Periodic Fever Syndromes and Other Inherited Autoinflammatory Diseases

Genetics and Pathogenesis

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, resulting from mutations in MEFV , ^, which encodes the protein pyrin. Pyrin is expressed primarily in innate immune cells, including granulocytes, cytokine-activated monocytes, dendritic cells, and serosal and synovial fibroblasts. The N-terminal domain of pyrin defines a motif, the PYRIN domain, which, under certain conditions, binds the cognate PYRIN domain of ASC (apoptosis-associated speck-like protein containing caspase activation and recruitment domain), resulting in the assembly of a macromolecular complex termed the pyrin inflammasome . The pyrin inflammasome is one of several such cytoplasmic complexes that serves as a scaffold for the activation of caspase-1 molecules, which in turn cleave pro-IL-1β and pro-IL-18 into biologically active cytokines and cleave gasdermin D to initiate a proinflammatory form of cell death known as pyroptosis (see Chapter 4 for further discussion).

FMF was initially thought to be an autosomal-recessive disease resulting from loss-of-function mutations in pyrin. Several clues from human studies and mouse models began to cast doubt on the loss-of-function hypothesis. Approximately one-third of people with clinical FMF have only one identified mutation in MEFV, despite extensive searches for a second mutation. In addition, some asymptomatic carriers of MEFV mutations have evidence of inflammation with elevated acute phase reactants. Furthermore, no null mutations in MEFV have been identified in people with FMF. Analysis of mouse models also supports the concept that FMF-associated mutations are gain-of-function with a gene-dosage effect. In humans, a single mutation may result either in subclinical biochemical inflammation or overt FMF, whereas the carriage of two mutations is more likely to be clinically significant.

The assembly of the pyrin inflammasome is triggered by bacterial toxins that inactivate RhoA, an intracellular GTPase that is critical for leukocyte cytoskeletal assembly in host defense. RhoA also regulates the phosphorylation status of pyrin. ^, When pyrin is phosphorylated at residues 208 and 242, inhibitory 14-3-3 proteins bind to pyrin and prevent the assembly of the pyrin inflammasome. RhoA inhibition leads to pyrin dephosphorylation, reduced 14-3-3 protein binding to pyrin, and assembly of the pyrin inflammasome. FMF-associated mutations in pyrin reduce the affinity of 14-3-3 proteins for pyrin, thereby lowering the threshold for pyrin inflammasome activation. The pyrin inflammasome is one of the first documented examples of an indirect “guard” mechanism of innate immune activation in the animal kingdom. The emerging concept of the pyrin inflammasome as an innate immune sensor has led to a better understanding of host responses to other pathogen virulence factors, including those from Yersinia species, ^, Clostridium botulinum and Clostridium difficile, and Burkholderia cepacia. ^, Mutations in human pyrin have been proposed to confer a survival benefit against certain infectious disease, perhaps including pandemic plague resulting from Yersinia pestis. ^,

FMF occurs most frequently among Sephardi and Ashkenazi Jewish, Arab, Armenian, Italian, and Turkish populations, with carrier frequencies as high as 1:3 to 1:5 in population-based surveys. FMF may occur at lower frequencies in other populations and ethnicities.

Clinical Manifestations

The first clinical episode usually occurs during childhood or adolescence, with 90% of patients having had onset by age 20 years old ( Table 39.1 ). ^, FMF attacks last between 12 and 72 hours and consists of inflammation involving the peritoneum, pleura, joints, or skin, sometimes in combination. Between episodes, patients usually feel completely well and remain so for a few days to a few months. In children, fever may be the only sign of FMF, although other symptoms generally develop progressively with time. The attacks vary not only between patients but also between episodes in a given affected individual. The exact mechanism of triggering periodic attacks in FMF is unclear, with patients often noting menstruation or stress associated with the onset of an attack.

Abdominal symptoms often accompany the fever and range from mild discomfort and distention to severe pain with rigidity. ^, Constipation is more common than diarrhea, and in extreme cases, peristalsis may cease and result in paralytic ileus. Pain can be generalized or focused in a quadrant, sometimes mimicking acute appendicitis. Pleural pain is generally unilateral, occurring with decreased breath sounds. Less commonly, a small effusion, friction rub, or atelectasis may be present.

Joint manifestations are common and are sometimes the first sign of the disease in children. Arthralgia occurs more frequently than arthritis. Arthritis in adults usually is monoarticular, although children may have involvement of several joints, symmetrically or asymmetrically, with pain and large effusions. Synovial aspirates from joints are sterile but may demonstrate leukocyte counts as high as 100,000/mm ³ . Muscle pain is a classical manifestation of FMF and occurs in about 20% of patients. Usually the pain is not severe, appears in the lower extremities after physical exertion (mostly in the evenings), lasts from a few hours to 2 or 3 days, and subsides with rest. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) may be needed. Protracted febrile myalgia is an uncommon dramatic manifestation of FMF and requires treatment with corticosteroids. It is important to differentiate colchicine-induced myopathy, a rare side effect, from an attack of prolonged febrile myalgia, an even rarer disease manifestation. Fever, high erythrocyte sedimentation rate (ESR), normal creatine kinase (CK) levels, and the evidence of inflammatory myopathy on electromyogram (EMG) should help rule out colchicine as a likely causative factor.

Cutaneous findings are less common than serosal or synovial involvement. Most commonly, there is an erysipeloid erythematous rash on the dorsum of the foot, ankle, or lower leg. ^{, ,} The rash may occur alone or in conjunction with other manifestations. Biopsies of the rash are characterized by a prominent mixed cellular infiltrate.

Findings less commonly associated with FMF include episodes of unilateral acute scrotal pain in prepubescent boys ^, and diverse cutaneous manifestations including Henoch–Schönlein purpura (IgA vasculitis). Rarely, pericarditis is observed. Behçet disease, ^{, ,} polyarteritis nodosa, ^, microscopic polyarteritis, ^, glomerulonephritis, and inflammatory bowel disease may occur more frequently in FMF patients than in the general population. The M694V mutation in MEFV is a known independent risk factor for Behçet disease and ankylosing spondylitis. ^,

Laboratory Investigations

During attacks, concentrations of acute phase reactants such as C-reactive protein (CRP), serum amyloid A (SAA), and complement increase. Leukocytosis and an increased ESR are also commonly observed. The continuous elevation of these acute phase serum proteins during and even between attacks ^, predisposes to the development of AA systemic amyloidosis, the most serious sequela of FMF ( Fig. 39.1 ). SAA deposition occurs in several organs, including the gastrointestinal tract, spleen, kidneys, adrenals, thyroid, and lungs, but usually not the tongue, peripheral nerves, or heart. The risk of amyloidosis increases with a positive family history of this complication, male sex, the α/α genotype at the SAA1 locus, and poor compliance with colchicine therapy. In most studies, homozygosity for the M694V mutation also predisposes patients to amyloidosis, to arthritis, and to erysipeloid erythema. For reasons not clear, the country of origin influences the phenotype of FMF and is a key risk factor for amyloidosis in FMF, with a decreased incidence of amyloidosis in patients living in the United States. An early indicator of impaired renal function is microalbuminuria, and periodic urinalyses are an important part of continuing care for FMF patients. After proteinuria occurs, amyloidosis can be confirmed by biopsy of the kidney or rectum. Although kidney biopsy is more sensitive, abdominal fat pad or rectal biopsy are preferred because they are safer and less invasive.

Diagnosis

The clinical diagnosis of FMF is based on the presence of short (12 to 72 hours), recurrent (three or more) febrile episodes, with abdominal, chest, joint, or skin manifestations and no discernible infectious cause. ^, Appropriate ethnicity, positive family history, onset before the age of 20 years old, and a favorable response to colchicine also support the diagnosis. Genetic testing has become a valuable adjunct to clinical diagnosis, particularly in North America and Europe. More than 300 variants have been described in MEFV ( https://infevers.umai-montpellier.fr/web/index.php but only about 10% are known or considered likely to be pathogenic. The majority of FMF-associated mutations are missense changes clustered in exon 10, which encodes the C-terminal B30.2 domain of the pyrin protein. The most common mutations are the substitutions of valine or isoleucine for methionine at position 694 (M694V and M694I, respectively), the substitution of isoleucine for methionine at residue 680 (M680I), and the substitution of alanine for valine at position 726 (V726A). Exon 2 of MEFV includes a number of missense substitutions that are variously considered to be functional polymorphisms or mild mutations, the most notable of which is the substitution of glutamine for glutamic acid at residue 148 (E148Q).

Some rare mutations appear to cause clinically typical FMF, inherited in a multigeneration dominant fashion, ^, whereas approximately 30% of patients with clinical signs of FMF have only one demonstrable mutation. Mutations at S208 and S242 block pyrin phosphorylation, leading to a dominantly inherited chronic inflammatory condition termed pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). The clinical and ethnic spectra of FMF have definitely expanded with the availability of genetic testing, suggesting that a combination of clinical evaluation and genetic testing for selected patients is the most sensible diagnostic approach.

Treatment

Colchicine therapy is highly effective for most patients in preventing febrile episodes and systemic amyloidosis. Daily therapy is generally more effective in controlling the attacks of FMF than intermittent treatment at the time of attacks, and daily therapy has the important added benefit of reducing the subclinical inflammation between episodes that potentially leads to amyloidosis. Colchicine is generally safe in children, although colchicine pharmacokinetics may differ in younger patients, and doses adjusted for body weight may be greater in children than those used in adults. The recommended adult colchicine dose is 1.2 to 1.8 mg/day given by mouth. Dosage should be started as low as possible (one-half of a 0.6-mg tablet once daily in children) and slowly increased, titrating to maximize efficacy and minimize side effects, but usually not exceeding 1.8 mg/day in single or divided doses. A gradual increase in dose often prevents or lessens diarrhea, the most common adverse effect. Some patients develop lactose intolerance because of colchicine, and a lactose-free diet may help control gastrointestinal symptoms. In children with FMF, development of myopathy with progressive proximal muscle weakness and generalized myalgia is rarely observed on regular dosage. Bone marrow alterations (hemolytic or aplastic anemia, pancytopenia, neutropenia, and thrombocytopenia) have been reported in cases of acute intoxication but are rarely observed in the usual doses given orally. Toxicity is more common with intravenous therapy and when given together with other drugs that are metabolized by CYP3A4, such as erythromycin and cimetidine.

Based on the role of pyrin, the FMF protein, in IL-1 activation, IL-1 inhibitors have been increasingly used in FMF patients who are unresponsive to or cannot tolerate therapeutic doses of colchicine. Based on a randomized, double-blind, placebo-controlled trial, canakinumab, a monoclonal antibody targeting human IL-1β, was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of colchicine-unresponsive or colchicine-intolerant FMF.

Outcome and Prognosis

When diagnosed and treated early, the prognosis for FMF is excellent. For those patients who develop amyloidosis, intensive treatment to normalize acute phase reactants may arrest the progression of amyloidosis and even reduce the extent of deposits over an extended period of time. Studies have confirmed little difference in patient and graft survival between FMF and control kidney transplant recipients. Transplantation (with oral colchicine administration to prevent amyloidosis in the transplanted kidney) is the preferred treatment for renal failure.

Genetics and Pathogenesis

Mutations in TNFRSF1A, which encodes the 55-kDa tumor necrosis factor (TNF) receptor TNFR1, cause tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a dominantly inherited syndrome. TRAPS has been reported in patients of many ethnicities and is the second most common hereditary periodic fever disorder. More than 150 gene variants have been reported as of this writing, with about two-thirds known or predicted to be pathogenic ( https://infevers.umai-montpellier.fr/web/index.php ). Two specific variants, denoted P46L and R92Q, are now considered functional polymorphisms that are only associated with symptoms in a minority of individuals. TRAPS-associated missense mutations often affect cysteine residues in the extracellular portion of the receptor, disrupting highly conserved disulfide bonds that are important for protein folding. Studies of animal models indicate that both mutant and wild type receptor must be expressed in order to observe an inflammatory phenotype.

It was initially thought that these mutations prevented metalloprotease-mediated ectodomain cleavage of TNFR1 and release of soluble receptor. However, impaired cleavage does not seem to correlate with disease severity, suggesting that there must be other mechanisms by which TNFRSF1A mutations cause autoinflammatory disease. The current consensus is that TRAPS-associated mutations lead to impaired receptor trafficking to the cell surface. This may trigger multiple proinflammatory pathways, including the noncanonical unfolded protein response (UPR), increased mitochondrial reactive oxygen species, impaired autophagy, and NF-κB activation. These pathways sensitize cells to the effects of other innate immune stimulation, resulting in enhanced production of proinflammatory cytokines.

Clinical Manifestations

The clinical manifestations of TRAPS include episodic fever and inflammation with serosal, synovial, and cutaneous manifestations ( Table 39.1 ). Distinguishing characteristics of TRAPS include longer attacks (1 to 4 weeks or more) and conspicuous eye and skin symptoms. ^{, ,} TRAPS attacks may be precipitated by minor trauma or infection or by stress and physical exertion. During attacks, patients exhibit vigorous acute phase responses that sometimes persist between symptomatic episodes.

Cutaneous symptoms associated with TRAPS are often distinctive, consisting of macular areas of erythema that occur on the torso or on an extremity ( Fig. 39.2 ). ^, These cutaneous lesions are warm and tender, may resemble cellulitis or bruises, and consist of superficial and deep perivascular infiltrates of mononuclear cells. When lesions occur on the limbs, they often migrate distally. There may be associated myalgia because of inflammation of the underlying fascia. Magnetic resonance imaging (MRI) of affected muscle groups reveals focal areas of edema in discrete muscular compartments and intramuscular septa ( Fig. 39.2 ). Other types of rash may also occur, including annular patches and generalized serpiginous plaques.

Clinical attacks may include peritoneal inflammation or pleurisy, or both. Abdominal pain with tenderness is often a major feature resembling an acute abdomen. Recurrent pericarditis has also been reported. Ocular inflammation with periorbital edema or conjunctivitis is common ( Fig. 39.2 ). Arthralgia is more prominent than arthritis, and it generally involves single joints, especially the hip, knees, and ankles. Scrotal inflammation may occur. Amyloidosis, although less common than in untreated FMF, affects about 10% of patients and can lead to renal failure. The risk of amyloidosis appears to be greater among patients with cysteine mutations or the T50M mutation.

Laboratory Investigations

Levels of SAA, CRP, and serum complement components are increased during flares, and most patients exhibit leukocytosis and thrombocytosis, with an elevated ESR. Acute phase reactants may remain elevated between clinical attacks, suggesting an elevated level of baseline inflammatory activity and increased risk of developing amyloidosis.

Diagnosis

The specific diagnosis is defined by mutations in TNFRSF1A. The majority are single nucleotide missense mutations in exons 2 to 4, encoding the first or second cysteine-rich extracellular domains (CRD1 and CRD2). ^, Genotype-phenotype studies have shown that mutations at cysteine residues are associated with a more severe phenotype and a higher incidence of amyloidosis. ^, As noted previously, the P46L and R92Q variants are not fully penetrant and are associated with a milder phenotype. These latter variants are not associated with the same signaling abnormalities that are seen with more severe mutations.

Treatment

Treatment depends on the severity of the underlying disease. For some patients with relatively infrequent episodes, tapering doses of prednisone at the time of attacks may be effective and relatively safe. For patients with more severe disease, etanercept (the recombinant TNF receptor antagonist), given weekly (once or twice a week), is effective in preventing attacks in some patients. Treatment with anti-TNF monoclonal antibodies has led to exacerbation of the disease in some cases and should be avoided. Treatment with IL-1 inhibition has been shown to be effective in controlling the clinical and laboratory manifestations in most patients with TRAPS. ^{, ,} Based on a randomized, double-blind, placebo-controlled trial, canakinumab was recently FDA approved for the treatment of TRAPS, without failing any other treatment. Colchicine usually has no effect on symptoms or the development of amyloidosis. The prognosis depends on the development of amyloidosis. In patients with demonstrated amyloidosis, the goal should be to maintain the SAA levels at less than 10 mg/L. More aggressive therapy may be indicated in patients with a positive family history of amyloidosis or mutation at cysteine residues to suppress subclinical inflammation.

Genetics and Pathogenesis

Mevalonate kinase is an enzyme in the mevalonate pathway, which produces cholesterol, a structural component of cellular membranes and precursor for bile acids and steroid hormones. In addition, the mevalonate pathway produces nonsterol isoprene compounds. Isoprenes are involved in a variety of cellular functions, including electron transport, protein glycosylation and synthesis, and prenylation of proteins involved in cell proliferation and differentiation. The shortage of geranylgeranylated proteins is thought to be the link between the mevalonate pathway, increased IL-1β production, and the febrile attacks of MKD. ^, Geranylgeranyl moieties are required for the proper trafficking of a number of proteins, including RhoA, to cell membranes. MVK mutations lead to a deficiency of geranylgeranyl moieties, thus mistargeting and inactivating RhoA, with consequent activation of the pyrin inflammasome and IL-1β release.

Clinical Manifestations

MKD-mild manifests in early childhood, often by the age of 6 months ( Table 39.1 ). Attacks last 3 to 7 days, usually separated by one to two months, symptom-free intervals. Episodes are often heralded by chills and headache, a rising fever, abdominal pain, nausea, and vomiting, sometimes precipitated by immunizations, surgery, trauma, and mild infections. The mevalonate kinase enzyme in patients with MKD-mild loses activity at supraphysiologic temperatures, perhaps explaining the association of immunizations, upper respiratory infections, and other inflammatory provocations with attacks.

During attacks, widespread erythematous macules that are sometimes painful develop. ^, The rash is usually not migratory, differentiating it from the rash associated with TRAPS, and it has no predilection for the lower legs, unlike that of FMF. The MKD rash may be a diffuse maculopapular eruption ( Fig. 39.3 ) extending to the palms and soles, or it can be nodular, urticarial, or morbilliform. Skin biopsies show perivascular inflammatory cells and deposits of antibody or complement component C3, or both. Oral and vaginal aphthous ulcers may be present. Henoch–Schönlein purpura and erythema elevatum diutinum (a benign type of IgA vasculitis) ^, have been reported. Cervical lymphadenopathy is a common manifestation of MKD-mild, as are severe headache and splenomegaly. Pleurisy is uncommon. Although amyloidosis has been considered rare, in a recent series, 5 of 114 patients had amyloidosis, most often associated with the V377I/I268T genotype.

Patients with MKD-severe (mevalonic aciduria) have nearly complete deficiency of mevalonic kinase and have developmental delay of varying severity, hematological abnormalities, dysmorphic features, and hepatosplenomegaly. These patients have been known to develop periodic crises characterized by fever, rash, and arthralgia.