Inheritance pattern: 1. Familial cold autoinflammatory syndrome (FCAS) 2. Muckle-Wells syndrome (MWS) 3. Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

1. Inherited 2. Inherited 3. Sporadic

Triggers: 1. Familial cold autoinflammatory syndrome (FCAS) 2. Muckle-Wells syndrome (MWS) 3. Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

1. Cold induced 2. None 3. None

Neurological involvement of: 1. Familial cold autoinflammatory syndrome (FCAS) 2. Muckle-Wells syndrome (MWS) 3. Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

1. None 2. None 3. Chronic aseptic meningitis

Auditory involvement: 1. Familial cold autoinflammatory syndrome (FCAS) 2. Muckle-Wells syndrome (MWS) 3. Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

1. None 2. Sensorineural hearing loss 3. Sensorineural hearing loss

Amyloidosis: 1. Familial cold autoinflammatory syndrome (FCAS) 2. Muckle-Wells syndrome (MWS) 3. Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

1. Rare 2. Frequent 3. Frequent

Genetic testing for NLRP3 mutations: 1. Familial cold autoinflammatory syndrome (FCAS) 2. Muckle-Wells syndrome (MWS) 3. Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

1. Almost all are mutation-positive 2. Almost all are mutation-positive 3. Not all have a detectable mutation

39 - Autoinflammatory Disorders Flashcards by dvojnd rivera

Autoinflammatory disorders are diseases of the _____ immune system

Innate

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Cryopyrin-associated periodic syndromes (CAPS) are caused by gain of function mutations in ______, the gene encoding ______

NLRP3

NLRP3 or cryopyrin

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The spectrum of Cryopyrin-associated periodic syndromes (CAPS) includes

Familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells syndrome (MWS)
Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

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Inheritance pattern:

Familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells syndrome (MWS)
Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

Inherited
Inherited
Sporadic

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Common characteristic feature in cryopyrin-associated periodic syndromes (CAPS), and usually the first sign of disease

Urticarial skin lesions

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Cryopyrin-associated periodic syndromes (CAPS) and Schnitzler syndrome vs common urticaria

CAPS and Schnitzler syndrome - usually nonpruritic or only slightly itchy; unresponsive to antihistamines

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Triggers:

Familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells syndrome (MWS)
Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

Cold induced
None
None

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Neurological involvement of:

Familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells syndrome (MWS)
Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

None
None
Chronic aseptic meningitis

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Auditory involvement:

Familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells syndrome (MWS)
Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

None
Sensorineural hearing loss
Sensorineural hearing loss

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Amyloidosis:

Familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells syndrome (MWS)
Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

Rare
Frequent
Frequent

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CAPS: Radiographs of the long bones reveal epiphyseal overgrowth that is characteristic and unique to

Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

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Genetic testing for NLRP3 mutations:

Familial cold autoinflammatory syndrome (FCAS)
Muckle-Wells syndrome (MWS)
Chronic infantile neurologic cutaneous and articular syndrome (CINCO) or Neontal-onset multisystem inflammatory disease (NOMID)

Almost all are mutation-positive
Almost all are mutation-positive
Not all have a detectable mutation

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First drug use to treat Cryopyrin-associated periodic syndromes (CAPS)

Anakinra

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Two longer-acting IL-1 antagonists

Rilonacept

Canakinumab

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Coexistence of a monoclonal IgM gammopathy is a diagnostic feature of

Schnitzler syndrome

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Some Schnitzler syndrome patients have been shown to have mosaicism of ______ mutations

NLRP3

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Patients with Schnitzler syndrome present with the first syndrome around

50 years of age or older

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Usually the first sign of Schnitzler syndrome

Recurrent urticarial skin lesions

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Characteristic feature of Schnitzler syndrome and distinguishes it from Cryopyrin-associated periodic syndromes (CAPS)

Monoclonal gammopathy, mostly IgM kappa light chain

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Prognosis of Schnitzler syndrome depends on the

Possible evolution to lymphoproliferative disorder

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Deficiency of the IL-1 receptor antagonist (DIRA) is cause by mutations in _____, the gene coding ______

IL1RN

IL-1Ra

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Manifests as perinatal to several months of age-onset pustular skin eruption, with oral mucosal lesions, failure to gain weight and painful joint swelling

Deficiency of the IL-1 receptor antagonist (DIRA)

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Characteristic radiographic findings include balloon-like widening of the anterior rib ends, periosteal elevation of multiple long bones, and multifocal osteolytic lesions

Deficiency of the IL-1 receptor antagonist (DIRA)

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Not a typical feature of Deficiency of the IL-1 receptor antagonist (DIRA)

High fever

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Deficiency of the IL-36 receptor antagonist (DITRA) is caused by mutations in _____, the gene coding ______

IL36RN | IL-36 receptor antagonist (IL-36Ra)

Lack of the negative regulator IL-36Ra leads to aberrant IL-36 signaling and subsequent overproduction of _____, a strong neutrophil chemoattractant, in keratinocytes

IL-8

Deficiency of the IL-36 receptor antagonist (DITRA) is termed as a monogenic form of

Generalized pustular psoriasis

Deficiency of the IL-36 receptor antagonist (DITRA) disease flares are thought to be triggered by

``` Viral or bacterial infections Medications (amoxicillin) Mensturation Pregnancy Withdrawal of retinoid therapy ```

Deficiency of the IL-36 receptor antagonist (DITRA) vs Generalized pustular psoriasis

DITRA - no joint involvement

CARD14-mediated pustular psoriasis (CAMPS) or psoriasis 2 (PSORS2) is caused by a gain-of-function mutations in

CARD14 or CARMA2

CARD14 is primarily expressed in

Epidermal keratinocytes

Most common and the first genetically characterized monogenic autoinflammatory disorder

Familial Mediterranean fever (FMF)

Familial Mediterranean fever (FMF) is caused by mutations in _____, the gene encoding _____

MEFV | Pyrin

Pyrin is expressed predominantly in the

Cytoplasm of cells of myeloid lineage including neutrophils, along with synovial fibroblasts and dendritic cells

Characterized by recurrent short febrile attacks associated with peritonitis, pleuritis, synovitis, and erysipelas-like skin lesions

Familial Mediterranean fever (FMF)

May trigger an attack of Familial Mediterranean fever (FMF)

Cold exposure Fatigue Emotional stress Mensturation

Most severe complication is _____, which can lead to _____, a major cause of mortality in patients with Familial Mediterranean fever (FMF)

Secondary amyloidosis | Renal failure

Some do not tolerate colchicine mainly because of its

Gastrointestinal side effects

Elderly patients and those with renal impairment treated with colchicine may develop

Myopathy or neuropathy

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) or Mevalonate kinase deficiency (MKD) is caused by mutations in _____, the gene encoding _____

MVK | Mevalonate kinase

Severe and fatal form of Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) or Mevalonate kinase deficiency (MKD) in which the enzyme activity of mevalonate kinase is below 1%

Mevalonic aciduria

FDA-approved therapy for Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) or Mevalonate kinase deficiency (MKD) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Anti-IL-1 therapy with canakinumab

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) or Mevalonate kinase deficiency (MKD) flares are generally triggered by

Immunizations Trauma including surgery Physical and emotional stress

Most common skin lesions in Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) or Mevalonate kinase deficiency (MKD)

Widespread erythematous macules and papules

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is caused by mutations in ______, the gene coding _____

TNFRSF1A | TNF receptor-1 (TNFR1)

Initially termed familial Hibernian fever

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Second most common known inherited periodic fever syndrome

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

TNF receptor-1 (TNFR1) is expressed on

Leukocytes | Endothelial cells

Episodes of Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) usually occur spontaneously, but may also be triggered by

Infection Minor injury Stress Exercise

Most frequent skin lesions in Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Erythematous patches and plaques that can be migratory and associated with underlying myalgia

Haploinsufficiency of A20 (HA20) is caused by loss-of-function mutations in _____, the gene encoding _____

TNFAIP3 | A20/TNFAIP3

The symptoms of Haploinsufficiency of A20 (HA20) are indistinguishable from

Behcet’s disease

Otulipenia or OTULIN-related autoinflammatory syndrome (ORAS) is caused by loss-of-function mutations in

OTULIN or GUMBY/FAM105B

_____ is a deubiquitinase that negatively regulates the NF-kB signaling pathway by cleaving linear ubiquitin chains, whereas _____ deubiquitinase does so by cleaving K63 ubiquitin chains

OTULIN | A20

Relapsing nodular panniculitis with neutrophil infiltrate are typically observed

Otulipenia or OTULIN-related autoinflammatory syndrome (ORAS)

Otulipenia or OTULIN-related autoinflammatory syndrome (ORAS) can be treated with

TNF-alpha inhibitor

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) or proteasome-associated recessive disorder (PRAAS) is caused by homozygous or compound heterozygous mutations in

PSMB8

Recurrent fever, pernio-like and nodular erythema-like eruptions, long, clubbed fingers, and progressive lipodystrophy are characteristic features

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) or proteasome-associated recessive disorder (PRAAS)

Sporadic form of Blau syndrome (BS)

Early-onset sarcoidosis (EOS)

Blau syndrome (BS) or early-onset sarcoidosis (EOS) are caused by mutations in _____, the gene encoding _____

NOD2 or CARD15 | NOD2

Typically the first sign of Blau syndrome (BS) or early-onset sarcoidosis (EOS), occurring before 4 years of age

Granulomatous dermatitis

Triad of granulomatous dermatitis, arthritis and uveitis

Blau syndrome (BS) or early-onset sarcoidosis (EOS)

NOD2 or CARD15 is mainly expressed in the

Cytoplasm of monocytes, macrophages, granulocytes, and dendritic cells

NOD2 recognizes _____, a cell wall component of both gram-positive and gram-negative bacteria

Muramyl dipeptide

_____, often present in sarcoidosis, is absent in Blau syndrome (BS) or early-onset sarcoidosis (EOS)

Bilateral hilar lymphadenopathy

Arthritis in Blau syndrome (BS) or early-onset sarcoidosis (EOS) has a characteristic phenotype of

Chronic, symmetrical, and mostly painless polyarthritis

Can be the most difficult manifestation to treat and is the main cause of long-term complications in Blau syndrome (BS) or early-onset sarcoidosis (EOS)

Uveitis

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA) syndrome is caused by mutations in _____, the gene encoding _____

``` PSTPIP1 PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) ```

PSTPIP1 can interact with _____, mutations of which cause _____

Pyrin | Familial Mediterranean fever (FMF)

Typically, the symptoms of Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA) syndrome get (milder/more severe) with age

Milder

Majeed syndrome is caused by mutations of the _____ gene, the gene encoding _____

LPIN2 | Lipin-2

Symptom triad of Majeed syndrome

Chronic recurrent multifocal osteomyelitis (CRMO) Congenital dyserythropoietic anemia (CDA) Neutrophilic dermatosis resembling Sweet syndrome

Congenital dyserythropoietic anemia presents as

Hypochromic, microcytic anemia

Most frequent cutaneous manifestation of Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome

Palmoplantar pustulosis | Severe acne

Major osteoarticular manifestation of Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome are

Oligoarthritis and osteitis mainly affecting the anterior chest wall

Onset of Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome

Middle-aged adults

First line of treatment in Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome

NSAIDs

Treatment for: Cryopyrin-associated periodic syndromes (CAPS) Schnitzler syndrome Deficiency of the IL-1 receptor (DIRA)

IL-1 antagonists

Treatment for familial Mediterrenean fever (FMF)

Colchicine

Autosomal recessive disorders

Deficiency of the IL-1 receptor antagonist (DIRA) Deficiency of the IL-36 receptor antagonist Familial Mediterranean fever (FMF) Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) or Mevalonate kinase deficiency (MKD) Otulipenia or OTULIN-related autoinflammatory syndrome (ORAS) Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) or proteasome-associated recessive disorder (PRAAS)

Sporadic disorders

Schnitzler syndrome Early-onset sarcoidosis (EOS) Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome

Autosomal dominant disorders

Cryopyrin-associated periodic syndromes (CAPS) CARD14-mediated pustular psoriasis (CAMPS) or psoriasis 2 (PSORS2) Less common AD Familial Mediterranean fever (FMF) Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) Haploinsufficiency of A20 (HA20) Blau syndrome (BS) Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome Majeed syndrome