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.
CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES
- Perhaps the most clinically diverse hereditary autoinflammatory syndromes are the cryopyrin-associated periodic syndromes (CAPS). There are three overlapping phenotypes: Familial cold autoinflammatory syndrome (FCAS)
- Muckle-Wells syndrome (MWS)
- Neonatal-onset multisystemic inflammatory disorder (NOMID).
Mutations in NLRP3
CAPS symptoms stem from mutations within the NLRP3 gene (NOD-like receptor family, pyrin domain), which encodes the protein, cyropyrin.48NLRP3 mutations result in an abnormal cryopyrin structure, abnormal inflammasome activity, and increased IL-1 beta production.49,50
There is poor genotype-phenotype association in CAPS; the same NLRP3 point mutation can result in variable features, typically of either FCAS and MWS or MWS and NOMID overlapping phenotypes, supporting the hypothesis that modifier genes play a role in phenotypic expression.
Inheritance patterns in CAPS are autosomal dominant, but spontaneous mutations are also common. In fact, approximately two-thirds of patients with mutation-negative NOMID have somatic NLRP3 mutations, indicating that somatic NLRP3 mosaicism contributes to the clinical syndrome.51
Clinical features of the CAPS
The hallmarks of the CAPS include recurrent fevers, urticarial rash, and central nervous system inflammation. Characteristically, CAPS patients present in the neonatal period through early childhood, but adult-onset cases, which may have less typical features, have been reported.
Patients with FCAS develop brief episodes (< 24 hours) of fever, joint pain, and urticarial rash when exposed to sudden drops in ambient temperature.
Patients with MWS have more frequent, prolonged attacks, which may or may not be related to changes in ambient temperature. They also develop fever and urticarial rash and may develop arthritis and headaches from aseptic meningitis.
Patients with NOMID often present with fever and persistent urticarial rash shortly after birth and suffer from chronic aseptic meningitis, which can lead to papilledema and optic nerve atrophy. Frontal bossing of the skull and overgrowth of the epiphyseal regions of long bones with accompanying growth delay are also characteristic of NOMID.
IL-1 antagonists offer relief from CAPS
Many patients with FCAS do not require treatment and may move to a warmer climate to avoid rapid swings in ambient temperature. Otherwise, control of IL-1 beta activity is essential to the successful treatment of CAPS. Patients with MWS and NOMID require treatment with IL-1 antagonists, and the biologic drugs anakinra, rilonacept, and canakinumab (Ilaris) offer the possibility of symptomatic relief and long-term control of the disease.52–54
Prognosis depends on the phenotype
The overall prognosis for patients with CAPS largely depends on phenotype.
Patients with FCAS generally have progressive improvement in attack frequency and severity over time and are at minimal risk of amyloidosis.
Patients with MWS have a relatively good prognosis when treated with IL-1 antagonists, making them at low risk of amyloidosis and sensorineural hearing loss.
However, patients with NOMID are at high risk of sensorineural hearing loss, growth delay, and amyloidosis unless the condition is recognized and treated early in its course. Mortality rates historically are as high as 20% in untreated patients with NOMID.55
OTHER AUTOINFLAMMATORY SYNDROMES
More recently, other autoinflammatory syndromes of known genetic etiology have been described.
NLRP12-associated autoinflammatory disorders
A subset of patients with clinical manifestations attributable to CAPS but without mutations at the NLRP3 locus have mutations in another NLRP family member expressed in peripheral blood mononuclear cells on the NLRP12 gene. They are therefore labeled as having an NLRP12-associated autoinflammatory disorder.56,57
Deficiency of interleukin 1 receptor antagonist
IL-1 receptor antagonist is a naturally occurring antagonist of IL-1 alpha and IL-1 beta. In patients with deficiency of IL-1 receptor antagonist (DIRA), the action of these potent proinflammatory proteins is unopposed, leading to severe pustular rash and osteitis.58,59
Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome
Patients with PAPA syndrome also have increased IL-1 production, in this case due to a mutation in the cytoplasmic adapter protein proline-serine-threonine phosphatase-interacting protein (PSTPIP1) gene, leading to the development of the symptoms included in the PAPA acronym.60
Majeed syndrome
Majeed syndrome is caused by a mutation in the LPIN2 gene, resulting in the early onset of chronic recurrent multifocal osteomyelitis, neutrophilic dermatosis, and dyserythropoietic anemia.61
Blau syndrome
Some patients with Blau syndrome (granulomatosis, arthritis, and uveitis) have NOD2/CARD15 gene mutations.62 Cases of DIRA, PAPA, and Blau syndrome have been reported that responded favorably to treatment with IL-1 antagonists.
Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome
Although symptoms of the periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome typically begin in childhood, adult-onset cases have been reported.63
Patients with PFAPA syndrome develop predictable, stereotypic febrile attacks that last on average 5 days and occur approximately every 4 weeks. Between attacks, patients are healthy; during attacks, they may experience oral ulceration (aphthous stomatitis), exudative or nonexudative pharyngitis, and enlarged and tender cervical lymph nodes. Up to 60% of PFAPA patients also experience abdominal pain.
No single genetic mutation has been identified, although it has been shown that 45% of PFAPA patients have a parent or sibling with recurrent fever and 12% have a parent or sibling with a PFAPA-like phenotype, suggesting that the disease has a genetic basis.64 Recent studies have demonstrated that T-cell–regulated complement activation and IL-1 production are altered in PFAPA patients, thus supporting the hypothesis that PFAPA is an autoinflammatory syndrome.65
Treatment. In view of the syndrome’s self-limited nature, treatment is reserved for patients with a severe presentation or for patients whose condition is especially burdensome.
The fever’s height may partially respond to nonsteroidal anti-inflammatory drugs, but these drugs have little effect on the duration or frequency of fever.
One or two doses of prednisone (1 mg/kg) within 6 hours of fever onset is effective in aborting the febrile episode in 90% of patients; however, up to 50% of patients may experience an increased frequency of attacks after treatment with systemic corticosteroids.66,67
Additional options include daily colchicine, which may lengthen the time between attacks, and cimetidine (Tagamet), which has been shown to prevent PFAPA attacks in approximately one-third of patients.67–69
The prognosis of PFAPA is quite favorable, and without intervention 40% of patients experience a significant reduction in the severity and frequency of fever attacks within 5 years of diagnosis. To date, there have been no reports of amyloidosis or hearing loss in PFAPA patients.
