Tag Archives: autoinflammatory

301 patients with PFAPA–what do they look like?

This month, an interesting article about PFAPA appeared in the journal Rheumatology.  PFAPA (periodic fevers, aphthous stomatitis, pharyngitis, and adenitis) is an autoinflammatory disease that affects children.  It is manifested by episodes of fevers lasting a few days, in addition to the features that make up the name of the disease.  Unlike other autoinflammatory diseases, episodes of fever occur at very specific intervals (parents mention that the fevers occur “like clockwork,” and they can predict when the next episode will occur on a calendar).  Fortunately, most patients respond well to steroids during fever episodes, and the disease usually resolves within a few years without sequellae.

This study represents the largest group of patients with PFAPA ever published.  They found that the average age of onset of symptoms was about 2 years of age, and it often took several years to make the diagnosis of PFAPA.  Most patients were diagnosed before age 6.  On average, episodes of fever lasted 4 days, and recurred every 4 weeks.  Only 44% of patients with PFAPA had the classic triad of apthous ulcers (oral ulcers), adenitis (swollen, tender lymph nodes in the neck), and pharyngitis (sore throat); the rest had only one or two of these symptoms.   Interestingly, children often complained of abdominal pain, joint pain, muscle pain, and headaches during episodes.  

This study highlights one of the biggest difficulties of PFAPA–making an accurate diagnosis.  Patients don’t need to have the classic triad of symptoms to be diagnosed with PFAPA, and many children complain of additional symptoms during episodes that are likely underrecognized.  Perhaps it is time to create new diagnostic criteria for this disease!

What do you think?  Have you or a loved one been diagnosed with PFAPA?  How long did it take for your doctors to make the diagnosis?

It’s in your genes, or is it? The genetics of autoinflammatory diseases

Autoinflammatory diseases have a variety of causes.  Some are clearly genetic–they are caused by single mutations in specific genes.  These abnormal genes produce abnormal proteins that cause unprovoked episodes of inflammation.  If you have the abnormal gene (for the most part) you develop the disease.  If you don’t have the gene, you don’t develop the disease.  Familial Mediterranean Fever (MEFV), cryopyrin associated periodic syndrome (NLRP3), and the TNF-receptor associated periodic syndrome (TNFRSF1A), are examples of autoinflammatory diseases associated with mutations in single genes.  These diseases are often called hereditary periodic fever syndromes, although they are not always “hereditary” (passed down from parent to child); many are caused by new mutations that arise in the embryo.

Some types of autoinflammatory diseases have associations with specific genes, such as Behcet’s disease with the gene HLA-B51.  Behcet’s is characterized by recurrent oral and genital ulcers, rash, and episodes of eye inflammation (uveitis).  Unlike the genetic diseases above, having the gene HLA-B51 is not sufficient to have the disease.  This complex disease is likely caused by interplay between HLA-B51, other genes, and the environment (it is interesting to note that patients with Behcet’s that live in the Middle East have a more severe disease than patients with Behcet’s that live in the United States).

Finally,  some autoinflammatory diseases do not appear to be associated with any specific gene.  PFAPA (periodic fevers, aphthous stomatitis, pharyngitis, and adenitits), is such an example.  This is an autoinflammatory disease that commonly affects children, and it is characterized by periodic episodes of fever and the associated symptoms that give it its name.  To date, no specific gene has been associated with the development of this disease.  The fact that removal of the tonsils appears to be curative for many patients suggests that perhaps an infection that resides in the tonsils contributes to the expression of this disease.

We are still just beginning to understand the causes of these fascinating autoinflammatory diseases.  It is still unclear what makes patients with the same genetic mutation have mild or severe disease. We also don’t know how the environment plays a role in the expression of this disease.  Further research over the next few years should be able to give us better answers to these important questions.

To review the wide variety of autoinflammatory syndromes (and their specific causes), please refer to this comparison chart by the Autoinflammatory Alliance, by far the most complete chart of autoinflammatory diseases I’ve seen.

Autoinflammatory vs. autoimmune….what’s the difference?

Last week during our weekly physician conference,  I discussed a patient with an 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 (accumulation of amyloid fibers in the kidney causing kidney failure), 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.  Even at  the conference, some physicians were  unaware of these group of diseases.

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 several types of white blood cells such as neutrophils, macrophages, and natural killer cells.  These cells are the first responders to an infection because any one of them is able to recognize common patterns that are present in many types of pathogens (such as the cell wall in a bacteria).  In response to a pathogen, these cells secrete inflammatory molecules (cytokines) that alert other cells of the immune system and get the body ready to fight.

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 (production of inflammatory cytokines, recruitment macrophages, neutrophils, etc).  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, which causes recurrent, brief attacks (12 to 72 hours) of fever, abdominal pain, chest pain, joint pain, and evidence of inflammation on blood tests.

In contrast, autoimmune diseases arise from problems in the adaptive (humoral) immune system.  The adaptive immune system is more sophisticated than the innate, and  is made up of very specialized B cells and T cells.  Each B and T cell in our body is unique, and is only able to recognize a specific  pathogen.  Thus, it takes much longer for a B or T cell to recognize that a pathogen has invaded the body.  However, once the pathogen is identified, the cell divides and multiplies, leading to a very effective and direct attack on the pathogen.  B cells also produce antibodies, which help to neutralize the pathogen.  Unlike the innate immune system, the humoral 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 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 often target the kidney, lungs, or heart, often leading to damage or destruction of these organs.  However, autoimmune diseases can target almost any organ in the body.  For example, in multiple sclerosis,  cells attack the brain.   In rheumatoid arthritis, the joint is the target organ.  In pemphigus, the body attacks the skin.  For reasons that are still unknown, autoimmune diseases more often affect women, whereas autoinflammatory diseases usually affect both sexes equally.

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  are still underdiagnosed and poorly understood.  It seems like every month, a new autoinflammatory disease is discovered (take a look at this week’s New England Journal of Medicine).  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.