During our weekly physician conference, I discussed a patient with a suspected autoinflammatory disease. An elderly male, he had a history of recurrent fevers, hives, and elevated inflammatory markers, which had gone untreated for many years. Eventually, he developed renal amyloidosis, and was finally referred to rheumatology clinic for further evaluation. Although he had many of the classic signs and symptoms of an autoinflammatory disease, his physicians had not recognized it. His kidneys were failing, and he was being prepared to undergo hemodialysis as a result. Even during the case conference, in the presence of several prominent physicians of various specialties, I still heard the same question I’ve been hearing since I began to care for patients with these rare illnesses: “Autoinflammatory? You mean autoimmune, right?” Wrong!
Autoinflammatory diseases are a newly described set of illnesses that cause systemic inflammation due to problems in the innate immune system. The innate immune system includes neutrophils, macrophages, and natural killer cells, which are usually the first cells to respond to an infection because they recognize common molecular patterns present in many types of pathogens. When they are activated, these cells normally secrete cytokines that trigger inflammation, a process which causes an influx of cells into the area of infection, designed to attack and contain the invading pathogen.
Autoinflammatory diseases are often caused by genetic mutations within the cells of the innate immune system. These mutations lead to episodes of unprovoked activation of the immune system (with the release of the pro-inflammatory cytokine, IL-1). In a sense, the body acts as if an infection were present, even when there is none. This is why many of the symptoms of autoinflammatory diseases — such as fever, rashes, joint pain — mimic infections, and why these diseases are often difficult to diagnose. The best characterized autoinflammatory condition is Familial Mediterranean Fever (FMF), which causes recurrent, brief attacks (12 to 72 hours) of fever, abdominal pain, chest pain, joint pain, and evidence of systemic inflammation on blood testing.
In contrast, autoimmune diseases arise from problems in the adaptive (humoral) immune system. The adaptive immune system, made up of specialized B and T cells, is more sophisticated than the innate. Each B and T cell in our body is unique, only recognizing a specific antigen on a specific pathogen. Once an antigen is recognized, it takes time for the cell to divide and multiply, as well as to produce effective neutralizing antibodies.
However, activation of the adaptive immune system eventually leads to a very effective and direct attack on the pathogen. Unlike the innate immune system, the adaptive immune system develops “memory,” so that it is better able to fight the pathogen when it reencounters it in the future.
In autoimmune diseases such as lupus, the B and T cells of the adaptive immune system lose the ability to differentiate self from non-self. That is, they start seeing specific antigens present in various organs in the body as foreign (almost as if they were pathogens!), and thus begin to mount an attack against those organs, often leading to organ damage or destruction. In lupus, B and T cells commonly target the kidney, lungs, or skin, leading to many of the manifestations of this disease. However, autoimmune diseases can target almost any organ in the body. For reasons that are still unknown, autoimmune diseases more often affect women, whereas autoinflammatory diseases seem to affect both sexes equally.
Treatment for these disorders varies widely. Because most of the damage of autoinflammatory diseases is a direct result of inflammation, medications that directly inhibit inflammation, such as IL-1 antagonists, have been incredibly effective. In contrast, inflammation does not appear to play a prominent role in autoimmune diseases. These diseases are usually managed by the use of immunomodulators that impair the immune system.
In the end, I think my patient may have had Muckle-Wells syndrome, an autoinflammatory disease caused by mutations in the NLRP3 gene. Autoinflammatory disorders are still underdiagnosed and poorly understood. New autoinflammatory diseases are being discovered every month.
Furthermore, various pathways that are abnormal in autoinflammatory diseases have been implicated to play a role in more common diseases such as heart disease and diabetes. Thus, by understanding these rare disorders, we may gain a better understanding of diseases that afflict millions of people throughout the world.
Jonathan S. Hausmann is a rheumatology fellow who blogs at Autoinflammatory diseases.