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CAPS is an extremely rare hereditary disorder believed to affect one or two people in every million of the population. It is a multi-system inflammatory disease; symptoms include fever, rash, joint pain, fatigue, headache, and eye irritation.1,2 

What is CAPS? 

CAPS is the term given to a group of rare autoinflammatory diseases caused by mutations (changes) in the NLRP3 gene.3 

The CAPS spectrum includes phenotypes with three levels of severity:4 

  • Familial cold autoinflammatory syndrome (FCAS) – mildest form 
  • Muckle-Wells syndrome (MWS) – intermediate form 
  • Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological cutaneous articular (CINCA) syndrome – most severe form 

The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic.5 

What does CAPS stand for? 

CAPS stands for cryopyrin-associated periodic syndrome, or syndromes (plural). 

Other names for CAPS 

  • NLRP3-associated autoinflammatory disease (NLRP3-AID) has been proposed as another name for CAPS.
  • It is also sometimes called cryopyrinopathy.7

Note: the abbreviation CAP or CAPS is also used for two unrelated diseases, not to be confused and not the subject of this article: community-acquired pneumonia (CAP); and catastrophic antiphospholipid syndrome (CAPS). 

Cryopyrin: a crucial immune system component 

Cryopyrin is a protein in our cells that plays an important role in controlling inflammation.8 Its job is to help the immune system respond to danger signals, such as when there is an infection. These signals tell the body that something is wrong and needs to be dealt with. 

Normally, when the body detects danger signals, cryopyrin activates a process that leads to inflammation. Inflammation is the body’s way of fighting off infections or dealing with injuries. It involves sending immune cells to the affected area to help with healing. 

Cryopyrin works by influencing the production of interleukin-1 beta (IL-1β). 

In people with CAPS, there is a problem with how cryopyrin works. Due to mutations in the NLRP3 gene, cryopyrin becomes overactive and produces too much IL-1β. This leads to excessive inflammation to even in the absence of triggers such as infections.9 

Why “periodic”? 

CAPS is called a “periodic” syndrome because the symptoms come and go in episodes, or periods, at least in the less severe forms of the disease. People with FCAS and MWS experience flare-ups of symptoms followed by periods of relative calm. 

The CAPS spectrum10 

Cryopyrin associated periodic syndromes (CAPS) symptoms

How common is CAPS? 

CAPS is extremely rare. Somewhere in the region of 1 to 5 people in every million of the population are believed to be affected by CAPS.11,12 The disease does not appear to affect specific ethnic groups more than others.13  

It is difficult to accurately estimate the prevalence, partly because CAPS may be underdiagnosed. This is a challenge common to many rare diseases. Many doctors will never have seen a CAPS patient and may not recognise the symptoms. 

What are the symptoms of CAPS? 

Similar to several other AID, CAPS is a multi-system inflammatory disease, affecting eyes, skin, muscles, joints, bones, kidneys, and the central nervous system. Some signs of inflammation are commonly associated with distinct subtypes of the CAPS spectrum, whereas others are present in all subgroups. The symptoms of the milder forms can also be present in individuals with the more severe forms. But the higher levels of severity also have certain distinct symptoms.14,15

 

What are the different types of CAPS syndrome and how do they differ from each other? 
FCAS symptoms16,17

Symptoms of familial cold autoinflammatory syndrome include: 

  • Recurring fever 
  • Conjunctivitis; red eyes 
  • Joint pain 
  • Rash (urticaria) 
  • Chills 
  • Nausea 
  • Severe thirst 
  • Headaches 

An episode may last for a day. 

MWS symptoms18,19,20
 

Symptoms of Muckle-Wells syndrome symptoms include: 

  • Longer episodes of fever 
  • Conjunctivitis; red eyes 
  • Episcleritis – inflammation around the eyes 
  • Joint pain 
  • Rash (urticaria) 
  • Chills 
  • Severe headaches with vomiting 
  • Loss of hearing 

An episode may last for two to three days. 

NOMID symptoms21,22

Neonatal-onset multisystem inflammatory disease symptoms include the following:

  • Fever and inflammation in multiple organs 
  • Abnormally low growth and weight 
  • Decreased cognition 
  • Neck stiffness 
  • Reduced vision 
  • Bony overgrowth of the knees 
  • In some cases, chronic meningitis causing severe headaches, blindness, neurologic problems and hearing loss 

*NOMID symptoms may be present in addition to the symptoms of the milder forms of CAPS in children who grow up with NOMID.

Possible complications of CAPS 

If left untreated or treated suboptimally, CAPS can lead to: 

  • Kidney damage – prolonged inflammation can affect kidney function and potentially lead to kidney problems (secondary amyloidosis).23 
  • Cardiovascular complications – chronic inflammation can contribute to cardiovascular issues, including an increased risk of heart disease.24,25 

How is CAPS diagnosed? 

CAPS is diagnosed clinically and genetically.  Making a CAP diagnosis can be challenging as patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. A doctor may suspect CAPS if a patient is found to have several of the classic symptoms. The diagnosis can be confirmed by one or more of: genetic test; skin biopsy; eye examination; hearing test; test on joint fluid from the lower spine; X-ray of affected joints; MRI scan of the brain.26,27,28 

What causes CAPS? Genetic insights 

CAPS is caused by a genetic mutation in the NLRP3 gene, that results in defective production of cryopyrin. CAPS can be passed on from parent to child by autosomal dominant inheritance. The gene can also change spontaneously during conception. 29,30

What is autosomal dominant inheritance?31,32 

  • Dominant means that an individual cannot be a ‘carrier’ without having, or being at risk of developing, symptoms – because only one copy of the gene from one parent is needed to cause the disease. If either parent has the disease, each child has a 50% chance of inheriting it in a potentially active form. 
     
  • Autosomal means that the gene is carried on a chromosome other than the sex chromosome, so males and females are equally likely to be affected. 

Risk factors – the role of genetics  

CAPS is a genetic condition passed on from parents to children or resulting from a spontaneous mutation. It is not directly linked to specific risk factors such as lifestyle choices. The role of genetics is the main factor. 33,34

However, there are some risk factors to consider: family history, genetic testing, and prompt diagnosis. 

Having a family member with CAPS or a related condition can increase the likelihood of developing the syndrome. People with a family history of CAPS or related symptoms might choose to undergo genetic testing to find out whether they have the mutations associated with CAPS. Early diagnosis and treatment can help prevent or minimise any complications associated with CAPS.35 

What treatments are available for CAPS? 

Recent research shows that biologic drugs targeting interleukin-1 are efficacious and safe for treating CAPS. These treatments must be taken life-long but can allow children to lead near-normal lives.36,37,38 

Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids can reduce symptoms.39 

In addition to medication to prevent or treat symptoms, some individuals may need physical therapy, splints to treat joint alignment, or surgery to correct joint deformities.40 

How can people living with CAPS improve their lives? 

People living with CAPS – or the parents of children with the condition – can take various measures to improve their lives and manage their condition effectively. 

Early detection is the key to getting appropriate treatment to manage the symptoms of CAPS and prevent or minimise any complications. Therefore, individuals with symptoms that resemble CAPS should seek medical attention for evaluation and management. And, once diagnosed and being treated, they should be sure to have regular check-ups.41 

Although the disease is not directly linked to specific risk factors such as lifestyle choices, people with CAPS can help themselves by adopting a healthy lifestyle, maintaining a balanced diet, staying physically active within their limitations, getting adequate sleep, and managing stress. And by resting during any flare-ups.42 

The need for awareness of CAPS43,44

 

  • Early and correct diagnosis can make all the difference to the patient’s life, and reduce suffering. 
  • Most people with CAPS struggle with their symptoms for years before they are correctly diagnosed and treated.
  • Many doctors have never seen a CAPS patient – they need more guidance on how to care for their patients. 
  • The Autoinflammatory Alliance (formerly known as the NOMID alliance) is actively seeking to help raise awareness. See under Resources, below. 

 

Outlook – leading as near normal a life as possible 

The long-term outlook, especially for children with CAPS, has improved due to the identification of interleukin-1 as an effective treatment option. Children can live near-normal lives.45 

Getting support 

Support of friends, family, and counsellors is important for anyone living with or caring for child with CAPS.46 A number of organisations make resources and support available for individuals with CAPS and their families. The Autoinflammatory Alliance (formerly known as the NOMID alliance) provides details af a number of support groups. 

Related links

Explore the following resources to learn more about Cryopyrin-associated periodic syndromes.

Immunology

The role of the immune system

Living With Rare Autoinflammatory Diseases. CAPS: Cryopyrin-Associated Periodic Syndromes.
https://www.autoinflammatorydiseases.com/cryopyrin-associated-periodic-syndromes 

Cryopyrin-associated periodic syndromes. National Library of Medicine.
https://medlineplus.gov/genetics/condition/cryopyrin-associated-periodic-syndromes/ 

Welzel,T. et al. Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today? National Library of Medicine. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794776/

Welzel, T. et al. Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today? National Library of Medicine. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794776/

Ahmadi et al. Cryopyrin-Associated Periodic Syndromes: Otolaryngologic and Audiologic Manifestations. National Library of Medicine. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407887/ 

6 A unique presentation of NLRP3-associated autoinflammatory disease: case report. National Library of Medicine. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9743682/ 

Cryopyrin-associated periodic syndromes. Medicine Plus.
https://medlineplus.gov/genetics/condition/cryopyrin-associated-periodic-syndromes/ 

Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation.
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

Booshehri, L.M.; Hoffman, H.M. CAPS and NLRP3. National Library of Medicine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575304/ 

10 Wallert, M.; Börmel, L.; Lorkowski, S. (2020). Inflammatory Diseases and Vitamin E – What Do We Know and Where Do We Go?. Molecular Nutrition & Food Research. 65. 2000097. 10.1002/mnfr.202000097.

11 Welzel, T. et al. Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today? National Library of Medicine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794776/  

12 Rowczenio, D.M. et al. Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism—UK Single Center Experience. ORIGINAL RESEARCH article. Frontiers.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01410/full

13 Cryopyrin-associated periodic syndrome (CAPS). Rheumatology Advisor.
https://www.rheumatologyadvisor.com/home/decision-support-in-medicine/rheumatology/cryopyrin-associated-periodic-syndrome-caps/ 

14 Cryopyrin-Associated Autoinflammatory Syndromes (CAPS). American College of Rheumatology.
https://rheumatology.org/patients/cryopyrin-associated-autoinflammatory-syndromes-caps 

15 Cryopyrin-associated periodic syndrome (CAPS). Rheumatology Advisor.
https://www.rheumatologyadvisor.com/home/decision-support-in-medicine/rheumatology/cryopyrin-associated-periodic-syndrome-caps/ 

16 Familial Cold Autoinflammatory Syndrome. NORD.
https://rarediseases.org/rare-diseases/familial-cold-autoinflammatory-syndrome/ 

17 Hoffman, H.M. Familial Cold Autoinflammatory Syndrome. National Library of Medicine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321996/ 

18 Muckle-Wells Syndrome. NORD.
https://rarediseases.org/rare-diseases/muckle-wells-syndrome/#symptoms 

19 Cryopyrin-associated periodic syndromes. National Library of Medicine.
https://medlineplus.gov/genetics/condition/cryopyrin-associated-periodic-syndromes/ 

20 IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting. Nature Reviews – Rheumatology. 
https://www.nature.com/articles/s41584-022-00797-1 

21 Neonatal-Onset Multisystem Inflammatory Disease. NORD.
https://rarediseases.org/rare-diseases/neonatal-onset-multisystem-inflammatory-disease/#symptoms 

22 Autoimflammatory Alliance. NOMID/CINCA.
https://www.nomidalliance.org/nomid.php 

23 Recognising and understanding cryopyrin-associated periodic syndrome in adults. National Library of Medicine. 
https://pubmed.ncbi.nlm.nih.gov/31597069/ 

24 Imaizumi et al. A case of cryopyrin-associated periodic syndrome with kidney transplant failure. National Library of Medicine. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411619/ 

25 Sönmez et al. Cardiovascular manifestations of monogenic periodic fever syndromes. National Library of Medicine. 
https://pubmed.ncbi.nlm.nih.gov/36622520/ 

26 Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today? National Library of Medicine. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794776/ 

27 Cryopyrin-Associated Autoinflammatory Syndromes (CAPS). American College of Rheumatology.
https://rheumatology.org/patients/cryopyrin-associated-autoinflammatory-syndromes-caps 

28 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation.
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

29 Mutations in the NLRP3 (CIAS1) Gene Cause CAPS. Autoinflammatory Alliance.
https://www.nomidalliance.org/capsgen.php 

30 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation. 
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

31 Autosomal dominant inheritance. National Cancer Institute.
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/autosomal-dominant-inheritance

32 What are dominant and recessive alleles? Your Genome. 
https://www.yourgenome.org/theme/what-are-dominant-and-recessive-alleles/

33 Mutations in the NLRP3 (CIAS1) Gene Cause CAPS. Autoinflammatory Alliance.
https://www.nomidalliance.org/capsgen.php 

34 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation. 
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

35 Tatjana Welzel et al. Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today? National Library of Medicine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794776/

36 Arnold et al. Systematic Review of Safety and Efficacy of IL-1-Targeted Biologics in Treating Immune-Mediated Disorders. National Library of Medicine. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296857/

37 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation. 
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

38 Cryopyrin-Associated Autoinflammatory Syndromes (CAPS). American College of Rheumatology.
https://rheumatology.org/patients/cryopyrin-associated-autoinflammatory-syndromes-caps 

39 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation.
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

40 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation.
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

41 Welzel, T. et al. Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today? Section 9. Monitoring. National Library of Medicine.  
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794776/

42 Cryopyrin-associated Periodic Syndromes. uCan Health.
 https://ucanhealth.com/bio/d@342@Cryopyrin-associated%2Bperiodic%2Bsyndromes

43 CAPS, Cryopyrin-Associated Periodic Syndromes. Autoimflammatory Alliance. 
https://www.autoinflammatory.org/downloads/finalCAPSbrochure_web.pdf 

44 Recognising and understanding cryopyrin-associated periodic syndrome in adults. BJN. 
https://www.magonlinelibrary.com/doi/full/10.12968/bjon.2019.28.18.1180

​​​​45 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation. 
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome

46 Cryopyrin-Associated Periodic Syndromes (CAPS). Arthritis Foundation.
https://www.arthritis.org/diseases/cryopyrin-associated-periodic-syndrome 

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Apr, 2024