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.
DIAGNOSTIC EVALUATION OF SUSPECTED AUTOINFLAMMATORY DISEASE
The autoinflammatory syndromes pose a true diagnostic challenge for physicians. Tremendous advances have been made in molecular and genetic testing. Nevertheless, the history and careful physical examination can lead the astute clinician to the proper diagnosis when evaluating a patient with a suspected autoinflammatory syndrome.
Critical elements in the history include age at the onset of attacks, duration of attacks, associated symptoms (serositis, adenopathy, myalgias, arthralgias, arthritis, ocular symptoms, central nervous system symptoms, rash), family members with similar symptoms, and ethnic background.
Internists should remember that autoinflammatory syndromes are part of the differential diagnosis in adult patients with a recurrent febrile illness. A vigorous search for malignancy and infection (especially tuberculosis) should be conducted in all patients. However, the repetitive, stereotypic nature of autoinflammatory syndromes differentiates them from typical confounders.
The utility of acute-phase reactants in the diagnostic evaluation is limited, as many conditions result in abnormal values. However, serial monitoring of inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein level in patients with a formally diagnosed autoinflammatory syndrome can be useful in tracking disease activity, identifying flares, and monitoring the efficacy of therapy.
In cases of suspected HIDS, assessment of IgD levels is not recommended, since IgD can be elevated in a number of autoinflammatory and rheumatologic conditions. Instead, preference should be given to testing mevalonic acid levels in the urine in patients with HIDS or suspected HIDS.
Patients with central nervous system symptoms should undergo a thorough examination, including a formal ophthalmologic evaluation, imaging, and possibly lumbar puncture to assess intracranial pressure and inflammatory changes in the cerebrospinal fluid.
Dermatologic manifestations should be examined firsthand and assessed as needed with magnetic resonance imaging to elucidate fascial inflammation or with full-thickness biopsy.
Gross bony abnormalities should be evaluated with plain radiography.
Audiologic testing may be indicated in the diagnostic evaluation of patients with recurrent fever.
Renal or hepatic biopsy may be indicated in the evaluation for amyloidosis; amyloid deposition has been reported in patients with TRAPS and clinical FMF not presenting with fever.70,71
Genetic testing is commercially available for patients with suspected hereditary autoinflammatory syndromes. However, clinicians should be cautioned that up to 30% of patients with phenotypic manifestations characteristic of a given autoinflammatory syndrome have normal results on genetic testing. In addition, the results of genetic testing may take several months to return and may cost patients and families up to several thousand dollars, as some insurers refuse to cover this procedure. Genetic testing may ultimately be indicated for proper counseling of reproductive risk.
Responses to short courses of medications such as colchicine, prednisone, and IL-1 receptor antagonists also represent diagnostic tools.
Figure 2 provides a proposed diagnostic algorithm for patients with suspected recurrent fever syndromes. Table 1 summarizes clinical and genetic features of the common autoinflammatory syndromes.
NEW INSIGHT INTO MORE COMMON CONDITIONS
Advances in the understanding of the autoinflammatory syndromes have provided new insight into the role of the innate immune system in other, more common conditions.72 Indeed, abnormal regulation of the innate inflammatory pathway has been implicated in the pathogenesis of conditions as phenotypically diverse as gout, type 2 diabetes, atherosclerosis, and epilepsy.73,74
Table 2 presents examples of the innate immune system’s involvement in the pathogenesis of several common chronic conditions.
Further study of autoinflammatory syndromes will add to our understanding of the innate immune system. These advances will lead to continued improvement in the care we give patients, both for the classic autoinflammatory syndromes and for other, more common, genetically complex conditions.
Our 22-year-old patient’s fever, abdominal pain (presumed peritonitis), erysipelas-like skin lesion, and arthritis are typical of FMF. Therefore, genetic testing was performed, which revealed a single MEFV gene mutation (M694V). Colchicine has been efficacious in preventing flares of his disease.
