Autoinflammatory syndromes: Fever is not always a sign of infection

A 22-year-old man of Turkish ancestry presents to your office for an urgent visit. One day before the visit, he abruptly developed a fever with temperatures as high as 104°F (40°C), abdominal pain, joint pain, and a red rash on the lower right leg. He has no cough, nasal congestion, rhinorrhea, ear or eye pain, oral ulcers, vomiting, or diarrhea. After reviewing his chart, it becomes apparent that he has experienced similar intermittent, random, and self-limited episodes over the last 4 years.

On examination, he is febrile with diffuse abdominal tenderness and guarding. Bowel sounds are normal, and there is no rebound. The left knee is slightly swollen and limited in range of motion, and there is a large, non-palpable, blanching, erythematous lesion over the anterior lower leg.

While pondering diagnostic possibilities, you remember reading about autoinflammatory syndromes that result in recurrent episodes of fever and multisystemic inflammatory symptoms but cannot recall the evaluation and therapeutic options for these conditions.

These syndromes pose diagnostic challenges for physicians. Although these conditions are uncommon and may mimic malignancy or infection, they should be considered in patients who have recurrent febrile illness. While the autoinflammatory syndrome of familial Mediterranean fever (FMF), the diagnosis in the case above, is well known, our growing understanding of genetics and the immune system has unearthed a growing number of autoinflammatory syndromes.

A GENETICALLY DIVERSE BUT CLINICALLY SIMILAR GROUP OF CONDITIONS

The autoinflammatory syndromes are a group of genetically diverse but clinically similar conditions characterized by recurrent attacks of fever, rash, serositis, lymphadenopathy, and musculoskeletal involvement. This category of diseases is rapidly expanding and was built on the discovery of the genetics behind FMF, hyperimmunoglobulin D syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and the cryopyrin-associated periodic syndromes (CAPS). More recent additions to the list include Blau syndrome and the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA).

In autoinflammatory syndromes, genetic mutations lead to dysregulation of the innate immune system and to episodic manifestations of systemic inflammation. Many patients have first- or second-degree relatives with similar symptoms, reflecting the genetic abnormalities underlying this class of conditions. Unlike patients with other rheumatic diseases, patients with autoinflammatory diseases do not have autoreactive T lymphocytes, and they typically lack pathogenic autoantibodies.

The characterization of genetic autoinflammatory syndromes shows the importance of a well-regulated innate immune system and sheds light on the role of the innate immune system in common medical conditions such as gout and type 2 diabetes (see below).

THE INNATE IMMUNE SYSTEM : OUR FIRST LINE OF DEFENSE

The innate immune system is the first line of immune defense. It is evolutionarily conserved. Unlike the adaptive immune response, the innate immune response is not antigen-specific, and its activation does not produce a memory response. Generally speaking, it is composed of certain white blood cells (neutrophils, dendritic cells, macrophages, natural killer cells), proinflammatory signaling proteins (cytokines), and the complement system. Interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF) alpha are the critical and most potent proinflammatory cytokines of the innate immune system.

To date, nearly all mutations that have been linked to the autoinflammatory syndromes disrupt regulation of inflammatory signaling within the innate immune system. This disruption generates a proinflammatory state, often leading to a final common pathway ending with activation of the inflammasome.

The inflammasome is a complex of distinct proteins which, when brought together, serve to convert inactive prointerleukin 1 beta to the active proinflammatory cytokine IL-1 beta.¹ Formation of the inflammasome can be mediated by multiple different signals including microbial products, endogenously produced substances such as cholesterol and uric acid, or by proinflammatory cytokines and chemokines (Figure 1).

FAMILIAL MEDITERRANEAN FEVER

FMF is the most common and well characterized autoinflammatory syndrome. Described in 1949, its etiology was not understood until the genetic mutation that causes it was discovered in 1997.^2–4

The Mediterranean fever gene MEFV encodes pyrin, a protein with an important role in controlling IL-1 production. Mutations in MEFV affect pyrin-mediated regulation, and IL-1 production increases.

Classically, FMF is described as autosomal recessive, although many patients have only one abnormal allele.⁵ Possibly, the abnormal allele confers an evolutionary advantage in resisting an endemic pathogen, an idea reflected in the carrier frequencies of different MEFV mutations in certain Mediterranean and Middle Eastern ethnic populations (Sephardic Jews, Turks, Arabs, Armenians).^6,7 Also, carriage of mutations in MEFV in patients with Crohn disease has been associated with a higher risk of extraintestinal manifestations and colonic stricture,⁸ and their carriage in patients with multiple sclerosis has been associated with a rapid progression of that disease.⁹