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.
usually the first sign of Schnitzler syndrome and can precede the other symptoms for years
Recurrent urticarial skin lesions
- The lesions are usually nonpruritic or only slightly itchy, resolve within 24 to 48 hours, and, invariably, antihistamines are ineffective.
- The frequency of urticarial skin changes ranges from daily to a few episodes per year.
second most common symptom of Schnitzler syndrome
intermittent fever
which can rise above 40°C (104°F)
Deficiency of the IL-1 receptor antagonist (DIRA) is caused by mutations in what gene?
IL1RN, the gene coding IL-1Ra
It should be considered in patients with recurrent episodes of urticarial skin lesions, **fever, and bone and joint pain **without evidence of infection or autoimmune disease.
Schnitzler syndrome
Mutations in IL1RN lead to complete absence or dysfunction of IL-1Ra and thus to unopposed and hyperactive IL-1 signaling.
Deficiency of the IL-1 receptor antagonist (DIRA)
- clinically manifests as perinatal to several months of age-onset pustular skin eruption, with oral mucosal lesions, failure to gain weight and painful joint swelling
- Fetal distress was present in 6 of 10 reported patients before birth.
- Characteristic radiographic findings include** balloon-like widening of the anterior rib ends, periosteal elevation of multiple long bones, and multifocal osteolytic lesions**.
- High fever is not a typical feature
- Cutaneous pustulosis can range from normal skin with rare individual pustules to discrete crops of pustules, generalized severe pustulosis, or ichthyosiform lesions (Fig. 39-3A).
- Oral mucosal vesicular lesions or aphthous ulcers are seen early in life in some patients, but do not seem to recur later in life.
- Nail changes, including onychomadesis and pits, also can be seen.
Deficiency of the IL-1 receptor antagonist (DIRA)
Lack of the negative regulator IL-36Ra leads to aberrant IL-36 signaling and subsequent overproduction of what interleukin?
IL-8, a strong neutrophil chemoattractant, in keratinocytes
Deficiency of the IL-36 receptor antagonist (DITRA) is caused by mutations in what gene?
IL36RN, the gene coding IL-36 receptor antagonist (IL-36Ra).
IL36RN mutations are also associated with some cases of localized pustular psoriasis such as palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau.
- typically presents as recurrent and sudden onset of flares of a generalized erythematopustular skin eruption, accompanied by high fever (40-42°C [104-107.6°F]), neutrophilia, and elevated hepatic acute-phase proteins
- The disease flares are thought to be triggered by viral or bacterial infections, medications (eg, amoxicillin), menstruation, pregnancy, and withdrawal of retinoid therapy
Deficiency of the IL-36 receptor antagonist (DITRA)
- No joint involvement is observed in DITRA, but nail dystrophy can occur. DITRA can be a life-threatening disease owing to severe complications resulting from the repeated flares of prominent systemic inflammation
CARD14-mediated pustular psoriasis (CAMPS)/ psoriasis 2 (PSORS2)
Gain-of-function mutations in CARD14 lead to aberrant mitogen-activated protein kinase activity and nuclear factor-kappa B signaling, resulting in overproduction of what interleukins?
IL-8 and IL-36γ
the most common and the first genetically characterized monogenic autoinflammatory disorder
Familial Mediterranean fever (FMF)
Familial Mediterranean fever (FMF) is caused by mutations in what gene?
MEFV, the gene encoding pyrin
Mutations in MEFV lead to pyrin-inflammasome activation and subsequent abnormal IL-1β secretion.
- characterized by** recurrent febrile attacks **associated erysipelas-like skin lesions, peritonitis, pleuritis, and synovitis.
- These attacks last for 1 to 3 days.
- Erysipelas-like skin lesions are well-demarcated, warm, tender, swollen, red skin lesions observed mainly on the front of the lower legs between the ankle and the knee, on the dorsum of the foot, or in the ankle region
- Patients are completely well between the attacks.
- Cold exposure, fatigue, emotional stress, and menstruation may trigger an attack.
Familial Mediterranean fever (FMF)
characteristic cutaneous feature of Familial Mediterranean fever (FMF)
Erysipelas (cellulitis)-like skin lesions
very effective in preventing attacks and minimizing progression of amyloidosis in Familial Mediterranean fever (FMF)
Colchicine
most-severe complication of Familial Mediterranean fever (FMF)
secondary amyloidosis
- which can lead to renal failure, a major cause of mortality in patients with FMF.
Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)/mevalonate kinase deficiency (MKD) is caused by mutations in what gene?
MVK
- the gene coding mevalonate kinase that is involved in many cellular functions via cholesterol and isoprenoid biosynthesis
- Mutations of MVK lead to reduced mevalonate kinase enzyme activity, which results in the production of IL-1β via a complex mechanism.
first FDA-approved biologic treatment for patients with Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)/mevalonate kinase deficiency (MKD)
Canakinumab
- Attacks manifest as high, spiking fever preceded by chills accompanied by abdominal pain, diarrhea, vomiting, headache, joint pain, cervical lymphadenopathy, and skin lesions
- Episodes last 3 to 7 days, recover spontaneously, and recur every 4 to 8 weeks, although the interval between attacks can vary significantly even in the same patient.
- Onset is usually before the age of 5 years.
- The flares are generally triggered by immunizations, trauma including surgery or physical and emotional stress
- Widespread erythematous macules and papules are the most common, followed in frequency by urticaria, annular erythema, erythematous nodules, and petechiae
- Half of patients may also have oral aphthous ulcers with or without genital ulceration.
* most typical finding is the consistently elevated serum IgD level
Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)/mevalonate kinase deficiency (MKD)
- The presence of oral aphthous ulcers in patients with recurrent fever episodes should lead to consideration of HIDS diagnosis
TNF receptor-associated periodic syndrome (TRAPS) is caused by mutations in what gene?
TNFRSF1A
gene coding TNF receptor-1 (TNFR1)
recurrent long-lasting febrile attacks occur accompanied by abdominal pain and the characteristic migratory muscle pain with overlying skin lesions
TNF receptor-associated periodic syndrome (TRAPS)
- Most patients experience myalgia resulting from a monocytic fasciitis with a sensation of deep cramping that is migratory from the torso and the proximal limb toward the distal arms and legs
Haploinsufficiency of A20 (HA20) is caused by loss-of-function mutations in what gene?
TNFAIP3 gene, the gene encoding A20/TNFAIP3
- rare autosomal dominant disorder characterized by features indistinguishable from Becet disease
- presenting with **fevers, bipolar ulceration of mucosal surfaces, particularly in the oral and genital areas, **skin lesions, uveitis, and polyarthritis.
- The skin lesions include erythematous papules, pseudofolliculitis, erythema nodosum-like lesions, and pathergy
- These patients may also develop retinal vasculitis, gastrointestinal ulcers, and CNS vasculitis
Haploinsufficiency of A20 (HA20)
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)/proteasome-associated autoinflammatory syndrome (PRAAS)
is caused by homozygous or compound heterozygous mutations in what gene?
PSMB8
- Within days to months after birth, patients present with severe systemic inflammation, manifesting with prolonged fever, rash, arthralgia, diarrhea, **progressive lipodystrophy, **and developmental delay
* Relapsing nodular panniculitis with neutrophil infiltrate and erythematous and pustular rash are observed in the skin.
Otulipenia/OTULIN-related autoinflammatory syndrome (ORAS)
- Recurrent fever,** pernio-like **and nodular erythema-like eruptions, long, clubbed fingers, and progressive lipodystrophy are characteristic features.
- Signs and symptoms generally develop during the first year of life.
- Later during infancy, patients develop long, clubbed fingers and toes with joint contractures and progressive lipomuscular atrophy mainly in the face and upper limbs
- Chronic anemia and an elevated CRP and ESR are typically present.
- Variable hypergammaglobulinemia and elevation of IgG, IgE, IgA, and IgM are present
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)/proteasome-associated autoinflammatory syndrome (PRAAS)
Blau syndrome (BS) is a rare autosomal dominant disorder; early-onset sarcoidosis (EOS) is a sporadic form of Blau syndrome.
BS/EOS are caused by mutations in what gene?
NOD2
typically the first sign of Blau syndrome (BS)/early-onset sarcoidosis (EOS), occurring before 4 years of age
Granulomatous dermatitis
- The skin lesions are asymptomatic, slightly scaly, discrete, yellowish to brown-red flat-topped papules on the trunk and extremities, observed in more than 90% of patients, classically children before the age of 4 years
- Histologically, **noncaseating granulomas composed of periodic acid-Schiff–positive **histiocytes and multinucleated giant cells located in the upper dermis are characteristic
- Bilateral hilar lymphadenopathy, often present in sarcoidosis, is absent in BS/EOS patients
Blau syndrome (BS) classically presents before the age of 4 years as a triad of?
- granulomatous dermatitis,
- arthritis,
- uveitis
Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disorder caused by mutations in what gene?
PSTPIP1
- clinical manifestations of this disorder include** sterile pyogenic arthritis, pyoderma gangrenosum, and nodulocystic acne**
- Arthritis begins in the first decade of life and is progressively destructive. The inflammatory episodes often begin unprovoked or after minor trauma, leading to neutrophil-rich purulent synovial inflammation
- during episodes of arthritis patients may present with fever.
- The cutaneous symptoms, pyoderma gangrenosum and severe acne, develop at the time of puberty.
- Pyoderma gangrenosum presents as poorly healing ulcers with typical undermined edges
Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome
- The diagnosis of PAPA syndrome should be suspected in individuals with relapsing sterile arthritis, cutaneous ulcer formation, and severe acne.
Majeed syndrome is caused by mutations of what gene?
LPIN2 gene, the gene encoding lipin-2.
symptom triad of Majeed syndrome
- chronic recurrent multifocal osteomyelitis (CRMO),
- congenital dyserythropoietic anemia (CDA),
- neutrophilic dermatosis resembling Sweet syndrome.
- begins in infancy or early childhood with recurrent episodes of pain and joint swelling.
- These symptoms typically persist into adulthood and can lead to short stature and joint contractures.
- CDA presents as hypochromic, microcytic anemia during the first year of life and ranges from mild to transfusion dependent.
- Most people with Majeed syndrome also develop neutrophilic dermatosis, resembling Sweet syndrome with unknown onset age and frequency.
- Patients can also develop erythematous plaques, psoriasis, and pustulosis.
most frequent cutaneous manifestations of Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome
The most frequent skin manifestation in SAPHO syndrome is palmoplantar pustulosis/PPP, followed by severe acne, including acne conglobata, acne fulminans, or hidradenitis suppurativa
major osteoarticular manifestations of Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome
painful oligoarthritis and osteitis
- The most common osteoarticular manifestations of SAPHO syndrome include oligoarthritis affecting sternocostal and sternoclavicular joints, sacroiliac joints, knees, and ankles, and osteitis affecting the anterior chest wall, such as the sternum, clavicle, and ribs, presenting with pain, tenderness, and sometimes swelling over the affected areas.
generally considered as the first line of treatment for SAPHO syndrome
NSAIDs
