Pearls in - 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 • associations Conflicts of Interest

None Overview

Lupus Erythematosus Systemic Sclerosis Mixed Connective Tissue Disease Sjögren’s Syndrome Dermatoses associated with arthritis

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

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 • 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 with/without

• 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 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 • 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 and • Vasculitis • Cutaneous signs of antiphospholipid syndrome: livedo reticularis, acrocyanosis, atrophie blanche • , 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 • / LE overlap Associations • + 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 • 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 • 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, AST • EMG or MRI helpful for myositis • Pulmonary function tests • Malignancy screening Heliotrope (DM) Poikiloderma (DM) Dermatomyositis

Poikiloderma D/Dx:

Dermatomyositis Actinic damage CTCL GVHD TMEP (not true poikiloderma) Radiation recall Chronic photodrug reaction Porphyrias Gottron’s Papules (DM) Knuckle Pads

Benign papulosquamous dermatosis Over MCP’s and IP’s Repetitive trauma (sports, occupational, etc) Gottron’s Sign (DM) Ragged Cuticles (DM) Ragged Cuticles (DM) Improved compliance with measurements Recommends 6.5 mg/kg/day (max 400 mg/day) Systemic Sclerosis Systemic Sclerosis

PSSc, Scc, • Autoimmune fibrosis of skin and organs • Localized and Systemic presentations – Systemic form is progressive and morbid • Epidemiology – F:M 15:1 – Dx occurs 30-50 yo – No racial predilection Systemic Sclerosis

Pathogenesis • Endothelial cell damage, inflammation, and collagen deposition • Unknown inciting factors – Spanish toxic oil, L-tryptophan, vinyl chloride, bleomycin • TGF-b overproduction • Different antibodies affect clinical expression Systemic Sclerosis

Variants • Localized – Localized and Generalized – of Pasini and Pierini – Linear Morphea • Generalized – CREST Syndrome – Progressive Systemic Sclerosis Systemic Sclerosis

Variants • Localized – Localized and Generalized Morphea – Atrophoderma of Pasini and Pierini – Linear Morphea • Generalized – CREST Syndrome • Calcinosis, Raynaud’s, Esophageal dysmotility, , Telangiectasias – Progressive Systemic Sclerosis Systemic Sclerosis Systemic Sclerosis

Skin Findings • Fibrosis – Generalized skin sclerosis – Inability to open mouth – “Bird Facies” – Sclerodactyly • Dystrophic calcinosis – Digital ulcers, pitting • Salt & Pepper sign (confetti depigmentation) • Nailfold Telangiectasias Systemic Sclerosis Systemic Sclerosis Systemic Sclerosis

Raynaud’s Phenomena • Vasomotor disease precipitated by cold • 2° phenomena associated with

• Distinguishable from 1° disease – Ischemic injury occurs – > 5 attacks per day – Lack of autoantibodies Systemic Sclerosis Treatment • Overall disease – Azathioprine, methotrexate, cyclophosphamide – CsA may worsen renal disease – d-Penicillamine may induce other AI disease • Renal disease: ACE inh • Vasospasm: CCB’s, peripherally acting • Calcinosis: CCB’s • Skin sclerosis: High dose UVA1 (340-400nm) • Reflux: PPI’s • Physical therapy • Smoking cessation Systemic Sclerosis

Differential Diagnosis • Only PSS displays Raynaud’s + autoAb’s • Mimickers – Eosinophilic – Scleromyxedema – Scleredema – Nephrogenic Systemic Fibrosis – Toxin-Induced – GVHD Systemic Sclerosis

DDx: • Precipitated by strenous activity • Fibrosis at the level of fascia, not dermis • Spontaneously remits • Peripheral eosinophilia Systemic Sclerosis

DDx: Scleromyxedema • Mucin depositional disorder • Varied clinical presentation (localized to systemic) • Monoclonal IgG λ-light chain gammopathy Systemic Sclerosis

DDx: Scleredema • Mucin depositional disorder • Three subtypes – Post-streptococcal – Gammopathy associated – Diabetes associated • Localized skin induration with internal involvement Systemic Sclerosis

DDx: Nephrogenic Systemic Fibrosis • AKA Nephrogenic Fibrosing Dermopathy • Progressive, diffuse fibrosis of skin and internal organs • Associated with Gadolinium exposure (MRI contrast) in patients with ESRD (Cr>5) • Mortality ~ 50% Systemic Sclerosis

DDx: Toxin Induced • Spanish Toxic Oil • L-tryptophan (Eosinophilia-Myalgia syndrome) • Bleomycin, peplomycin • Taxanes • Cisplatin, Carboplatin • Gemcitabine • Ergot Alkaloids • Cocaine • Vinyl Chloride (in autoclaves) • Tricholorethene/ethane • Epoxy resins • Silica

Mixed Connective Tissue Disease

MCTD • Raynaud’s, dactylitis, fever, arthritis • Heterogeneous expression of other features from SLE, DM, PSS • Heavily associated with U1RNP Ab’s – If also Sm (+), then dx of SLE is made Sjögren’s Syndrome

SS • Autoimmune disorder affecting secretory glands – Classic Triad: Keratoconjunctivitis sicca, Xerostomia, Arthritis • F:M 9:1 • Antibody: – Anti-fodrin 70% – SSA (Ro) 60% – SSB (La) 20% Sjögren’s Syndrome

SS • Xerophthalmia can be dx via Shirmer’s Test • Vasculitis a prominent feature • Interstitial pneumonitis and nepritis, CNS/PNS disturbances (peripheral neuropathy, etc) • Polyarthritis (most commonly knees and ankles) Dermatoses associated with arthritis Juvenile Idiopathic Arthritis

Bolognia, et al. Dermatology (2007) Adult-onset Still’s Disease

AOSD • Fever spikes in afternoon or early evening • Evanescent salmon-colored erythematous eruption • Koebner Phenomenon • Extremely high ferritin levels (>3000) • Arthritis: carpal ankylosis JIA / Adult Still’s Disease

D/Dx • Infectious: Parvovirus, EBV, Malaria • Childhood Leukemia • Familial Mediterranean Fever (FMF) • Hyper-IgD syndrome with periodic fever (HIDS) • TNF-receptor associated fever syndrome (TRAPS) • Cryoporin-associated periodic fever syndromes (CAPS) – Muckle Wells Syndrome – Familial Cold Autoinflammatory Syndrome – Neonatal onset multiorgan inflammatory syndrome Parvovirus

Caused by ssDNA virus

AKA: B19, 5th disease

Viral prodome

3 phases

• Slapped cheek (spares NLF), lasts 2-4 days

• Then morbilloform rash → lacy rash (2-8 days)

• Adults present atypically, with more systemic manifastations. Check Parvovirus IgM if suspicious. Parvovirus & RA

Adult cases mimic RA Slapped-cheek uncommon Lacy, transient rash common B/L, symmetric of the hands, wrists and feet Transient RF (+) in 20% Check B19 IgM Parvovirus & AOSD Mimics Adult-onset Still’s Dz Salmon-colored patches are evanescent Appears for a few hours with the “noon fever spike” RF, ANA, CCP (-) Check B19 IgM

Erythema Marginatum

Mimics Adult-onset Still’s Dz Seen in 5% of acute patients Extremely evanescent Both entities have arthralgias 70% of ARF pts recall antecedent pharyngitis (+) cardiac findings Rheumatoid Arthritis Skin findings • Rheumatoid Nodules – High RF titers, periarticular on extensor surfaces – Rheumatoid nodulosis: seen after initiation of MTX • Rheumatoid Vasculitis – High RF titers, late stage RA, may affect any size vessel – Bywater’s lesions: LCV on distal digits • Felty’s Syndrome – RA, granulocytopenia, splenomegaly, leg ulcers • Neutrophilic dermatoses – , Sweet’s syndrome

RA Vs and NMSC

Psoriasis patients already have a 22% increase baseline risk of liver fibrosis

Ultrasonography and Liver biopsy no longer recommended

Recommend PIIINP testing Manchester Guidelines Where do you send it?

QUEST and LABCorp do not perform the test…... References

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Use of all clinical pictures granted with permission by:

Karthik Krishnamurthy, DO

Molecular cartoons adapted from Bolognia, et al. Dermatology (2007)

Tables adapted from Mutasim, et al. JAAD. 42:2 (2007)