What are Autoinflammatory Diseases (AID) Syndromes?

Affecting less than 5 out of every 10,000 people1, recurrent autoinflammatory diseases (also known as Periodic Fever)  syndromes are not common, and are classified as rare diseases. Although they involve the immune system, they are not autoimmune diseases. They can be caused by a change to the genetic recipe (DNA) of the non-specific innate immune system, which quite simply means the immune system activates to attack invaders that are not present in the body, causing damage to the body in the process.

Initial symptoms of these autoinflammatory diseases include recurrences of fevers lasting more than 24 hours, which are often accompanied by rashes and joint pain. Long-term, damage may occur due to the effects of continuous (chronic) inflammation.[1]

Diagnosing a recurrent, periodic fever can be difficult and complicated, not only because they occur rarely, but because the symptoms are common to many other diseases. Successful diagnosis of a periodic fever may involve several diagnostic tests before the correct cause or condition is identified.

References: 
1. Ciccarelli F, De Martinis M, Ginaldi L. Curr Med Chem 2014; 21: 261–269.

 

What are autoinflammatory diseases?

A healthy immune system is essential to fight off invading germs that can cause illnesses or disease – common viruses like the flu, or bacteria such as streptococcus. When germs enter the body, the immune system responds in two ways.

  1. The innate immune system, through the process of inflammation, will attract and, in effect. “eat” the invading cells. If this is not sufficient to destroy them, the acquired immune system assists.
  2. The acquired immune system develops antibodies specifically targeted to that germ, which bind to the germs so they can be destroyed.

With autoinflammatory disease, the innate immune system activates “on its own” in response to germs that are not actually present in the body. This results in an inflammatory response that affects the entire body,[1] causing a disease flare with typical symptoms including fever, rash, joint swelling, pain, and fatigue.[1] These periodic flares can occur recurrently in some people or continuously (chronically) in others.
 

What causes autoinflammatory disease?

There are various causes of recurrent periodic fever syndromes and autoinflammatory diseases:[1]

Genetic mutations

  • Hereditary
  • Caused by changes in the “instructions” (DNA) for the innate immune system
  • Includes periodic fever syndromes (CAPS, FMF, TRAPS, and HIDS/MKD)

Trigger factors

  • Substances created during chemical reactions in the body (metabolic products) or foreign substances
  • Cold or cooling air, or temperature changes (CAPS), stressors (all periodic fever syndromes), or even vaccinations (HIDS/MKD)

Multiple/unknown causes

  • Can cause a patient to develop: Systemic juvenile idiopathic arthritis, or and several commonly occurring diseases, such as gout, pseudogout, type II diabetes, and atherosclerosis 

CAPS: Cryopyrin-associated periodic syndromes, FMF: Familial Mediterranean fever, TRAPS: Tumor necrosis factor receptor associated periodic syndrome, HIDS/MKD: Hyperimmunoglobulinemia D syndrome/Mevalonate kinase deficiency

How does IL-1β affect autoinflammatory disease?

Interleukin-1 beta (IL-1β) is a messenger of the nonspecific innate immune system. It plays a special role in many autoinflammatory diseases, promoting the inflammatory response[2] and communicating to immune cells to come to where supposed invaders are in the body.

References:
1. Ciccarelli F, De Martinis M, Ginaldi L. Curr Med Chem 2014; 21: 261–269.
2. Dinarello CA: JEM 2005; 201: 1355–1359.
3. Dall, L, Standford JF. Available from: http://www.ncbi.nlm.nih.gov/books/NBK324.
4. Ceciliani F, Giordano A, Spagnolo V. Protein Pept Lett 2002; 9: 211–223.
5. Nouri AME, Panayi GS, Goodman SM. Clin Exp Immunol 1984; 55: 295–302.
6. Rare Diseases UK. About Rare Diseases. Available from: https://www.raredisease.org.uk/what-is-a-rare-disease/


What is it like living with Periodic Fever Syndrome?

From a practical and emotional point of view, periodic fever syndromes can be quite overwhelming to live with for everyone, with lots of challenges to overcome. But with us understanding more and more about these recurrent diseases, improvements are being made to make diagnosis quicker and more accurate. As a result, there is more support and, indeed, more support groups for people affected by periodic fever syndromes and autoinflammatory diseases than ever before.

How difficult are rare autoinflammatory and periodic fevers syndromes to diagnose?

Because of the lack of knowledge and understanding around rare diseases, such as recurrent autoinflammatory conditions like SJIAAOSD and Periodic Fever syndromes like FMFTRAPSHIDS/MKDCAPS ,[1] more than 25% of people with rare diseases can wait anything from 5 to 30 years from when their symptoms first appear to when they receive an appropriate diagnosis. And up to 40% of people with rare diseases are initially diagnosed  incorrectly.[2] This has implications not only that person’s health, but on their social and personal lives.


Why is it so difficult to diagnose rare diseases like periodic fever syndromes?

  • Similarity in symptoms: Diagnosis can be challenging because other conditions like appendicitis, acute rheumatic fever and drug allergies have similar symptoms that mimic them. [3,4,5]
  • Periodic fevers are rare: Some doctors may not have come across these diseases before, so may not suspect them for quite some time.[3] There is no ‘typical’ picture with periodic fevers. From one person to the next, the pattern of symptoms and flare-ups can vary widely.[3]
  • Lack of scientific knowledge: Due to the rarity of diseases like periodic fever syndromes, many doctors might only have limited, if any, exposure to patients with these conditions. [1,2]
  • Lack of information: Due to the limited level of medical knowledge and exposure, people with periodic fever syndromes can have trouble accessing expert knowledge as they will often not be referred to the appropriate specialist immediately. [1,2]

Raising awareness and educating people about rare diseases is one of the most important things we can do to help people who affected by these conditions to help ensure they receive the right diagnosis at the right time and get the understanding and support they need.

Your help to spread the word about rare autoinflammatory conditions such as periodic fever syndromes and the challenges associated with diagnosing these diseases is vital. Follow us on Facebook and share the video above with the people around you.

References:
1. “Rare Diseases: Understanding this Public Health Priority” 11/14, Eurordis, November 2005: http://www.eurordis.org/IMG/pdf/princeps_document-EN.pdf (Accessed May 2016)
2. “The Voice of 12,000 patients - Experiences and Expectations of Rare Disease Patients on Diagnosis and Care in Europe” Eurordis, 2003 - 2006 http://www.eurordis.org/IMG/pdf/voice_12000_patients/EURORDISCARE_FULLBOOKr.pdf (Accessed May 2016)
3. National Amyloidosis Centre. Available from: http://www.amyloidosis.org.uk/fever-syndromes/inherited-fever-syndromes/ (Accessed March 2016)
4. American College of Rheumatology. Familial Mediterranean Fever (Juvenile). Available from: http://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Familial-Mediterranean-Fever-Juvenile (Accessed May 2016)
5. Song, SJ et al. A Case of Adult Onset Still’s Disease Misdiagnosed as Septic Arthritis. Knee Surg Relat Res, Vol. 23, No. 3, Sep. 2011
6. NORD – National Alliance of Rare disorders. Available from http://rarediseases.org/even-well-known-rare-diseases-pose-diagnosis-problems/ (Accessed May 2016)
7. American Cancer society. What are the most common types of childhood cancers? Available from: http://www.cancer.org/cancer/cancerinchildren/detailedguide/cancer-in-children-types-of-childhood-cancers (Accessed May 2016)


What are the symptoms of recurrent fever syndromes?

This booklet will help you understand what hereditary recurrent fever syndromes are, their most common symptoms, how these autoinflammatory diseases work, how they are diagnosed, and how you or anyone affected by periodic fever syndromes learn to live with these life-changing conditions.
 

What do all these big words to do with autoinflammatory diseases mean?  

This helpful glossary should help explain all of terms, abbreviations and acronyms you will discover as you learn about periodic fever syndromes and autoinflammatory conditions. 
 

What are the challenges that rare autoinflammatory diseases pose for children? 

Dr. Michaël Hofer is a pediatric immunologist and rheumatologist based at CHUV, the University of Lausanne, Switzerland. He is an expert in rheumatic diseases affecting children and teenagers, including autoinflammatory syndromes. Here, he outlines the difficulties as children transition from childhood to adulthood.
 

How do you find a rare autoinflammatory disease specialist?

When it comes to autoinflammatory disease, a specialist doctor can provide you with all of the information, advice and care that you and your child need. Here are some things you’ll want to consider in choosing a specialist:

1) Specialist or primary care physician?

Your child’s regular doctor, pediatrician or primary care physician will always play an important role in their care, but it’s important to remember that they are not experts in every single disease, so may not have the deep understanding of your child’s specific rare autoinflammatory disease. A specialist will have that expert knowledge you need and be able to offer individual, tailored advice to you and your child.

2) What kind of specialist?

There are a number of different specialists that may be able to help, depending on your child’s condition. If your child has systemic juvenile idiopathic arthritis (SJIA) for example, a rheumatologist, who specializes in joints and arthritis, may be recommended. Genetic specialists or counsellors could also be important to consider as they can provide information on the cause of the disease and can help in understanding how other family members may be affected. The best thing to do is ask your child’s primary care physician, as they should have an idea of the kind of specialist care your child will benefit from most. If your child has multiple health needs, they may need multiple specialists. In this case, it will be important to put each specialist in touch with the other members of your child’s specialist team, so that they can make sure all suggested treatments are complementary and ensure your child is receiving safe, effective care.

3) What if you have to travel?

Travelling with an unwell child can be difficult, so it’s important to find a specialist not too far away. Some specialist centers provide transport, and some insurance policies may cover cost of travel too, so be sure to check before making your decision.

4) Does your insurance cover the care?

If you live in a country that requires health insurance, it’s important to create an open line of communication between you and your provider, as much as possible. Before you book an appointment with a specialist, check your policy will cover it and what information your provider requires. Talk to your provider if you have any doubts or questions.

Speak to your primary care physician first as they are likely to know about a number of different experts in your area and can use their connections to find out more.

Resources such as Orphanet can also help. Orphanet provides access to a directory of expert services and centers for rare diseases or groups of diseases. We would always recommend checking with your doctor once you’ve found a specialist through Orphanet, to make sure they agree with the choice. Your child is special and finding them a specialist doctor can help ensure they are receiving all the care they need.

References:
1. WebMD. (2018). How to Choose a Doctor. [online] Available at: https://www.webmd.com/health-insurance/how-to-choose-a-doctor#2 [Accessed 5 Sep. 2018].
2. nhs.uk. (2018). Amyloidosis. [online] Available at: https://www.nhs.uk/conditions/amyloidosis/

 

How do you prepare for a medical appointment?

Good communication with doctors and other healthcare professionals is important in helping you fully understand what your child’s diagnosis means, what treatment options are available, and how to care for your child. Here’s a step-by-step guide on what to do before, during and after medical appointments:

Take notes:

  • Make sure to write down all of your questions before you go to your appointment. Why not use a list app on your phone to keep track and note questions down as you think of them?
  • It is helpful for your doctor to know what symptoms your child has been experiencing and the more detail the better! Use your phone to keep track of your symptoms in a separate list.
  • Bring a record of your child’s previous treatments with you, as this will help the doctor in making any decisions.

During your appointment:

  • Take detailed notes while you’re there. Maybe even record the conversation using your phone. Just be sure to ask permission from the doctor first.
  • Bring a family member or friend. They can support you in asking hard questions, and provide an extra pair of ears in case you miss anything.
  • Be honest and try to be specific when talking to your doctor about your child. It’s not always easy, which is why it’s important to prepare.
  • Agree your next appointment date before you leave the office or hospital.

Afterwards:

  • Go over your notes and make sure you understand everything you spoke about with the doctor. If you are unsure about anything, talk it through with the person who was in the room with you, give the doctor a call, or book a follow-up appointment.
  • Update your family and friends so they can support you and your child with the next steps.

Doctor’s appointments don’t have to be scary, stressful or negative experiences. Once you take the right steps to prepare, you can leave an appointment feeling well-informed and positive about you and your child’s next steps.

References
1. National Institutes of Health (NIH). (2018). Talking to Your Doctor. [online] Available at: https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/clear-communication/talking-your-doctor [Accessed 5 Sep. 2018].
2. WebMD. (2018). How to Talk to Doctors When They Don’t Listen. [online] Available at: https://www.webmd.com/a-to-z-guides/features/be-heard-by-dr#1 [Accessed 5 Sep. 2018].
 

Find out what all the complex wording around periodic fever syndromes is in plain language

When you understand what all of the complicated sounding terms and medical language to do with autoinflammatory diseases mean, you will be able to have much better conversations with doctors about them.
 

What are the questions people ask most about periodic fever syndromes?

Dr. Isabelle Koné-Paut, currently Head of the Department of Pediatric Rheumatology at the Paris SUD, Bicêtre University Hospital and coordinator of the National Reference Centre for Autoinflammatory Disorders answers them all here. If you don’t see the question you want to ask, please visit our Facebook page and post them there.
 

How is the presence of a periodic fever syndrome determined?

Marco Cattalini, Head of Pediatric Rheumatology at the Pediatric Clinic, Spedali Civili di Brescia and Assistant Professor of Pediatrics at the University of Brescia, Italy, shares his insights on the signs of periodic fever symptoms and how to find a specialist treatment center that fits your child’s needs.
 

What should you do if you suspect your child has a periodic fever syndrome?

The correct diagnosis of a periodic fever syndrome can be a challenge to doctors and physicians for three main reasons:

  1. Periodic fevers are very rare diseases in most countries and physicians - with the exception of those working in specialized centers - are often unfamiliar with their clinical presentation.
  2. Since the diseases are very rare, the index of suspicion is usually low.
  3. Clinical manifestations are usually not pathognomonic (distinctively characteristic of a particular disease or condition), but may overlap with much more common conditions (such as airway infections).

Start a "Fever Diary"

One of the main characteristics of periodic fever syndromes, from the mild to the more severe, is the recurrence of symptoms, such as high fever. It is our experience that the attention of the family first and the referring physicians thereafter are attracted by the recurrence of identical episodes. For this reason, if you suspect your child has an autoinflammatory disease, one of the best things you can do is to keep a “fever diary.” It’s not unusual that when we first see a child with “recurrent fevers” and we cannot come to a definitive diagnosis, we ask the parents to come back in a matter of months (depending on the severity of clinical manifestations) with the fever diary completed. In this diary you should note:

  • Exact date of each fever episode
  • Exact duration of each fever episode
  • If the child has symptoms associated with the fever (i.e., coughing, diarrhea). In the case of cutaneous manifestations (i.e., skin rashes) taking a photograph can be very useful
  • What was the therapy prescribed?
  • If laboratory or other tests have been prescribed, what were the results?

It is also very important that you ask your pediatrician to visit your child every time he/she has a fever and to help you fill in the diary with the precise signs associated with the fever.

Keep track of lab tests

During an attack, your physician may ask for laboratory tests (complete hemogram, ESR, CRP, urine analysis) that may be useful to see if inflammatory markers (an indication of inflammation in the body) are high during fever attacks and to rule out infections (i.e., pharyngeal swab, urine culture). If your pediatrician suspects an autoinflammatory disease, and there is a history of recurrent fever episodes with a high level of inflammatory markers during the attacks, it is also very important to take laboratory tests between the attacks, to see if the inflammatory markers normalize. One inflammatory marker that may be useful to check is Serum Amyloid A (SAA). Persistently elevated SAA levels may suggest a chronic inflammatory state, and it will be important to rule out a periodic fever syndrome.

If your diary shows recurrent episodes of systemic inflammation (i.e., fever, with elevated inflammatory markers and signs/symptoms of organ inflammation detected by your doctor) without evidence of bacterial origin, probably the most useful thing to do is to consult a physician with expertise on periodic fever syndromes for further work-up.  (You can find a link to the Orphanet Directory of centers in the Links and Downloads section of this website)

If people live in remote regions where specialist treatment centers are not as accessible as they are for those who live in large cities, what are the three top tips you can give them, so they don’t miss a moment in their care?

Periodic fever syndromes are very rare diseases and many physicians are not familiar with them. As specialized centers are not always easily accessible, a few strategies may help to optimize the care of every child with autoinflammatory disease:

      1. Ask for a medical letter:

The final diagnosis of periodic fever syndrome is usually done in a referral center. At that time, ask the medical team to provide you a detailed medical letter that includes the following:

  • Main clinical characteristics of the disease your child suffers from, and the therapy needed (not only medical treatment but also other needs, such as physical therapy, etc.), explaining what the more common side-effects could be and how they could be managed
  • How frequently the child has to be seen by a physician, and what tests should be run. This “follow-up plan” may be individualized, according to how difficult it is for you to reach a specialist center: in many cases, it is possible to agree on visiting the referral centers just once/twice a year and to refer to local hospital/primary physicians for more regular follow-up. This plan, of course, depends on the final diagnosis, on the treatment regimen, and on how your child is doing under treatment
  • Whether the disease or related treatment contraindicate normal life activity (i.e., school, sports, etc.) or universal medical procedure (i.e., vaccination)
  • What to do in case of common childhood diseases (i.e., upper respiratory tract infections, gastroenteritis) and, if relevant, what drugs should be avoided
  • When it is crucial to contact the medical team of the referral center

     2. Get contact details:

Ask the medical team for contacts (phone numbers, email addresses) where you or your primary care physician could contact the center in case of need and provide the referral center with the contacts of your primary care physician. Specialized centers can provide you and your primary care physician with all the information necessary to support you and your child. After a diagnosis is made:

      1. Request patient association contact:

Ask for a patients’ association contact: patients’ associations for periodic fevers usually have their headquarters in referral centers, to be easily accessible, and are an invaluable help to manage your child’s needs. Referral centers may usually also suggest websites that provide verified information on periodic fever syndromes.

       2. Call your doctor:

Promptly contact your primary care physician and share all the information gathered.

As with all rare diseases, the parents of children with periodic fever syndromes usually feel isolated and helpless, even after the diagnosis. It is very important you understand that, although rare, there are other families facing the same difficulties, and people working constantly to help you and your child to have the best possible lives. Keep in contact with them and help this community to grow stronger.

 Download and Explore our Patient eBooks.

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Uncover the complexities of autoinflammatory diseases and learn how we are focused on helping individual through awareness, connection, community, progress and change.