Cryopyrin-Associated Disorders - Causes, Symptoms, and Treatment

What Are Cryopyrin-Associated Disorders?

Cryopyrin is a protein involved in the body’s immune regulation. It is expressed in various cells involved in the body’s defense. Cryopyrin-associated disorders encompass a range of diseases. These are called Cryopyrin associated periodic syndromes (CAPS). CAPS are infrequent, and there is no gender inclination. It affects approximately 2 to 5 persons out of a million. The global distribution might be affected by external factors such as weather. FCAS is the most common among the three, followed by MWS and NOMID. CAPS is also known as cryopyrinopathy and NLRP-3 associated autoinflammatory disease.

CAPS are divided into three conditions, namely, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID).

How Are CAPS Caused?

CAPS are a group of genetically inherited disorders. A mutation in even one gene copy of the parent can lead to disease in the child (autosomal dominant inheritance pattern).

CAPS are caused by a mutation in the NLRP3 gene, which is responsible for the production of cryopyrin. Inflammation is a natural phenomenon in which the body’s white blood cells arrive at the site of injury to protect from foreign bodies. Cryopyrin is involved in the body’s adequate inflammatory response. However, the mutation leads to the malfunctioning of cryopyrin. As a result, impaired body mechanisms managing inflammation develop.

What Are the Signs and Symptoms of CAPS?

CAPS affects multiple body organs. These are most commonly seen in infants or young children. It typically contains a body rash, fever, and joint pain provoked by cold, stress, or fatigue. CAPS is a name collectively given to the three disorders varying in severity listed below:

1. FCAS - In FCAS, cold exposure triggers a painful rash lasting from a few hours to days. The rash mainly affects the body and limbs and might spread to the face, thighs, and upper limbs. Skin lesions resemble a raised lesion called a papule/plaque. Wrist, knee, and ankle joints also are affected. Other symptoms include headache, nausea, vomiting, lethargy, muscle pain, and eye redness.

2. MWS - In MWS, spontaneous skin rash, fever, and joint pain may occur. Ear involvement is common. If left untreated, young children and adolescents might develop hearing loss that progresses with age. In addition, skin lesions and abnormal deposition of a protein called amyloid might occur in the kidneys.

3. NOMID - This variant is the most severe of all three. The clinical features develop early after birth and remain throughout the patient’s life. Also, patients develop resistance to movement due to joint deformities and swelling. Dry eyes and eye inflammation (conjunctivitis) are common in NOMID patients affecting both eyes. Eye lesions may progress and can lead to permanent blindness. NOMID patients also suffer from central nervous system (CNS) involvement. In advanced cases, inflammation of the meninges (layers protecting the brain) called meningitis can occur. This leads to prolonged headaches, vomiting, seizures, strokes, and brain atrophy.

How Are CAPS Diagnosed?

A systematic approach to diagnosing CAPS includes patient history, thorough clinical examination, and diagnostic procedures. These are laboratory tests, skin biopsies, and genetic testing. Laboratory tests include;

• Serum Investigations: C-reactive protein (CRP) and serum amyloid-A (SAA) inflammatory proteins are raised five times more than normal. Therefore, serial measurements of the same are recommended.

• Routine Blood Workup: Increased number of acute inflammatory cells (neutrophils), platelets, and percentage of red blood cells (hematocrit) is found. Anemia is also one of the findings.

• Renal Function Test: A complete urine analysis should be done to check the presence of urine proteins. If positive, a diagnosis of nephrotic syndrome is advised (a complication of systemic amyloidosis).

• Cerebrospinal Fluid (CSF) Assessment: CSF assessment is paramount to check CNS involvement. During disease flares, CSF testing may indicate increased protein levels.

• High-Frequency Pure Tone Audiometry (HF-PTA Test): High frequency pure tone audiometry is done to assess hearing loss.

• Brain Magnetic Resonance Imaging (MRI)- A brain MRI to assess brain functioning is indicated. Further, a spine MRI also shows thickening and enhancement of the lumbar and spinal nerve roots.

• Bone MRI and X-Ray: Bone involvement is an integral part of CAPS. Hence, bone MRI and x-ray are important to assess muscle and bone involvement.

• Skin Biopsy: A skin biopsy from the rash is important to assess neutrophil invasion in the skin layers. It can assist in a prompt diagnosis of CAPS.

• Genetic Testing: The only commercially available gene sequence testing kit for CAPS is GeneDx. The disadvantage of genetic testing is the high cost and limited availability.

What Are the Other Disorders Similar to CAPS?

Many disorders need to be differentiated from CAPS as they may have a similar clinical presentation. These include:

1. Cold Contact Urticaria: Skin rash occurs only in areas that are localized to contact. Body involvement is more than CAPS. A differentiating test is the ice cube test, in which a raised area of itchy skin appears within five minutes of ice contact. Ice cube test is absent in CAPS.

2. Adult Onset Still’s Disease (AOSD): Although the signs and symptoms of AOSD are similar to CAPS, the onset of AOSD is late teenage years.

3. Schnitzler Syndrome: Schnitzler syndrome occurs in elderly individuals (60 years). Skin biopsy also shows a different result than CAPS (monoclonal cells).

4. Deficiency in Interleukin-1 Receptor Antagonist (DIRA): Clinical manifestations are the same as NOMID. However, the skin has pus eruptions similar to psoriasis (CAPS has an itchy rash).

What Is the Treatment of CAPS?

The management of CAPS is aimed at prolonging the patient’s life span and symptom improvement. Treatment primarily consists of medication, supportive care, physiotherapy, and psychosocial therapy.

1. Medications: The FDA has approved three drugs that act at a molecular level, namely, Anakinra, Rilonacept, and Canakinumab. Anakinra and Rilonacept are injected subcutaneously (under the skin) weekly. Similarly, Canakinumab, a monoclonal antibody, is administered subcutaneously every four to eight weeks. These medications are safe and effective against CAPS. These drugs are advised to continue throughout the patient’s life to prevent complications (such as amyloidosis). The dose depends on the condition’s severity. VX-765, a Caspase-1 inhibitor, is under clinical trials against CAPS.

2. Supportive Care: Supportive care reduces fever, joint pains, and eye and ear complications. Anti-inflammatories, antihistaminics, and corticosteroids are helpful. Immunosuppressants have also been tried. Hearing aids are encouraged to counteract deafness. Patients are advised to use warming therapy to protect against the cold.

3. Physiotherapy: Physical therapy and splints are advised for joint health. In advanced cases, surgery is needed to manage joint abnormalities.

4. Psychosocial Support: CAPS patients suffer from depression, anxiety, and isolation risk, which greatly affects their quality of life. Parents suffer from emotional and financial stress dealing with their child’s disease. Psychosocial support considerably improves disease outcomes.

Conclusion

Many patients suffering from CAPS develop advanced complications such as blindness and hearing loss. However, medications such as Anakinra, Rilonacept, and Canakinumab have significantly improved the disease prognosis. Early diagnosis and treatment, regular observation, and follow-up are essential to improve patient health and well-being.