Autoinflammatory syndromes: Fever is not always a sign of infection
ABSTRACTAutoinflammatory syndromes are a newly understood group of conditions characterized by recurrent episodes of fever, rash, and serositis. Generalists and specialists should know about and consider these syndromes in the differential diagnosis of recurrent fever. This article reviews the genetics, pathophysiology, clinical presentation, and treatment of several of these relatively recently discovered diseases.
KEY POINTS
- In many of the autoinflammatory syndromes, genetic abnormalities and consequent disordered regulation of the innate immune system lead to overactivity of proinflammatory cytokines and subsequent inflammatory symptoms.
- Early recognition and treatment with immunoregulatory agents may improve quality of life and reduce the risk of disease sequelae.
- Abnormal regulation of the innate inflammatory pathway has also been implicated in the pathogenesis of conditions as phenotypically diverse as gout, type 2 diabetes, atherosclerosis, and epilepsy.
Brief episodes of fever and serositis
Although FMF usually presents at ages 5 to 15, about 20% of patients with FMF suffer their first inflammatory attack after age 20 years.
Attacks are characterized by brief episodes of fever with temperatures higher than 102°F (38.9°C), lasting less than 72 hours, accompanied by intense serositis. Abdominal serositis may be severe enough to mimic appendicitis and lead to exploratory surgery.
About 70% of patients experience arthritis (predominantly in the legs), and 40% develop erysipeloid erythema, an intensely erythematous, warm, tender, and plaque-like lesion on the lower extremities. Biopsy of involved skin shows a diffuse, primarily neutrophilic, inflammatory cell infiltrate.
Laboratory examination reveals marked elevation of acute-phase reactants, which may normalize between episodes. The diagnosis can be made using a combination of clinical suspicion, sequencing of the MEFV gene, and a positive response to a trial of colchicine (Colcrys).
Without treatment, repetitive attacks of inflammation may result in amyloidosis of the kidneys or liver. The risk of amyloidosis is related to several discrete risk factors, such as country of residence, MEFV genotype, and serum amyloid A genotype.10–12 Patients should be monitored for physical manifestations of amyloidosis at least annually.
FMF patients have also been described who develop vasculitides such as Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease.
Colchicine is the mainstay of FMF treatment
Colchicine has been the mainstay of therapy for patients with FMF for almost 40 years.13–15 Its benefits in FMF are clear: symptoms cease in nearly 70% of patients treated with colchicine, and an additional 25% have a reduction in the severity and frequency of attacks.
Only 5% to 10% of patients have no response to colchicine; this may be partially due to individual dose limitations imposed by common drug-associated gastrointestinal side effects.16–18 For these patients, newer biologic drugs that inhibit IL-1 activity, such as anakinra (Kineret) and rilonacept (Arcalyst), offer great promise.
Typically, FMF attacks become less frequent and less severe with age. However, the overall prognosis in FMF is related mainly to the individual’s genotype and the associated risk of amyloidosis.19
HYPERIMMUNOGLOBULIN D SYNDROME
HIDS is another autosomal recessive autoinflammatory syndrome.20
The genetic defect underlying HIDS lies within the mevalonate kinase gene MVK.21 Mevalonate kinase, an enzyme, plays an important role in the cholesterol biosynthesis pathway, following the initial step by 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. Mutations are primarily missense mutations in highly conserved areas of protein that result in decreased MVK activity (1% to 5% of normal).22,23 Decreased production of geranylgeranyl pyrophosphate resulting from disruption in the HMG-CoA reductase pathway subsequently leads to increased release of IL-1 beta from peripheral blood mononuclear cells and triggers inflammatory symptoms.24
Attacks of HIDS begin early in life
HIDS attacks begin early in life, with more than 70% of patients suffering their first attack before age 2, but adult-onset disease has been reported. Patients may report that routine childhood vaccinations triggered attacks, a historical finding unique to HIDS.
Attacks typically last 4 days; a longer duration can help the clinician differentiate HIDS from FMF.
More than 90% of patients have cervical lymphadenopathy, and 80% have an erythematous rash characteristically located on the palms and soles. About 70% of patients have headache, arthritis, and abdominal pain.
During attacks, laboratory examination reveals elevated acute inflammatory reactants. As the name implies, serum levels of immunoglobulin D (IgD) are elevated. However, this finding is not specific to HIDS and may also be found in patients with Still disease or FMF or in those who smoke cigarettes. Serum IgD levels fluctuate throughout life, and the sensitivity of commercially available IgD test kits is variable.
Assessment of mevalonic acid levels in the urine during febrile attacks offers a more sensitive, specific, and reliable diagnostic test for HIDS.25 While genetic sequencing is the gold standard of diagnostic testing, close to 30% of patients meeting clinical criteria for HIDS have no definable mutation.26
Treatment of HIDS can be challenging
Oral corticosteroids are effective in HIDS, but their long-term side effects are undesirable. Patients rarely respond to colchicine, differentiating them from FMF patients.
Etanercept (Enbrel), a fusion protein composed of the soluble TNF receptor and the Fc portion of the human IgG1 protein, has been efficacious in some patients.27,28 IL-1 inhibitors have also been used with increasing efficacy in the treatment of HIDS attacks.29,30
Although the frequency of attacks decreases with age, long-term follow-up of 28 Dutch HIDS patients found that their quality of life was still lower than that in country-matched controls.31
TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME
In 1982, a large multiplex family from Scotland and Ireland was described who had a newly recognized syndrome termed familial Hibernian fever, characterized by recurrent fever, rash, and abdominal pain.32 In 1998, the genetics of this autosomal dominant condition were characterized,33–35 and it is now known by the acronym TRAPS.
TRAPS has a variable presentation owing to a variety of mutations in the gene encoding the cell surface receptor for TNF (TNFRSF1A). TNFRSF1A mutations affecting conserved cysteine residues important for protein folding correspond to severe disease phenotypes.
The R92Q mutation has an allele frequency of up to 4% of the population. It has no impact on the structure and function of the TNF receptor protein and is associated with a heterogeneous disease course. In contrast, the P46L mutation has an allele frequency of 1% of the population and typically is associated with a milder disease course characterized by older age of onset, shorter episodes, and a low frequency of amyloidosis.36–39
The R92Q and T61I mutations, which have low penetrance, have been increasingly reported in adult patients with the autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.40–42 Their influence is believed to contribute to proinflammatory responses but not to provide additional genetic susceptibility as provided by human leukocyte antigen (HLA) genotypes for susceptibility for these autoimmune diseases.
TRAPS attacks last longer than FMF and HIDS attacks
TRAPS attacks last 7 days or more, differentiating TRAPS from FMF and HIDS. Patients may present from infancy into adulthood, but more typically present in the toddler period.
Most patients experience intense myalgia as well as abdominal and pleuritic chest pain. A single-center series in 2002 described close to half of patients diagnosed with TRAPS as having had an intra-abdominal surgical procedure; in 10% necrotic bowel was identified, yet the biopsy typically revealed only a serosal mononuclear infiltrate.43
Like FMF and HIDS, TRAPS can cause an erythematous rash. The rash usually appears on an extremity, is centrifugal, and travels proximal-to-distal in concert with symptoms of myalgia. Deep tissue biopsy often demonstrates an intense, neutrophilic fasciitis sparing the underlying musculature. Painful conjunctivitis with periorbital edema also may occur.
Laboratory values reflecting widespread systemic inflammation and elevated acute-phase reactants are encountered during attacks and in some cases may persist between episodes.
Genetic testing can be used to confirm the diagnosis. The probability of finding a mutation in TNFRSF1A depends highly on whether the patient has affected relatives. In a series of 28 patients with recurrent inflammatory syndromes and TNFRSF1A mutations, 9 (32%) had a family history of recurrent inflammatory syndromes, while in 176 patients with sporadic, nonfamilial “TRAPS-like” symptoms, TNFRSF1A mutations were uncommon.37,38
Etanercept is effective for TRAPS
Systemic corticosteroids may be effective for treating TRAPS, but ever-increasing doses are often required.
Etanercept’s ability to bind both soluble and bound TNF explains its relative efficacy in treating TRAPS even though other TNF inhibitors have proven ineffective.44,45 With etanercept, the prognosis of TRAPS patients is typically good. Etanercept has even been effective in treating cases of renal amyloidosis from long-standing TRAPS, although it has not been shown to facilitate regression of renal amyloid mass.46,47 However, responses to treatment with etanercept may wane with time, and resistant cases have been reported.
IL-1 blockade with anakinra has been shown to be effective in the short term and long term in small case series, providing a reasonable alternative for patients who are difficult to manage.
