Periodic fever syndromes and the autoinflammatory diseases (AIDs)

2.1. Familial Mediterranean Fever (FMF)

FMF is an autosomal recessive disease characterized by recurrent systemic inflammatory attacks with fever and serositis. It is the most common monogenic AID. FMF originates from the Middle East with the highest prevalence among Sephardic Jews, Armenians, Turks and Arabs; it later spreads towards the Mediterranean area, and towards the “new world” more recently following migrations [14]. In 1997, two different groups identified the underlying genetic cause of FMF in mutations of MEFV gene located on chromosome 16, encoding for a protein called pyrin [15,16]. So far, more than 340 MEFV sequence variants have been reported (https://infevers.umai-montpellier.fr/web/search.php?n=1), although many of those have no clear pathogenic role; thus, a careful interpretation of genetic results is advocated [17,18]. Clinical phenotype of FMF may be present also in subjects harboring heterozygous mutations of MEFV gene and those patients typically show a good response to colchicine treatment [19,20].

The involvement of other genes encoding for proteins implicated into FMF pathogenesis may influence clinical expression and severity. Serum amyloid A (SAA; particularly SAA1a allele) and MHC class I polypeptide-related sequence A (MICA) have been related to disease severity and outcome, including the risk of amyloid A (AA) deposition [[21], [22], [23]]. A further complication in the understanding of FMF is represented by the combination of heterozygous MEFV mutations and mutations of other monogenic AIDs genes leading to clinical manifestations of autoinflammation, as well as the rising role of environment that influences clinical phenotype [[24], [25], [26]].

Once activated, pyrin usually assembles the inflammasome through the ASC-dependent mechanism [27]. Negative control of this path is guaranteed by the GTPase RhoA that activates regulatory proteins 14-3-3 and PKN [28]. When mutated, pyrin escapes to its constitutive inhibition leading to inflammasome formation and uncontrolled production of IL-1β through caspase 1 activation [29].

The disease typically appears within the second decade of life and the majority of patients presents the first clinical manifestation during the pediatric age [[30], [31], [32]]. However, delayed onset of FMF may occur and is characterized by an attenuated disease course, particularly in males, and a good response to colchicine [33,34].

Fever attacks usually are recurrent without a predictable periodicity and last between 12 and 72 ​h. FMF clinical manifestations are reported in Table 2.

The most concerning complication of FMF is the accumulation of AA. Amyloidosis accounts for the majority of morbidity and mortality related to FMF [35]. SAA is the circulating precursor of AA and reflects amyloidogenesis. Underlying inflammation is detectable in about 30% of FMF patients during free-intervals between the attacks; moreover, some asymptomatic carriers may have a constant elevation of SAA, with the risk of developing amyloidosis over time [36]. The persistent inflammation in children with FMF impacts growth and bone mineralization [37,38]. The risk of AA amyloidosis is higher in the presence of M694V mutations and SAA1a allele [35].

The diagnosis of FMF is principally clinical and genetic results should be carefully interpreted.

Colchicine is the milestone of the MF treatment since it inhibits the activation of pyrin inflammasome [39]. When colchicine fails, European League Against Rheumatism (EULAR) recommendations suggest starting an anti-IL-1β medication along with the microtubule-depolymerizing drug [40]. This class of biological drugs has been proven to prevent attacks and reduce systemic inflammation [41,42].

2.2. Mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS)

Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disease caused by mutation of the gene encoding for mevalonate kinase (MVK). MKD is also known as hyper IgD syndrome (HIDS) given the increase of immunoglobulins D during the attacks that later has been recognized absent in almost 20% of MKD cases [48,49]. The impairment of MVK enzyme leads to alteration into cholesterol and non-sterol isoprenoids pathway. According to the residual enzyme activity, the severity of the disease ranges from MKD/HIDS with a residual enzymatic activity ranging between 1.8% and 28% of normal and preponderant autoinflammatory features to mevalonic aciduria (MA) with almost no remaining enzymatic function, dysmorphic features and significant neurological involvement [50].

MKD is more common in the west area of Europe; indeed, several studies reported MKD patients with Dutch, French and Italian origin [49,51,52].

MKD is due to loss of function mutation of MVK gene on chromosome 12; so far more than 210 sequence variants of this gene have been reported (https://infevers.umai-montpellier.fr/web/search.php?n=3). The most frequent mutation is V377I either in homozygous or as compound heterozygous with I268T mutation; patients carrying V377I/I268T genotype have the risk of amyloidosis despite the fact that this complication is very rare in MKD patients [52].

The loss of function of MVK reduces the prenylation of proteins such as geranylgeranyl pyrophosphate. This latter is necessary for RhoA activation and consequently the persistent inhibition of pyrin inflammasome. Low levels of geranylgeranyl pyrophosphate compromise this regulation and facilitate pyrin inflammasome assembly [53].

The disease usually appears during the first year of life with abrupt onset of fever lasting 3–7 days associated with several signs and/or symptoms and an increase of acute phase reactants (Table 2). Attacks recur with a monthly frequency and may be triggered by vaccination, stress and infections. The frequency of disease flares tends to decrease over time, although some of the patients continue to have more than 6 attacks per year during adulthood [49].

Clues for diagnosis are the very early onset along with classical clinical manifestations and the increase of urinary mevalonic acid during the attacks [54].

Clinicians treat acute attacks of MKD with nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids; colchicine and statins have shown poor efficacy in preventing disease flares [52]. Anakinra administered daily or “on-demand” during the attacks has been proven to be quite effective, comparable results have been achieved with canakinumab [52,55].

2.3. TNF receptor-associated periodic fever syndrome (TRAPS)

TNF receptor-associated periodic fever syndrome (TRAPS) is an autosomal dominant disease due to a mutation of the TNF receptor super-family member 1 ​A. It has been initially described in a large Scottish/Irish family and named as familial Hibernian fever, however, all ethnicities can be affected [6]. This monogenic dominant disease is caused by a missense mutation of TNFRSF1A on chromosome 12 encoding for the 55-KF receptor of TNF-α; 158 sequence variations, mainly on exon 2, 3 and 4, are known so far (https://infevers.umai-montpellier.fr/web/search.php?n=2). The majority of pathogenic mutations acts by altering cysteine–cysteine disulfide bonds in the extracellular domain (e.g. T50 ​M and C33Y). More than one-third of patients harbor R92Q and P46L mutations, although these low penetrance sequence variants have an unclear role and often result in milder disease [59].

Despite several speculations on defective receptor shedding and apoptosis [6,60], the most accredited effect of TNFRSF1 mutation is the altered trafficking of TNF receptor type I (TNFRI) that accumulates into the endoplasmic reticulum. This results in impaired receptor clearance and an increase of reactive oxygen species (ROS) enhancing NF-kB and mitogen-activated protein kinase (MAPK) pathway [[61], [62], [63]]. Autophagy is the process by which unfolded and accumulated proteins are removed by cells; the overload of TNFRI in TRAPS patients impairs this process fostering ROS production and may indirectly lead NLRP3 inflammasome activation [62,64].

Typically TRAPS is characterized by prolonged attacks lasting up to 3–4 weeks, however, sometimes inflammatory episodes may be longer or may disappear in less than a week depending on the underline genotype. Peculiarities of TRAPS are the periorbital edema and pseudo-cellulitis rash. Mean age at onset is around 4 years with a mean diagnostic delay of one decade, however, one-fifth of patients have experienced first symptoms during the adulthood [59]. Recognizable triggers are found in a quarter of patients (emotional stress, menstrual cycle, exercise, infections and vaccination). AA is a possible complication, accounting for up to 18% of TRAPS adult patients [65].

Treatment of TRAPS is based on controlling clinical and subclinical inflammation in order to guarantee a good quality of life and to avoid AA. Corticosteroids decrease the severity of clinical manifestations but their long-term use is not advised. Despite promising results with etanercept [66], many patients discontinue the anti-TNFα treatment because of loss of efficacy and others do not respond [67,68]. As in other monogenic AIDs the blockage of IL-1 has been demonstrated to be efficacious in preventing attacks of TRAPS and AA. Both anakinra and canakinumab have shown good results [69,70].

2.4. Cryopyrin associated periodic syndrome (CAPS)

Cryopyrin associated periodic syndrome (CAPS) represents the prototype of inflammasomopathies in which a gain of function mutation of NLRP3 gene is responsible for inflammasome overactivation and the consequence hyperinflammatory status. Under the term CAPS are included 3 clinical entities distinguishable for their increasing severity: family cold autonflammatory syndrome (FCAS), Muckle Wells syndrome (MWS), and chronic infantile articular neurological periodic syndrome (CINCA) also known as neonatal onset multisystem inflammatory disease (NOMID) [73]. CAPS is a rare and world spread disease without any ethnicity preference.

NLRP3 gene formerly known as cold-induced autoinflammatory syndrome 1 (CIAS1) gene, is located on chromosome 1q44 and encodes for cryopyrin, a protein with a key role in NLRP3 inflammasome assembling. CAPS is caused by an AD inherited or de novo missense mutation in the NACHT domain of NLRP3 gene [73]. So far more than 200 sequence variants of NLRP3 gene are known (https://infevers.umai-montpellier.fr/web/search.php?n=4), mainly on exon 3. Furthermore, a not negligible portion of patients with CINCA clinical phenotype does not harbor any NLRP3 mutation at conventional studies due to the presence of mosaicism or to unknown epigenetic factors [74,75].

The pathogenesis of CAPS has provided the model of caspase dependent IL-1β production [76]. Indeed cryopyrin activates caspase 1 leading to the cleavage of pro-IL-1 to IL-1β. NLRP3 gain of function mutations foster this process resulting in overactivation of IL-1β through NLRP3 inflammasome [76].

CAPS displays a chronic or acute intermittent course according to disease severity; acute phase reactants are almost persistently elevated. Patients with FCAS have recurrent cold-triggered episodes of inflammation with fever, urticaria-like rash, arthralgia and conjunctivitis. MWS is more chronic rather than recurrent without recognizable triggers. Sensorineural hearing loss and eye involvement are common features of MWS and the risk of AA increases with the age.

CINCA patients manifest the classical triad of cutaneous, neurological and articular involvement with very early onset (Table 2). Long-term complications include failure to thrive and cognitive disability as well as AA [73].

Clinical manifestations of CAPS correlate with the underlying genotype; indeed, patients harboring the T348 ​M variant have a chronic course with an early-onset disease and hearing loss, whereas neurological involvement is rare in patients carrying V198 ​M, E311 K and A439 V mutations [73].

The inhibition of IL-1 in CAPS patients is extremely effective; this finding is not surprising considering its pathogenesis. The chronic blockage of IL-1 is recommended in CAPS patients with active disease, whereas NSAIDs and corticosteroids may be used as symptomatic therapy [77]. Both anakinra and canakinumab have been demonstrated efficacious in CAPS patients giving their capacity of abrupting systemic inflammation and arresting organ damage [[78], [79], [80]].

2.5. Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is an autosomal dominant AIDs characterized by joint and severe skin involvement (Table 2). The mutated gene is located on chromosome 15 and codifies for proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1; also known as CD2-binding protein 1) [89]. PSTPIP1 plays a role in cytoskeletal scaffolding and cellular dynamics of innate immune cells. The underlying mechanism of PAPA is not completely clear, however, it seems related to pyrin inflammasome activation through direct interaction between PSTPIP1 and pyrin [89]. Sterile pyogenic arthritis that may be triggered by mild trauma and severe cystic acne represent the hallmarks of the disease. Joint involvement appears in early childhood and tends to regress over time; on the contrary skin lesions typically develop in puberty and persist. Furthermore, some patients present pyoderma gangrenosum with or without hidradenitis suppurativa; the latter clinical manifestation along with the other skin features has been named PASH syndrome (pyoderma gangrenosum, acne, and hidradenitis suppurativa) [90]. The clinical spectrum of PSTPIP1 associated mutation is expanding, indeed PAMI (PSTPIP1-Associated Myeloid-related-proteinemia Inflammatory syndrome) is a newly recognized clinical entity characterized by severe systemic inflammation. PAMI is caused by p.E250K and p.E257K mutations resulting in charge reversal in the y-domain of PSTPIP1 and increased interaction with pyrin. Besides PAPA-like manifestations, PAMI patients have hepatosplenomegaly, pancytopenia and growth failure [91].

PAPA patients present a variable response to steroids and cytokines targeting agents such as IL-1β blocking agents and TNFα inhibitors [89,92]. The variability in treatment response reflects the many different pathways in which PSTPIP1 is involved.

3.1. NLRC4-inflammasomopathies

Since 2014 two clinical phenotypes have been related to mutations of NLR-family CARD domain-containing protein 4 (NLRC4) gene: autoinflammation and infantile enterocolitis (AIFEC) fever characterized by recurrent episodes of MAS and very early onset enterocolitis [95,96] and Familial cold autoinflammatory syndrome 4 (FCAS4) with neonatal-onset, cold-induced urticarial rash and arthralgia resembling FCAS [97]. Both AIFEC and FACS4 are caused by autosomal dominant NLRC4 gain-of-function mutations. So far, more than 10 sequence variants that exhibit complete penetrance have been related to AIFEC (https://infevers.umai-montpellier.fr/web/search.php?n=25). Two patients harboring somatic mutations have been identified, both with severe phenotypes: one with AIFEC and the other with CINCA-like clinical features and very high IL-18 serum levels [98,99]. It is unclear how gain-of-function mutations of NLRC4 can produce such different clinical patterns, although a partial explanation might be the different protein domain interested by mutations [100]. Human NLRC4 inflammasome has been identified in myeloid cells and mucosal tissues; indeed, it has been detected in mouse intestinal epithelial cells playing a role in defense against gastrointestinal pathogens [101]. NLRC4 inflammasome fosters both IL-1β and IL-18. Interestingly, AIFEC patients experienced the resolution of enterocolitis after the first year of age despite persistent elevated IL-18 serum levels; the reasons for this are unknown although they might be related to microbiota and mucosal immunity [102]. Elevated serum IL-18 concentration is a distinctive feature of MAS in AIFEC. FCAS4 patients have milder phenotypes dominated by skin manifestations (cold-induced urticarial rash). Skin biopsies revealed a lymphohistiocytic infiltrate [103]. Since there are no NLRC4 target drugs, the treatment of AIFEC patients is challenging and is based on anecdotal reports, whereas FCAS4 may benefit from NSAIDs during acute phases [96,99,103]. However, IL-18 recombinant binding protein has been successfully employed in an AIFEC patient with a refractory disease [104]. A phase III trial testing Tadekinig α, an IL-18 recombinant binding protein, is ongoing (NCT03113760).

3.2. NLRP1-associated autoinflammation with arthritis and dyskeratoisis (NAIAD)

A group recently described 3 subjects from 2 families with early onset of dyskeratosis, oligo/polyarthritis and recurrent fever episodes along with immunological dysfunction and vitamin A deficiency. All patients harbored a mutation of NLR family pyrin domain containing 1 (NLRP1) gene: 2 cousins of Algerian family born from related parents were homozygous for R726W and one Dutch patient was heterozygous for P1214R. The different inheritance patterns might be due to the different sites of mutations [105]. The authors named this disease NLRP1-associated autoinflammation with arthritis and dyskeratosis (NAIAD). Chronic or recurrent infections were reported in two patients. All patients showed high serum levels of caspase-1 and IL-18. These findings suggest that both keratinocyte differentiation and regulation of inflammation are influenced by NLRP1 inflammasome. Furthermore, abnormal B-cell distribution was found in all patients in terms of either a high absolute number of circulating transitional B cells or a reduced number of circulating CD27 ​⁺ ​B cells (marginal zone or memory B cells) when compared with unaffected subjects. Two patients had ocular involvement: uveitis and corneal dyskeratosis. Skin manifestations improved with acitretin treatment in all three patients, whereas one patient responded to IL-1 blockage with the resolution of arthritis and systemic inflammation [105].

3.3. NALP12 periodic fever syndrome

NLRP12 plays a role in the persistent inhibition of NF-kB signaling and its mutation may alter this control. Indeed in 2008, 3 patients (2 monozygotic brothers and 1 girl) of two unrelated families, were found to harbor a heterozygous mutation of the NLRP12 gene [106]. These patients had a very early onset disease with periodic fever lasting several days associated with arthralgia and headache and triggered by cold exposure. All three patients had a positive family history, although with a milder phenotype. Interestingly the two brothers developed urticaria and sensorineural hearing loss without acute phase reactant elevation, whereas aphthous ulcers and lymphadenopathy were observed in the other subject. The NLRP12 mutations observed in these 2 families (p.Arg284X and p.Val635ThrfsX12 respectively) altered the constitutive inhibition of NF-kB [106]. Later, the p.D294E missense mutation of NLRP12 was identified in another Caucasian family with some affected family members presenting FCAS-like phenotype. Interestingly this mutation affects the ROS production rather than NF-kB signaling leading to increase IL-1β production [107]. Very few is known about the treatment of these patients. Anakinra led only to partial clinical improvement and no biological response in the two previously described brothers [108].

3.4. Pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND)

A mutation located in exon 2 of the MEFV gene (S242R) is associated with an autosomal dominant disease characterized by early onset of fever episodes associated with arthromyalgia and neutrophilic dermatosis named pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Severe acne, pyoderma grangenosum, sterile skin abscesses and neutrophilic small vessel vasculitis have been observed in PAAND patients [109]. S242R mutation interferes with 14-3-3 role of hindering pyrin causing induction of inflammasome assembly. The importance of 14-3-3 role was reinforced by the identification of another mutation, E244K, altering this function and resulting in a PAAND like clinical phenotype with pustular acne, suppurative hidradenitis and neutrophilic panniculitis [110]. PAAND patients have been treated with anakinra which resulted very effective, however, one patient who partially responded to IL-1 inhibition was also successfully treated with anti-TNFα therapy [109,110].

3.5. Autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID)

An autosomal dominant inherited mutation of PLCγ2, named autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID), is responsible for a syndrome with recurrent blistering skin lesions, cellulitis, interstitial pneumonitis, arthralgia, ocular ulceration and erosions, enterocolitis and mild immunodeficiency features such as recurrent sinopulmonary infections and low circulating antibodies (IgM and IgA) [111].

Skin manifestations range from epidermolysis-bullosa-like lesions to erythematous plaques and vesiculo-pustular eruptions; interestingly, high temperature and sun exposure make them worse. Biopsy reveals polymorphic dense infiltrate with neutrophils, eosinophils, histiocytes, and lymphocytes. PLCγ2 encodes for a constitutively repressed phospholipase; its mutation (p.Ser707Tyr) removes this inhibition with the consequent increase of Ca²⁺release by the endoplasmic reticulum and enhanced NLRP3 inflammasome activation [112]. So far, reported patients showed a good response to corticosteroids whereas IL-1 blockage did not lead to full disease activity control [111].

3.6. Periodic fever immunodeficiency and thrombocytopenia (PFIT)

This disease was first described in 2 sisters born from related parents of Pakistani origin, who presented with very early onset of recurrent fever episodes (lasting up to 7 days), mucosal ulcerations, thrombocytopenia and elevated acute phase reactants along with hyperferritinemia. Interestingly, both had recurrent invasive infections [113].

The underlying mutation was on WD40 repeat protein 1 (WDR1) gene encoding for a protein involved in actin depolymerization. This missense mutation leads to actin accumulation, resulting in pyrin activation and IL-18 release. Similar to what happens in Wiskott-Aldrich syndrome, the cytoskeleton alteration causes impairment of several cell lines including T cells and megakaryocytes [113,114]. Corticosteroids and colchicine were partial effective as well as anakinra, while hematopoietic stem cell transplantation (HSCT) was effective in one case [113].

4.1. NOD2/CARD 15-associated diseases

Nucleotide-binding oligomerization domain containing 2 (NOD2) or caspase recruitment domain-containing protein 15 is a cytosolic protein that binds several PAMPs such as muramyl dipeptide [115]. NOD2/CARD15 sequence variants are associated with Blau syndrome (BS) and Crohn’s disease (CD) (see Table 3) [116,117]. The gain of function mutations are associated with BS and lead to activation of NF-κB signaling even in the absence of any ligands, with activation of proinflammatory transcriptional genes [118]. Autosomal dominant (Blau Syndrome; BS) or de novo (early onset sarcoidosis) mutations result in a quite definite clinical phenotype with the classic triad of skin rash, granulomatous uveitis and symmetrical polyarthritis occurring in early childhood [116]. Almost all patients have tenosynovitis along with large joint arthritis, while the involvement of proximal interphalangeal joints leads to camptodactyly. The appearance of the rash in the first year of life may be misleading and often atopic dermatitis and ichthyosis are misdiagnosed. Maculo or micropapular lesions are typical, and sometimes the rash may resemble eczema; biopsy shows noncaseating granulomas. Uveitis is usually the last manifestation in order of appearance and is granulomatous, often involving all ocular cameras configuring a panuveitis framework [116]. According to the severity and type of organ involvement, several immunosuppressants and biologic agents have been used for BS and EOS, however, corticosteroids remain still frequently employed for the management of these patients [119,120].

CD is a fascinating condition on the verge between autoinflammation and autoimmunity [7]. Nowadays the definition of NF-κβ activation disorder makes autoinflammation prevails [121]. Furthermore, sequence variants of LRRs domain of NOD2/CARD15 (R702T, G908R and L1007fsinsC) have been identified as susceptible loci predisposing for CD, thus reinforcing its proximity to BS [117].

4.2. Familial pityriasis rubra pilaris/CARD14-associated psoriasis

Pityriasis rubra pilaris is characterized by the triad of erythematous plaques (mixed with normal skin), keratotic follicular papules and palmoplantar keratoderma (thick skin in palms and soles). Mutations of gene encoding caspase recruitment domain-containing protein 14 (CARD14) have been firstly reported in familial cases with a dominant inheritance pattern and variable penetrance. Later on, de novo mutations of CARD14 with variable penetrance have been also identified [125]. CARD14 is manly expressed on keratinocytes and its gain of function mutations lead to activation of the NF-kB pathway fostering skin inflammation. Typically skin lesions appear before 3 years of age with a mild lymphocytic infiltrate [126]. Several immunomodulatory agents have been used for the treatment of this condition, recently a patient successfully treated with ustekinumab, an IL-12 and IL-23blocking agent, has been reported [127].

4.3. Ubiquitinopathies

Ubiquitination defines the destiny of proteins through post-traduction changes starting with ubiquitin chains assembling after proper stimulation via innate immunity receptors. The linear ubiquitin chain assembly complex (LUBAC) assembles linear ubiquitin chains [128]. LUBAC is formed by heme-oxidized IRP2 ubiquitin ligase 1 ​L (HOIL-1), SHANK-associated RH domain-interacting protein (SHARPIN) and the catalytic subunit HOIL-1L-interacting protein (HOIP) [129,130]; this aggregate contributes to the steadiness of several receptors including TNFR1 and IL-1R [131,132]. According to the type and site of the bond between ubiquitin chains and the target protein, intracellular sensors ultimately determine the destiny of the protein [131,132]. The process by which ubiquitin chains are removed from proteins is named deubiquitination; several enzymes, including A20 and otulin, hydrolyze these bonds. Both ubiquitination and deubiquitination modulate the transcription of proinflammatory cytokines through the NF-kB pathway, in particularly deubiquitination acts as negative regulator of this path [131,132].

Defects in ubiquitination and deubiquitination are associated with NF-kB pathway activation and consequent hyperproduction of proinflammatory cytokines. So far very few patients with these disorders have been identified, thus, available data are poor [131].

5.1. Aicardi Goutieres Syndrome (AGS)

The neonatal onset of severe encephalopathy, basal ganglia calcifications, hepatic dysfunction, and skin involvement along with elevated acute phase reactants is characteristic of Aicardi Goutieres Syndrome (AGS). This disorder presents many clinical overlaps with transplacental congenital infections, named TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus and Herpes simplex); indeed AGS results from the buildup of nucleic acids misinterpreted as viral/non-self by the innate immune system that leads to type I IFN driven inflammation [141].

AGS is due to defective function of enzymes involved in the regulation of acid nucleic metabolism; loss of function mutations, mainly autosomal recessive, of exonuclease (TREX1), ribonuclease (RNASEH2), phosphohydrolase (SAMHD1) and the dsRNA-specific adenosine deaminase (ADAR1), and autosomal dominant gain of function mutations of dsRNA sensor (IFIH1) have been identified in AGS patients [140]. Nevertheless, how these mutations lead to AGS is not completely known, although the accumulation of nucleic acids seems to play an important role in the pathogenesis of this condition. The CNS involvement in AGS is characterized by progressive leukoencephalopathy with loss of white matter leading to lifelong disabilities. Over time these patients develop fever episodes, chilblains, livedo reticularis, glaucoma and autoimmunity features with low autoantibodies titers [142].

5.2. STING-associated vasculopathy with onset in infancy (SAVI)

The autosomal dominant or sporadic gain of function mutation of TMEM173 gene encoding for stimulator of interferon genes (STING) is accountable for a vasculopathy involving skin and lungs along with systemic inflammation known as STING-associated vasculopathy with onset in infancy (SAVI). STING is an adaptor molecule involved in signal transduction through cGAS leading to hyperactivation of type I IFN pathways [143]. In addition to systemic features (fever, anemia, failure to thrive), SAVI presents painful and mutilating skin lesions of the extremities (loss of toes or fingers is not uncommon); Raynaud phenomenon may be present with nailfold capillary unspecific alteration. Skin biopsies show microthrombotic changes and neutrophilic infiltrate of capillaries.

Interstitial lung disease (ILD) can develop over time, and cough and tachypnea are common; computed tomography shows ground-glass opacities along with other typical features of ILD such as bronchiectasias and septal thickening. SAVI patients may have autoantibodies that may cause misdiagnosis and diagnostic delay; for instance, the detection of antineutrophil cytoplasmic antibodies (cANCA) along with pulmonary and skin involvement in these patients may be misdiagnosed as granulomatosis with polyangiitis [144].

5.3. Proteasome-associated autoinflammatory syndromes (PRAAS)

The defective function of the proteasome is associated with a range of diseases grouped under the term of proteasome-associated autoinflammatory syndromes (PRAAS). Several clinical conditions are included in PRAAS: joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced lipodystrophy syndrome (JMP), Nakajo-Nishimura syndrome and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) [81].

The proteasome system is the effector of intracellular misfolded protein removal and generates many antigenic peptides recognized by the immune system [145].

It is formed by four rings (two α rings and two β rings) assembled together in a cylindrical shape. Each rings consist of 7 in different α or β protein subunits; β-subunits, once activated by IFN signaling, show active sites for degradation of proteins [146].

Loss of function mutations of immunoproteasome components causes upregulation of the type I IFN pathway. Indeed, mutations of proteasome ring proteins (PSMB8, PSMB4 PSMA3, PSMB9) or of proteins involved in proteasome assembly such as proteasome maturation protein (POMP) have been associated with PRAAS [147]. Despite the identification of causative mutations, the link to IFN stimulation is still a matter of research. Clinical phenotype of PRAAS consists in the early onset of lipodystrophy, joint contractures of extremities, abundant neutrophil infiltrates in perivascular derma resulting in chronic dermatitis ranging from nodular to pernio-like lesions. Periodic fever episodes, failure to thrive, hepatosplenomegaly, abdominal protrusion due to intra-abdominal fat deposition, panniculitis, basal ganglia calcifications, anemia, hypergammaglobulinemia are other common features of PRAAS [140].

5.4. Singleton-Merten Syndrome (SMS)

Singleton-Merten Syndrome (SMS) is due to autosomal dominant gain of function mutation of dsRNA sensors (IFIH1 and RIG-I). It results in hyperactivity of these PRRs that drives to constitutive activation of IFNs [148,149]. Typical SMS, due to mutation of IFIH1, consists of progressive calcifications of large blood vessels (i.e. aorta), dental and skeletal abnormalities, and osteoporosis. Less common features are psoriasis, glaucoma and systemic muscle weakness [148]. Atypical SMS was described in patients harboring mutation of RIG-I (also known as DDX58 gene), these patients did not have dental alterations and showed variable expression of glaucoma, aortic calcification, and skeletal abnormalities [149]. Mutations of the gene encoding for the RNA sensor melanoma differentiation-associated protein 5 (MDA5) have been associated with both AGS and SMS phenotypes; interestingly, clinical overlaps of these two interferonopathies have been reported in patients harboring Arg822Gln and Ala489Thr mutations in IFIH1 gene [150,151].

5.5. Treatment of interferonopathies

Since their discovery, a wide range of immunosuppressive agents has been employed in interferonopathies resulting in limited effects. The blockage of IL-1 and TNF-α is poorly effective, whereas some patients benefited form IL-6 inhibition [152,153].

Since the JAK/STAT pathway is involved in the IFNs signal transduction, JAK inhibitors (baricitinib and tofacitinib) have been tested in patient cells leading to the reduction of ISGs expression [152,154]. Recent researches have pointed out the effectiveness of baricitinib, a JAK1/JAK2 inhibitor, in CANDLE and SAVI patients; its clinical effects were associated with dose-dependent decreases of IFN biomarkers [155,156]. A phase II study on reverse transcriptase inhibitors in AGS is ongoing (NCT02363452) although initial results seem encouraging [157]. Monoclonal anti IFN-α antibodies are promising drugs for these conditions; these drugs have shown good results in trials on SLE patients [158,159].

6.1. Adenosine deaminase 2 (ADA2) deficiency

Adenosine deaminase 2 (ADA2) deficiency is a monogenic autoinflammatory disease characterized by vasculopathy and hematologic alterations along with mild immunodeficiency features [163]. It is due to homozygous or compounds heterozygous loss of function mutations of the ADA2 gene (formerly known as Cat Eye Syndrome Chromosome Region candidate 1; CERC1) located on chromosome 22 [163]. ADA2 is an enzyme involved in purine catabolism and is expressed in myeloid cells. The pathogenesis of ADA2 deficiency is not completely clear; ADA2 mutations skew macrophage differentiation towards pro-inflammatory activity (M1 subsets) rather than an anti-inflammatory one (M2 subsets) with the result of alteration in vascular integrity [163]. ADA2 acts as a growth factor involved in the proliferation and differentiation of macrophages and promotes proliferation of monocyte-activated CD4⁺ T cells [164]. Furthermore, a prominent interferon signature has been identified in ADA2 deficient patients [165]. Typically the disease onset is in early childhood with the clinical phenotype of medium and small size vasculitis that often overlaps with polyarteritis nodosa (PAN). Vasculopathy represents the main feature with skin and CNS as the major sites of involvement although gastrointestinal tract, liver and kidney may also be affected. As in other autoinflammatory diseases, recurrent episodes of fever with elevated inflammatory markers are common.

More than half of patients shown neurological involvement, mostly due to lacunar ischemic strokes with MRI showing involvement of deep brain nuclei, brainstem and typical white matter sparing. Immune dysregulation affects principally the humoral arm of the immune system with hypogammaglobulinemia (especially low IgM) as major manifestation, and some patients displaying a complete framework of common variable immunodeficiency (CVID) [166,167]. The hematological involvement varies widely from mild anemia to pancytopenia [168].

Treatment is based on anti-TNF therapies capable both to control inflammatory vasculopathy and to prevent strokes. The use of antiplatelet drugs is still matter of debate, because of the risk of hemorrhagic events [163]. Immune defects benefit of substitutive immunoglobulins therapy, whereas for severe hematological involvement hematopoietic stem cell transplantation (HSCT) can be an option [169].

6.2. Sideroblastic anemia, immunodeficiency, fevers and developmental delay (SIFD)

Sideroblastic anemia, immunodeficiency, fevers and developmental delay (SIFD) is a disorder due to an autosomal recessive loss of function mutation of the TRNT1 gene. This gene encodes for a polymerase involved in the maturation of cytosolic and mitochondrial transfer RNAs. The disease onset is in early childhood with severe microcytic anemia, fragile hair, fever episodes, neurological involvement ranging from epilepsy to sensorineural hearing loss and development delay and multiorgan failure [176,177]. Increased number of immature B cells causing hypogammaglobulinemia and B cell lymphopenia are characteristics of SIFD [178].

6.3. Deficiency of IL-36 receptor antagonist (DITRA)

Episodes of generalized pustular psoriasis and fever along with systemic inflammation are characteristic of another monogenic AID named deficiency of IL-36 receptor antagonist (DITRA) [179]. Autosomal recessive loss of function mutations of IL-36 receptor antagonist gene results in the decrease of NF-κB pathway inhibition, leading to inflammation particularly in keratinocytes.

Typically palmoplantar sterile pustular rash and fever episodes develop during infancy and may be accompanied by arthritis and nail dystrophies. Treatment is not codified, and both anakinra and infliximab have been successfully used; moreover promising results have been achieved with ustekinumab and secukinumab [[180], [181], [182], [183]].

7.1. Systemic-onset juvenile idiopathic arthritis (SoJIA)

Systemic-onset juvenile idiopathic arthritis (SoJIA) is well separated from the other forms of JIA on both clinical and pathogenic basis with several consequences in terms of treatment and outcomes [184]. SoJIA is characterized by the presence of systemic features (high spiking fever, skin rash, lymphadenopathy and serositis) while arthritis may manifest later [184].

Laboratory and clinical features of SoJIA have pointed out the pivotal role of innate immunity, expressed through the aberrant activation of phagocytes leading to overproduction of certain cytokines (IL-1, IL-6, and IL-18) and other inflammatory proteins (e.g. S100A8, S100A9, and S100 A12) [184]. Among other severe complications (osteopenia, growth retardation, erosive arthritis, and amyloidosis), a major burden is represented by macrophage activation syndrome [184,185]. The therapy of SoJIA is based upon IL-1 blocking agents similar to several AIDs [186]. Il-6 inhibition is also effective and approved for this indication [187]. Although SoJIA is considered the result of the interaction between polygenic susceptibility and environmental factors, monogenic forms have been described [188]. Indeed an autosomal recessive mutation of the LACC1/FAMIN gene has been associated to SoJIA; LACC1 encodes the enzyme laccase (multicopper oxidoreductase) domain–containing 1 that catalyzes the oxidation of several molecules (polyphenols, aromatic amines and inorganic ions), even if its exact activity is not yet well understood. All patients harboring this particular genotype experienced an early onset (from 1 to 3 years of age) of systemic features along with polyarthritis [189]. Adult onset Still’s disease (AOSD) represents the adult counterpart of SoJIA, sharing comparable clinical and pathogenic features; thus, AOSD and SoJIA are more likely the same autoinflammatory disease with a clinical phenotype that develops at different ages [190].

7.2. Idiopathic pericarditis

Pericarditis may be due to several causes, even though, in developed countries, it is frequently labeled as idiopathic. The underlying mechanism is not completely known although viral agents may act as triggers resulting in activation of the IL-1 pathway [191]. Pericarditis shares several similarities with AIDs. The intermittent pattern of AIDs retraces the spontaneous onset of pericarditis along with their recurrences, moreover many AIDs may present pericarditis as one of their manifestations and others may have pericarditis as only clinical manifestation [192]. The other major similarity regards treatment. NSAIDs represent first line therapy for idiopathic pericarditis, with indomethacin (2 ​mg/kg daily, divided every 6–12 ​h) and ibuprofen (30–50 ​mg/kg daily, divided every 6–8 ​h) as drugs of choice; on the contrary, steroids should be avoided and, when necessary, employed at the lowest effective dose [193]. Furthermore, colchicine, drug extensively used in FMF patients, has shown to decrease recurrences in patients with idiopathic pericarditis and it is frequently administered in combination with NSAIDs [193]., The AIRTRIP randomized trial demonstrated the efficacy of anakinra in difficult to treat patients with recurrent pericarditis [194]. More recently canakinumab has been also used in pericarditis [195]. For all these reasons, the role of innate immune in the pathogenesis of idiopathic pericarditis is becoming prominent. Indeed, identified autoantibodies in pericarditis show low titers and low specificity [196,197].

8.1. Chronic Recurrent Multifocal Osteomyelitis (CRMO)

Chronic Recurrent Multifocal Osteomyelitis (CRMO) is a rare disease occurring in childhood. The onset of clinical manifestations is subtle and variable, mimicking infections or neoplasms; laboratory and radiological features are non-specific. CRMO is progressively being grouped under the term chronic non-bacterial osteomyelitis (CNO) in which sterile osteomyelitis is the shared feature [81]. The adult counterpart of CRMO is the synovitis, acne, pustulosis, hyperostosis and osteitis syndrome (SAPHO) [198]. The majority of CRMO patients do not show a clear genetic background although, susceptible loci have been identified [199]. Furthermore, both CRMO familial cases and other inflammatory diseases (psoriasis, inflammatory bowel disease) amongst relatives have been documented [200]. Even if CRMO pathogenesis is mostly unknown, an aberrant regulation of the innate immune system seems to promote the recurrence of bone inflammation [201]. Indeed, CRMO patients present cytokine disproportion toward a proinflammatory state (high levels of IL-1, IL-6 and TNF-α and low level of IL-10) leading to an alteration in bone metabolism. Mononuclear cells from CRMO patients express an overproduction of proteins such as IL-1β, ASC and caspase 1 [202]. On the contrary, IL-10 levels are downregulated in these patients; this may lead to inflammatory bone loss through NLRP3 inflammasome [203].

CRMO onset is often insidious, with nonspecific systemic symptoms such as low-grade fever, pain, malaise and fatigue. The disease course is characterized by recurrent episodic attacks that may last few weeks to months, with a self-limited trend [204]. Bone lesions are often multifocal, most frequently located within the long bones (typically femur and tibia) with symmetrical distribution; however, the whole skeleton can be affected. Spinal involvement can lead to debilitating consequences. Laboratory investigations may result negative; a mild elevation of white blood cell count and inflammatory markers can also occur [205]. Imaging is very useful to detect bone lesions. Conventional radiography is not able to identify initial lesions, while it can show the presence of osteolytic lesions with sclerosis (typical of an advanced stage of disease). On the other hand, whole-body MRI (with STIR sequences) is a more sensitive technique that can detect early bone lesions and unrecognized vertebral compressions [206]. Bone biopsy is the most useful technique in order to exclude the presence of neoplastic disease and to document the presence of bone marrow infiltrate. Indeed CRMO is a diagnosis of exclusion established by clinical presentation, imaging studies, and culture-negative bone biopsy [207]. In order to not miss any possible alternative diagnosis, several approaches depending on clinical, radiological and laboratory features have been proposed [205,208]. NSAIDs are recognized as first line therapy for CRMO, with good efficacy on pain relief and bone damage prevention [209]. Bisphosphonates are used in case of spinal involvement as first line therapy or after the failure of NSADIs when no systemic features are present. A trial on pamidronate in CRMO patients is now in the recruiting phase (NCT02594878). Since TNF-α is involved in bone resorption and osteoclastogenesis, anti-TNFα agents are also not surprisingly very effective in CRMO patients [210]. IL-1 blocking agents are not usually employed.

8.2. Majeed syndrome

Majeed syndrome, also known as LPIN2-CNO, is a monogenic bone autoinflammatory disease characterized by dyserythropoietic anemia with or without a neutrophilic dermatosis (Sweet syndrome or pustulosis) along with sterile osteomyelitis. It is caused by autosomal recessive loss of function mutation of LPIN2 gene encoding for a phosphatidic acid phosphatase named LIPIN2 and involved in lipid metabolism [215]. Recently, LIPIN2 deficiency in mouse has been related to P2X7R activation leading to alteration of cytosolic K+ with the final result of NLRP3 inflammasome hyperactivity [216]. The classic triad (sterile osteomyelitis, anemia and dermatosis) is not always present; indeed several Majeed patients do not develop skin involvement. The onset is very early in life, typically before 2 years of age, and it is often accompanied by fever episodes, failure to thrive and joint contractures [217]. The efficacy of IL-1 blocking agents has indirectly confirmed the autoinflammatory pathogenesis of Majeed syndrome [218].

8.3. Deficiency of IL-1 receptor antagonist (DIRA)

The deficiency of IL-1 receptor antagonist (DIRA) leads to systemic inflammation along with skin and bone involvement, usually without fever. DIRA is caused by recessive mutation of the IL1RN gene that codifies for IL-1 receptor antagonist (IL-1RA). Thus, IL-1β and IL-1α lack their physiological inhibition resulting in pro-inflammatory imbalance [219].

The onset is usually within the first months of life with pustular lesions along with the increase of inflammatory markers followed by osteitis and periostitis; these patients rarely develop mild fever [219]. Bone involvement is severe with multiple osteolytic lesions and periostitis, prevalently over long bones (proximal femur) and vertebral bodies [220]; biopsy shows sterile neutrophilic osteomyelitis, fibrosis and sclerosis [219]. Classically imaging pattern of DIRA includes diffuse osteolytic lesions, widening of anterior rib ends and periostitis of long bones [219,220]. Moreover, osteolytic lesions of the scalp, widening of the clavicles and heterotopic ossification of the proximal femurs have been described [219]. DIRA patients respond very well to exogenous IL-1RA, anakinra [219].

8.4. Cherubism

The development of osteolytic lesions of mandibles and the following fibrotic dysplastic soft tissues overgrowth within these lesions confer typical puffy cheeks face to patients with cherubism. This disease is due to heterozygous missense mutations of the SH3 binding protein 2 (SH3BP2) gene with variable penetrance and expressivity amongst members of the same families; moreover, sporadic mutations are not uncommon [221]. Interestingly, similar lesions of jaws can be detected in patients with other genetic diseases such as Noonan syndrome and neurofibromatosis [222,223]. Recently, the name “SH3BP2 deficiency with multilocular cystic disease of the mandibles (SDCM)” has been proposed instead of the biblical “cherubism” in order to reinforce both genetic and clinical disease features [81]. SH3BP2 is a protein that binds several other proteins with different functions in both innate and adaptive immunity cells [224]; furthermore, SH3BP2 plays a crucial role in bone remodeling and its mutations are related to hyperfunction of osteoclast resulting in an increase of bone resorption [225]. The course of the disease is characterized by the early development of osteolytic lesion (around 2–5 years of age) of mandibles followed by reparative mechanisms with activation of fibroblasts and osteoblasts [226]. Although facial involvement is the predominant feature, lesions of ribs may be detected [226]. Cherubism treatment is driven by anecdotal reports in which adalimumab and bisphosphonates have been used, but not always with satisfactory effects [227,228].