Hereditary Periodic Fever Syndromes and Other Systemic Autoinflammatory Diseases

Familial Mediterranean Fever

FMF is a recessively inherited autoinflammatory disease usually characterized by recurrent, short-lived (1-3 days), self-limited episodes of fever, serositis, mono- or pauciarticular arthritis, or an erysipeloid rash, sometimes complicated by AA amyloidosis. Most patients with FMF present with symptoms in childhood, with 90% presenting before age 20. Clinical features of FMF may include fever, serositis presenting as pleuritic chest pain or severe abdominal pain, arthritis, and rash. The pleural pain is typically unilateral, whereas the abdominal pain (sterile peritonitis) can be generalized or localized to 1 quadrant, similar to other forms of peritonitis. FMF-associated arthritis occurs primarily in the large joints, may be accompanied by large, neutrophil-rich effusions, and is usually nonerosive and nondestructive. The hallmark cutaneous finding is an erysipeloid erythematous rash that overlies the ankle or dorsum of the foot ( Fig. 188.2 ). Other clinical findings include scrotal pain caused by inflammation of the tunica vaginalis testis, febrile myalgia, exercise-induced myalgia (particularly common in children), and an association with various forms of vasculitis, including Henoch-Schönlein purpura, in as many as 5% of pediatric patients. FMF episodes may be triggered by stress, menses, or infections. Between flares, patients are generally symptom free but may have persistent elevation of their inflammatory markers. The attack frequency can vary from weekly to 1-2 flares per year. Table 188.6 lists diagnostic criteria for FMF.

FMF is caused by autosomal recessive mutations in MEFV , a gene encoding a 781 amino acid protein denoted pyrin (Greek for “fever”). Pyrin is expressed in granulocytes, monocytes, and dendritic cells (DCs) and in peritoneal, synovial, and dermal fibroblasts. The N-terminal approximately 90 amino acids of pyrin are the prototype for a motif (the PYRIN domain) that mediates protein-protein interactions and is found in >20 different human proteins that regulate inflammation and apoptosis. Many of the FMF-associated mutations in pyrin are found at the C-terminal B30.2 domain of pyrin, encoded by exon 10 of MEFV. More than 50 such FMF mutations are listed in an online database ( http://fmf.igh.cnrs.fr/ISSAID/infevers/ ), almost all of which are missense substitutions. Homozygosity for the M694V mutation may be associated with an earlier age of onset, arthritis, and an increased risk of amyloidosis. The substitution of glutamine for glutamic acid at residue 148 (E148Q) is considered either a mild mutation or a functional polymorphism in the pyrin protein. The carrier frequency of FMF mutations among several Mediterranean populations is very high, suggesting the possibility of a heterozygote advantage.

FMF occurs primarily among ethnic groups of Mediterranean ancestry, most frequently Jews, Turks, Armenians, Arabs, and Italians. Because of a higher frequency of the M694V mutation, FMF is more severe and more readily recognized in the Sephardic (North African) than the Ashkenazi (East European) Jewish population. With the advent of genetic testing, mutation-positive FMF has been documented worldwide, although at lower frequency than in the Mediterranean basin and Middle East.

Through PYRIN-domain interactions, pyrin can activate caspase-1 , the enzyme that converts the 31 kDa pro–IL-1β molecule into the biologically active 17 kDa IL-1β, which is a major mediator of fever and inflammation. FMF mutations lead to a gain-of-function activation of caspase-1 and IL-1β–dependent inflammation, with a gene-dosage effect. These results may explain why as many as 30% of heterozygous carriers of FMF mutations have biochemical evidence of inflammation.

Prophylactic daily oral colchicine decreases the frequency, duration, and intensity of FMF flares. This regimen also prevents the development of systemic AA amyloidosis. Colchicine is generally well tolerated and safe in children, with the most common side effects being diarrhea and other gastrointestinal (GI) complaints. Some patients develop lactose intolerance while taking colchicine. GI side effects can be minimized by initiating therapy at a low dose (for young children, 0.3 mg/day) and slowly titrating upward. A dose-related transaminitis may also be observed; bone marrow suppression is rarely seen at the dosages prescribed for FMF. Pediatric patients may require doses of colchicine similar to those needed in adults (1-2 mg/day), reflecting that children metabolize the drug more rapidly than adults. It is not always possible to find a tolerated dose of colchicine at which all symptoms are suppressed, but approximately 90% of patients have a marked improvement in disease-related symptoms. A small percentage of FMF patients are either unresponsive to or intolerant of therapeutic doses of colchicine. Based on the role of pyrin in IL-1β activation, a trial demonstrated the safety and effectiveness of rilonacept, an IL-1 inhibitor, in FMF; there are case reports of the effectiveness of anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist.

Amyloidosis is the most serious complication of FMF, and in its absence FMF patients may live a normal life span. Amyloidosis may develop when serum AA, an acute-phase reactant found at extremely high levels in the blood during FMF attacks, is cleaved to produce a 76–amino acid fragment that misfolds and deposits ectopically, usually in the kidneys, GI tract, spleen, lungs, testes, thyroid, and adrenals. Rarely, cardiac amyloidosis may develop; macroglossia and amyloid neuropathy are generally not seen with the amyloidosis of FMF. The most common presenting sign of AA amyloidosis is proteinuria. The diagnosis is then usually confirmed by rectal or renal biopsy. In a small number of case reports, mostly from the Middle East, amyloidosis may actually precede overt FMF attacks, presumably because of subclinical inflammation. Risk factors for the development of amyloidosis in FMF include homozygosity for the M694V MEFV mutation, polymorphisms of the serum AA gene (encoding AA), noncompliance with colchicine treatment, male gender, and a positive family history of AA amyloid. For unclear reasons, country of origin is also a major risk factor for amyloidosis in FMF, with patients raised in the Middle East having a much higher risk than genotypically identical patients raised in the West. Aggressive lifelong suppression of the acute-phase reactants should be the goal in patients with FMF amyloidosis, and documented cases show this may result in resorption of amyloid deposits. The natural history of untreated amyloidosis in FMF is the inexorable progression to renal failure, often within 3-5 yr.

Hyperimmunoglobulinemia D With Periodic Fever Syndrome

HIDS, also known as mevalonate kinase deficiency , was initially described in a cohort of Dutch patients and occurs primarily in patients of Northern European descent. HIDS is recessively inherited and caused by mutations of MVK , a gene that encodes mevalonate kinase (MK). The clinical features of HIDS generally appear within the 1st 6 mo of life. Febrile attacks last 3-7 days, with abdominal pain often accompanied by diarrhea, nausea, and vomiting. Other clinical manifestations include cervical lymphadenopathy, diffuse macular rash, aphthous ulcers, headaches, and occasional splenomegaly ( Figs. 188.3 to 188.5 ). Arthritis or arthralgia can be present in an oligoarticular or polyarticular pattern. Inflammatory disease–like illness and Kawasaki disease–like presentation have also been reported. Attacks are often precipitated by intercurrent illness, immunizations, and surgery. Families frequently recount flares around the time of birthdays, holidays, and family vacations. The symptoms of HIDS may persist for years but tend to become less prominent in adulthood. Patients with HIDS usually have a normal life span. Unlike FMF and TRAPS, the incidence of AA amyloidosis is quite low. Complete MK deficiency results in mevalonic aciduria that presents with severe mental retardation, ataxia, myopathy, cataracts, and failure to thrive (see Chapter 103 ).

MK is expressed in multiple tissues and catalyzes the conversion of mevalonic acid to 5-phosphomevalonic acid in the biosynthesis of cholesterol and nonsterol isoprenoids. Patients with HIDS-associated mutations have greatly reduced, but not absent, MK enzymatic activity. HIDS patients usually have low-normal serum cholesterol levels, but the deficiency of isoprenoids may cause increased IL-1β production by aberrant activation of the small guanosine triphosphatase Rac1. Temperature elevation may further exacerbate this process by more complete inhibition of MK activity, leading to a possible positive feedback loop.

The diagnosis of HIDS may be confirmed either by 2 mutations in MVK (approximately 10% of patients with seemingly typical disease have only a single identifiable mutation) or by elevated levels of mevalonate in the urine during acute attacks. HIDS-associated mutations are distributed throughout the MK protein, but the 2 most common mutations are the substitution of isoleucine for valine at residue 377 (V377I), a variant that is quite common in the Dutch population, and the substitution of threonine for isoleucine at residue 268 (I268T). The eponymous elevation in serum IgD levels is not universally present, especially in young children; IgA levels can also be elevated. Conversely, serum IgD levels may be increased in other autoinflammatory disorders as well as in some chronic infections. During attacks, leukocytosis and increased serum levels of acute-phase reactants and proinflammatory cytokines are frequently present. Table 188.7 lists diagnostic criteria for HIDS.