On Tuesday, I challenged readers to figure out the cause of a girl’s jaw swelling and pain. Over 130 people read the story, and seven people submitted their responses on this website. You can read the original case here. Read below for the complete case, in addition to comments about the correct diagnosis. Continue reading Jaw swelling and pain: a biography of CRMO
Autoinflammatory diseases are a relatively new category of illnesses caused by disorders of one arm of the immune system. Many of these diseases are characterized by recurrent fevers, rash, chest and abdominal pain, and evidence of systemic inflammation on blood tests; these manifestations often mimic infectious or other illnesses, and it may take several years for the diagnosis to be made.
Most autoinflammatory diseases are genetic (inherited), start in childhood, and persist throughout adult life. These diseases are often present in several members of a family. Other autoinflammatory diseases appear to be acquired, perhaps due to the interplay of genetic and environmental factors, and can present at any time during childhood or adulthood.
The list of autoinflammatory diseases continues to grow every month. Here is a list of the autoinflammatory diseases as they stand so far:
- Familial Mediterranean Fever (FMF)
- TNF receptor associated periodic syndrome (TRAPS)
- Hyperimmunoglobulin-D syndrome (Hyper-IgD syndrome, HIDS, also known as mevalonate kinase deficiency, MVK)
- Cryopyrin-associated periodic syndromes (CAPS):
- Familial cold autoinflammatory syndrome (FCAS, also known as familial cold urticaria)
- Muckle-Wells syndrome
- Neonatal onset multisystem inflammatory disease (NOMID, also known as CINCA)
- Deficiency of the interleukin-1-receptor antagonist (DIRA)
- Deficiency of the interleukin-36-receptor antagonist (DITRA)
- Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA)
- Blau syndrome
- Pyogenic sterile arthritis, Pyoderma gangrenosum, Acne (PAPA)
- Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (SAPHO)
- Adult-onset Still’s disease (AOSD)
- Macrophage activation syndrome (MAS)
- Behcet’s disease
- Schnitzler’s syndrome
- Chronic recurrent multifocal osteomyelitis (CRMO, also known as chronic non bacterial osteomyelitis (CNO))
- Deficiency of adenosine deaminase 2 (DADA2)
- STING-associated vasculopathy of infancy (SAVI)
When I was little, I used to get a lot of fevers. With my fevers, I would develop pain in one or both of my ears, and I felt so drained that I just wanted to be left alone to watch TV (or play Atari). If my fever spiked in the middle of the night, my parents would soak me in a tub of lukewarm water to lower my temperature (how I hated those baths!). On the following day, I would visit my pediatrician, who would invariably diagnose me with an ear infection. He prescribed a delicious bubble-gum flavored antibiotic that my parents kept at the top shelf in the refrigerator (out of my reach so I wouldn’t overdose). I’m not sure if it was the taste or the active ingredient, but this antibiotic always made me feel better. After what seemed like the millionth episode of fever, my pediatrician recommended that I get tubes in my ears, and the episodes of fever and ear pain subsided.
Recurrent infections, like those I had when I was a child, are the most common cause of frequent fevers in children. Usually, these infections are due to viruses, such as the ones that cause the common cold. Children with colds often develop symptoms attributable to the virus, including a runny nose, nasal congestion, or cough. Multiple infections, one after the other, are especially common in children attending daycare or school, where they trade viruses like I used to trade baseball cards with my friends. When I see these the worried parents of these children in my office, I have to remind them that it is normal for a child to have 9-12 colds every year. Fortunately, these children continue to grow and gain weight without difficulty, and they are healthy between episodes. “As your child grows,” I tell the parents, “her immune system will become better at fighting infections, and the frequency and severity of fevers will diminish.” Aside from stressing the importance of hand washing among all family members, there is not much that can (or needs) to be done about these episodes.
However, if the episodes do not clearly match the above description, other diagnoses should be considered. In this post, I will provide some tips that may help parents and physicians recognize a rare cause of fever in children: autoinflammatory diseases. The most common autoinflammatory disease in children is called PFAPA, which stands for Periodic Fevers, Aphthous stomatitis (canker sores or oral ulcers), Pharyngitis (sore throat) and Adenitis (enlarged glands in the neck). This disease usually presents in children less than 5 years of age, and causes episodes of fevers in addition to the features that make up the name of the disease (oral ulcers, sore throat, enlarged glands in the neck). The fever usually lasts about 4 days, and it recurs at regular intervals, usually every month. What is unique about PFAPA is that parents can usually predict when the child is “due” to get ill. The episodes of fever are so regular as to be predictable. This regularity is rare in most other diseases. PFAPA is commonly misdiagnosed as frequent Strep infections, and testing for Strep throat is usually negative. Patients do not readily respond to antibiotics, although their symptoms can disappear with one dose of steroids.
Another clue that the child may have an autoinflammatory disease is that all of the episodes of fever look alike. For example, if the child always develops abdominal and joint pain with the fevers, then he may have familial Mediterranean fever (FMF). If, in addition to fever, she always develops a painful rash, muscle pain, and red eyes, then she may have TNF-receptor associated periodic fever (TRAPS). If he develops fevers, rashes, and joint pain after exposure to cold weather, then the child may have familial cold-induced autoinflammatory syndrome (FCAS).
The length and frequency of fever, associated symptoms, and age at which the fevers began can help differentiate between these (and other) autoinflammatory diseases. Thus, it is very helpful to keep a fever diary, specifying the characteristics of each episode. Because many of these autoinflammatory diseases are inherited (genetic), there is often a history of other family members having similar symptoms. In addition, it is important to note that some autoinflammatory diseases are more common in people of certain ethnic backgrounds, such as FMF in Sephardic Jews, Turks, and Armenians.
In addition to autoinflammatory diseases, there are some features of recurrent fevers that should warrant a closer look by a child’s pediatrician. These include prolonged episodes of fever (more than one week), recurrent fever without symptoms attributable to a viral infection, difficulty growing or gaining weight, or if the child does not return to his baseline between episodes. Other causes of fever that should be considered in these instances include:
- Immunodeficiencies: problems in the immune system that makes the child more susceptible to infections
- Anatomic and metabolic abnormalities: abnormalities in certain organs that make them more prone to infections (like my ears), or diseases such as cystic fibrosis
- Inflammatory bowel disease: inflammation of the intestines
- Cancer: such as leukemia or lymphoma
With this knowledge, parents and pediatricians alike can help distinguish between the majority of children that develop recurrent fevers because of frequent viruses, from causes which may require additional workup or treatment.
When I meet someone for the first time and tell them that I’m a rheumatologist, I usually get blank stares, as if I had spoken to them in a foreign language. It doesn’t matter if they are a medical student, family member, or even an immigration officer. It doesn’t matter if they have a Ph.D. or they are a high school dropout. I even see patients in my rheumatology clinic who have no idea what rheumatology is, nor how I’m supposed to help them.
I can’t blame them. Rheumatology is a weird field. Just look at the origin of the word “rheumatology.” The prefix “rheuma,” meaning “to flow,” was first used by a Greek physician 2000 years ago, referring to the phlegm that flows from the nose when a person is ill. But rheumatology, as it is practiced today, has nothing to do with phlegm (talk about false advertising!). Cardiologists don’t have this identity problem because they, of course, manage the heart. Dermatologists treat your skin. Proctologists…well, you get the picture.
A quick web search about rheumatology is not fruitful either. Rheumatology is defined as: “the medical specialty that manages rheumatic diseases.” My rheumatology textbook doesn’t even try to define what field is all about.
In addition, we’re not a popular specialty. I don’t know of one famous rheumatologist. We’re not usually in the news. We’re not the heroes in any movie. In fact, I don’t think I’ve ever seen a TV character who is a rheumatologist (even though there is at least one paleontologist on TV!). The TV character that most closely approximates what a rheumatologist does is my hero Dr. House (no relation, unfortunately) on the TV show House, MD. He is actually board certified in nephrology and infectious diseases, but he gets consulted on very complicated cases, much like rheumatologists often do. However, he’d make a lousy rheumatologist because, according to him, “it’s never lupus!”
As I see it, rheumatology is the study of inflammation (swelling, redness, warmth, and pain) occurring in the structures that hold up the body, such as the bones, muscles, and joints. Arthritis, or inflammation of the joints, is the most common disease that we see, both in children and adults (kids get arthritis too!). Arthritis comes in a variety of flavors, including juvenile, rheumatic, psoriatic, gouty, osteoarthritis, etc..
We also take care of complex diseases such as systemic lupus erythematosus, systemic sclerosis, and dermatomyositis, in which the immune system attacks various different organs. Vasculitis, or inflammation of a blood vessel, is another disease which we treat. Other strange illnesses (with even stranger names) such as Kawasaki disease, Sjögren syndrome, and relapsing polychondritis are all within the field of rheumatology.
Most of the above-mentioned diseases are considered autoimmune, in which the immune system loses the ability to recognize self from non-self. When a cell of the immune system passes through the kidney, it should be able to recognize it and say: “Hello! You are my kidney, I will protect you against infections!” However, in autoimmune diseases, the immune cell gets confused and says: “Whoa! What is this bean-shaped organ doing here? You look foreign, I will fight you to the death!” As a result, the immune cell begins a process of inflammation that causes organ damage. Many different organs can be affected in autoimmune diseases, and the name of the disease depends on which organ is affected.
At the other end of the rheumatology spectrum are autoinflammatory diseases (my favorite!). These diseases occur when the machine that produces inflammation goes awry. Immune cells are tightly regulated to produce inflammation only when needed (such as in response to a microbe or to damaged tissue). However, in most autoinflammatory diseases, there is a mutation in the inflammation machine that causes it to produce inflammation at inappropriate times. The immune cell in autoinflammatory diseases says: “Darn, I’m leaking inflammatory fluid yet again!” Thus, the patient develops episodes of fevers, rashes, and joint pain without any other explanation.
As you can see, rheumatologists manage a wide variety of illnesses that affect many different organs. Most of these diseases do not have clear causes, which makes rheumatology a fascinating field to study. At least until a smart marketing team comes up with a better name for our specialty (I vote for “inflammatology!”), you won’t have to look at me weird when I tell you what I do for a living.
Some links provided are affiliate links, which means that I earn a small commission at no cost to you if you decide to purchase a product. Your purchase of these products helps to keep this site running. Please visit my disclosures for further information.