Hereditary Periodic Fever Syndromes

Fever is one of the most common signs of illness in children. Most febrile episodes are acute, of short duration, and usually caused by upper respiratory infections. The differential diagnoses of febrile attacks are extensive and include infectious, malignant, and autoimmune disorders, as well as factitious and iatrogenic fever. If these attacks persist for longer than 1 year, especially if they are associated with a family history of periodic fever, the possibility of hereditary periodic fever syndrome (HPFS) should be raised.

The term periodic fever syndrome is defined as 3 or more episodes of unexplained fever in a 6-month period, occurring at least 7 days apart. ^[1] These conditions may demonstrate strict periodicity or recur with varying intervals between attacks.

Hereditary periodic fevers were once grouped based on clinical findings and Mendelian patterns of inheritance into 9 distinct groups. ^[3]

Syndromes with an autosomal-dominant pattern are as follows:

• Tumor necrosis factor receptor–associated periodic syndrome (TRAPS)
• Familial cold autoinflammatory syndrome (FCAS)
• Muckle-Wells syndrome (MWS)

• Neonatal-onset multisystem inflammatory disease (NOMID), also called chronic infantile neurological cutaneous and articular syndrome (CINCA)
• Cyclic hematopoiesis (CH), also called cyclical neutropenia
• Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome

Syndromes with an autosomal-recessive pattern are as follows:

• Familial Mediterranean fever (FMF)
• Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
• Deficiency of IL-1 receptor antagonist (DIRA)

These diseases were reclassified based on the innate immunity mechanisms and the inflammasome, a protein complex containing caspases involved in the proteolytic cleavage of interleukin (IL)–1 precursors to produce active forms of IL-1 (explaining the pathogenesis of fevers in these individuals) (see Table 1). ^[2]

Table 1. Types of Hereditary Periodic Fever Syndromes. ^[3] (Open Table in a new window)

Cryopyrin (also called NALP3, PYPAF1, or NACHT, leucine-rich repeat [LRR], and PYD domains-containing protein 3) is a member of the APAF-1/NOD1–like protein family, which regulates apoptosis and inflammation. In healthy individuals, cryopyrin and apoptosis-associated speck-like protein (ASC) interact via the oligomerization of ASC to induce both apoptosis and activate nuclear factor (NF)–kappa B.

Pathogenesis of hereditary periodic fever syndrome

In patients with HPFS, various mutations lead to changes in the above-mentioned mechanism, in turn causing activation of an inflammatory response and a release of pyrogens; NLRP3 (CIAS1) mutations are gain-of-function mutations that cause constitutive activation of the inflammasome, a complex with pro-IL-1–processing activity, and macrophage necrosis. ^{[2, 5]} MEFV mutation leads to formation of pyrin-marenostrin complex, which interacts with ASC and disrupts the cryopyrin-ASC interaction and specifically inhibits apoptosis and NF-kappa B activation. Furthermore, pyrin interacts with proline-serine-threonine phosphatase-interacting protein (PSTPIP1), also known as CD2-binding protein 1 (CD2BP1), which is a tyrosine-phosphorylated protein involved in cytoskeletal organization and thereby involved in immunologic cellular interactions.

Familial Mediterranean fever (FMF) is the most common Mendelian autoinflammatory syndrome in the Mediterranean region (as the name suggests), resulting from autosomal-recessive mutations in the MEFV (Mediterranean fever) locus of chromosome 16. MEFV is composed of 10 exons that encode a 781–amino acid protein called pyrin, or marenostrin, which is expressed primarily in the innate immune system, including granulocytes, cytokine-activated monocytes, dendritic cells, and serosal and synovial fibroblasts. ^{[28, 29]}

The N-terminal domain of pyrin defines a motif, called the pyrin domain (PYD), which is similar to the structure of the caspase recruitment domains (CARDs), so, through homotypical domain interactions, pyrin binds the ASC with a CARD and participates in at least 3 important cellular processes: apoptosis, recruitment, and activation of procaspase-1 (also known as IL-1 beta converting enzyme), with associated processing and secretion of IL-1 and IL-18 and activation of the NF-kappa B transcription factor. ^[10]

Wild-type pyrin has been found to inhibit or accentuate caspase-1 activity through the interaction of its N-terminal PYD with ASC, a key molecule in the inflammasome. The net effect of pyrin and the molecular mechanisms of FMF-associated mutations remain controversial. Recent genetic data on patients with FMF suggest that FMF actually may result from gain-of-function mutations in a pro-inflammatory molecule, as opposed to the previous model, in which loss-of-function mutations in an anti-inflammatory molecule were considered the cause of FMF. Regardless of the underlying mutation that causes FMF, the ultimate mutation appears to increase activation of IL-1 beta and accentuates innate immune activation. This supports the use of IL-1 inhibitors as a therapy for resistant cases (see below).

FMF is most common among Sephardic and Ashkenazi Jewish and Arab, Armenian, Italian, and Turkish populations, with carrier frequencies as high as 1:3-5 in population-based surveys. ^{[11, 12]} FMF occurs at lower frequencies in other populations and ethnicities.

The National Institutes of Health (NIH) reported the following rates of FMF in a US population-based survey: 19% of those with mutations were of Italian ancestry, 21% were Ashkenazi Jews, 27% were Armenian, and 17% were Arabs. The remainder were of non-Ashkenazi Jewish, Cuban, Turkish, and northern European heritage. ^[12] The male-to-female ratio of cases consistently has been reported to be about 1.5-2:1, raising the possibility that the mutation has reduced penetrance in women. ^[12]

Clinical presentation

Approximately 90% of patients with FMF are younger than 20 years at onset, and 60% are younger than 10 years. Late-onset disease usually is more clinically benign than early-onset disease. In children, fever may be the only sign of FMF, although other symptoms generally develop progressively with time. FMF attacks last 12-72 hours and consist of inflammation involving the peritoneum, pleura, joints, or skin, sometimes in combination. Patients typically feel completely well between attacks. Stress usually is associated with attack onset, but the exact mechanism that triggers periodic attacks in FMF remains unclear.

The most common manifestation of FMF is abdominal pain, which can be generalized or limited to 1 quadrant and sometimes can be confused with acute surgical abdomen. Pain severity can vary from mild and self-limiting to severe, requiring acute medical attention. Constipation is more common than diarrhea, and, in extreme cases, peristalsis may cease and result in paralytic ileus. ^{[16, 17, 18]}

About 70% of patients with FMF present with recurrent episodes of arthritis. The most frequently involved joints are knees and ankles. Joint involvement can be symmetrical or asymmetrical with large joint effusions. The pain usually is not severe, is worse after physical exertion, lasts from hours to 2-3 days, and subsides with rest, requiring NSAIDs only rarely. Arthritis is nonerosive, but severe cases can manifest as juxta-articular osteoporosis, erosions, and osteonecrosis.

Forty percent of patients with FMF present with pleurisy and other constitutional symptoms. Unilateral chest pain is more commonly reported. Patients may have decreased breath sounds or pleural friction rub. Common skin manifestations include erysipelas or lower-extremity erythema.

Myalgia is another frequent finding in patients with FMF (reported in 20% of cases). The febrile myalgia syndrome can be severe and disabling, lasting for weeks, and does not respond well to colchicine. ^{[16, 17, 18]} Less than 5% of patients with FMF present with acute scrotum secondary to inflammation of tunica vaginalis testis. These attacks usually are unilateral and self-limiting.

Other rare manifestations of FMF include pericarditis, meningitis, and headache during attacks. ^[15] Behçet disease, polyarteritis nodosa, microscopic polyarteritis, and glomerulonephritis may occur more frequently in patients with FMF than in the general population. ^{[20, 21]}

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 erythrocyte sedimentation rate (ESR) commonly are observed. Synovial aspirates from joints are sterile and rarely demonstrate high leukocyte counts (up to 100,000/μL). Since FMF predisposes to amyloidosis, few researchers recommend periodic urinalysis and protein electrophoresis. An early indicator of impaired renal function due to amyloidosis is microalbuminuria. Further confirmation can be done by performing kidney biopsy, which is highly sensitive.

Differential diagnoses

Since the clinical presentation of FMF is nonspecific, the list of differential diagnoses is long and includes the following, based on the initial presentation:

• Abdominal pain, lower quadrant predominant: Acute appendicitis, porphyria, hereditary angioedema, pancreatitis (with hypertriglyceridemia)
• Chest pain/pleurisy: Pneumonia, infectious pleuritis, infectious pericarditis
• Mono-articular joint pain: Septic arthritis, gout, juvenile rheumatoid arthritis (JRA), systemic onset
• Febrile myalgia syndrome should be differentiated from colchicine-related myopathy; EMG, CPK, and ESR help in differentiating colchicine-related myopathy from febrile myalgia syndrome.
• Acute scrotum: Testicular torsion, epididymitis, orchitis
• Other hereditary periodic fever syndromes, especially hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), cyclic neutropenia

Diagnosis

The clinical diagnosis of FMF is based on the presence of short (12-72 hours), recurrent (≥3) febrile episodes, with abdominal, chest, joint, or skin manifestations and no discernible infectious cause. Appropriate ethnicity, positive family history, onset before age 20 years, and a favorable response to colchicine also support the diagnosis.

Genetic testing has expanded with the diagnosis of FMF in low-prevalence countries, and a combination of clinical evaluation with genetic testing in selected patients is the most sensible diagnostic approach.

More than 70 mutations have been described in FMF, and a subset of MEFV mutations (usually E148Q in exon 2 and M680I, M694V, and V726A in exon 10) may account for 80% of FMF cases in classically affected populations. ^{[19, 23, 24, 25]} Based on an autosomal-recessive mode of inheritance, patients with FMF ideally should be homozygous for a single mutation or heterozygous for 2 different mutations. Some mutations have functional polymorphism and occur at a relatively lower frequency. DNA samples are commonly screened for the most common mutations in the laboratory, so patients with rare mutations may appear to have no mutations or only 1. Hence, diagnosis of FMF should not be solely excluded based on the results of genetic testing.

Diagnostic criteria for familial Mediterranean fever diagnosis  ^[22]

Major criteria are as follows:

• Recurrent febrile episodes of peritonitis, synovitis, or pleuritis
• Amyloid-associated protein (AA)–type amyloidosis with no predisposing disease
• Favorable response to continuous colchicine treatment

Minor criteria are as follows:

• Recurrent febrile episodes
• Erysipelas-like erythema
• Familial Mediterranean fever in a first-degree relative

A definitive diagnosis is based on 2 major or 1 major and 2 minor criteria. A probable diagnosis is based on 1 major and 1 minor criteria.

Treatment

Colchicine therapy is highly effective in preventing febrile episodes and systemic amyloidosis in most patients with FMF. ^[14] Approximately 95% of patients demonstrate a marked improvement in symptoms, whereas almost 75% have a near-complete remission. Continuous therapy is generally more effective in controlling FMF attacks 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 lead to amyloidosis.

Colchicine is generally safe in children, although doses adjusted for body weight may be greater in children than those used in adults. The recommended colchicine dose in adults is 1.2-1.8 mg/day given by mouth. The dosage should be started as low as possible (0.6 mg daily dose) and slowly increased, titrating to a maximize dose of 1.8 mg/day in single or divided doses.

Guidelines from the European League Against Rheumatism (EULAR) recommend the following starting dosages of colchicine ^[14] :

• Children younger than 5 years: ≤0.5 mg/day (≤0.6 mg/day if tablets contain 0.6 mg)
• Children aged 5-10 years: 0.5-1 mg/day (1.2 mg/day if tablets contain 0.6 mg)
• Children older than 10 years and adults: 1-1.5 mg/day (1.8 mg/day if tablets contain 0.6 mg)

A gradual dose increase often prevents or lessens diarrhea and abdominal pain (the most common adverse effects).

Episodes of febrile myalgia syndrome respond to corticosteroids but not colchicine. A systematic review found that, among patients who do not respond to or are intolerant of colchicine, anti–IL-1 treatment resulted in a complete response to therapy, without a single attack during treatment, in 76.5% of patients treated with anakinra and 67.5% of those treated with canakinumab. In addition, anti–IL-1 treatment was able to reverse proteinuria in patients with established type AA amyloidosis.

Canakinumab was approved by the US Food and Drug Administration (FDA) for FMF based on the phase 3 of CLUSTER study, which showed disease control beginning at Day 15 and lasting through 16 weeks when compared with placebo. Canakinumab is a human monoclonal anti–human IL-1 beta antibody of the IgG1/kappa isotype. It binds to human IL­-1 beta and neutralizes its activity by blocking its interaction with IL-1 receptors. ^[14]

Rilonacept, given via once-weekly subcutaneous injection, has been shown, in combination with continuation of colchicine, to reduce the number of attacks in patients who did not respond optimally. ^[14] Interferon-alpha has been used in an intermittent fashion and as prophylaxis, with varying results. ^[14]

Adverse effects of medications

A common adverse effect of colchicine is diarrhea, which usually improves with gradual dose increasing. Colchicine should be used with caution in elderly patients and patients with mild-to-moderate cardiac, GI, renal, or liver disease. Dosage reduction is recommended in patients who develop weakness or GI symptoms (anorexia, diarrhea, nausea, vomiting) related to drug therapy.

Bone marrow alterations (hemolytic or aplastic anemia, pancytopenia, neutropenia, thrombocytopenia) have been reported in cases of acute intoxication but rarely are observed in the usual doses given orally. Colchicine-related myopathy has been rarely described with lower doses (used commonly for FMF). Toxicity is more common with intravenous therapy and when given together with other drugs that are metabolized by CYP3A4, such as erythromycin and cimetidine.

Colchicine is pregnancy category C (PO formulation) or D (parenteral formulation). Colchicine is known to arrest mitotic and meiotic chromosomal segregation in vitro; therefore, birth defects are a potential concern if the drug is used during pregnancy. However, no study to date has conclusively demonstrated that colchicine is responsible for chromosomal abnormalities or other birth defects. ^[14] Amniocentesis is still suggested to screen for chromosomal defects if either parent is taking the drug. Colchicine enters breast milk; therefore, caution should be used in breastfeeding patients; the American Academy of Pediatrics rates this as compatible.

Complications

The continuous elevation of acute-phase serum proteins during and between attacks predisposes to the development of AA systemic amyloidosis, the most serious sequela of FMF. SAA deposition occurs in several organs, including the GI tract, spleen, kidneys, adrenals, thyroid, and lungs, but usually not the tongue, peripheral nerves, or heart.

Before effective treatment was available, renal failure occurred by age 40 years in many patients with FMF. The risk for 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. ^[13] In most studies, homozygosity for the M694V mutation also predisposes to amyloidosis, arthritis, and erysipeloid erythema. ^{[31, 32, 33]}

Transplantation (with oral colchicine administration to prevent amyloidosis in the transplanted kidney) is the preferred treatment for renal failure. Rare patients have a chronic abdominal disease caused by peritoneal adhesions due to recurrent inflammation of the peritoneal membranes.

TRAPS is a dominantly inherited disorder characterized by episodic attacks of fever, abdominal pain, severe myalgia, and painful erythema on the trunk or extremities, usually lasting longer than 1 week. Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) was earlier denoted as familial Hibernian fever. After the discovery of mutations in the TNFRSF1A gene, located in chromosome 12p13, which encodes the 55-kDa tumor necrosis factor (TNF) receptor in this family and in several other families of non-Irish ancestry, the current TRAPS nomenclature was proposed. TRAPS-related attacks tend to last longer than those of other HPFS diseases.

Patients presenting with TRAPS commonly have northern European ancestry. Although TRAPS was originally described in patients of Irish or Scottish ancestry, mutations have been reported among patients from different ethnicities, including African American, French, Belgian, Dutch, Arab, Jewish, and others. ^{[64, 65]} A male-to-female ratio of 3:2 is reported. ^[64] The reason that women are more protected than men is still unknown. The median age of onset is 3 years, with the age at initial presentation ranging from 2 weeks to 53 years. The age of onset varies within and among families.

Pathogenesis

TRAPS is inherited as an autosomal-dominant trait. It is the second most common hereditary periodic fever disorder, with more than 50 known mutations in TNFRSF1A. The 55 kDa TNF receptor is widely expressed on cell membranes and mediates numerous pro-inflammatory effects. TNF-alpha activates TNFRSF1A. The extracellular portion of the gene undergoes cleavage and subsequent shedding from the cell membrane. This process is thought to contribute to the clearance of TNFRSF1A from the membrane and produces a pool of soluble receptors that may attenuate the inflammatory response by competing with membrane-bound receptors. ^{[64, 65, 66]}

Most mutations in TNFRSF1A mediate their effect via decreased shedding of TNFRSF1A, thereby decreasing the amount of soluble receptor available to bind soluble TNF and subsequently initiate and maintain the inflammatory response. Moreover, impaired cleavage does not seem to correlate with disease severity, suggesting that there must be other mechanisms by which TNFRSF1A mutations cause auto-inflammatory disease, ^[50] including reduced cell surface expression of mutant receptors, an abnormal oligomerization or misfolding with retention in the endoplasmic reticulum, decreased binding of mutant forms of receptor to TNF, ligand-independent signaling, and reduction in TNF-induced apoptosis. ^[67] The accumulation of misfolded proteins within the endoplasmic reticulum may induce stress responses, prompting the release of pro-inflammatory cytokines.

Clinical manifestations

The clinical manifestations of TRAPS include episodic fever, cutaneous manifestations, and inflammation of serosal and synovial membranes. The rate and duration of the inflammatory attacks widely vary. On average, they occur once every 6 weeks and last longer than 1 week. Few patients have daily pain without a clear resolution of symptoms.

Distinguishing characteristics of TRAPS include longer attacks (1-4 weeks or more) and conspicuous eye and skin symptoms. ^{[64, 66, 67]} TRAPS attacks may be precipitated by minor trauma or infection or by stress and physical exertion.

Clinical attacks may include peritoneal inflammation, pleurisy, or both. Abdominal pain with tenderness is often a major feature resembling an acute abdomen and is reported in 90% of patients with TRAPS. About 84% of patients with TRAPS present with cutaneous symptoms consisting of macular areas of erythema that occur on the torso or on an extremity with centrifugal spread (see image below). These lesions are warm and tender.

Other types of rash may occur, including annular patches and generalized serpiginous plaques. There may be associated myalgia due to inflammation of the underlying fascia. ^{[64, 65, 66]} Pleurisy is commonly noticed and reported in approximately 60% of patients with TRAPS, and recurrent pericarditis has been documented. Ocular inflammation with periorbital edema or conjunctivitis is common. ^[41] Arthralgia is more prominent than arthritis and generally involves single joints, especially the hip, knees, and ankles. Scrotal inflammation may occur.

Ancillary tests

Levels of SAA, CRP, fibrinogen, haptoglobin, ferritin, and serum complement components are increased during flares, and most patients exhibit leukocytosis and thrombocytosis. Some exhibit polyclonal gammaglobulinopathy. Levels of acute-phase reactants may remain elevated between clinical attacks, suggesting underlying subclinical disease activity. The levels of soluble TNFRSF1A in the serum may be reduced during or between attacks.

Magnetic resonance imaging (MRI) of affected muscle groups reveals focal areas of edema in discrete muscular compartments and intramuscular septa. Skin biopsy highlights superficial and deep perivascular infiltrates of mononuclear cells. Muscle biopsy may reveal monocytic fasciitis or lymphocytic vasculitis (but not myositis).

The specific diagnosis of TARPS is defined by mutations in TNFRSF1A. Fifty-eight mutations have been reported, the most common of which are single-nucleotide missense mutations in exons 2-4 encoding the first or second cysteine-rich extracellular domains (CRD1 and CRD2). Genotype-phenotype studies showed that mutations at cysteine residues are associated with more severe phenotype and a higher incidence of amyloidosis. Although most TRAPS-associated mutations are fully penetrant, P46L and R92Q (2 TNFRSF1A variants) have been identified in asymptomatic family members and at low frequency in healthy populations.

Diagnosis

The clinical characteristics suggestive of TRAPS (below) can be used as indications to order further testing.

Recurrent episodes of the following inflammatory symptoms spanning a period longer than 6 months:

Table 2. Clinical Characteristics Suggestive of TRAPS. (Open Table in a new window)

Differential diagnoses

Other hereditary periodic fever syndromes (HPFS), especially FMF, should be considered in the differential diagnoses of TRAPS. In patients with severe abdominal pain, acute peritonitis is a common differential diagnosis, and a careful history and early disease confirmation can prevent explorative laparotomy and appendectomy.

Treatment

Treatment depends on the severity of the underlying disease.

In patients with relatively infrequent episodes, tapering doses of prednisone at the time of attacks may be effective and relatively safe. The adult dosage is 5-60 mg/d orally (PO) in divided doses given 1-4 times/day. The pediatric dosage is 0.05-2 mg/kg/d PO divided 1-4 times daily. ^{[68, 69]}

In patients with more severe disease, etanercept (recombinant TNF-receptor antagonist) given once or twice a week is effective in preventing attacks in some cases. ^{[68, 69]} The adult dosage is 50 mg SC given once weekly or 25 mg given twice weekly every 72-96 hours. In children aged 4-17 years, once-weekly dosing is 0.8 mg/kg SC (not to exceed 50 mg/dose), and twice-weekly dosing is 0.4 mg/kg SC (not to exceed 25 mg/dose).

Experience with infliximab (anti-TNF monoclonal antibodies) is limited. Treatment with infliximab has led to exacerbation of the disease in some cases, possibly resulting from failure to shed infliximab-bound TNF/TNFR1 from the cell surface, leading to an increase in cytokine secretion and an increased pro-inflammatory response.

Anakinra (IL-1 receptor antagonist) has been shown to be effective in controlling the clinical and laboratory manifestations in some patients with TRAPS.

No response to colchicine has been noted. ^[71]

In patients with demonstrated amyloidosis, the goal should be to maintain the SAA levels at less than 10 mg/L. The prognosis depends on the development of amyloidosis. More aggressive therapy may be indicated in patients with a positive family history of amyloidosis. Etanercept is reported to reverse the progression of systemic AA amyloidosis in these patients. However, treatment may need to be continued, possibly for life, to prevent end-stage disease.

Adverse effects of medications

Adverse effects may be slightly more common in pediatric patients. Adverse effects include headache, dizziness, nausea, injection-site reactions, respiratory tract infection, rhinitis, sinusitis, positive antinuclear antibodies (ANAs) and anti–double-stranded DNA antibodies, rash, abdominal pain, dyspepsia, vomiting, and weakness. Allergic reactions may occur (< 2%), but anaphylaxis has not been observed. Rare events include lymphadenopathy, malignancies (including lymphoma), membranous glomerulopathy, myocardial infarction, mouth ulcer, multiple sclerosis, myocardial ischemia, pancreatitis, polymyositis, pulmonary embolism, renal calculus, sarcoidosis, thrombophlebitis, vasculitis (cutaneous), and pancytopenia. Etanercept is class B in pregnancy.

Complications

Amyloidosis, although less common in TRAPS than in untreated FMF, affects about 10% of patients and can lead to renal failure. ^[69] The risk for amyloidosis appears to be greater among patients with cysteine mutations. ^[70] A positive family history of amyloidosis may increase the risk in relatives.

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is an autosomal-recessive disease that initially was described in several patients of Dutch heritage. ^[39] HIDS is caused by mutations in the MVK gene, on chromosome 12, which encodes mevalonate kinase. ^[39] The carrier frequency of MVK mutations in the Dutch population was calculated to be 1:65. The predicted disease incidence is far more than actually observed, suggesting reduced penetrance of the most common mutation.

HIDS manifests in early childhood, often by age 6 months. Patients may have no symptoms between attacks. However, in some patients, the attacks may be so frequent that the symptoms persist. The male-to-female ratio was equal in 1 study but about 3:2 in another large series. ^[39] This last finding raises the possibility of reduced penetrance in women.

Genetics and pathogenesis

HIDS is caused by mutations in the MVK gene that result in depressed enzymatic activity, which has been confirmed in fibroblasts from patients with hyperimmunoglobulinemia D with periodic fever syndrome. Mevalonate kinase is the first enzyme to follow 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the mevalonate pathway and converts mevalonic acid to 5-phosphomevalonic acid. The mevalonate pathway 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. ^{[6, 40, 41]}

Isoprenes are involved in various cellular functions, including electron transport, protein glycosylation and synthesis, and prenylation of proteins involved in cell proliferation and differentiation. Mutations associated with HIDS lead to markedly reduced mevalonate kinase enzymatic activity, whereas the mutations in the clinically more severe mevalonic aciduria result in the absence of enzymatic activity. ^{[6, 40]}

Although excessive production of pro-inflammatory cytokines by HIDS mononuclear cells may result from excessive accumulation of mevalonic acid substrate, recent data support an alternative hypothesis related to deficiencies in nonsterol isoprenoids synthesized through the mevalonate pathway. If the latter possibility is correct, a shortage of geranylgeranylated proteins may be the link between the mevalonate pathway, increased IL-1 beta production, and the febrile attacks of HIDS. ^[42] The mevalonate kinase enzyme in patients with HIDS-associated mutations loses activity at supraphysiologic temperatures, perhaps explaining the association of immunizations, upper respiratory infections, and other inflammatory provocations with attacks. ^{[43, 44]}

Clinical manifestations

Attacks last about 3-7 days, usually separated by 1- to 2-month symptom-free intervals. Episodes often are heralded by chills and headache, a rising fever, abdominal pain, nausea, and vomiting. Common precipitating factors are immunizations, surgery, trauma, and mild infections. ^[30] About 80% of the patients develop a nondestructive polyarticular arthritis, usually in the large joints.

During attacks, 82% of patients with HIDS develop widespread erythematous macules that sometimes are painful and have predilection for palms and soles. ^[30] Compared with rash in TRAPS, rash seen in HIDS usually is not migratory. Oral and vaginal aphthous ulcers may be present. Cervical lymphadenopathy is a common manifestation of HIDS, as are severe headache and splenomegaly. Pleurisy is uncommon. Amyloidosis has not been reported in patients with HIDS.

Laboratory investigations

The most typical finding is the consistently elevated serum IgD level (>100 U/mL, comparable to 141 mg/L). In a 2001 report, 22% of patients with HIDS had normal IgD levels, ^[63] suggesting that an elevated IgD concentration may be an epiphenomenon. Occasionally, IgA levels are also elevated.

During attacks, an acute-phase response occurs, with high C-reactive protein (CRP) levels, increased ESR, and leukocytosis. Increased urine concentrations of mevalonic acid are found during severe episodes of fever but not between crises (as measured on mass spectrometry or proton nuclear magnetic resonance [NMR] spectroscopy). In addition, increased urinary excretion of neopterin is correlated with disease activity.

Mutation analysis reveals mutations in the gene for MK in 76% of clinically affected patients. Approximately 90% of patients are compound heterozygous. About 80% of mutations are missense. V377I and I268T are the most common mutations. ^[45] These mutations cause a moderate (5-15%) functional defect of MVK, as tested in cultured fibroblasts or lymphocytes, compared with undetectable findings in MVA. Most laboratories perform HIDS screenings for only the most common V377I and I268T mutations. ^{[45, 46, 47]} However, even with complete sequencing of the coding region of MVK, genetic testing may be inconclusive. Among patients with recurrent fevers and typical associated findings, up to 25% may be mutation-negative. Skin biopsies show perivascular inflammatory cells, deposits of antibody or complement component C3, or both.

Differential diagnoses

Chronic infections, acquired immunodeficiency syndrome, Hodgkin disease, and other periodic fever syndromes are included in the differential diagnoses.

Diagnosis

Diagnosis may require several lines of inquiry, including clinical observation, genetic testing, serum IgD measurement, and urine assay of mevalonate. The genetic and biochemical basis of disease in such patients remains to be elucidated. Hence, Drenth and van der Meer recommended the following diagnostic strategy ^{[47, 48]} :

• Review the clinical and family history.
• Measure IgD and IgA. IgD should be measured on 2 occasions at least 1 month apart.
• Measure urinary mevalonic acid. These tests help in detecting only a slight elevation and are generally ineffective.
• Perform genetic testing to screen for the most common V377I mutation. Sequencing of the gene in highly suspicious cases with negative V377I mutation is a possibility, although the large size of the gene and the nonavailability of this testing in many countries are major obstacles.
• In rare cases, measure MK activity.

Treatment

Occasional patients with HIDS respond to colchicine. Glucocorticoids, intravenous immune globulin, and cyclosporine have been tried with varying success rates. Small studies demonstrated improvement with etanercept and simvastatin. ^[61] Consistent with the involvement of IL-1 beta in this disease, early studies suggest the efficacy of anakinra; however, larger confirmatory studies are needed. ^{[61, 62]}

Complications

HIDS is not generally associated with a shortened lifespan. Although very rare, HIDS-associated amyloidosis has been reported. 

Familial cold auto-inflammatory syndrome (FCAS) first was described in 1940. ^[31] This autosomal-dominant syndrome is characterized by recurrent short and self-limited episodes of fever, rash, and arthralgia precipitated by generalized exposure to cold. ^{[27, 34]}

The cold sensitivity in FCAS is unlike that in other cold-related disorders such as cryoglobulinemia; it is induced not only by a cool absolute ambient temperature but also by a rapid decrease in temperature. Air conditioning may be very problematic for individuals with FCAS in hot climates and provides a clear example of an environmental influence on a genetic disease. ^[27]

Early onset of the disease, at birth or within the first 6 months of life, is characteristic. The mean age at presentation is 47 days, with a range of 2 hours to 10 years. Males and females are equally affected. Most of the reported cases are from Europe and North America, but data from other areas are unclear.

Genetics and pathogenesis

Mutations in the NLRP3 (CIAS1) gene are associated with the cryopyrin-associated periodic syndromes (Muckle-Wells syndrome [MWS], familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous articular syndrome [CINCA]/neonatal-onset multisystem inflammatory disease [NOMID] syndrome). The mechanism is similar to that explained above, which involves the interaction of cryopyrin with ASC, leading to activation of caspase 1 and subsequent release of IL-1. ^{[8, 35]}

Clinical manifestations

The severity of FCAS does not appear to vary based on the age of onset. The urticaria is maximal in early adult life. Conjunctivitis is frequently observed. Other commonly reported symptoms include muscle pain, profuse sweating, drowsiness, headache, extreme thirst, and nausea. Common triggers are weather changes and exposure to air conditioning. The typical urticarial rash in FCAS does not necessarily occur on exposed areas of skin, unlike the classic urticarial rash in the more common acquired cold urticaria, in which direct contact with cold objects causes pruritic hives at the site of exposure. ^{[35, 37]}

Many patients with FCAS also show evidence of chronic inflammation between attacks, particularly a daily pattern of rash developing in the afternoon that can be associated with headache, myalgia, and fatigue by the evening.

Laboratory diagnosis

Leukocytosis and increased acute-phase reactants accompany episodes of inflammation. Skin biopsy findings from samples obtained during attacks reveal an intense inflammatory infiltrate around dilated blood vessels. This infiltrate includes neutrophils, eosinophils, and lymphocytes, with moderate edema in the upper part of the dermis. Chronic perivascular inflammation with interstitial neutrophils and mononuclear cells has also been reported as the main histologic finding. ^[30]

Hoffman and colleagues proposed a set of diagnostic criteria for FCAS, as follows ^[28] :

• Recurrent intermittent episodes of fever and rash that primarily follow natural, experimental, or both types of generalized cold exposure
• Autosomal-dominant pattern of disease inheritance
• Age of onset before 6 months
• Duration of most attacks is less than 24 hours
• Presence of conjunctivitis associated with attacks
• Absence of deafness, periorbital edema, lymphadenopathy, and serositis

Treatment

Rilonacept administration (100 mg) in 5 patients with familial cold auto-inflammatory syndrome improved rash, fever, and joint pain/swelling within days, and inflammation markers (ESR, C-reactive protein [CRP], and SAA) showed significant reductions. ^[77] Doses of 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain, and, in the acute phase, reactant levels were lower. No serious drug-related adverse events were seen in the study.

In February 2008, the IL-1 antagonist rilonacept was approved by the US Food and Drug Administration (FDA) based on studies reporting improvement in symptoms such as joint pain, rash, fever/chills, eye irritation and pain, and fatigue. Recently, the FDA approved canakinumab for treatment of FCAS. ^{[50, 51, 52]}

Muckle-Wells syndrome (MWS) was described in 1962 by Muckle and Wells as a perplexing syndrome of fever, urticarial rash, and limb pain that eventually led to progressive hearing loss and amyloidosis. ^[74] MWS usually is inherited as an autosomal-dominant trait, but apparent sporadic cases also occur. No racial difference has been reported. MWS usually manifests at birth or early infancy. Males and females are equally affected.

Clinical manifestations

The disease course of MWS varies among individuals from the typical recurrent attacks of inflammation to more persistent symptoms. There are no known precipitating factors. MWS is characterized by episodes of fever and rash associated with joint and eye manifestations, although fever is not always present. ^{[72, 73]} Urticarial rash is the most common skin manifestation. No triggers in the development of rash have been identified. Patients develop brief episodes of arthralgia involving predominantly large joints. ^[74] Conjunctivitis is common, and episcleritis and iridocyclitis have been reported. Sensorineural hearing loss is seen in approximately 70% of cases and usually begins in late childhood. Abdominal pain and headache may occur in some cases.

Laboratory investigations/diagnosis

Similar to other hereditary periodic fever syndromes, ESR elevation and leukocytosis are common features of MWS. Results of cold-contact tests (with an ice cube and a cold-arms bath) are negative. Skin manifestations are likely similar to chronic urticaria. Clinical manifestations of mild forms of MWS resemble those of FCAS, and more severe phenotypes overlap with NOMID.

Management

Based on literature review and research, Hawkins et al reported a favorable response to recombinant human IL-1 receptor antagonist (anakinra) in patients with MWS and reported significant reduction in SAA levels. Anakinra is given in an adult dosage of 100 mg SC once daily or a pediatric dosage of 1 mg/kg SC once daily.

The IL-1-beta inhibitor rilonacept has shown impressionable improvement in patients with MWS. The loading dose is 320 mg administered as 2 subcutaneous (SC) injections of 160 mg each on day 1 at 2 different injection sites, and the maintenance dose is 160 mg SC every week. ^{[75, 76, 77]}

Canakinumab, another IL-1 inhibitor, was approved for cryopyrin-associated periodic syndrome (CAPS).

UV radiation may be administered to treat skin lesions.

Unsuccessful treatments that have been attempted include low-dose corticosteroids, chlorambucil, antihistamines, dapsone, azathioprine, mycophenolate mofetil, and infliximab.

Complications

Similar to other hereditary periodic fever syndromes, MWS predisposes to a higher likelihood of amyloidosis. 

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) is associated with the most severe phenotype in the cryopyrin spectrum of diseases, although the clinical manifestations vary in severity. This syndrome was first described by both Prieur and Goldsmith in the early 1980s as a chronic inflammatory disease with rash, articular involvement, and chronic aseptic meningitis. Most cases of NOMID appear sporadic, with a few reports of autosomal-dominant transmission. NOMID affects females and males equally. No significant ethnic predilection has been reported. ^[49]

Genetics and pathogenesis

Mutations in NLRP3 (CIAS1) that encode cryopyrin causes NOMID/CINCA. Cryopyrin interacts with ASC, leading to activation of caspase 1 and the subsequent release of IL-1, as well as the activation of NF-kappa B, which results in the release of many proinflammatory cytokines. IL-1 is a key proinflammatory cytokine that contributes to increased synthesis of SAA protein by hepatocytes during the acute-phase response; SAA finally accumulates in different organs, causing amyloidosis.

Feldmann and colleagues (2002) proposed that NLRP3 (CIAS1) mutations may have an antiapoptotic effect that can explain the bone overgrowth (arthropathy) in patients with NOMID/CINCA. ^{[8, 53, 54, 55]}

Clinical manifestations

This dominantly inherited disease is characterized by neonatal onset and the triad of skin rash, chronic aseptic meningitis, and arthropathy. ^[53] First symptoms occur at birth or in early infancy.

The typical features include persistent and migratory urticarial rash (which is often present from birth), fever, adenopathy, and hepatosplenomegaly.

An urticarialike rash is usually present at birth or during the first months of life. The rash is nonpruritic and papular. Approximately two thirds of patients develop joint manifestations, including asymmetric joint involvement, arthralgia, and transient swelling without effusion. Knees are most commonly involved.

Bone manifestations are severe and usually begin within the first year of life. They usually involve the metaphyses and epiphyses of the long bones and lead to bony overgrowth, resulting in gross deformity of the joints, loss of range of motion, and significant joint pain. ^{[55, 56]} These epiphyses demonstrate erratically ossified, markedly coarsened trabeculae arranged in a random reticular pattern. The borders of the ossified portions of the epiphyses are spiculated and uneven. Eventually, long bones develop bowing of the ends and shortening of the diaphysis. Other radiographic findings include osteoporosis and prominent periosteal new bone formation along the diaphyses and metaphyses of affected long bones.

Prematurity and dysmaturity are observed in one third of patients.

Neurological manifestations, including chronic aseptic meningitis, cerebral ventricular dilation, cerebral atrophy, uveitis, optic disc edema, and high-frequency progressive hearing loss caused by chronic cochlear inflammation have been reported.

Ocular manifestations can progress to blindness, and 25% of patients have a significant ocular disability.

Chronic headache, vomiting, and papilledema are frequently observed consequences of chronically increased intracranial pressure. Spastic diplegia and epilepsy may develop. Progressive cognitive impairment occurs in severely affected patients. In patients with elevated intracranial pressure, closure of the anterior fontanelle may be delayed, and macrocrania, frontal bossing, and saddle nose appearance are frequently noted. ^[56]

Ancillary testing/diagnosis

Patients with NOMID/CINCA usually have elevated ESR, CRP, leukocytosis, eosinophilia, and hyperglobulinemia, but autoantibodies are generally not demonstrated.

Splenomegaly is often noted.

Cerebral spinal fluid (CSF) examination demonstrates variable hypercellularity with increased polymorphonuclear leukocytes, elevated protein levels, and an increased opening pressure. Following radiologic manifestations, swelling of the periarticular soft tissues develops, often with visible enlargement of the non-ossified portion of the epiphyses and bizarre enlargement of the ossified portions of the epiphyses of the involved joints, which is the hallmark of the disease.

CT scanning or MRI results may be normal or reveal mild ventricular dilatation and enlarged subdural fluid spaces, suggesting mild cerebral atrophy. ^[22]

In some patients, calcification of the falx cerebri and dura mater is noted, and leptomeningeal enhancement is observed on MRI after gadolinium injection.

Bone biopsy may show poorly organized cartilaginous columns on hematoxylin and eosin staining, nonhomogeneous spread of chondrocytes with staining for proteoglycans with Alcian blue, and a complementary pattern of calcification seen on von Kossa staining for calcium. ^[21]

Evaluation of skin samples may reveal mild perivascular leukocytic and eosinophilic infiltrates.

Differential  d iagnoses

The differential diagnoses of NOMID/CINCA include Still disease and other hereditary periodic fever syndromes (HPFSs), especially MWS and familial cold autoinflammatory syndrome (FCAS). FCAS, MWS, and CINCA/NOMID appear to represent a spectrum of disease. FCAS has a relatively benign presentation, while NOMID/CINCA typically has a severe disease presentation and complications.

Treatment

NSAIDs, corticosteroids, and TNF inhibitors provide an unsatisfactory response.

Based on research by Sibley et al and Frenkel et al, anakinra was approved by the FDA for use in patients with CINCA/NOMID. Anakinra has shown to prevent disease progression in the CNS, ears, and eyes. Canakinumab was also approved by the FDA as an orphan drug for inflammation associated with cryopyrin-associated periodic syndrome (CAPS). ^{[58, 59, 60, 76, 77]}

Complications

Common complications of CINCA/NOMID include dysmaturity, facial dysmorphism, chronic meningitis, bilateral papilledema, sensorineural deafness, intellectual disability, and cerebral atrophy.

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal-dominant autoinflammatory syndrome characterized by early-onset episodes of destructive inflammation of joints and skin.

Genetics and pathogenesis

PAPA is caused by mutations in the proline serine threonine phosphatase-interacting protein (PSTPIP1, or CD2 binding protein 1 [CD2BP1]) on chromosome 15, and the encoded cytoplasmic protein modulates T-cell activation, cytoskeletal organization, and IL-1 beta release. PSTPIP1 interacts with pyrin, and PAPA-associated PSTPIP1 mutations increase the strength of this interaction. Increased PSTPIP1-pyrin interaction causes increased IL-1 beta activation. Alternatively, increased avidity of PSTPIP1 for pyrin may lead to the formation of macromolecular complexes, denoted pyroptosomes, leading to cell death and inflammatory cytokine release. ^[9]

Clinical manifestations

PAPA syndrome typically manifests with recurrent episodes of sterile erosive arthritis in early childhood. Occasionally, patients with PAPA syndrome develop significant joint destruction.

Dermatologic manifestations also are episodic and recurrent and are characterized by debilitating aggressive ulcerative skin lesions, often of the lower extremities. The other component of this triad is cystic acne, which begins in adolescence and persists into adulthood. Other possible manifestations of PAPA syndrome include pathergy (formation of sterile abscesses at injection sites), sporadic episodes of irritable bowel syndrome, aphthous ulcers, and, rarely, pancytopenia after administration of sulfa-containing medications.

Ancillary testing

While the synovial fluid and skin lesions may have the appearance of an infectious process, culture of skin and joints are sterile.

Radiographic findings include periosteal proliferation of involved bones and, in some cases, ankyloses.

Treatment

Consistent with this proposed pathogenesis, there are reports of successful treatment with anakinra, etanercept, and infliximab in some patients.

Deficiency of the IL-1 receptor antagonist (DIRA) is a rare autosomal-recessive auto-inflammatory disease caused by mutations affecting the gene IL1RN encoding the endogenous IL-1 receptor antagonist.

Genetics and pathogenesis

Mutations in the IL1RN gene result in a prematurely truncated protein that is not secreted, resulting in patient cells being hyperresponsive to IL-1 stimulation and, consequently, an increased production of proinflammatory cytokines.

Mutations are commonly found in Puerto Rico, Newfoundland, the Netherlands, and the Lebanon-Israel border. ^{[1, 78, 79]} A patient from Newfoundland was homozygous for a deletion of 2 bp (c.156_157delCA) that caused a frameshift mutation, N52KfsX25, followed by the incorporation of 24 aberrant amino acids and a termination codon. Of the 5 patients of Dutch ancestry, 3 were homozygous for a nonsense mutation affecting the amino acid at position 77 (E77X). Patients from a consanguineous Lebanese family were homozygous for a nonsense mutation (Q54X). A patient from Puerto Rico was homozygous for a deletion of approximately 175 kb on chromosome 2q that includes 6 genes from a cluster of IL-1–related genes: IL1RN and the genes encoding IL-1 family, members 9 (IL1F9), 6 (IL1F6), 8 (IL1F8), 5 (IL1F5), and 10 (IL1F10). It has since been found that this is a relatively common mutation in the Puerto Rican population, with an allele frequency of the founder mutation in the Puerto Rican population around the area of Arecibo to be approximately 1.3%.

Subsequently, a novel 15-bp (in-frame) deletion on the IL1RN gene was reported from Brazil in two unrelated patients. ^{[80, 81]} The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1 alpha or IL-1 beta led to oversecretion of proinflammatory cytokines.

Another novel mutation has been reported from Turkey, which resulted in intrauterine death, raising the possibility that some cases may be misclassified as intrauterine infections. ^[80]

Clinical manifestations

Children with DIRA present with bone pain and skin manifestations ranging from groupings of small pustules to a generalized pustulosis from birth to age 2 weeks. Of note in the original series, fever was not a presenting feature. Vasculitis and interstitial lung disease were also noted. Elevated ESR and CRP are features.

Patients with DIRA have characteristic radiographic findings of multifocal sterile osteolytic bone lesions, widening of multiple anterior ribs, and periosteitis. Three of the original 9 patients described had cervical vertebral fusion secondary to collapsing vertebral osteolytic lesions.

Treatment

In the original and subsequent reports, patients had minimal response to high-dose corticosteroid and immunosuppressive therapy. Patients treated with anakinra, an IL-1 receptor antagonist, exhibited rapid clinical and immunological response and improved skeletal lesions. ^[81]

A growing body of research indicates that the ubiquitin pathway is important in the pathophysiology of many different human diseases. For example, haploinsufficiency of A20 (HA20) results from a germline mutation that causes dysregulated ubiquitination and an inflammatory phenotype. ^[83] The team of researchers identified 3 unrelated patients from Turkey and Pakistan who had a similar phenotype of pronounced inflammation. Patient 1 was born prematurely and soon developed a fever and rash. Patient 2 presented at age 4.5 months with prolonged fevers and pustular scarring rashes. Patient 3 presented with neonatal onset fever, as well as prominent cutaneous lesions, such as an erythematous rash with painful skin nodules. ^{[83, 82]} The patients all had increased serum levels of pro-inflammatory cytokines.

Researchers believe that this group is a recessively inherited auto-inflammatory disease caused by excessive linear ubiquitination in innate immune signaling pathways, which is denoted as otulipenia. OTULIN deficiency leads to increased linear ubiquitination of target proteins, which is associated with enhanced NF-kappa B activity, increased TNFR1 signaling, and NLRP3 inflammasome activity. The phenotype is very severe and potentially lethal if left untreated. During their study, researchers were able to successfully prescribe cytokine inhibitors to efficiently suppress the patients’ constitutive inflammation, suggesting that targeted cytokine therapies may be useful in diseases related to defects in the ubiquitin pathway. ^{[82, 83]}