female with cherubism (From Jain and Sharma (2006). Reprinted with permission from Springer Science + Business Media). (D) Histologic findings in cherubism of multinucleated giant cells in collagen stromal tissue (From Meng et al. (2005). Reprinted with permission from Elsevier). (E) Periodontitis and root resorption in a patient with Singleton-Merten syndrome (SMS) (From Rutsch et al (2015). Reprinted with permission from Elsevier). (F) Oral ulcer in a patient with an undifferentiated autoinflammatory disease. (G) Root resorption and delayed tooth eruption in a young adult with SMS (From Lu C et al (2014). Reprinted with permission from Taylor & Francis Group). (H) Exfoliated tooth with root resorption in a patient with SMS (From Lu C et al (2014). Reprinted with permission from Taylor & Francis Group).

List of Abbreviations of disorders

FMF

Familial Mediterranean Fever

TRAPS

TNF receptor associated periodic syndrome

MKD

Mevalonate kinase deficiency

HIDS

Hyperimmunoglobulinemia D and periodic fever syndrome

CAPS

Cryopyrin associated periodic syndromes

FCAS

Familial cold autoinflammatory syndrome

MWS

Muckle-Wells syndrome

NOMID

Neonatal-onset multisystem inflammatory disease

CINCA

Chronic infantile neurologic, cutaneous and arthritis syndrome

DIRA

Deficiency of interleukin 1 receptor antagonist Majeed syndrome

PAPA

Pyogenic arthritis, pyoderma gangrenosum and acne (syndrome)

DITRA

Deficiency of interleukin 36 receptor antagonist

CAMPS

CARD14- mediated psoriasis

PRAAS

Proteasome associated autoinflammatory syndrome

CANDLE

Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperatures

DADA2

Deficiency of ADA2

SAVI

STING- associated vasculopathy with onset in infancy

SPENCDI

Spondyloenchondrodysplasia with immune dysregulation

PGA

Pediatric granulomatous arthritis

PLAID

PLCG2-associated antibody deficiency and immune dysregulation

APLAID

PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation

HA20

Haploinsufficiency of A20

SIFD

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay

AGS

Aicardi-Goutières syndrome