Pearls in Rheumatology- Dermatology Karthik Krishnamurthy, DO Associate Professor Albert Einstein College of Medicine Residency Program Director Orange Park Medical Center Introduction Rheumatologic diseases • Aka connective tissue diseases, collagen vascular diseases • Polygenetic & heterogeneous group of autoimmune disorders with classic cutaneous and extracutaneous findings • Autoantibody associations Conflicts of Interest None Overview Lupus Erythematosus Dermatomyositis Systemic Sclerosis Mixed Connective Tissue Disease Sjögren’s Syndrome Dermatoses associated with arthritis Autoantibodies Circulating immunoglobulins detected in autoimmune diseases Profile contributes to disease phenotype Etiology / inciting event not completely understood Autoantibodies ANA Histone PM-Scl SSA (Ro) RF Centromere SSB (La) Ku Scl-70 dsDNA Mi-2 Calpastatin ssDNA Jo-1 HMG Sm Se Fer U1RNP PCNA Mas U2RNP A-fodrin KJ Th/To RNP PL-7 SRP Cardiolipin PL-12 C1q B2-glycoprotein I OJ/EJ U3RNP (fibrillarin) Antinuclear Antibody (ANA) Screening tool • Good sensitivity (assay-dependent) • Low disease specificity • False positives Antinuclear Antibody (ANA) Assays used to identify ANA • Immunofluorescence – Directed against nuclear antigens on Hep-2 cells (human SCC tumor line) – ↑ # of antigens, ↑ sensitivity, ↑$ • ELISA – Solid phase immunoassay – ↓ # antigens, ↓sensitivity, ↓$ Antinuclear Antibody (ANA) Immunofluorescence staining pattern A: Homogeneous B: Peripheral C: Speckled D: Nucleolar E: Centromeric Bolognia et al. Dermatology. 2007 Antinuclear Antibody (ANA) Mutasim, et al. JAAD Feb 2000 Antinuclear Antibody (ANA) False Positives Mutasim, et al. JAAD Feb 2000 Antinuclear Antibody (ANA) “Normal” ANA cut-off < 1:160 Mutasim, et al. JAAD Feb 2000 Antinuclear Antibody (ANA) Centromere CREST dsDNA Nephritis SSA (Ro) Photosensitivity Vasculitis 90% of La (+) are also Ro (+) 50% of Ro (+) are also La (+) Overview Lupus Erythematosus Dermatomyositis Systemic Sclerosis Mixed Connective Tissue Disease Sjogren’s Syndrome Dermatoses associated with arthritis Lupus Erythematosus (LE) Lupus Erythematosus (LE) Chronic Cutaneous LE Subacute Cutaneous LE Acute (systemic) LE Lupus Erythematosus (LE) Epidemiology • SLE • F:M 6:1 (? Hormonal) • African Americans 4X more likely than whites • CCLE • F:M 3:1 • CCLE → SLE ~ 5-20% Lupus Erythematosus (LE) Pathogenesis • Genetic? • Foreign antigen/molecular mimickry? • Autoantibodies not organ specific Chronic Cutaneous LE CCLE • Classic Discoid LE • Tumid LE • Lupus Panniculitis • Chilblain LE Chronic Cutaneous LE Discoid LE • Face, scalp, ears, with associated alopecia • Less frequently on trunk and ext’s • Mucosa: lips, oral, nasal, genital • No clear association with UV exposure • May have arthralgias Chronic Cutaneous LE Discoid LE • Erythematous papules evolve into scaly plaques • Follicular plugging • Carpet tack / cat-tongue scale • Disfigurement is the worst sequela • Scarring alopecia • Atrophic, hypopigmented plaques • Rarely, SCC may develop in older lesions Discoid LE (CCLE) Discoid LE (CCLE) Langue au chat “Cat’s tongue” Carpet-tack scale Chronic Cutaneous LE • Superficial, deep, interface and periadnexal lymphocytic infiltrates • Epidermal atrophy with/without hyperkeratosis • Follicular plugging • Colloid bodies • Melanin incontinence • May see mucin Escholarship.org Lupus Pernio Rosacea Discoid Lupus Lupus Vulgaris Chronic Cutaneous LE Bolognia, et al. Dermatology (2007) Chronic Cutaneous LE Tumid LE • Erythematous dermal plaques • Lacks scale or follicular plugging • No residual scar or atrophy • Can leave residual dyspigmentation • Head/neck, upper trunk, proximal UE’s • Reproducible with UV exposure • Same / similar to entity Jessner’s Lymphocytic Infiltrate Chronic Cutaneous LE Lupus Panniculitis • Deep, tender, inflammatory nodules occuring at the lever of subcutaneous fat • Heal with scarring and depression of overlying skin (lipoatrophy) • Favors face, UE’s, upper trunk, breast, buttock, thighs • Chronic, remitting and relapsing course • Only 10-15% meet criteria for SLE • If DLE overlies panniculitis, referred to as Lupus Profundus Chronic Cutaneous LE Chilblain LE • Red-purple papules and plaques on acral skin • Fingers, toes, nose, elbows, knees, LE’s • Exacerbated by cold • Chronic • May be differentiated from ordinary chilblains by evolution in discoid lesions both clinically and histologically Chilblain LE Subacute Cutaneous LE SCLE • Classic • Papulosquamous and Annular variants • Neonatal LE • Complement deficiency syndromes • C2 and/or C4 defieciency • Resembles classic SCLE Subacute Cutaneous LE Classic type • Papulosquamous and/or Annular eruption • Predilection for UV-exposed areas • No follicular plugging or scarring • Can leave dyspigmentation • Ro (SSA) antibodies (90% via ELISA) • Many “meet criteria” for SLE • Many cases are drug induced (more later) • Diltiazem (CCB), HCTZ, Terbenafine, NSAIDS, Griseofulvin Subacute Cutaneous LE Subacute Cutaneous LE Neonatal LE • Newborns of (+) Ro, La, or RNP mothers • Erythematous thin scaly plaques • UV sensitive: face/ext’s > trunk • May be present at birth (intrauterine) • May leave residual dyspigmentation or telangiectasia • Usually resolves by 6 months (maternal Ab’s degraded) Subacute Cutaneous LE Neonatal LE • Congenital heart block (3rd degree) • Permanent, 20% mortality • Up to 2/3 require a pacemaker • Hepatobiliary disease • Thrombocytopenia • EKG, CBC, LFT’s, aggressive sun protection • 25% risk with subsequent pregnancies Neonatal LE (SCLE) Neonatal LE (SCLE) Acute Cutaneous LE ACLE • Malar Rash • Discoid Lesions • Diffuse non-scarring alopecia • Raynaud's phenomenon • Nailfold telangiectasias and erythema • Vasculitis • Cutaneous signs of antiphospholipid syndrome: livedo reticularis, acrocyanosis, atrophie blanche • Palmar erythema, dorsal erythema sparing IP joints. • Papular and nodular mucinosis Acute Cutaneous LE SLE Criteria • Discoid Lesions • Oral ulcers • Photosensitivity • (+) ANA • Malar Rash (butterfly rash) • Immunologic markers (dsDNA, Sm) • Neuropsychiatric disturbances • Renal (nephritis) • Arthritis • Serositis • Hematologic (hemolysis, anemia, thrombocytopenia) Malar Rash (ACLE/SLE) Palmer Erythema / Vascular(ACLE/SLE) Special Considerations Bullous SLE • Ab’s to Collagen VII • SLE may occur with other blistering disease Overlap syndromes • Lichen Planus / LE overlap Associations • Erythema Multiforme + SLE = Rowell’s Syndrome • Pemphigus Foliaceus + SLE = Senear-Usher Syndrome Drug-Induced SLE SLE • <30% have skin manifestations • Musculoskeletal and serosal complaints • Procainamide, Hydralazine, Isoniazid, Chlorpromazine, Phenytoin, Methyldopa, Minocycline • Induces anti-Histone Ab’s • Etanercept & d-Penicillamine induce dsDNA ab’s • Methimazole and PTU induce ANCAs (1) Acute Cutaneous Lupus OR Subacute Cutaneous Lupus •Acute cutaneous lupus: lupus malar rash (do not count if malar discoid), bullous lupus, toxic epidermal necrolysis variant of SLE, maculopapular lupus rash, photosensitive lupus rash (in the absence of dermatomyositis) •Subacute cutaneous lupus: nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias) (2) Chronic Cutaneous Lupus •Classic discoid rash localized (above the neck) or generalized (above and below the neck), hypertrophic (verrucous) lupus, lupus panniculitis (profundus), mucosal lupus, lupus erythematosus tumidus, chillblains lupus, discoid lupus/lichen planus overlap (3) Oral Ulcers OR Nasal Ulcers •Oral: palate, buccal, tongue •Nasal ulcers •In the absence of other causes, such as vasculitis, Behcet’s disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, and acidic foods (4) Nonscarring alopecia •Diffuse thinning or hair fragility with visible broken hairs, in the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia Dermatomyositis Dermatomyositis DM • Proximal, extensor, symmetric, inflammatory myositis • Photodistributed and classic skin findings • May overlap with other rheumatologic diseases • Adult forms associated with internal malignancy • Amyopathic form exists Dermatomyositis Epidemiology • Adult F:M 6:1 • Juvenile F:M 2:1 Pathogenesis • Genetic, humoral immunity, cellular immunity, drug precipitants, infectious etiology • Paraneoplastic phenomenon Dermatomyositis Skin Findings • Photodistributed poikiloderma (neck, shawl) • Heliotrope rash (periorbital erythema) • Scalp dermatitis • Nailfold telangiectasias • Gottron’s papules: violaceous papules over IP’s • Gottron’s sign: over knees and elbows • Calcinosis cutis (more in juvenile variant) • Mechanic Hands: ragged cuticles, hyperkeratosis, scaling, and fissuring of distal fingers Dermatomyositis Extracutaneous • Proximal muscle weakness • Pulmonary disease – Interstitial lung disease – Anti-tRNA synthetase Ab’s (Jo-1) • Other – If GI, Renal, arthritis, or Raynaud’s, consider overlap – Anti-SRP Ab’s associated with cardiac disease – Anti-Ku Ab’s associated with DM and SSc overlap – Anti-Mi-2 Ab’s associated with shawl sign and good prognosis Dermatomyositis Malignancy Risk • Up to 50% in Adult form • #1: Ovarian Cancer • Less commonly breast, lung, gastric Dermatomyositis Juvenile Variants • Brunsting Type (more common) – Myositis + calcinosis – Indolent, progressive, steroid responsive • Banker Type – Vasculitis of muscles and GI tract – Rapid, difficult to treat, high mortality Dermatomyositis Work-up • Muscle enzymes: CK, aldolase,