What are autoinflammatory diseases?

Autoinflammatory diseases are a diverse group of disorders where fever and organ-specific inflammation is caused by an over-active inflammatory response. The term was first applied to a group of periodic fever syndromes where patients had episodes of unexplained fever, a red skin rash, and/or other organ problems. These episodes can affect a child’s ability to be active and perform typical activities such as going to school. 

Without effective treatment, autoinflammatory diseases can lead to permanent damage including skin scarring, vision and/or hearing loss, trouble breathing, kidney failure, inflammatory bowel disease (IBD), joint contractures, HLH and more. 

Autoinflammatory diseases are often divided into:  

• IL-1 mediated diseases, or “IL-1opathies,” which include most periodic fever syndromes such as familial mediterranean fever, cryopyrin-associated periodic syndrome (CAPS), and hyper IgD syndrome. These diseases often involve a group of inflammatory proteins called the inflammasome, and some show a remarkable response to blocking the cytokine IL-1. Some of the genes involved include: MEFV, NLRP3, MVK, TNFRSF1A, PSTPIP1, IL1RN, and NLRC4. 
• Interferon-mediated diseases, or “interferonopathies,” which are caused by an over-production of proteins that our bodies usually use to fight viral infections (called interferons). While these patients don’t always have a fever, they can experience devastating brain inflammation, blood cell problems, muscle inflammation, and/or interstitial lung disease. Some of the genes involved include: PSMB8 and other proteasome genes, STING, TREX1, SAMHD1, and IFIH1.
• NF-kB mediated diseases are caused by overactivity of one of the body’s most important inflammatory pathways. Patients can have uveitis (swelling in the eye), intestinal inflammation, deep skin rashes, and/or nodules of inflammation called granulomas. Some of the genes involved include: NOD2, TNFAIP3 (A20), OTULIN, and RIPK1. 
• Many patients don’t fit neatly into one of these categories, but still suffer from autoinflammatory diseases. Some of the genes involved include: ADA2, PLCG2, UBA1, and XIAP.    

Causes of autoinflammatory disease

Mutations in any of dozens of different genes can cause autoinflammatory disease. In most cases, we still don’t know how a particular genetic change leads to an individual’s symptoms. Many patients with autoinflammatory diseases have no known genetic cause. Many of these patients experience frequent and/or severe infections (immunodeficiency), swelling of the lymph nodes, or symptoms that overlap with other kinds of immune-system problems (like autoimmunity). 

Symptoms of autoinflammatory disease

Inflammation is a normal, transient part of every child's response to infection, stress or wound healing. If your child has an autoinflammatory disease, you may notice symptoms like: 

• Unexplained fever 
• Fatigue 
• Intermittent or chronic red rash 
• Raised lumps under the skin, especially in the neck or underarm 
• Other organ problems 

Because our immune system lives in every part of the body, autoinflammatory diseases can affect any organ. If your child has unexplained fevers, red rashes, lumps in the neck or underarm, or other concerning symptoms of inflammation, your child should see a doctor to determine if they might have an autoinflammatory disease.  

Diagnosing autoinflammatory disease

We know it can be confusing and scary when you can’t figure out why your child is sick or find a treatment that works to relieve their symptoms.  

Many patients with autoinflammatory diseases can be diagnosed and managed in the Division of Rheumatology. For more complicated cases, the Immune Dysregulation Program at Children's Hospital of Philadelphia (CHOP) provides a single place your family can consult when your child is experiencing unexplained symptoms affecting multiple organs or symptoms that have not responded to treatment.  

Our multidisciplinary team will review your child’s medical history and perform a detailed physical exam. We will also perform a variety of tests to help determine if your child has an autoinflammatory disease and to rule out other possible causes of unexplained inflammation, including: 

• Blood and urine tests – Not all inflammation is the same, and these tests can help understand whether there is inflammation and often what kind of inflammation. These tests can also detect other health problems like anemia, liver or kidney damage, and any other irregularities in your child’s blood. These tests can also help rule out infections or other diseases since autoinflammatory diseases can overlap with other disorders that affect the immune system. 
• Imaging tests – An ultrasound, CT scan, or PET scan can look for enlarged lymph nodes and assess any irregularities in the liver or spleen. The tests may also be helpful to determine if any previous treatments are working successfully.  
• A skin, lymph node, or tissue biopsy – After removing a piece of tissue from your child’s skin, lymph node, or other area of concern, specialists can examine it in our laboratory. These tests can sometimes help diagnose an autoinflammatory disorder but can also be used to evaluate your child’s body for infection, cancer, or other types of disorders.  

Treating autoinflammatory diseases

CHOP providers in the Division of Rheumatology and the Immune Dysregulation Program include international experts in the management of autoinflammatory diseases. For complex care, the Immune Dysregulation Program includes experts from many medical specialties and subspecialities at Children’s Hospital of Philadelphia, including immunology, allergy, rheumatology, gastroenterology, hepatology and others.  

We work with other specialists, as necessary, to fully understand your child’s condition. After using state-of-the-art testing to diagnose your child, we work with you to create a personalized treatment plan designed to improve your child’s health. Treatment will vary depending on which type of autoinflammatory disease your child has.  

Regardless of which autoinflammatory disease your child has, if it includes severe inflammation and needs to be treated quickly, we will often prescribe glucocorticoids (often called steroids) like prednisone. If used long-term, steroids can have significant side effects. Our team works proactively to identify medicines that will specifically target your child’s inflammation with the fewest side effects.  

If your child is diagnosed with an Interleukin-1 (IL-1) mediated disease, treatment may include medication like: 

• Colchicine, which treats inflammation and pain, or 
• Drugs that specifically block IL-1 such as: 
  • Anakinra, which is often used to treat active rheumatoid arthritis,  
  • Rilonacept, which is FDA-approved to treat recurrent pericarditis, or  
  • Canakinumab, a human IgGk monoclonal antibody used to treat multiple immune disorders 

For children diagnosed with an Interferon-mediated disease, treatment may include medications that target interferons such as: 

• JAK inhibitors, medicines that block the activity of certain immune system proteins. This category includes:  
  • Tofacitinib 
  • Ruxolitinib 
  • Baricitinib  
  • Upadacitinib 
• Anifrolumab-fnia, a monoclonal antibody that specifically blocks the two main forms of Interferon: a and b. It is sometimes used to treat severe systemic lupus erythematosus.

If your child is diagnosed with an NF-kB mediated disease, treatment might include drugs like: 

• Adalimumab, a biological anti-inflammatory therapy and monoclonal antibody that blocks the effects of TNF  
• Tocilizumab, a biological anti-inflammatory therapy and monoclonal antibody that blocks the effects of interleukin-6 (IL-6) 
• Tofacitinib, a JAK inhibitor  

Our team has extensive experience managing the most complex autoinflammatory and immune dysregulation diseases in children and youth. We work with multiple specialties to find creative and customized solutions to best treat your child’s condition and symptoms.  

Follow up care and long-term outcomes  

Most patients with autoinflammatory diseases need long-term treatment and monitoring to remain fully active. Your child may need follow-up exams, including blood tests and imaging, to remain healthy. Follow-up visits are generally coordinated between your child’s local pediatrician, a rheumatologist or other specialists. Some patients benefit from coordinated follow-up with a multidisciplinary team like the one offered by CHOP’s Immune Dysregulation Program. 

In rare cases, autoinflammatory diseases can lead to more serious conditions such as hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS) or other life- or organ-threatening inflammation. In these cases, CHOP’s unique inpatient consultation service may be beneficial. At CHOP, our team is committed to partnering with you, your child and your local providers to determine and provide treatment that will result in your child’s best possible health.