Other rheum diseases and auto inflammatory disease Flashcards
What lab corresponds to disease activity in adult-onset still’s disease?
Ferritin
What is a key clinical sign of relapsing polychondritis?
It spares the ear lobe (no cartilage)
DDx for saddle nose deformity?
-Relapsing polychondritis -Wegener’s granulomatosis -nasal natural killer/t-cell lymphoma -Mucocutaneous leishmaniasis -Syphilis
What is the most common autoantibody in Sjogren syndrome?
Anti-Ro/SS-A
What is the most specific antibody for Sjogrens syndrome?
Anti-fodrin
What is the pattern of the ANA in the mixed connective tissue disease?
Speckled nuclear pattern
What is Still disease?
Systemic-onset juvenile idiopathic arthritis
What percentage of juvenile idiopathic arthritis is Still disease?
20%
What other types of juvenile idiopathic arthritis exist?
RF (-) polyarthritis (5%): favors small joints (hands and feet); usually non-erosive; RF (-), ANA (-) RF (+) polyarthritis (15%): Favors small joints (hands and feet); usually erosive; shares features of adult RA🡪 rheumatoid nodules, RF (+) in 100%, usually ANA (+) Oligo/pauciarticular arthritis (60%): MC form of JIA; favors knees; subdivided into two types Type 1 (MC subtype), onset =1-8yo; uveitis in 50%; ANA (+), RF (-) Type 2, onset 9-16yo; strongly a/w HLA-B27; RF (-), ANA (-) Other rare forms: Enthesitis-related arthritis (A/w HLA-B27), PsA (ANA-negative, a/w anterior uveitis)
What is the age range for Still disease?
= 16 y/o, mean age is 6 y/o
Pathogensis of Still disease?
Autoinflammatory syndrome (disorder of innate immune system) Activation of innate immune system 🡪 increased IL-1 production by the inflammasome 🡪 downstream effects Up to 3x increased risk of JIA in kids exposed to multiple courses of antibiotics
What is the diagnostic criteria for Still disease/ systemic-onset juvenile idiopathic arthritis?
-High episodic fevers (>38.9 C) daily for >/= 2 weeks and documented to be quotidian (daily) for more than 3 days. [often occurs in late afternoon or early evening] -Plus, one of the following features - Transient evanescent, salmon pink, blanching eruption (90%) [these correspond w/ fever spikes, genrelized distribution tho can favor axilla and waist, koebnerizaiton w/ linerar lesions, can also have persistent papules, plaques, periorbital edema, rheumatoid nodules - like lesions -generalized lymphadenopathy -hepatomegaly/splenomegaly -serositis (pericarditis, pleuritis, peritonitis) -symmetric polyarthritis > oligoarthritis; erosive in 20%
Skin findings in Still disease or systemic-onset juvenile idiopathic arthritis?
Transient evanescent, salmon pink, blanching eruption (90%) Typically arises in late afternoon/evening (corresponds w/ fever spikes) p/w generalized distribution (favors axilla and waist) Koebnerization w/ linear lesions Less common: persistent papules and plaques, periorbital edema, rheumatoid nodule - like lesions
Histology of Still disease/Systemi-onset juvenile idiopathic arthritis?
wo types of cutaneous lesions Evanescent transient exanthem: edema of superficial dermis, superficial, perivascular, and interstitial neutrophilic infiltrate (denser and more neutrophil-predominant than urticaria) in absence of vasculitis Persistent papules/plaques: same as above + parakeratosis, superficially-scattered necrotic keratinocytes
Labratory testing in Still disease (Systemic-onset juvenile idiopathic arthritis)
Leukocytosis, anemia, and thrombocytosis Increase ESR/CRP Increased Ferritin (extremely high, >4000) RF-negative (>95%) ANA negative (>95%)
Epidemiology of adult-onset Still disease?
Vast majority <30 y/o, slight female predominance (M=F in juvenile form)
Pathogensis of adult-onset Still disease?
Possibly a reactive condition triggered by an infectious agent, a/w numerous HLA groups, suggesting genetic element
Clincal presentation of Adult-onset Still disease?
Prodrome of flu-like illness w/ sore throat, constitutional symptoms, high fever, arthralgias, myalgias Fever usually >39 C w/ spiking pattern (later afternoon to early evening) Skin manifestations Salmon patch exanthema (asymptomatic and transient) Occurs w/ fever spikes Trunk and site of pressure w/ keobnerization Violaceous to reddish brown, scaly, persistent papules and plaques (50%)
Skin findings in adult-onset Still disease?
Salmon patch exanthema (asymptomatic and transient) Occurs w/ fever spikes Trunk and site of pressure w/ keobnerization Violaceous to reddish brown, scaly, persistent papules and plaques (50%)
Systemic manifestations of adult-onset still disease?
Systemic manifestations Arthralgias/arthritis (65-100%) Typically knees, wrists, ankles symmetrically Carpal ankylosis (characteristic feature): limited ROM w/ minimal pain Hepatosplenomegaly Complications: macrophage activation syndrome (15%)🡪 life-threatening!
What is the feared systemic complication of adult-onset still disease?
Macrophage activation syndrome (15%) –> life-threatening!
What lab levels correlate with disease severity in Adult-onset still disease?
Ferritin
Lab findings in Adult-onset still disease?
Negative ANA and RF Anemia, leukocytosis, thrombocytosis Increased ESR/CRP Increased Ferritin Levels correlate w/ disease activity A/w chronic pattern of disease, recurrent flares, poor prognosis Lab abnormalities a/w macrophage activation syndrome (MAS
What is the treatment for Adult-onset still disease?
Majority require systemic steroids (pred 40-60 mg/d) May add steroid-sparing agent (MTX=first choice) Inhibitors of IL-1 receptor (anakinra), and IL6 receptor (tocilizumab) may be beneficial
Prognosis of Adult-onset still disease?
Benign, non-fatal course, w/ low mortality (3-10%) Deaths due to infections, ARDS, multiple organ failure from MAS and thrombotic microangiopathy
Epidemiology of relapsing polychondritis?
Age of onset 20-60 y/o, a/w second autoimmune disease in 30%, M=F incidence
Pathogenesis of relapsing polychondritis?
Intermittent episodes of articular inflammation + non-articular cartilage –> chondrolysis + structural collapse Autoantibodies titers against type II collagen correlate w/ disease activity, but are only present in 30-50% of patients A/w HLA-DR4
What HLA group is relapsing polychondritis a/w?
HLA-DR4
What autoantibody is a/w relapsing polychondritis and how often are these found?
Type II collagen, 30-50% of patients
These correlate with dz activity
What is the diagnostic criteria for relapsing polychondritis?
3/6 criteria for dx
- recurrent chondritis of both auricles (90%) [presenting sign in 25%]
- Chondritis of nasal cartilages
- Inflammation of ocular structures
- Chondritis of respiratory tract
- Cochlear and/or vestibular damage
What is this?
Relapsing polychondritis
Clinical appearance of recurrent chondritis of both auricles?
Presenting sign in 25%
Bright red, swollen, tender cartilaginous portion of eras, and sparing of earlobes
Recurrent episodes leading to floppy (“cauliflower”) ears
May lead to conductive hearing loss due to collapse and edema of the external auditory canal
Clinical presentation of chondritis of nasal cartilages?
nasal congestion, rhinorrhea, crusting, epistaxis, decreased sense of smell
May lead to saddle nose deformity (more common in females and younger patients)
Clinical of non-erosive inflammatory polyarthritis in relapsing polychondritis?
50-75% of patients
Episodic, migratory, asymmetric, non-erosive oligo-or polyarthritis, typically effecting knees, wrists, MCPs, and PIPs
Peripheral arthritis has worse prognosis
Other joints involved: Costochondritis, sternoclavicular, sternomanubiral joints
Ddx for saddle nose deformity?
- Relapsing polychondritis
- Wegener’s granulomatosis
- Nasal natural killer/t-cell lymphoma
- Mucocutaneous leishmaniasis
What is the # 1 cause of mortality in relapsing polychondritis?
Pneumonia, can be caused from airway collapse/obstruction which increases risk of pneumonia
What changes can be seen in hearing from relapsing polychondritis?
Conductive hearing loss from collapse of the external auditory canal, or neural hearing loss from neurosensory hearing loss which may present with hearing loss, tinnitus, or vertigo.
What is the 2nd most common cause of death in relapsing polychondritis?
Vasculitis, ranges from cutaneous small-vessel vasculitis to large vessel vasculitis w/ aneurysmal dilation, Most commonly involving the abdominal or thoracic aorta
What cardiovascular complications can result from relapsing polychondritis?
Valvulopathy: usually mitral or aortic valve regurgitation
Vasculitis
Portends worse prognosis (2nd MC cause of death)
Ranges from cutaneous small vessel vasculitis to large vessel vasculitis w/ aneurysmal dilation, Most commonly involving abdominal or thoracic aorta
What other skin findings can be seen in relapsing polychondritis?
Non-specific skin/mucosal findings (35%)
Aphthous ulcers, erythema nodosum
What is MAGIC syndrome?
MAGIC syndrome (Mouth and Genital Ulcers with Inflamed Cartilage) = Behcet’s disease + Relapsing polychondritis
What hematologic malignancies are a/w relapsing polychondritis?
Myelodysplastic syndrome
Histopathology of relapsing polychondritis?
Early: cartilaginous neutrophilic infiltrate
Later: Lymphoplasmacytic infiltrate w/ replacement of cartilage by granulation tissue and fibrosis
Lab abnormalities in relapsing polychondritis?
Normochromatic/normocytic anemia (a/w worse prognosis), Increase ESR/CRP, mild leukocytosis, Increased Cr/BUN and microscopic hematuria (if vasculitis affects kidney)
Treatment for relapsing polychondritis?
First line: Prednisone (0.5-1mg/kg/d, or higher if systemic involvement)
Adjunct: NSAIDs, colchicine and dapsone for fever, auricular chondritis, and arthralgias
Immunosuppressive agents have variable response (MTX most effective)
Prognosis in relapsing polychondritis?
W/ treatment, survival rates are >95% at 8 years
Chronic course w/ acute flares lasting days to weeks –> destruction of cartilage and collapse of supporting structures
Poor prognostic factors: anemia, saddle nose deformity, arthritis, vasculitis
Mean age for Sjogren Syndrome?
Mean age of onset = 30-50 y/o
Sex predilection for Sjogren’s sydndrome?
Strong female predominance (F:m = 9:1)
What percentage of those with Sjogren’s have extraglandular disease?
1/3
What is the pathogenesis of Sjogren’s syndrome
Lymphocytic infiltration of exocrine glands (lacrimal and salivary glands)
Frequently a/w Anti-Ro/SS-A (60-70%) and anti-La/SS-B (20-40%) antibodies
What antibodies are a/w Sjogren’s syndrome and what is their significance?
Anti-Ro/SSA (60-70) and Anti-La/SSB (20-40%), and having these puts you at increased risk of early age of onset and increase risk of extraglandular disease
What are the dx criteria for Sjogren’s syndrome?
2/3 objective features for diagnosis
Anti-SSA/Ro and/or anti-SSB/La OR positive RF and ANA titer > 1:320
Positive labial salivary gland biopsy
Keratoconjunctivitis sicca w/ ocular staining score >/=3
Clinical of mucosal xerosis seen in Sjogren’s syndrome?
Mucosal Xerosis occurs later in dz course after >50% of glands are destroyed, so early dz may present w/ only non-specific symptoms of fatigue, arthralgias, myalgias
What test is used to test for Xeropthalmia (keratoconjunctivitis sicca)?
Schirmer test: Whatman paper wick fold over lower eye (tear film migrates <5mm in 5 min = positive test)
Rose Bengal test: measure quality of ocular surface epithelium
Clinical of xeropthalmia/keratoconjunctivitis sicca in Sjogren’s syndrome?
Due to involvement of lacrimal gland
Sx: dry eyes, pain, photophobia, foreign body sensation
Complications: keratitis, corneal ulceration, recurrent infections
Signs of impaired lacrimal gland function (uncommonly performed)
Clinical of xerostomia in Sjogren’s syndrome?
2/2 involvement of major (parotid and submandibular) and minor salivary glands
Sx: dry mouth, sore/burning mouth/lips, dysphagia, transient bilateral or unilateral swelling of parotid and submandibular glands
If persistent swelling –> consider workup for lymphoma
Complications from Xerostomia in Sjogren’s?
Complications: perleche, thrush, dental caries, severe GERD
What tests can be performed to check for xerostomia in Sjogren’s?
Tests for impaired salivary gland function/ flow rate: salivary gland scintigraphy, sialometry, or parotid sialography (uncommonly performed)
Clinical and complications that can arise with vaginal xerosis in Sjogren’s?
Sx: dyspareunia, dryness, burning
Complications: bacterial and candida overgrowth
What is the most common skin finding in Sjogren’s?
Xerosis/pruritus
What is the most important skin finding to look out for in Sjogren’s?
Vasculitis (Most important skin finding b/c of associated complications)
What types of vasculitis may be associated with Sjogren’s?
May present as small-large vessel vasculitis (any size)
Class LCV (+/- cryoglobulins)
Urticarial vasculitis (either hypo-or normocomplementemic)
PAN-like subcutaneous nodules and ulcers
What things in Sjogren’s is vasculitis associated with?
Systemic involvement (arthritis, peripheral neuropathy, Raynaud’s phenomenon, renal involvement)
Positive serology (anti-Ro/SS-A, ANA, RF) + Increased ESR
Lymphoma
What is Annular erythema of Sjogren Syndrome?
Clinically similar to SCLE; mostly in Japanese
What is the most sensitive and specific lab test for Sjogren syndrome?
Anti-fodrin (70% have this)
What other skin findings can be associated with Sjogren’s besides vasculitis, pruritus, and xerosis?
Annular erythema of Sjogren Syndrome (AE-SS)
Raynaud’s phenomenon
Purpura w/ capillaritis on histology
Waldenstrom’s hypergammaglobulinemic purpura
Erythema nodosum
Livedo reticularis
What systemic signs and symptoms may become apparent in Sjogren’s?
Neuropathy: distal, symmetric, painful sensory or sensorimotor polyneuropathy (MC)
Other: memory loss, hearing loss, Devic syndrome (aka neuromyelitis optica; variant of MS w/ optic neuritis and transverse myelitis), lymphomas, glomerulonephritis, neonatal lupus, polyarticular arthritis
Neonatal lupus
What is the risk of lymphoma that Sjogren’s confers and what type of lymphoma is most often associated with Sjogren’s?
19x increased risk of non-Hodgkin lymphomas, predominantly extranodal marginal zone B-cell lymphomas (aka MALT=mucosa-associated lymphoid tissue), usually involving organs in which SjS is most active, such as major salivary glands (MC)
What is the concern with a pregnant woman with Sjogren’s?
Increased risk of neonatal LE in mother w/ anti-Ro/SSA antibodies
What is the histopathology of Sjogren’s?
Salivary gland histology
Presence of focal lymphocytic sialoadenitis w/ two or more aggregates of 50 or more lymphocytes per 4mm of glandular tissue
A mixture of T cells and B cells w/ a normal CD4: CD8 ratio
What is the most sensitive/specific test for Sjogren’s Syndrome?
Anti-Fodrin (70%) most sensitive and specific test
Treatment for eye involvement in Sjogren’s?
Preservative-free artificial tears during the day, lubricating ointments at night, punctae occlusion: plugs placed in lacrimal puncta to increase the accumulation of tear film, cyclosporine (0.05%) eye drops BID for moderate to severe dry eyes
Prognosis of Sjogren’s?
On average, mortality rate similar to general population, but is two to three times higher in patients with extraglandular disease
Adverse prognostic factors a/w increased mortality: hypocomplementemia, cryoglobulinemia, vasculitis, and lymphoproliferative diseases
Sex predilection for Mixed connective tissue disease?
Strong female predominance (9:1)
Age range for mixed connective tissue disease?
2nd to 4th decades
Pathogenesis of mixed connective tissue disease?
CTD characterized by overlapping features of >/= two of the following: SLE, PM/DM, scleroderma, or RA
Anti-U1RNP (high titers) antibodies thought to play pathogenic role
a/w HLD-DR4
What antibodies play a pathogenic role in mixed connective tissue disease?
Anti-U1RNP
What HLA subtype is mixed connective tissue disease associated with?
HLD-DR4
What is the earliest and most common sign of mixed connective tissue disease?
Raynaud’s phenomenon (in 100% of pts)
What scleroderma-like clinical findings are associated with mixed connective tissue disease?
Raynaud’s phenomenon, Esophageal dysmotility (85%), Edema of hands, sausage digits, Sclerodactyly, Periungual telangiectasias w/ dropout areas
Pulmonary HTN (25%), Pulmonary fibrosis (usually mild)
Do NOT see sclerodermoid involvement of face, trunk, proximal extremities
What is the most serious complication of mixed connective tissue disease that can lead to death?
Pulmonary HTN
What are the dermatomyositis-like findings associated with mixed connective tissue disease?
Inflammatory myopathy +/- poikilodermatous areas on upper trunk and proximal extremities
Do NOT usually see DM specific signs (Gottron’s papuls, heliotrope, psoriasiform scalp dermatitis)
What lupus-like findings are associated with mixed connective tissue disease?
DLE, SCLE, or ACLE like skin lesions
Other findings: arthralgias/arthritis (50-70%), serositis (pleuritis and pericarditis), neurologic findings, cytopenias, APLS, glomerulonephritis
What labs are seen in mixed connective tissue disease?
(+) ANA w/ speckled nuclear pattern
High titer anti-U1RNP autoantibodies (serologic hallmark)
Lacks anti-dsDNA, smith antibodies, and hypocomplementemia –> helps differentiate from SLE
Cytopenias
Antiphospholipid autoantibodies
What ANA pattern is seen in mixed connective tissue disease?
Speckled nuclear pattern
What is the treatment of mixed connective tissue disease?
First line: prednisone
Adjuncts: NSAIDs, antimalarials
Lupus, RA, and DM like features are more likely to be steroid-responsive compared with scleroderma like features (e.g. sclerodactyly, Raynaud’s, and pulmonary HTN)
MTX is first-line for severe arthritis but should be used w/ caution due to frequent pulmonary fibrosis in MCTD patients.
What percentage of mixed connective tissue disease patients evolve into one of the six diffuse connective tissue diseases?
40% evolve
What do labs/signs suggest evolution to a connective tissue disease in those with mixed connective tissue disease?
Anti-dsDNA –> SLE
Presence of esophageal hypomotility/dilation or sclerodactyly –> evolution to systemic sclerosis
Causes of death in Mixed connective tissue disease?
Mortality is due to: pulmonary artery HTN (40%)> acute cardiovascular events, TTP/HUS> infections
Histopathology of RA nodules
- Early lesions: interstitial granulomatous or neutrophilic infiltrate +/- LCV
- Later lesions: large palisading granulomas surrounding degenerated eosinophilic connective tissue (necrobiosis) and fibrin in the deep dermis or subcutaneous tissue, often w/ neutrophilic debris
What percentage of patients with RA do rheumatoid nodules occur in?
20-30%
What is rheumatoid nodulosis?
Pts w/ multiple ulcerative nodules and high RF, but in absence of active joint disease.
What is therapy-induced rheumatoid nodulosis?
Occurs in in pts w/ preexisting RA, classically following initiation of MTX (termed MTX-induced accelerated nodulosis= “MAIN”)
Also w/ initaiton of TNF alpha inhibitors
p/w acute onset numerous symmetrically group rheumatoid nodules, often painful
Fingers, helix of ears, soles of feet, penis, chest, surgical incision sites
Can patients get rheumatoid nodules with negative RF titers?
No! RF is required for nodule formation
Clinical of rheumatoid nodules?
Firm, non-tender papules or nodules over bony prominences (esp. extensor forearm, dorsal hands, and elbow) but can occur anywhere including visceral organs
Nodules in dermis, subq, or attached to periarticular capsule or tendons🡪 may lead to tendon rupture
What is rheumatoid vasculitis?
Late complication in pts w/ history of severe erosive RA (but joint dz is now burnt out), high titer RF and rheumatoid nodules)
CSVV or PAN like eruption w/ systemic vasculitis (neuropathies, alveolitis, carditis, cerebral infarction)
a/w high mortality (up to 40%)–> must refer to rheumatology for aggressive tx (cyclophosphamide+ systemic steorids.
What DIF is seen with rheumatoid vasculitis?
Strong IgM and C3 in small and medium-sized vessels (vs weaker and limited to medium-sized vessels in classic PAN)
What should be performed in a pt with suspected rheumatoid medium vessel vasculitis and negative inconclusive cutaneous histologic findings?
Nerve conduction studies/electromyography. If this is negative, then angiogram if strong suspicion. If + then a sural nerve bx and muscle bx should be performed. This may show the rheumatoid vasculitis.
What are bywater’s lesions?
They are purpuric papules on digital pulp; demonstrate LCV histologically.
Not a/w systemic vasculitis of organs (vs rheumatoid vasculitis)
What is superficial ulcerating necrobiosis? (also known as rheumatoid necrobiosis)
Atrophic, shiny, telangiectatic, yellow plaques w/ red-brown edges resembling NLD w/ ulceration
Typically numerous lesions on bilateral lower extremities
In pts w/ severe RA w/ high titer RF and rheumatoid nodules
What neutrophilic dermatoses are associated with RA?
Erythema elevatum diutinum, Sweet’s syndrome, Pyoderma gangrenosum, Rheumatoid neutrophilic dermatitis/ dermatosis, MTX induced papular eruption, PNGD (palisading neutrophilic), IGDA (interstitial granulomatous dermatitis w/ arthritis)
What is erythema elevatum diutinum?
It is rare form of LCV, you see firm symmetrical smooth nodules and plaques on extensor surfaces, particularly joints. Buttocks, face, palms, soles, and genital areas may also be involved.
What is rheumatoid neutrophilic dermatosis?
Consider this when a pt with longstanding severe RA gets symmetrically distributed papules, nodules, plaques, urticarial lesions, or palpable purpura on the extensor aspects of the extremities. Usually located over joints. Upper extremities are favored.
Pathogensis of auto-inflammatory diseases?
Key to note that this is a disorder of the innate immune system.
- Increased production of proinflammatory cytokines 2/2 aberrant signaling.
- Cytokine receptors, receptor antagonists, and components of the inflammasome are involved. Enables autocatalytic activation of inflammatory caspases, driving the release of proinflammatory cytokines
Key clinical features of all the autoinflammatory diseases?
Fever, and is often periodic
What is the histology of most of the autoinflammatory diseases (except PAPA and Blau)?
Moderate-dense dermal perivascular and interstitial neutrophils (“neutrophilic urticarial dermatitis”) +/- dermal edema
Treatment for autoinflammatory diseases?
Anakinra, etanercept, canakinumab
Colchicine is crucial in preventing amyloidosis in patients with FMF
What gene is associated with familial cold autoinflammatory syndrome
CIAS-1/NLRP3 (cryopyrin)
What is the inheritance pattern of familial cold autoinflammatory syndrome?
AD (CIAS-1/NLRP3 gene)
Clinical of familial cold autoinflammatory syndrome?
Age of onset = infancy
Skin findings: cold-induced urticaria that favors extremities more than face and trunk)
Systemic findings: arthralgia, conjunctivitis
Attacks are short (minutes-3 days)
Treatment for familial cold autoinflammatory syndrome?
IL-1 antagonists
What gene is defective in Muckle-Wells syndrome?
CIAS-1/NLRP3 (cryopyrin)
The inheritance pattern of Muckle-Wells syndrome?
AD, CIAS-1/NLRP3 gene defect
Clinical of Muckle-Wells Syndrome?
Age of onset: any
Skin: widespread urticaria
Systemic: abdominal pain “lancing”, extremity pain, conjunctivitis, optic disk edema, arthralgia/arthritis, and sensorineural hearing loss.
Febrile attacks last 1-2 days
High risk of secondary AA amyloidosis (25%)
Treatment for Muckle-Wells syndrome?
IL-1 antagonists
Which of the autoinflammatory diseases are associated with AA amyloidosis?
Familial Mediterranean fever, TNF-receptor-associated periodic syndrome (TRAPS), NOMID/CINCA, Muckle-Wells syndrome
What is the gene defect in NOMID/CINCA?
CIAS-1/NLRP3 (cryopyrin)
The inheritance pattern for NOMID/CINCA
AD (CIAS-1/NLRP3)
Skin findings in NOMID/CINCA?
age of onset: neonatal
Skin findings: Widespread urticaria +/- oral ulcers, dysmorphic facies (frontal bossing and protuberant eyes)
What are the 3 cryopyrin-associated periodic syndromes?
Familial cold autoinflammatory syndrome, muckle-wells syndrome, NOMID/CINCA
What are the 3 monogenic periodic fever syndromes?
Hyper-IgD syndrome (mevalonate kinase deficiency), TNF-receptor-associated periodic syndrome (TRAPS), Familial Mediterranean fever
What is the genetic defect in Hyper-IgD syndrome (mevalonate kinase deficiency)?
MVK (mevalonate kinase)
What is the inheritance pattern in Hyper-IgD syndrome (mevalonate kinase deficiency)
AR, (MVK, mevalonate kinase)
Clinical in Hyper-IgD syndrome (mevalonate kinase deficiency)?
Age of onset: infancy
Skin findings: Widespread polymorphous eruption (morbilliform or urticarial most commonly)
Systemic findings: arthralgia, abdominal pain, vomiting, diarrhea, arthritis, cervical LAN, HSM
Febrile attacks last up to 7 days
Increased incidence in Dutch and Northern Europeans
Increased serum IgD and urinary mevalonate levels
What lab test is abnormal in Hyper-IgD syndrome (mevalonate kinase deficiency)?
IgD levels are increased
Treatment for Hyper-IgD syndrome (mevalonate kinase deficiency)
IL-1 antagonists, TNF-a antagonists
What is the genetic defect in TNF-Receptor-associated periodic syndrome (TRAPS)?
TNFRSF1A (TNF receptor superfamily 1A/p55 TNF receptor)
What is the inheritance pattern in TNF-Receptor-associated periodic syndrome (TRAPS)?
AD
Clinical of TNF-Receptor-associated periodic syndrome (TRAPS)?
Age of onset: Any
Skin findings: Painful, migratory/serpiginous plaques (often edematous) on extremities; may become ecchymotic
Systemic: serositis, periorbital edema, scrotal pain, migratory myalgias (underlying rash)
Febrile attacks often long (1-6 weeks)
Secondary AA amyloidosis (15%)
What labs are abnormal in TNF-Receptor-associated periodic syndrome (TRAPS)?
Decreased serum soluble TNF receptor levels
What is the genetic defect in Familial Mediterranean fever?
MEFV (pyrin/marenostrin)
Genetic inheritance of Familial Mediterranean fever?
AR (MEFV, pyrin/marenostrin)
Clinical of Familial Mediterranean fever?
Age of onset: any
Skin findings: Erysipelas-like rash, favors legs/feet
Systemic: serositis and arthritis
Febrile attacks last 1-3 days, increased incidence in Mediterranean populations
Secondary amyloidosis (mainly in homozygotes; prevented by colchicine)
What are the 3 autoinflammatory pyogenic disorders?
Pyogenic arthritis, pyoderma gangrenosum, acne syndrome (PAPA), Deficiency of the IL-1 receptor antagonist (DIRA), Generalized pustular psoriasis/deficiency of the IL-36 receptor antagonist (DITRA)
What is the defective gene in pyogenic arthritis, pyoderma gangrenosum, acne syndrome (PAPA)?
PSTPIP1/CD2BP1 (PROLINE-SERINE-THREONINE PHOSPHATASE-INTERACTING PROTEIN 1/CD2 ANTIGEN BINDING PROTEIN 1)
What is the inheritance pattern in pyogenic arthritis, pyoderma gangrenosum, acne syndrome (PAPA)?
AD
Clinical of pyogenic arthritis, pyoderma gangrenosum, acne syndrome (PAPA)?
Age of onset: childhood
Skin: pyoderma gangrenosum and nodulocystic acne
Systemic: sterile pyogenic oligoarthritis, afebrile
Treatment for pyogenic arthritis, pyoderma gangrenosum, acne syndrome (PAPA)?
TNF-a antagonists, IL-1 antagonists
What is the defective gene in the Deficiency of the Il-1 receptor antagonist (DIRA)?
IL1RN (IL-1 receptor antagonist)
What is the inheritance pattern in Deficiency of the Il-1 receptor antagonist (DIRA)?
AR
Clinical of Deficiency of the Il-1 receptor antagonist (DIRA)?
Age of onset: Neonatal
Skin findings: Neutrophilic pustular dermatitis, ichthyosis
Systemic symptoms: Sterile multifocal osteomyelitis, periostitis, afebrile
Treatment for Deficiency of the Il-1 receptor antagonist (DIRA)?
IL-1 Antagonists
What is the defective gene in generalized pustular psoriasis/deficiency of the IL-36 receptor antagonist (DITRA)
IL36RN (IL-36 receptor antagonist)
What is the inheritance pattern in generalized pustular psoriasis/deficiency of the IL-36 receptor antagonist (DITRA)?
AR
Clinical findings of generalized pustular psoriasis/deficiency of the IL-36 receptor antagonist (DITRA)?
Age of onset: Infancy, childhood
Skin findings: Generalized pustular psoriasis
Systemic: malaise, multiorgan failure
What is the treatment for generalized pustular psoriasis/deficiency of the IL-36 receptor antagonist (DITRA)?
NSAIDs, Vitamin D analogs, Systemic retinoids, TNF-a inhibitors, IL-1 inhibitors
What is autoinflammatory granulomatous disease?
Blau syndrome/early-sarcoidosis
What gene is defective in Blau syndrome/early-sarcoidosis?
NOD2/CARD15 (nucleotide-binding oligomerization domain 2/caspase recruitment domain 15)
What is the inheritance pattern of Blau syndrome/early-sarcoidosis?
AD, sporadic
Clinical of Blau syndrome/early-sarcoidosis?
Age of onset: childhood
Skin: Sarcoidal granulomatous dermatitis, ichthyosiform dermatitis
systemic: Fever (30%), polyarticular arthritis (favors hands/feet), synovitis, and tenosynovitis
Treatment for Blau syndrome/early-sarcoidosis?
Corticosteroids, IL-1 antagonists, TNF-a antagonists
What is the classic presentation of relapsing polychondritis of the ear?
Bright red, swollen, tender cartilaginous portion of the ear that spares the earlobes (no cartilage)
What is the most common cause of mortality in relapsing polychondritis?
Pneumonia (#1)>systemic vasculitis >large artery aneurysm dissection/rupture, airway collapse, renal failure, and malignancy
What is the significance of + auto-antibodies in Sjogren’s dz?
(+) autoantibodies a/w decreased age of onset and increased risk of extraglandular disease
What genetic abnormality increases risk of antigen-driven B-cell lymphomas in Sjogren’s syndrome?
Germline abnormality of TNFAIP3 –> increased risk of antigen-driven B-Cell lymphomas
Sjogren syndrome leads to an increased risk of what lymphomas?
19x increased risk of non-Hodgkin lymphomas, predominantely extranodal marginal zone B-cell lymphomas (aka MALT=mucosa-associated lymphoid tissue), usually involving organs in which SjS is most active, such as major salivary glands (MC)
Treatment for oral involvement of Sjogren syndrome?
Artificial saliva (not usually tolerated well), frequent water ingestion, salivary stimulants (e.g. acid free and sugar free gum containing xylitol and sorbitol; pts need salivary gland function)
Sialagogue therapy: pilocarpine and cevimeline
Meticulous dental hygiene and fluoride treatments to prevent dental caries
Avoid alcohol, smoking, and low pH drinks (e.g. soda)
Treatment of severe Sjogren syndrome with extraglandular disease?
Immunosuppressive meds only for severe extraglandular systemic involvement
Rituximab may be considered for refractory cases
Systemic findings in NOMID/CINCA?
Systemic: Deforming arthropathy, arthritis, epiphyseal overgrowth, significant ocular involvement which may go to blindness, sensorineural hearing loss, LAD, HSM, seizures, aseptic meningitis
febrile attacks occur simultaneously with attacks
Secondary AA amyloidosis
this one has significant morbidity and mortality in childhood if left untreated.
What underlying conditions can drive severe pernio (extensive involvement)?
Autoimmune disease and hematologic malignancies
What lab tests should be checked in chilblains/pernio?
SPEP, immunofixation, and ANA
- This is to rule out autoimmune conditions and also hematologic malignancies (multiple myeloma, monoclonal gammopathies, etc)
- This is especially true for severe disease, older onset, and persistant dz
