Common Features

Periodicity and fever are the cardinal features of many AD, but some may have a more chronic and/or afebrile course. The inflammatory response is typically localized to serosa, skin, eyes, lymph nodes and the musculoskeletal, gastrointestinal and nervous systems. The majority of AD present with recurrent episodes of inflammatory states, typically with fever and elevated inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], serum amyloid A proteins [SAA]). Tables 14-1 and 14-2 summarize the typical features of these disorders. In addition, blood count abnormalities (leukocytosis, thrombocytosis, anemia) and elevated immunoglobulin levels are commonly seen. Patients are usually asymptomatic between the attacks, though in the severe forms longer duration of symptoms may occur. Variability of features is seen within each syndrome, even within the same family. There may be a prodromal period with nonspecific features, such as fatigue and headaches.

When a patient presents with recurrent fevers, the differential remains broad and includes infectious, rheumatologic and oncologic/lymphoproliferative causes, as well as immunodeficiencies. The longer the period of repeated, stereotypical episodes, especially with fevers and systemic features affecting skin, mucosa, eyes, musculoskeletal, gastrointestinal and nervous systems, the greater the likelihood of an AD. Since the penetrance of the mutations is not 100% and de novo mutations may occur, a negative family history does not exclude a particular diagnosis. A family history of amyloidosis, chronic renal disease and deafness would strengthen the possibility.

When AD are considered, genetic testing may be helpful in confirming the diagnosis. However, up to 60% or more patients may have negative genetic testing, despite classic features consistent with a particular syndrome, which could be a result of unknown genetic defects in the same inflammatory pathway, epigenetic factors, somatic mosaicism or phenotypic variability.

Genotype databases and other collaborative registries (e.g. Infevers: http://fmf.igh.cnrs.fr/infevers ; Eurofever, EuroTRAPS) have been established and more than 1,000 sequence variants of these diseases have been registered, including many variants of unclear significance.

In recent years, based on the inheritance pattern, age of onset, duration, frequency and associated features of the attacks and ethnicity, decision-making trees have been proposed in the evaluation of patients with periodic inflammatory episodes, but these algorithms are most applicable in areas of higher prevalence.

Pathogenesis

An exaggerated inflammatory response appears to occur, due to increased sensitivity to normal or insignificant stimuli, or due to the inability of the immune system to dampen normal responses in an efficient and timely manner. Most of the mutated proteins in these disorders are members of the death-domain fold (DDF) family, which are involved in apoptosis, NF-κB activation and proinflammatory cytokine production. More recently, another mechanism was found: the role of protein misfolding in increasing cellular stress, causing an increase in reactive oxygen species, which in turn triggers an exaggerated inflammatory response with only minimal secondary stimuli such as lipolysaccharide. In addition, defects in autophagy and proteasome function are other possible pathways causing autoinflammation. There have been conflicting results of the studies; these may be related to differences in experimental models. It is possible that these proteins assume different roles under different situations and that the dosage of gene and other modifier genes have effects on the immune/inflammatory pathways contributing to the variable presentations of the diseases.

Familial Mediterranean Fever (FMF)

FMF was the first described autoinflammatory disease: in 1908 by Janeway and Rosenthal in a Jewish girl, and in 1945 by Siegal. The initial spread of FMF can be traced back to Mesopotamia 2,500 years ago. It is an autosomal recessive condition reported worldwide, but most patients have ancestry in the Mediterranean basin, particularly in the Middle East, where the prevalence is 1:250 to 1:1,000, with a carrier frequency as high as 1 in 3 to 5, suggesting survival via an enhanced innate immune response. Carriers of the FMF gene have a heightened inflammatory response, supporting this hypothesis. After mapping of the FMF susceptibility locus to chromosome 16p in 1992, the mutated gene, named MEFV (MEditerranean FeVer) was discovered by two independent groups using positional cloning in 1997. The deduced protein pyrin (the Greek for ‘fever’)/ Marenostrin (the Latin ‘Mare Nostrum’ for ‘our sea’) is 781amino acids long and is primarily expressed in the cytoplasm of neutrophils but is also found in other cells. Almost all mutations are missense mutations: via its N-terminal death domain (pyrin domain-PYD), pyrin interacts with the pyrin domain of the adapter protein ASC (apoptosis-associated speck-like protein) to assemble and activate inflammatory complexes. These proteins have been found to play a role in controlling IL-1β production by regulating caspase-1. The exact physiologic role and underlying mechanisms of mutated pyrin are not well understood. Pyrin mutations result in gain of function but the expression of the disease depends on how much mutated protein is produced.

Mutations in position 694 usually cause a more severe phenotype, especially M694V. Low penetrance mutations, such as E148Q, are also described. The allele frequency of E148Q is 10% to 20% in Asians and 1% to 2% in Caucasians.

FMF episodes may be triggered by physical or emotional stress, infections, exercise, menstruation and diet. An attack may be preceded by malaise, irritability and decreased appetite. Major features are fever and abdominal pain due to serositis, mostly peritonitis (95%), recurrent attacks of which may cause adhesions. Pleuritis, which is usually unilateral, is seen in about 40% of patients, while pericarditis is rare in FMF. Orchitis occurs in about 5% and is more common in children. Arthritis/arthralgia affects primarily the lower extremities and is transient, resolving without any sequelae, though some patients may develop chronic destructive arthritis. Exercise-induced myalgia may occur during an episode. The erysipelas-like rash, commonly seen around the ankles, is a relatively unique feature of FMF and occurs in about 20% to 30% of patients. Prolonged, severe muscle pain affecting lower extremities and abdominal muscles, known as protracted febrile myalgia, may rarely occur and is responsive to steroid therapy. Occasionally, there is an accompanying vasculitic rash. Laboratory investigation reveals leukocytosis and elevated inflammatory markers. SAA and S100A2 levels may be used to follow disease activity.

Diagnosis is still primarily clinical because about 25% of the patients have a negative genetic analysis for MEFV mutation. Furthermore, a significant number of patients with homozygosity never develop clinical features, while about 30% to 40% of the patients with FMF are heterozygotes. This variability is thought to be due to the dose effect of the mutated protein. Clinical criteria for diagnosis in adults were proposed by Livneh in 1997 and guidelines for diagnosis in children have been published. Both sets of criteria are highly specific and sensitive in areas of high prevalence, but not in less prevalent areas. Certain vasculitides such as Henoch-Schönlein purpura (HSP) and polyarteritis nodosa (PAN) have increased frequency in FMF patients. Behçet’s disease is also more common in carriers and FMF patients.

Colchicine is the mainstay of the treatment of FMF and eliminates or substantially decreases symptoms in about 95% of patients. More importantly, regular use of colchicine prevents the development of amyloidosis, the major contributor to morbidity and mortality in these patients. Before colchicine use, up to 75% of patients would develop amyloidosis after the age of 40 years. Risk factors for amyloidosis include M694V mutation, male gender, SAA α/α genotype and family history of amyloidosis. Environmental factors also play a crucial role in the development of amyloidosis.

To date, the mechanism of action of colchicine in FMF is not well understood. Colchicine accumulates primarily in neutrophils and is postulated to affect neutrophil adhesion and mobility by binding to the cytoskeleton of the cells and preventing microtubule elongation. It is generally well tolerated with minimal side-effects, diarrhea being the most common (10–20%). Acute toxicity from an overdose can be very serious since it has a narrow therapeutic window. Studies have suggested that it is safe to use during pregnancy and lactation and does not affect fertility. Colchicine is used as a preventative therapy. Intermittent use or increasing the dose during attacks has no role in management of FMF. Colchicine resistance is rare (< 5%), therefore an alternative diagnosis or noncompliance should be considered in nonresponsive patients. IL-1-blocking drugs (anakinra, rilonacept, canakinumab) are the drugs of choice in colchicine resistant or intolerant patients.

TNF Receptor-Associated Periodic Fever Syndrome (TRAPS)

TRAPS, an autosomal dominant AD, was formerly known as ‘Hibernian fever’. It was first described in Ireland in 1982 and is most common in Irish and Scottish populations but is now known to occur worldwide ( http://fmf.igh.cnrs.fr/ISSAID/infevers/ ).

The association of this syndrome with mutations in the TNFRSF1A gene on chromosome 12p13 was discovered in 1999. This gene encodes the TNF receptor type 1 (also known as p55TNFR). Binding of TNF-α to its receptor initiates the intracellular activation cascade through the death domain, leading to the activation of both NF-κB and apoptosis pathways.

The pathogenesis of TRAPS is still not clear and several mechanisms have been proposed. To date, more than 130 mutations have been described ( http://fmf.igh.cnrs.fr/ISSAID/infevers/ ). Among these mutations R92Q is the most common variant in Caucasians and P46L in African-Americans. The R92Q substitution has been found in chromosomes of 1% to 35% of the general population. These mutations may have reduced penetrance, leading to atypical presentations of TRAPS.

Fevers in TRAPS generally last longer than those in other forms of periodic fever syndromes, ranging from 1 to 3 weeks. Attacks occur at irregular intervals from once to seven times a year. In a subset of patients, the symptoms are present continuously. The age of onset is about 3 years (ranging from 1 to 63 years). Common features of TRAPS include severe abdominal pain (92%) due to serositis with risk of adhesions, painful centrifugally migrating myalgia (due to monocytic fasciitis) that can be associated with an overlying painful erythematous rash, ocular inflammation with conjunctivitis, uveitis, unilateral periorbital edema and arthralgia (less commonly arthritis) primarily affecting large joints. Other findings may include chest pain due to pleuritis, pericarditis, myocarditis and scrotal swelling. Similar to other AD, elevated inflammatory markers are found. In addition, some patients have low soluble TNF receptor levels between episodes. The risk of amyloidosis is greatest in patients with mutations involving cysteine substitutions, reported to be as high as 24% without treatment.

Nonsteroidal antiinflammatory drugs (NSAIDs), steroids and colchicine are used with some success in this condition. Etanercept, a dimeric fusion protein consisting of the p75 portion of TNFR linked to Fc portion of IgG1, decreases the severity of the attacks in the majority of patients but the effect seems to wane over time in some patients. Furthermore, the efficacy of this therapy may wane over time. Interestingly, infliximab and adalimumab, which are monoclonal antibodies against TNF-α, paradoxically trigger exacerbations of febrile episodes in some patients. Etanercept nonresponders may respond to the IL-1 receptor antagonists (anakinra).

Mevalonate Kinase Deficiency (MKD)/Hyper IgD Syndrome (HIDS)

MKD, formerly known as HIDS because of the initial observation of elevated IgD levels in patients, was first described in 1984 in 6 Dutch patients. An unexpected finding was that the gene causing MKD was found to encode mevalonate kinase, an enzyme in the cholesterol biosynthesis pathway. The enzyme was already known to be implicated in mevalonic aciduria (MA), which is a metabolic disorder that presents in infancy with devastating neurologic abnormalities (mental retardation, cerebellar ataxia, cataracts, hypotonia, dysmorphic features) and eventually leads to early death. MA shares many of the features of HIDS, hence the name was changed to MKD. HIDS and MA are a phenotypic continuum of mevalonate kinase deficiency, from mild to severe disease.

Heightened inflammatory response caused by abnormal functioning of an enzyme in the cholesterol biosynthesis pathway was ultimately shown to be connected to the IL-1β pathway.

The most common mutation in MKD is at position V377I, a founder effect from a common ancestor. High frequency of this mutation in Northern Europe is thought to be a selective advantage related to higher consumption of saturated fat. Urine mevalonic acid level increases during the episodes in HIDS, while it is persistently high in MA. Enzyme activity is 1–10% in HIDS but < 1% in MA. The activity of the mutated enzyme decreases even further with fevers. Mevalonic acid accumulates and end products, which are important in isoprenylation of proteins, decrease. The shortage of some of these end products, especially geranylated proteins, is involved in increased IL-1β production. Not every patient with MKD has elevated IgD levels, especially children. Elevated IgD levels have also been described in infections such as tuberculosis and other inflammatory conditions, including other periodic fever syndromes. Polyclonal IgA elevation may also be seen in HIDS.

Onset is often in infancy (90%) and is characterized by fevers recurring every 4 to 8 weeks, accompanied by painful cervical lymphadenopathy (90%), abdominal pain and vomiting (70%), an often maculopapular, occasionally urticarial, purpuric and erythema nodosum type skin rash (60%), arthralgia/myalgia (80%), aphthous and/or genital ulcers (50%) and hepatosplenomegaly (30%). Chills and sweating are also common. Arthritis affecting large joints and pleuritis are less common. Immunizations and other stressors such as trauma or infections usually trigger attacks. Features of MKD resemble those of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA). In the majority of the patients flare frequency decreases in adulthood. Amyloidosis is rare in MKD but not unheard of. Mild immunodeficiency features have been described in some patients.

Effective treatment for HIDS is not available. Steroids, etanercept and colchicine are beneficial in a small group of patients. Lately anakinra has shown some promise. Simvastatin, an HMG-CoA reductase inhibitor, may help in some patients with HIDS but it may exacerbate the condition in some patients with MA. There are also anecdotal reports of benefit from the leukotriene inhibitor, montelukast.