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Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by
interleukin 1β Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping
autoinflammatory syndrome Periodic fever syndromes are a set of disorders characterized by recurrent episodes of Systemic disease, systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by ...
s including
familial cold autoinflammatory syndrome Cold urticaria (essentially meaning cold hives) is a disorder in large red welts called hives (''urticaria'') form on the skin after exposure to a cold stimulus. The hives are usually itchy and often the hands and feet will become itchy and swoll ...
(FCAS, formerly termed familial cold-induced urticaria), the
Muckle–Wells syndrome Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness and recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and joint pain. As a result, MWS is ...
(MWS), and
neonatal-onset multisystem inflammatory disease Neonatal-onset multisystem inflammatory disease is a rare disease, rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthri ...
(NOMID, also called chronic infantile neurologic cutaneous and articular syndrome or CINCA) that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and
keratoendotheliitis fugax hereditaria Keratoendotheliitis fugax hereditaria is an autosomal dominantly inherited disease of the cornea, caused by a point mutation in cryopyrin (also known as NALP3) that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome ...
in which the autoinflammatory symptoms affect only the anterior segment of the eye.


Signs and symptoms

The syndromes within CAPS overlap clinically, and patients may have features of more than one disorder. In a retrospective cohort of 136 CAPS patients with systemic involvement from 16 countries, the most prevalent clinical features were fever (84% of cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disorders or failure to thrive), skin rash (either
urticarial Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
or
maculopapular rash A maculopapular rash is a type of rash characterized by a flat, red area on the skin that is covered with small confluent bumps. It may only appear red in lighter-skinned people. The term "maculopapular" is a compound: ''macules'' are small, flat ...
; 97% of cases) especially after cold exposure, and musculoskeletal involvement (
myalgia Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likel ...
,
arthralgia Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...
, and/or
arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
, or less commonly joint contracture, patellar overgrowth, bone deformity, bone erosion and/or
osteolytic lesion An osteolytic lesion (from the Greek words for "bone" (ὀστέον), and "to unbind" (λύειν)) is a softened section of a patient's bone formed as a symptom of specific diseases, including breast cancer and multiple myeloma. This softened are ...
; 86% of cases). Less common features included ophthalmological involvement (
conjunctivitis Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...
and/or
uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...
, or less commonly optic nerve atrophy,
cataract A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...
,
glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
or impaired vision; 71% of cases), neurosensory hearing loss (42% of cases), neurological involvement (morning
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
,
papilloedema Papilledema or papilloedema is optic disc swelling that is caused by increased intracranial pressure due to any cause. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare. I ...
, and/or
meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...
, or less commonly
seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
,
hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased intracranial pressure, pressure inside the skull. Older people may have headaches, double vision, poor ...
or mental retardation; 40% of cases), and
AA amyloidosis AA amyloidosis is a form of amyloidosis, a disease characterized by the abnormal deposition of fibers of insoluble protein in the extracellular space of various tissues and organs. In AA amyloidosis, the deposited protein is serum amyloid A protein ...
(4% of cases). In
keratoendotheliitis fugax hereditaria Keratoendotheliitis fugax hereditaria is an autosomal dominantly inherited disease of the cornea, caused by a point mutation in cryopyrin (also known as NALP3) that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome ...
, systemic symptoms are not reported whereas the patients experience periodical transient inflammation of the
corneal endothelium The corneal endothelium is a single layer of endothelial cells on the inner surface of the cornea. It faces the chamber formed between the cornea and the iris. The corneal endothelium are specialized, flattened, mitochondria-rich cells that li ...
and stroma, leading to short term blurring of vision and, after repeated attacks, to central corneal stromal opacities in some patients. Age of onset is typically in infancy or early childhood. In 57% of cases, CAPS had a chronic phenotype with symptoms present almost daily, whereas the remaining 43% of patients experienced only acute episodes. Up to 56% of patients reported a family history of CAPS. Previous studies confirm these symptoms, although the exact reported rates vary.


Pathogenesis

Cryopyrin-associated periodic syndromes are associated with a gain-of-function missense mutation in exon 3 of ''
NLRP3 NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...
'', the gene encoding
cryopyrin NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...
, a major component of the
interleukin 1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...
inflammasome Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
. In
keratoendotheliitis fugax hereditaria Keratoendotheliitis fugax hereditaria is an autosomal dominantly inherited disease of the cornea, caused by a point mutation in cryopyrin (also known as NALP3) that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome ...
, the mutation occurs in exon 1. Intracellular formation of the interleukin 1 inflammasome leads to the activation of the potent pro-inflammatory cytokines
interleukin 1β Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
and
interleukin-18 Interleukin-18 (IL-18), also known as interferon-gamma inducing factor) is a protein which in humans is encoded by the ''IL18'' gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non ...
through a cascade involving
caspase 1 Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis ...
. The IL-1 inflammasome may also be released from activated macrophages, amplifying the cytokine production cascade. The mutation in ''
NLRP3 NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...
'' leads to aberrant formation of this inflammasome and subsequent unregulated production of
interleukin 1β Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
. Up to 170 heterogenous mutations in ''
NLRP3 NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...
'' have been identified. Some reports suggest rare mutations are more frequently associated with a severe phenotype, and some mutations are associated with distinct phenotypes, probably reflecting the differential impact of the mutation on the activity of the inflammasome in the context of individual genetic background. Inheritance of these disorders is autosomal dominant with variable penetrance.


Diagnosis

Because CAPS is extremely rare and has a broad clinical presentation, it is difficult to diagnose, and a significant delay exists between symptom onset and definitive diagnosis. There are currently no clinical or diagnostic criteria for CAPS based solely on clinical presentation. Instead, diagnosis is made by genetic testing for ''
NLRP3 NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...
'' mutations. Acute phase reactants and white blood cell count are usually persistently elevated, but this is aspecific for CAPS.


Treatment

Since
interleukin 1β Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
plays a central role in the pathogenesis of the disease, therapy typically targets this cytokine in the form of monoclonal antibodies (such as
canakinumab Canakinumab (International Nonproprietary Name, INN), sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis (SJIA) and active Still's disease, including adult-onset Still's disease (AOSD). ...
), binding proteins/traps (such as
rilonacept Rilonacept, sold under the brand name Arcalyst, is a medication used to treat cryopyrin-associated periodic syndromes, including familial cold autoinflammatory syndrome, and Muckle–Wells syndrome; deficiency of interleukin-1 receptor antagonist ...
), or interleukin 1 receptor antagonists (such as
anakinra Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modifi ...
). These therapies are generally effective in alleviating symptoms and substantially reducing levels of inflammatory indices. Case reports suggest that
thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications of ...
and the anti-IL-6 receptor antibody
tocilizumab Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID19. It is a hu ...
may also be effective.


References

* Kubota T, Koike R
Cryopyrin-associated periodic syndromes: background and therapeutics.
Mod Rheumatol. 2010 Jun;20(3):213-21
Autoinflammatory Alliance CAPS Guidebook


External links

{{DEFAULTSORT:Cryopyrin-Associated Periodic Syndrome Rare syndromes Autoinflammatory syndromes