Sec 27 The Skin in Vascular and Connective Tissue and Other Autoimmune Disorders Flashcards
Identified as a candidate gene responsible for the development of autoimmune diseases; a transcription factor that regulates the ectopic expression of proteins, normally expressed in peripheral tissues, in the thymus, allowing for thymic expression of the latter and subsequent negative selection of self-reactive thymocytes before they migrate as mature T cells to the secondary lymphoid organs such as the spleen and lymph nodes.
Autoimmune regulator (AIRE) gene
Expressed on T cells providing an inhibitory signal upon their activation; also expressed on other immune cells including B cells and myeloid cells; encoded by the PDCD1 gene, with a SNP in its fourth intron associated with autoimmunity, including SLE and RA.
Programmed cell death 1 (PD-1)
Second most frequent clinical manifestation of LE after joint inflammation
Skin disease
The most common form of Chronic Cutaneous Lupus Erythematosus
Discoid Lupus Erythematosus
Fixed erythema, flat or raised, over the malar eminences, tending the spare the nasolabial folds
Malar rash
Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
Discoid rash
Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
Photosensitivity
SLE: Oral ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by a physician
SLE: Arthritis
Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion
SLE: Serositis
a. Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion Or
b. Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion
SLE: Renal disorder
a. Persistent proteinuria— >0.5 g/day or greater than 3+ if quantitation not performed Or
b. Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed
SLE: Neurologic disorder
a. Seizures—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) Or
b. Psychosis—in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance)
SLE: Hematologic disorder
a. Hemolytic anemia—with reticulocytosis Or
b. Leukopenia— <4,000 μL total on two or more occasions Or
c. Lymphopenia— <1,500/μL on two or more occasions Or
d. Thrombocytopenia— <100,000 μL in the absence of offending drugs
SLE: Immunologic disorder
a. Anti-DNA—antibody to native DNA in abnormal titer Or
b. Anti-Sm—presence of antibody to Sm nuclear antigen Or
c. Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of immunoglobulin G or immunoglobulin M anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
SLE: Antinuclear antibody
An abnormal titer of antinuclear antibody by immunofluorescence of an equivalent assay at any point in time and in the absence of drugs known to be associated with “drug-induced lupus” syndrome
Confluent symmetric erythema and edema are centered over the malar eminences and bridges over the nose. The nasolabial folds are characteristically spared. The forehead, chin, and V area of the neck can be involved, and severe facial swelling may occur.
Localized Acute Cutaneous Lupus Erythematosus
Presents as a widespread morbilliform or exanthematous eruption often focused over the extensor aspects of the arms and hands and characteristically sparing the knuckles. Has been indiscriminately referred to as the maculopapular rash of SLE, photosensitive lupus dermatitis, and SLE rash.
Generalized Acute Cutaneous Lupus Erythematosus
Initially presents as erythematous macules and/or papules that evolve into hyperkeratotic papulosquamous or annular/polycyclic plaques. Characteristically photosensitive and occur in predominantly sun-exposed areas. Typically heal without scarring but can resolve with long-lasting, if not permanent, vitiligo-like leukoderma, and telangiectasias.
Subacute Cutaneous Lupus Erythematosus
Most common form of CCLE, which begin as red-purple macules, papules, or small plaques and rapidly develop a hyperkeratotic surface. Early lesions typically evolve into sharply demarcated, coin-shaped erythematous plaques covered by a prominent, adherent scale that extends into the orifices of dilated hair follicles. Typically expand with erythema and hyperpigmentation at the periphery, leaving hallmark atrophic central scarring, telangiectasia, and hypopigmentation.
Discoid Lupus Erythematosus
Rare variant of CCLE in which the hyperkeratosis normally found in classic DLE lesions is greatly exaggerated. The extensor aspects of the arms, the upper back, and the face are the areas most frequently affected.
Hypertrophic Discoid Lupus Erythematosus
Occurs in approximately 25% of patients with CCLE. The oral mucosa is most frequently affected; however, nasal, conjunctival, and genital mucosal surfaces can be targeted. In the mouth, the buccal mucosal surfaces are most commonly involved, with the palate, alveolar processes, and tongue being sites of less frequent involvement. Lesions begin as painless, erythematous patches that evolve to chronic plaques that can be confused with lichen planus.
Mucosal Discoid Lupus Erythematosus
Rare form of CCLE typified by inflammatory lesions in the lower dermis and subcutaneous tissue. Approximately 70% of patients with this type of CCLE also have typical DLE lesions, often overlying the panniculitis lesions.
Lupus Erythematosus profundus/Lupus Erythematosus panniculitis (Kaposi-Irgang disease)
Lesions initially develop as purple-red patches, papules, and plaques on the toes, fingers, and face, which are precipitated by cold, damp climates and are clinically and histologically similar to idiopathic chilblains (pernio). As they evolve, these lesions usually assume the appearance of scarred atrophic plaques with associated telangiectases. They may resemble old lesions of DLE or may mimic acral lesions of small vessel vasculitis. Associated with anti-Ro/ SS-A antibodies, and is linked to Raynaud’s phenomenon.
Chilblain Lupus Erythematosus
Variant of CCLE in which the dermal findings of DLE, namely, excessive mucin deposition and superficial perivascular and periadnexal inflammation, are found on histologic evaluation. This results in succulent, edematous, urticaria-like plaques with little surface change.
Lupus erythematosus tumidus
Antigens with High disease specificity for SLE
dsDNA (doubled-stranded DNA)
Sm
rRNP
PCNA (proliferating cell nuclear antigen)
Antigens with Low disease specificity for SLE
ssDNA (single-stranded DNA) Histones U1RNP Ro/SS-A La/SS-B Ku
First line treatment for Lupus Erythematosus-Specific Skin Disease
Topical glucocorticoids
Topical calcineurin inhibitor
Class I steroid qd–bid for 2 weeks alternating with pimecrolimus 1% or tacrolimus 0.1% bid for 2 weeks;
Intralesional triamcinolone acetonide 2.5–10.0 mg/cc
Second line treatment for Lupus Erythematosus-Specific Skin Disease
Hydroxychloroquine 6.5 mg/kg/day ideal body weight
Chloroquine 3.0–3.5 mg/kg/day ideal body weight
Quinacrine (if monotherapy fails, add quinacrine to either hydroxychloroquine or chloroquine) 100 mg daily
Prednisone 5-60 mg/day (2-16 weeks)
Thalidomide 50-200 mg/day; taper to 50 mg qod on response (2-16 weeks)
Third line treatment for Lupus Erythematosus-Specific Skin Disease (safer immunosuppressives)
Azathioprine 1.5–2.5 mg/kg/day PO
Mycophenolate mofetil 2.5–3.5 g/day PO
Methotrexate 7.5–25 mg PO or SQ/wk
Fourth line treatment for Lupus Erythematosus-Specific Skin Disease (limited by side effects)
Cyclophosphamide 1.5–2.0 PO mg/kg/day
Clofazimine 1.5–2.0 PO mg/kg/day
Heterogeneous group of genetically determined autoimmune disorders that predominately target the skeletal musculature and/or skin and typically result in symptomatic skeletal muscle weakness and/or cutaneous inflammatory disease.
Idiopathic inflammatory myopathies
Autoantibodies with High Specificity for DM/PM
155 kDa and/or Se 140 kDa Jo-1 Mi-2 SRP PL-7 PL-12 OJ EJ Fer Mas KJ
Autoantibodies with Low Specificity for DM/PM
ANA (most common nuclear immunofluorescence patterns— specked and nucleolar) SsDNA PM-Scl (PM-1) Ro (52-kDa Ro) U1RNP Ku U2RNP
Pathogenesis of Dermatomyositis - Susceptibility phase
Genetic predisposition
Pathogenesis of Dermatomyositis - Induction phase
Loss of self-tolerance
Pathogenesis of Dermatomyositis - Expansion phase
Loss of immune regulation
Pathogenesis of Dermatomyositis - Injury phase
Clinical disease
Microvascular injury
Cellular cytotoxicity,
Weakness, fatigue
Etiology of Dermatomyositis - Susceptibility phase
Fetal cell microchimerism
HLA-DQA1 and other HLA genes, TNF-α, other unknown genes
Etiology of Dermatomyositis - Induction phase
UV light
Viruses (e.g., coxsackie, parvovirus B19, EB, retroviruses)
Etiology of Dermatomyositis - Expansion phase
Autoantibody formation
Autoreactive T-cell expansion
Etiology of Dermatomyositis - Injury phase
Autoantibody binding, complement fixation
Cytotoxic T-cell formation, cytokine production
Hallmark cutaneous feature of DM. The confluent macular violaceous erythema, most pronounced over the metacarpophalangeal/interphalangeal joints, extending in a linear array overlying the extensor tendons of the hand and fingers.
Gottron sign
Centromere
CENP proteins speckled pattern
20–30%
HLA-DRB1 HLA-DQB1
Limited skin sclerosis, severe gut disease, isolated PAH, calcinosis
Scl-70
Topoisomerase-1 speckled pattern
15–20%
HLA-DRB1 HLA-DQB1 HLA-DPB1
Diffuse skin sclerosis, pulmonary fibrosis and secondary PAH, increased SSc-related mortality rate
RNAP III
RNA polymerase III speckled pattern
20%
HLA-DQB1
Diffuse skin sclerosis, hypertensive renal crisis, correlated with a higher mortality rate
nRNP
U1-RNP speckled pattern
15%
HLA-DR2, -DR4 HLADQw5, -DQw8
Overlap features of SLE, arthritis
PM-Scl
Polymyositis/Scl nuclear staining pattern
3%
HLA-DQA1 HLA-DRB1
Limited skin sclerosis, myositis–sclerosis overlap, calcinosis
Fibrillarin
U3-RNP nuclear staining pattern
4%
HLA-DQB1
Diffuse skin sclerosis, myositis, PAH, renal disease
Th/To
7–2RNP nuclear staining pattern
2–5
HLA-DRB1
Limited skin sclerosis, pulmonary fibrosis
Major criteria: Rheumatic Fever
Carditis Migratory polyarthritis Sydenham chorea Subcutaneous nodules Erythema marginatum
Minor criteria: Rheumatic Fever
Clinical Fever Arthralgia Laboratory Elevated acute-phase reactants Prolonged p–r interval plus Supportive evidence of a recent group A streptococcal infection (e.g., positive throat culture or rapid antigen detection test, and/or elevated or increasing streptococcal antibody test)
Presents with acute onset of nonpitting induration of neck, shoulders, and upper back skin may be followed by involvement of the face and arms. Characteristically, the affected skin appears smooth and waxy, with tense dermal induration and prominent follicular ostia, at times imparting a “peau d’orange” appearance.
Scleredema
Histopathology: Punch biopsies of affected skin reveal a nontapered (square) appearance on low power. The proportion of dermis in dramatically increased in comparison to adjacent nonaffected skin. A decreased number or higher placement of eccrine units may be appreciated. Fibroblasts are normal in number and morphology. The collagen bundles are slightly thickened and separated from each other by subtle deposits of mucin.
Scleredema
Presents with confluent lichenoid plaques. Individual lesions and plaques may exhibit marked erythema or hyperpigmentation. The face is involved in most cases, resulting in significant deformity, “bovine facies”. The trunk and extremities are usually affected and often results in decreased flexibility and range of motion in the involved areas.
Scleromyxedema
Histopathology: superficial to mid-dermal mucin deposition with admixed fibroblast proliferation. The pannicular septae is not involved and tends to be restricted to the upper half of the dermis.
Scleromyxedema
Diagnostic Criteria of Relapsing Polychondritis
at least 3
- Bilateral auricular chondritis
- Nonerosive seronegative inflammatory polyarthritis
- Nasal chondritis
- Ocular inflammation
- Respiratory chondritis
- Audiovestibular damage
Drug-induced SLE (typically without skin involvement)
Hydralazine Isoniazid Antihyperlipidemic agents Minocycline Procainamide Anti-TNF biologics
Clinical Association: dsDNA
LE nephritis
Clinical Association: rRNP
CNS LE
Clinical Association: ssDNA
Risk for SLE in patients with DLE
Clinical Association: Histones
Drug-induced SLE
Clinical Association: U1RNP
Overlap Connective Tissue Disease (MCTD)
Clinical Association: Ro/SS-A
SLCE, Sjögren syndrome, neonatal LE
Clinical Association: La/SS-B
Sjögren syndrome, SCLE
Clinical Association: Ku
Overlap Connective Tissue Disease
DIF: Discoid Lupus Erythematosus
Continuous band of granular fluorescence at the dermal-epidermal junction
Clinical Association: 155 kDa and/or Se
Classic DM
Clinically amyopathic DM with increased risk of internal malignancy
Clinical Association: 140 kDa
Clinically amyopathic DM with increased risk for interstitial lung disease
