Familial Mediterranean fever (FMF) is the most common of the Mendelian autoinflammatory diseases. It is seen most frequently in the Armenian, Arab, Turkish, and Sephardi Jewish populations with carrier frequencies ranging from 1:3 to 1:10 in population-based studies. The disease prevalence is significantly lower due to reduced penetrance of many of the FMF-associated mutations. The high carrier frequency in multiple populations may confer selective advantage and resistance to a yet-unknown endemic pathogen. Typically, carriers for various FMF-associated mutations are asymptomatic but they may actually have subclinical evidence of inflammation or even be periodically symptomatic [26].

Patients with FMF have acute attacks of fever and localized inflammation that commonly involve the peritoneum, pleura, skin, or joints. The hallmark cutaneous finding is an erysipeloid erythematous rash on the dorsum of the foot or ankle (Fig. 3.1). Biopsies of the rash show a mixed cellular infiltrate [27]. Attacks begin during childhood with up to 90 % of patients experiencing their initial attack prior to age 20. Attacks typically last 1–3 days and subside spontaneously. Between attacks, patients generally feel well, although there may be some persistent acute phase reactant elevation on laboratory analysis. The quality and severity of attacks can vary from one attack to another and can differ significantly between members of the same family [22, 23].

FMF is an autosomal-recessive disease that results from mutations in the MEFV gene. The MEFV gene is located on chromosome 16p and contains ten exons that encode the pyrin/marenostrin protein. The FMF-associated mutations are found primarily in exon 10 that encodes the B30.2/PRYSPRY domain at the C terminal end of the protein. The pyrin protein is expressed predominately in neutrophils, but also in synovial fibroblasts and dendritic cells. Pyrin was found to interact with ASC, the apoptosis-associated speck-like protein, with a caspase-recruitment domain (CARD), through cognate pyrin domain (PYD) association and is involved in regulation of the caspase-1 pathway, which results in secretion of IL-1β(beta) [28]. The pyrin protein has also been shown to affect apoptosis and NF-κ(kappa)B activation [28–30]. In the Infevers database (fmf.igh.cnrs.fr/infevers), there are currently close to 300 MEVF sequence variants reported; however, only a minority of these are clearly FMF disease-associated mutations [31]. Four mutations (M680I, M694V, M694I, and V726A) account for most disease alleles in various Middle Eastern FMF populations. Mutations affecting the M680 and M694 amino acid residues are associated with early onset of FMF, severe disease, and an increased AA amyloidosis risk in all ethnic groups, whereas the V726A mutation is usually associated with milder FMF. NMR and crystallographic data indicate that severe FMF mutations map close to a putative binding pocket of the PRYSPRY domain, whereas a less severe mutation V726A is located on the opposite side of the domain [24]. Although by definition the diagnosis of FMF would require that two mutations be present (as it is an autosomal-recessive disease), there is a subset of patients who present with typical FMF symptoms but have only one demonstrable mutation in the MEFV gene despite sequencing of the entire MEFV gene [32, 33]. In addition, there are reports of families with clearly dominantly inherited mutations in MEFV who present with FMF-like disease [34, 35]. This could be possibly explained by observation from pyrin knock-in mouse model studies, which suggest that FMF is the result of gain-of-function mutations leading to the activation of IL-1β (beta) pathway [36]. In support of single mutation FMF, analysis of asymptomatic carriers has found evidence for subclinical inflammation as manifested by elevated acute phase reactants [26, 37].

The prevalence of AA amyloidosis in FMF patients in various case series has ranged from 0 % in Armenians living in America to 37 % in the Sephardi Jewish population. A multicenter study published by Touitou et al. found an overall prevalence of 11.4 % [38]. The incidence varied depending on the population frequency of homozygosity for the M694V mutation, male gender, SAA1 α/α (alpha/alpha) genotype, positive family history, and non-compliance with colchicine treatment [38, 39]. The large, multicenter study revealed that country of residence and its infant mortality rate strongly correlated with the development of AA amyloidosis. Patients residing in Armenia, Turkey, and Arabian countries had a three-fold increased risk of developing AA amyloidosis compared to other countries [38]. It is unclear as to why this risk factor is significant, but it has been speculated that environmental factors such as increased poverty levels, standards of health care, and infections may contribute to this finding. Of note, patients born in countries that carry a high risk for developing AA amyloidosis who immigrate to a low-risk country tend to develop AA amyloidosis at the lower rates after emigration. This was initially identified in a group of 100 Armenians with FMF who were living in the United States. None of them developed AA amyloidosis in comparison to the 24 % of FMF patients living in Armenia who had developed amyloidosis at the time of publication [39]. Recent studies from Turkey reported that, as it would have been expected, there has been a significant decrease in the rate of secondary amyloidosis; nevertheless, SAA amyloidosis was still present in 193/2,246 patients (8.6 %) [40] The main reason for this decline is better medical care with increased awareness and treatment of the disease [41]. The multicenter study by Touitou et al. also noted that FMF patients with the M694V/M694V mutations in the MEFV gene had a higher risk for AA amyloidosis, especially if they lived in Armenia, Israel, and Arabian countries. FMF patients with the SAA1 α/α (alpha/alpha) genotype have been observed to have a sevenfold increase in the risk for amyloidosis with a notable additional increase in patients who carry two copies of the severe mutation, M694V. One other risk factor identified in the multicenter study was disease duration [42].

The presence of M694V was also reported as the major risk factor for amyloidosis in a comprehensive review of the literature that included 3,505 patients with FMF from Turkey. Among 400 patients with amyloidosis and known genotypes, 47 % had the M694V/ M694V genotype, while an additional 21 % of patients carried at least one M694V mutation. The majority of other high-risk genotypes are also found in the exon 10 of MEFV, in particular mutations affecting the M694 and M680 amino acid residues [43]. FMF patients homozygous for the M694V mutation had the highest levels of SAA even during remission (Fig. 3.2). However, it should not go unstated that there are other non-exon ten mutations (S179I) that have been associated with the development of amyloidosis, although these cases are rare [42–44]. The development of amyloidosis in an E148Q patient is especially interesting considering that the carrier frequency of E148Q in certain populations is over 10 %. In general, patients with the E148Q mutation are thought to have milder and atypical FMF-like disease; however, there have been amyloidosis cases described in E148Q/E148Q patients [45]. In most cases, the E148Q variant has been observed in combination with a true FMF-associated mutation, inherited either in trans or in cis as a “complex allele” [44]. Some studies have suggested a gene dosage effect, with patients who have three or four MEFV mutations appearing to have more severe disease and susceptibility to amyloidosis [46].

FMF patients who develop amyloidosis generally have classic FMF with two inherited mutations. It is exceedingly rare, although not unheard of, for patients with single mutation FMF to develop amyloidosis. Such is the case with multiple members of a Spanish family with a H478Y mutation that causes an autosomal dominant form of FMF-like disease. AA amyloidosis has developed in many of the mutation positive members of this family [34].

Although it would seem logical that FMF patients who have frequent, severe attacks would be at the most risk for the development of AA amyloidosis, studies have found that is not always the case. There are patients who have had hundreds of attacks and never develop amyloidosis and there are patients who, at the age of five, passed away from amyloidosis-related complications. Even more intriguing is the subset of FMF patients who are referred to as phenotype II patients [47, 48]. These patients present with AA amyloidosis prior to experiencing their first FMF attack. In phenotype II patients, the distribution of the common MEFV mutations is not significantly different from that found in FMF patients with typical symptoms who do or do not develop amyloidosis. Patients homozygous for the M694V mutation have been observed most commonly in the phenotype II [49]. Lane et al., described 6/24 FMF patients with AA amyloidosis who did not have any symptoms of inflammation prior to diagnostic biopsy. These patients were either heterozygous carriers for one M694V mutation or carried other mild FMF-associated mutations [44]. Although unclear, it seems that secondary genetic or environmental factors play a significant role in the development of AA amyloidosis in patients with FMF [47–49].

The major histocompatibility complex (MHC) has been found to be associated with a number of inflammatory diseases such as Behçet’s disease, rheumatoid arthritis, and psoriatic arthritis. In the case of FMF, the MHC class I chain-related gene A (MICA) is of specific interest. Analysis of MICA in FMF patients has revealed that although certain MICA alleles are associated with earlier onset of symptoms (A9 allele) and decreased frequency of attacks (A4 allele), when specifically examining FMF patients with amyloidosis, no significant association has been found [50–52].

A hallmark event for patients with FMF came with the implementation of daily colchicine as primary therapy in the early 1970s [53]. Subsequent studies have shown that compliance with daily colchicine causes a marked decrease in FMF symptoms in 90 % of patients as well as a decrease in SAA levels [54, 55]. Additionally, Zemer et al. found that colchicine compliance reduced the risk of proteinuria development from 48.9 % in untreated/non-compliant patients to 1.7 % in colchicine compliant patients over the course of 11 and 9 years respectively [56]. A marked decrease in both the frequency of FMF flares as well as new cases of AA amyloidosis has been substantiated in subsequent studies [57, 58]. In recent years, patients who continue to have frequent attacks while on colchicine, patients who have persistently elevated inflammatory markers despite colchicine therapy, and patients who are intolerant to colchicine’s side effects, have had the IL-1 receptor antagonist, anakinra added to their regimen. Although large studies have not been conducted using anakinra, preliminary case reports have shown positive results with reduction in clinical symptoms and/or acute phase reactants [59, 60]. Anakinra had a strong effect in suppressing inflammation in FMF patients with amyloidosis and may change the prognosis of these patients [61].

Regarding FMF patients with amyloidosis who have undergone renal transplantation, a study was completed that compared long-term outcomes between FMF patients and patients transplanted for other conditions. Overall graft and patient survival was comparable to that of the non-FMF group and, with continuation of colchicine, amyloid infiltration of the transplanted kidney was held to 5 % [62]. At 5 years after transplantation, patient survival was at 89 %, while recurrence was noted only in 1/18 patients [62].

Since albuminuria is an early finding in FMF amyloidosis, patients should undergo periodic urinalyses, especially those who are at high risk. In one large series, the sensitivity of renal biopsy for detecting amyloidosis in FMF was 88 %, followed by rectal biopsy at 75 %, liver biopsy at 48 %, and gingival biopsy at 19 % [63]. Many physicians prefer rectal biopsy because it is relatively noninvasive. The sensitivity of bone marrow biopsy in a more recent small series was found to be 80 %, and the sensitivity of testicular biopsy is about 87 % [64, 65].

TRAPS was initially described clinically in a family of Irish/Scottish descent. At that time, it was given the appropriate name of familial Hibernian fever [66]. Additional cases of patients not of Irish or Scottish descent coupled with the discovery of the mutated gene being the TNFRSF1A gene, brought about its change in name to TRAPS [67]. Patients with TRAPS typically present within the first decade of life. They frequently have a history of prolonged fever episodes lasting for at least 3 days but commonly lasting many weeks. Additional clinical findings include abdominal pain frequently associated with constipation, diarrhea and bowel obstruction. Analysis of the abdominal cavity during flares has revealed sterile peritonitis. Other symptoms include periorbital edema, conjunctivitis and localized myalgias (Fig. 3.3). On imaging, affected muscle groups show focal areas of edema [22, 23]. Cutaneous findings include an erythematous macular rash that on biopsy contains superficial and deep perivascular infiltrates of mononuclear cells [68]. Patients often report the rash migrates distally during its course and clinically, can resemble cellulitis. Patients can also report erythematous annular patches. Arthralgias are fairly common but frank arthritis is relatively rare. Attacks are commonly associated with stress or physical exertion. During attacks, there is marked elevation in the acute phase reactants (ESR, CRP, SAA) as well as leukocytosis and thrombocytosis. In the interim period between attacks, acute phase reactants may return to normal or, in some cases, remain mildly elevated [22, 23].

TRAPS is an autosomal dominant disorder caused by missense mutations in the TNFRSF1A gene that is located on chromosome 12p13. The TNFRSF1A gene encodes the 55-kDa TNF receptor protein (also known as TNFR1, p55, CD120a) [22]. To date, there are more than 60 disease-associated mutations listed in the Infevers database and almost all of them are found in exons 2–4 that encode the first two cysteine rich domains (CRD1-CRD2) of the extracellular domain of TNFR1. Mutations associated with the most severe and penetrant disease phenotype and confer the highest risk to develop SAA amyloidosis affect cysteine residues that participate in the assembly of disulfide bonds important for TNFR1 folding [67]. Likewise, another common TRAPS-associated mutation, T50M, involves a highly conserved intra chain hydrogen bond critical for the folding of the extracellular domain of TNFR1. As a result of these structural changes induced by TRAPS mutations, the mutant receptor accumulates within the cell triggering innate immune responses and the production of various pro-inflammatory cytokines [69]. The wild type protein, made by the normal allele since TRAPS is caused by heterozygous mutations, is expressed on the cell surface and further amplifies the inflammatory loop. The real challenges in the diagnosis of TRAPS are patients who carry low-penetrance variants such as R92Q and P46L. Although these variants were initially reported as associated with TRAPS, further studies have questioned their clinical significance. The allele frequency of R92Q is in the range from 1 to 10 % in Caucasians, while the P46L variant is found at a frequency of close to 20 % in African and African-American patients. Testing patients for TNFR1 mutations identify many of them to have these variants; however, the phenotype of these patients is not similar to TRAPS patients with structural mutations, and thus the clinical significance of these variants is still controversial [70, 71].

It is estimated that between 14 and 25 % of patients with TRAPS develop AA amyloidosis [66]. Patients who have cysteine mutations appear to have an increased risk (the probability of developing life-threatening amyloidosis is 24 % versus 2 % for noncysteine residue substitutions) above that of TRAPS in general although there are non-cysteine mutation TRAPS patients who have developed amyloidosis [71, 72]. The highest risk factor for SAA amyloidosis in TRAPS patients is a positive family history, thus patients who have members with AA amyloidosis should be followed closely for the development of proteinuria and aggressively treated to normalize acute phase reactants [44]. This study by Lane et al., reported that, in 9/12 patients with TRAPS, a family history for amyloidosis is a more significant risk factor for amyloidosis than actual genotype. Only 5/12 patients carried a cysteine mutation or T50M. This series also demonstrated that in patients with established AA amyloidosis without severe renal impairment at the time of diagnosis, effective treatment of the underlying disease can lead to a regression of amyloid deposits. The outcome of renal transplantation in these patients was good.

The treatment of TRAPS has proven challenging. Originally, as many of the symptoms were similar to FMF, patients were prescribed colchicine but had little or no response to the medication. Colchicine has also not been found to affect the development of amyloidosis in TRAPS [72]. Tapering courses of corticosteroids have been found to be effective at ameliorating symptoms and inflammation; however, as corticosteroids have many potential adverse effects, they should be reserved for patients who have infrequent disease flares [72].

Biologic therapies have been met with some success in TRAPS patients. The soluble p75 TNFR:Fc fusion protein, etanercept, has been introduced for treatment of TRAPS based on the observation of reduced levels of the soluble p55 protein in the serum of TRAPS patients and has been successful in reducing the severity and frequency of attacks in some patients [72, 73]. There have also been patients with AA amyloidosis who have had a favorable renal response to etanercept. Conversely, there have been multiple reports of patients responding negatively to infliximab and adalimumab with resultant paradoxical reactions [74, 75]. Therefore, of the anti-TNF alpha agents, only the use of etanercept is supported.

The use of the IL-1 receptor antagonist, anakinra, has been met with substantial success in patients with TRAPS and AA amyloidosis. Patients report a marked decrease in the severity of attacks as well as decreased frequency. Acute phase reactants also show a marked decrease and sometimes, complete normalization [76]. Regression of proteinuria has been seen in some amyloidosis patients with daily administration of anakinra [77].

Within the spectrum of autoinflammatory disorders exist three clinically distinct diseases that have mutations in the NLRP3 gene. NLRP3 is also known as CIAS1 (cold-induced autoinflammatory syndrome 1) or NALP3. The three diseases are: familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal onset multisystem inflammatory disease (NOMID) that is also known as chronic infantile neurologic cutaneous and articular (CINCA) syndrome.

Cryopyrin-associated periodic fever syndromes (CAPS)-disease associated mutations are inherited in an autosomal dominant fashion or as de novo mutations in patients with the most severe disease, NOMID. Initially, up to 40 % of patients with CAPS were reported as mutation-negative by standard sequencing. The majority of these patients have subsequently been found to carry somatic mosaic mutations in NLRP3. The estimates of the level of somatic mosaicism vary widely, ranging from as low as 4.2 % up to 35.8 %, and mutant myeloid cells are predominantly responsible for driving inflammation in mosaic patients [78].

NLRP3 encodes the cryopyrin/NLRP3 protein located on chromosome 1q44 [79]. Cryopyrin is a component of a multi-protein complex known as the NLRP3 inflammasome. The NLRP3 inflammasome acts as an intracellular sensor for various pathogen-associated molecular patterns (PAMPS) and danger-associated molecular patterns (DAMPS). The disease causing mutations lead to a constitutively activated inflammasome, causing an increase in caspase-1 activation and secretion of IL-1 and IL-18 (Fig. 3.4). CAPS-associated mutations are subtle missense nucleotide changes found almost exclusively in exon 3 that encodes the NACHT/NBS domain. Interestingly, mutations affecting the same or adjacent residues can cause very different phenotypes. To date there are 172 NLRP3 gene variants published in Infevers; however, only about half of them are true disease-associated mutations. Although the majority of mutations are specific for one of the cryopyrinopathies, there are a number of mutations that have an associated overlap clinical phenotype particularly in the range of FCAS/MWS or MWS/NOMID. The clinical significance of variants such as V198M, Q703K, and R488K is still under discussion, because they are found at low allele frequencies in the general population or sometimes in unaffected patients.

Familial cold autoinflammatory syndrome is generally the least severe of the cryopyrinopathies. First described in 1940, clinical characteristics include recurrent episodes of urticarial rash, fever, conjunctivitis, and arthralgias that are triggered by exposure to cold temperatures and develop in infancy [80] (Fig. 3.5a). The episodes are brief and self-limited and typically begin 1–3 h after exposure with resolution occurring within 24 h [23]. There is a marked inflammatory response during episodes that may or may not persist after the episode resolves. AA amyloidosis rarely occurs in FCAS and, if it develops, it is typically in older patients [81].

First described in 1962, patients with Muckle–Wells syndrome have a clinical constellation of fevers, myalgias, arthralgias, urticarial-like rash, and progressive sensorineural hearing loss [82]. Ophthalmologic involvement manifests with conjunctivitis, episcleritis, or iridocyclitis [83]. Biopsies of the skin rash show a perivascular and interstitial infiltrate of neutrophils and lymphocytes in the papillary dermis [84] (Fig. 3.5b). Unlike FCAS, MWS attacks are not precipitated by cold exposure, and other precipitating factors are not well understood. Attacks are typically 24–48 h in duration but laboratory abnormalities may persist in quiescent times. This disease presents in childhood and may present during the first few days of life. AA amyloidosis is quite common in MWS, affecting up to one-third of the patients [22].

NOMID/CINCA is the most severe cryopyrinopathy. Patients commonly present immediately after birth and the disease almost universally presents in infancy. A non-pruritic, urticaria-like rash is typically present at birth. Other disease manifestations include short stature and a disabling arthritis that can result in a characteristic bony overgrowth pattern. Neurologic symptoms found in patients include: chronic aseptic meningitis, optic disc edema, cerebral atrophy, seizures, mental retardation, and headaches [85, 86]. Generally, patients have ongoing, continuous symptoms with exacerbated attacks and, historically, approximately 20 % of patients died prior to reaching adulthood [85]. There have been NOMID patients who develop AA amyloidosis as they get older although cases are not as frequent as those with MWS, possibly due to a shortened life span in these patients [85].