6 - 39 - AUTOINFLAMMATORY DISORDERS Flashcards
IL that plays a prominent role in a large subset of monogenic autoinflammatory disorders
Interleukin (IL)-1
Autoinflammatory disorders are, however, diseases of the what type of immune system?
innate immune system
characterized by recurrent episodes of systemic nflammation without the usual hallmarks of autoimmunity such as high autoantibody titers and the presence of antigen-specific T cells
pattern of inheritance of Cryopyrin-associated periodic syndromes (CAPS)
AD
Cryopyrin-associated periodic syndromes (CAPS) mutation
gain of function mutations in NLRP3
the gene encoding NLRP3, also known as cryopyrin.
Gain-of-function mutations in NLRP3 lead to inflammasome activation and subsequent abnormal secretion of what IL?
abnormal interleukin (IL)-1β secretion
The spectrum of CAPS include what syndromes?
- familial cold autoinflammatory syndrome (FCAS)
- Muckle-Wells syndrome (MWS)
- chronic infantile neurologic cutaneous and articular syndrome (CINCA) AKA neonatal-onset multisystem inflammatory disease (NOMID)
common characteristic feature in CAPS, and usually the first sign of disease
Urticarial skin lesions
very effective and the standard of care in treating CAPS
IL-1 antagonists
common clinical hallmarks of CAPS
Periodic fever and urticarial skin lesions
How are the manifestations of CAPS different from urticaria?
- They resemble common urticaria at first glance because the smooth, slightly elevated erythematous lesions (wheals) are migratory and skin returns to its normal appearance without residual pigmentation.
- The symptoms, however, tend to be atypical for common urticaria because lesions are usually nonpruritic or only slightly itchy and not associated with any particular sensation; some patients describe sensations of stinging, burning, and tightness.
- Unlike in common urticaria, urticarial skin lesions in CAPS are** unresponsive to antihistamines.**
mildest condition of CAPS
familial cold autoinflammatory syndrome (FCAS)
- The main clinical features are **urticarial skin lesions and low-grade fever **of short duration that develop usually 1 to 2 hours after exposure to cold temperature.
- Attacks are more common in winter and can occur upon exposure to cold outside temperatures and cold air-conditioned rooms.
- The ice-cube provocation test is negative for the urticaria.
- **Systemic cold exposure **is needed to trigger an intense episode.
- The flares tend to be brief, typically lasting less than 24 hours, and can also include arthralgia, conjunctivitis, headaches, nausea, and fatigue.
- The arthralgia mostly affects the hands, knees, and ankles.
- The attacks usually begin in infancy and early childhood.
familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells Syndrome was originally described as a triad of?
urticaria, deafness, and amyloidosis
- originally described as a triad of** urticaria, deafness, and amyloidosis.**
- Inflammatory episodes in can be frequent and random, and are only variably triggered by cold.
- Most attacks last 24 to 48 hours but can also be continuous.
- commonly have fevers, urticarial skin lesions, arthralgia, and headache that reflects aseptic meningitis
- Progressive sensory neural hearing loss often appears clinically during the second to third decade of life.
- Conjunctivitis and uveitis also can be present.
Muckle-Wells syndrome
- tend to have** persistent inflammation** and, in most cases, infants have diffuse erythema and fever at birth.
- Chronic aseptic meningitis is common, and without treatment with IL-1 antagonists, patients typically develop progressive brain atrophy and cognitive impairment
-
Conjunctivitis and uveitis starts shortly after birth and elevated CNS pressure causes** chronic papilledema**, which can lead to serious loss of vision.
*** Sensory neural hearing loss **develops typically within the first year of life. - Also, patients develop characteristic long-bone epiphyseal overgrowth and short stature, and amyloidosis develops after years of chronic inflammation
CINCA/NOMID
CINCA, chronic infantile neurologic cutaneous and articular syndrome
NOMID, neonatal onset multisystem inflammatory disease
Radiographs of the long bones showing epiphyseal overgrowth is unique and characteristic of what syndrome?
CINCA/NOMID
CINCA, chronic infantile neurologic cutaneous and articular syndrome
NOMID, neonatal onset multisystem inflammatory disease
recombinant IL-1 receptor antagonist
Anakinra
first drug used to treat CAPS
Anakinra (Kineret, a recombinant IL-1 receptor antagonist)
also known as IL-1 Trap, is a dimeric fusion protein comprised of the extracellular domain of the human IL-1 receptor fused to the Fc domain of human immunoglobulin (Ig) G1 , that binds and neutralizes IL-1
Rilonacept (Arcalyst)
human monoclonal antibody specific for IL-1β
Canakinumab (Ilaris)
approved by the U.S. Food and Drug Administration (FDA) for the treatment of FCAS and MWS
Rilonacept and canakinumab
diagnostic feature of Schnitzler syndrome
monoclonal IgM gammopathy
- patients may develop a lymphoproliferative disorder
- Monoclonal gammopathy, mostly IgMκ light chain, is seen in 85% of Schnitzler syndrome patients, which is a characteristic feature of the syndrome and distinguishes it from CAP
rare late-onset inflammatory disease characterized by **recurrent fever, urticarial skin lesions, arthritis and lymphadenopathy **accompanied by IgM gammopathy
Schnitzler syndrome
Patients present with the first symptoms typically around 50 years of age or older.