PHILADELPHIA—Research on the mechanisms of systemic autoinflammatory diseases is providing important information on the genetic control of inflammation and driving interest in the development of new targeted therapies for rheumatic diseases.
Daniel L. Kastner, MD, PhD, clinical director at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health in Bethesda, Md., noted the continuum between autoinflammatory and autoimmune diseases.
Speaking here at the ACR/ARHP Annual Scientific Meeting, Dr. Kastner said the systemic inflammatory diseases are characterized by episodes of seemingly unprovoked infection and the absence of high-titer autoantibodies or antigen-specific autoreactive T cells. The Mendelian autoinflammatory diseases “turn out to be inborn errors of the innate immune system,” Dr. Kastner said during the ACR’s basic research conference on the genetics of rheumatic diseases.
“The challenges that face us in the next several years will be further elucidation of the Mendelian autoinflammatory diseases, looking for a few genes and elucidating the susceptibility they confer on increased risk,” he said.
Dr. Kastner’s laboratory played a key role in the discovery of the gene for familial Mediterranean fever (FMF), one of the most common of the periodic fever syndromes. The variation in this gene is indicative of “ancient ancestral mutations,” he noted. An autosomal recessive disorder, FMF is marked by fever lasting about three days, abdominal pain, and elevation in peripheral white blood cell count. Fluid from the inflamed joints can exhibit leukocytosis with a predominance of neutrophils.
Dr. Kastner listed several challenges facing researchers in the field of autoinflammatory diseases: elucidating the immunobiology, adopting a pathophysiological rather than clinical classification of the diseases, developing animal models, and moving forward with development of targeted therapy.
TRAPS: Mutations in TNFR1
Richard M. Siegel, MD, PhD, principal investigator in the Autoimmunity Branch at NIAMS, outlined what is known about TRAPS, or tumor necrosis factor receptor–associated periodic syndrome, an autoinflammatory disease classified as one of the hereditary periodic fever syndromes. TRAPS is “a quite rare … Mendelian disease, one of nature’s experiments,” with dominant mutations in TNF receptor 1 (TNFR1), Dr. Siegel said.
Like other autoinflammatory diseases, TRAPS manifests as periodic episodes of fever, abdominal pain, conjunctivitis, and a migratory rash. Some flare-ups can extend beyond five days, and little is known about what triggers the flare-ups. Initially called familial Hibernian fever, TRAPS can present in infancy and even into adulthood and is not accompanied by any viral or bacterial infection. Amyloidosis can be a life-threatening complication, Dr. Siegel said.
Not much is known yet about how the polymorphism causes disease or about the mechanism, Dr. Siegel said. However, he noted, information about TRAPS has “opened up new understanding about TNF receptor 1.”
DIRA: Mutations in IL1RN
The recent discovery of DIRA, a deficiency of the interleukin-1 (IL-1) receptor antagonist, is helping researchers understand the potential role of IL-1 in other autoinflammatory diseases. Children diagnosed with DIRA have inherited mutations in IL1RN, a gene that encodes IL-1Ra.
Raphaela Goldbach-Mansky, MD, chief of the NIAMS Translational Autoinflammatory Disease Section, said that patients with DIRA present with bone tissue swelling, bone pain and deformity, inflammation of the periosteum, and rashes that can include extensive postulosis. A rare and potentially fatal disease, it has been successfully treated with anakinra, an IL-1 receptor antagonist, but the disease is unresponsive to steroids.
Other IL-1–related disorders include neonatal-onset multisystem inflammatory disease, also known as NOMID; chronic infantile neurologic, cutaneous, articular syndrome, which is also known as CINCA; familial cold autoinflammatory syndrome, also known as FCAS; and Muckle-Wells syndrome, or MWS. All belong to the disease spectrum called cryopyrin-associated periodic syndromes (CAPS).
Diseases classified as CAPS stem from overproduction of active IL-1b, and some have responded to treatment with anakinra, the IL-1 receptor antagonist. According to Dr. Goldbach-Mansky, patients with NOMID can have early hearing loss, joint contractures, headaches, and mental retardation. Early and aggressive treatment is vital for those patients, she said.
“NOMID and DIRA present the rare cases where a master cytokine pathway is known and clinically confirmed to play a pivotal role in human disease,” Dr. Goldbach-Mansky said. Identification of the IL-1–related disorders may also indicate a role for IL-1 in more common diseases, such as gout, type 2 diabetes, fibrosing lung disease, and Alzheimer’s disease, she said.
DIRA is also one of the inflammatory bone disorders that may be difficult to diagnose. Chronic recurrent multifocal osteomyelitis, or CRMO, is another that generally occurs in childhood, primarily among girls.
CRMO: Recurrent Fever and Bone Pain
Peggy Ferguson, MD, assistant professor of pediatrics at the University of Iowa in Iowa City, said that young patients diagnosed with CRMO present with recurrent fever and bone pain, and they develop multiple inflammatory bone lesions, sometimes with mandibular involvement. On X-ray, the osteolytic lesions are surrounded by sclerosis. CRMO can occur in association with palmoplantar pustulosis, pyoderma gangrenosum, and spondylarthropathy.
“Lab studies don’t help at all,” Dr. Ferguson said, adding that many children who present with CRMO have negative cultures. They do not respond to antibiotics. The trigger for CRMO remains unclear, Dr. Ferguson said. Infections have been suggested as a possible trigger, but no microorganism has been determined. For some children, a history of trauma may trigger the disease.
Another inflammatory bone disorder, Majeed syndrome, is an autosomal recessive disease attributed to defects in the LPIN2 gene. Patients present with recurrent fever, recurrent CRMO, congenital dyserythropoietic anemia (CDA), and Sweet syndrome.
Cherubism is an autosomal dominant disease that generally presents at age three or four years. There is symmetric jaw swelling and radiolucent cystic bone lesions, Dr. Ferguson said. Loss of bone in the mandible that is replaced by fibrous tissue leads to the “cherubic” appearance.
According to Dr. Ferguson, the inflammatory bone disorders are rare and have no known triggers, but a genetic component has been identified. Better understanding of these diseases, as well as the genetic mutations responsible, “may teach us something” about psoriasis, Chron’s disease, rheumatoid arthritis, and other inflammatory diseases, she said.
Genetic Disorder of Complement
John Atkinson, MD, professor of molecular biology at the Washington University School of Medicine in St. Louis, said that genetic disorders of complement are the “scourges of a dysfunctional immune system.”
The complement system is at the center of the host response to pathogens. Therefore, patients with disorders of complement can be susceptible to recurrent infections such as sinopulmonary infections, bacteremia, and meningitis. Some of the pathogens that may be involved are Streptococcus pneumoniae, Hemophilus influenzae type B, and Neisseria meningitidis.
Autoimmune diseases, such as systemic lupus erythematosus (SLE), can develop due to inherited deficiencies in the complement system.
One disorder of the complement system is hemolytic uremic syndrome, in which the endothelium is damaged and thrombosis occurs, along with extensive damage to the kidney. About 25% of children die acutely, and 25% have relapsing disease.
Researchers involved in PROMISSE, a prospective, observational study in pregnancy in SLE, reported at the ACR/ARHP meeting that the genetic variants linked with preeclampsia in women with SLE or antiphospholipid syndrome (APS) are in complement regulatory proteins.1
These mutations in complement regulatory proteins were present in 18% of patients in the PROMISSE trial who had preeclampsia. Dr. Atkinson said that this study underscores the importance of complement in preeclampsia and gives insight about the mechanisms for increased risk for certain patients.
Kathy Holliman is a medical journalist based in New Jersey.
Reference
- Salmon JE, Fremeaux-Bacchi V, Liszewski MK, et al. Mutations in complement regulatory proteins predispose to preeclampsia in patients with lupus or antiphospholipid antibodies. #121. Presented at ACR/ARHP Scientific Meeting. Oct. 18, 2009. Philadelphia.
