Cutaneous Manifestations of Systemic Diseases Hayden H. Franks, MD June 13, 2013

Who Is This Guy? Private practice Dermatologist Clinics in Little Rock and Texarkana Fellow of the American Academy of Dermatology Diplomate of the American Board of Dermatology Assistant Clinical Professor of Dermatology, UAMS AHEC SW Honorary Member of the Arkansas Academy of Family Physicians

Disease Categories Autoimmune Diseases Endocrine Diseases Cardiopulmonary Diseases Gastrointestinal Diseases Neurological Diseases Diseases not Otherwise Specifiied

Cutaneous Manifestations of Systemic Diseases Frequently encountered May be the initial sign of internal disease May occur late in the course of the disease May assist in making the diagnosis May be obvious or subtle Overlap of Family Practice and Dermatology

AUTOIMMUNE DISEASES Systemic Lupus Erythematosus Scleroderma Dermatomyositis Rheumatoid Arthritis

Systemic Lupus Erythematosus Autoimmune, systemic disease affecting multiple organ systems The most common connective tissue disease Especially prevalent in black women – Prevalence 1/250 Cutaneous lesions present in 85% of patients Of the 11 Classic Criteria for diagnosing SLE, 4 involve the skin or mucus membranes

Systemic Lupus Erythematosus Malar (Butterfly) rash is the “classic presentation” May be distinct or subtle

Systemic Lupus Erythematosus Fixed erythema, flat or raised, over malar eminences Spares the Nasolabial Folds

Systemic Lupus Erythematosus Discoid Rash is “classic” as well

Systemic Lupus Erythematosus Erythematous, patches and plaques, with adherent scales, follicular plugging and atrophic scarring

Systemic Lupus Erythematosus Photosensitivity – rash as an unusual reaction to sunlight

Systemic Lupus Erythematosus Oral Ulcers – usually painless and may be nasopharyngeal

Systemic Lupus Erythematosus Presentation isn’t always “classic” High index of suspicion Alopecia and rash may be anywhere on skin

Systemic Lupus Erythematosus Diagnosis is based on presence of multisystem disease and presence of antinuclear antibodies Treatment is multifactorial with corticosteroids being the mainstay still Sunscreen Antimalarials, methotrexate, dapsone and biologics now are commonly used

Scleroderma Chronic autoimmune disease of unknown cause that affects the microvasculature and loose connective tissue Characterized by fibrosis and obliteration of vessels in skin, lungs, GI tract, kidneys and heart May be localized (Morphea) or systemic (Systemic Scleroderma)

Scleroderma (Morphea) Morphea – benign and self limited Usually single or few in number Red, then white, atrophic, indurated with alopecia

Scleroderma (Morphea) Treatment is unsatisfactory Topical or intralesional steroids, PUVA

Systemic Scleroderma (SSc) Four times more common in women 10 year survival rate of 21-71% Clinical manifestations depend on the sites involved Initial complaints are usually Raynaud’s phenomenon or chronic, non pitting edema of hands and fingers or migratory polyarthritis Disease may extend to involve upper extremities, trunk, face and finally the lower extremities

Systemic Scleroderma (SSc)

Systemic Scleroderma (SSc)

Systemic Scleroderma (SSc)

Systemic Scleroderma (SSc) Diagnosis Autoantibodies to Fibrillin 1, Rheumatoid Factor, Anti SS DNA, Anti RNA Polymerase 3, Antitopoisomerase 1, Anticentromere Antibodies Skin Biopsy

Systemic Scleroderma (SSc) Treatment Treatment is unsatisfactory Immunosuppressive Drugs of numerous types Methotrexate, Cyclosporine, Imuran Biologics

Dermatomyositis The most common idiopathic inflammatory myopathy May occur at any age Unknown etiology Autoimmune Disease Progressive weakness of trunk and major limb muscles Difficulty in rising from a chair or climbing stairs Impaired mobility and some muscle tenderness

Dermatomyositis Bilateral muscle weakness that is progressive Skin lesions are almost always present from the onset Maculopapular erythema over bony prominences such as the knuckles, elbows and knees Red to violaceous plaques with telangiectasias and scales Gottron’s Papules – polymorphic, erythematous and atrophic plaques

Dermatomyositis

Dermatomyositis

Dermatomyositis Heliotrope Rash – Periorbital erythema Nail Margin Telangiectasias

Dermatomyositis Diagnosis Elevated serum muscle enzymes (CK) and Aldolase Antinuclear Antibodies Muscle biopsy – segmental muscle fiber fibrosis, interstitial inflammation and vasculopathy Skin biopsy – Focal vacuolar degeneration of basal cells, basement membrane degeneration and epidermal atrophy

Dermatomyositis Treatment Primary treatment remains Prednisone 1mg/kg/day Plasmapheresis Cyclosporine Dapsone ?Biologics Physical Therapy

Rheumatoid Arthritis Disease affects up to 2% of adult women Onset is sudden or insidious Symmetric polyarthritis that affects the proximal interphalangeal and metacarpophalangeal joints, the wrists, ankles, knees and cervical spine Stiffness, painful, warm and tender joints Fever, weight loss and anemia are prominent

Rheumatoid Arthritis Rheumatoid Nodules – discrete, non tender subcutaneous tumors

Rheumatoid Arthritis Vascular Lesions – erythema of palms and digital infarcts

Rheumatoid Arthritis

Rheumatoid Arthritis Gravitational ulcers – most common Arteritic ulcers – actually rare until advanced disease

Rheumatoid Arthritis Laboratory Workup – Rheumatoid Factor and ANA Treatment – Prednisone, Methotrexate, Biologics

ENDOCRINE DISEASES Diabetes Mellitus Thyroid Disease

Diabetes Mellitus The skin shares both in the effects of acute metabolic derangements and in the chronic degenerative complications of diabetes.

Diabetes Mellitus Infection Diabetic Dermopathy Thickened skin, stiff joints and Scleredema Adultorum Necrobiosis Lipoidica Diabeticorum Vitiligo Acanthosis Nigricans Kyrle’s Disease (Reactive Perforating Collagenosis)

Diabetes Mellitus Bacterial and fungal infections Furunculosis, Cellulitis, Erythrasma, and Candidiasis Hyperglycemia leads to abnormalities in leukocyte function including diminished chemotaxis and phagocytosis

Diabetes Mellitus Bacterial Infections

Diabetes Mellitus Cellulitis

Diabetes Mellitus Erythrasma

Diabetes Mellitus Candidiasis

Diabetes Mellitus Diabetic Dermopathy – atrophic, circumscribed brownish lesions usually on the lower extremities They resemble post traumatic scarring

Diabetes Mellitus Thickened Skin, Stiff Joints and Scleredema Adultorum 33% of Diabetics have tight, indurated and waxy skin over the dorsa of the hands Scleredema Adultorum is strongly correlated with IDDM Consists of induration of the skin beginning on the posterior and lateral aspect of the neck, is painless and may be progressive

Diabetes Mellitus

Diabetes Mellitus Scleredema Adultorum

Diabetes Mellitus Necrobiosis Lipoidica Diabeticorum Occurs in 0.3% of IDDM Patients Very distinct Asymptomatic, atrophic, yellow to brown patches classically on the lower extremities Telangiectasias are prominent

Diabetes Mellitus Necrobiosis Lipoidica Diabeticorum

Diabetes Mellitus Vitiligo Many times is associated with IDDM, Thyroid Disease and Systemic Lupus Erythematosus

Diabetes Mellitus Acanthosis Nigricans – characterized as velvety, papillomatous hyperplasia of the epidermis with intense hyperpigmentation Axillary, inguinal and inframammary folds and the neck Found in association with several endocrinopathies – including Cushing’s Disease, Polycystic Ovary Disease and IDDM

Diabetes Mellitus Acanthosis Nigricans

Diabetes Mellitus Kyrle’s Disease – rare and characterized by hyperkeratotic, follicular and perifollicular papules Transepidermal elimination of altered collagen Also strongly associated with renal disease

Diabetes Mellitus Kyrle’s Disease

Thyroid Disease Thyroid hormones have diverse primary sites of action at the level of the cell membrane, mitochondria and gene transcription that regulate functional properties and metabolism of most cells of the body including the keratinocytes and fibroblasts of the skin. Thyroid hormones affect production of collagen and mucopolysacccharides by dermal fibroblasts. Lack of thyroid hormone affects all of the above Excess thyroid hormone does not

Thyroid Disease Thyrotoxicosis (Hyperthyroidism) – due to Grave’s Disease or Toxic Nodular Goiter Skin is warm, moist, flushed and excess sweating Alopecia Uncommonly pruritus, vitiligo Pretibial Myxedema

Thyroid Disease Pretibial Myxedema – an infiltrative dermopathy, usually over anterior tibia and dorsa of feet. Bilateral, pink, violacous or flesh colored confluent papules Diffuse brawny edema Correction of thyrotoxicosis has no effect on the skin lesions Half of cases occur after patient has been rendered euthyroid

Thyroid Disease Pretibial Myxedema

Thyroid Disease (Hypothyroidism) Skin is cold, xerotic and pale Vasoconstriction Epidermis is thin, hyperkeratotic Fine wrinkling resembles parchment paper Yellow discoloration especially of palms, soles and nasolabial folds Hair is dry, coarse, brittle and grows slowly

Thyroid Disease (Hypothyroidism)

Thyroid Disease (Hypothyroidism) Myxedema – dermal accumulation of mucopolysaccharides (hyaluronic acid and chondroitin sulfate) Usually located acrally May be diffuse or focal (papules) Broad nose, thick lips, large smooth tongue Drooping eyelids and an expressionless face

Thyroid Disease (Hypothyroidism)

CARDIOPULMONARY DISEASES Coronary Heart Disease Subacute Bacterial Endocarditis COPD Cystic Fibrosis Asthma

Coronary Heart Disease Familial Hyperlipidemia – a group of metabolic disorders with elevated plasma cholesterol and or triglyceride levels. Often see Xanthomatosis on the skin Earlobe Crease – there is an association between CAD and a diagonally positioned skin crease along the earlobe that may be unilateral or bilateral. Post Bypass Skin changes

Coronary Heart Disease Xanthomatosis

Coronary Heart Disease Earlobe Crease

Coronary Heart Disease Postbypass Skin Changes – Saphenous Vein Graft Site Dermatitis Tinea Pedis Stasis Edema and Stasis Dermatitis

Coronary Heart Disease Saphenous Vein Graft Site Dermatitis

Coronary Heart Disease Tinea Pedis

Coronary Heart Disease Stasis Edema and Stasis Dermatitis

Coronary Heart Disease Stasis Edema and Stasis Dermatitis

Coronary Heart Disease Stasis Dermatitis vs Cellulitis

Actinic Purpura

Subacute Bacterial Endocarditis Petechiae are the most common mucocutaneous manifestation of bacterial endocarditis – small red or violaceous macules that don’t blanch – not associated with platelet dysfunction Osler’s Nodes Janeway Lesions Subungual Splinter Hemorrhages Cutaneous Purpura and Petechiae Conjunctival Petechiae (Roth’s Spots)

Subacute Bacterial Endocarditis Petechiae

Subacute Bacterial Endocarditis Osler’s Nodes – painful hemorrhagic macules and papules located on digital tufts

Subacute Bacterial Endocaridits Janeway Lesions- Nontender hemorrhagic macules and papules located on palms and soles

Subacute Bacterial Endocarditis Subungual Splinter Hemorrhages

Subacute Bacterial Endocarditis Conjunctival Petechiae (Roth’s Spots)

Chronic Obstructive Pulmonary Disease (COPD) Actually a group of disorders including chronic bronchitis, bronchiectasis, emphysema and asthma Incidence is increasing and actually approaching that of cardiac disease Environmental and genetic influences

Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD)

Cystic Fibrosis Autosomal Recessive disorder of the exocrine glands that subsequently involves the tracheobronchial tree, pancreas and GI tract Cutaneous features result from increased amounts of electrolyte in the sweat that leads to excess skin wrinkling of palms and soles when immersed in water.

Cystic Fibrosis

Asthma Asthma – Eczema Complex (Atopy) Association of asthma, atopic eczema and allergic rhinitis are well documented Mediators of this inflammatory response may be released by sensitized IgE – Mast cell complexes Dust, pollen, dander, heat, dry conditions, exercise and other allergens all may trigger an outbreak

Asthma Asthma – Atopic Dermatitis (Atopy)

Asthma Asthma – Atopic Dermatitis (Atopy)

GASTROINTESTINAL DISEASES Inflammatory Bowel Disease Celiac Disease Hepatitis

Cutaneous Manifestations of Gastrointestinal Diseases Jaundice Vascular Changes Melanosis Spider Telangiectasias Palmar Erythema Nail Changes Edema Purpura Pruritus

Inflammatory Bowel Disease Inflammatory Bowel Disease – Ulcerative Colitis and Crohn’s Disease Skin complications are similar in these two diseases Pyoderma Gangrenosum Erythema Nodosum Aphthous Ulcers Lichen Planus

Pyoderma Gangrenosum Pyoderma Gangrenosum Rare, destructive, inflammatory skin disease Progressively enlarging ulcers with raised, tender, undermined borders Most commonly seen on legs but may be anywhere May be solitary or multiple May be isolated or seen with Inflammatory Bowel Disease, Polyarthritis or certain malignancies Affects 5 to 10% of Inflammatory Bowel Disease patients

Pyoderma Gangrenosum Pyoderma Gangrenosum

Pyoderma Gangrenosum Pyoderma Gangrenosum

Erythema Nodosum Erythema Nodosum Cutaneous reaction pattern consisting of inflammatory, spontaneously regressing, tender, nodular lesions located primarily over the extensor surfaces of the lower legs Septal panniculitis without vasculitis Is associated with a wide variety of disease processes Immunologic pathogenesis In addition to occurring in Crohn’s and UC, also seen with infections, Sarcoidosis and drugs (Sulfonamides and Oral Contraceptives )

Erythema Nodosum Erythema Nodosum

Erythema Nodosum Erythema Nodosum

Aphthous Ulcers Aphthous Ulcers Small, shallow, well circumscribed ulcers Oral mucosa Appear suddenly and are painful Resolve within 2 weeks only to recur May be related to stress or menses Very common – may affect up to 20% of general population

Aphthous Ulcers Aphthous Ulcers

Aphthous Ulcers Aphthous Ulcers

Lichen Planus Lichen Planus Skin eruption consisting of violaceous, scaling, angular papules and plaques Flexor surfaces and mucus membranes are classic locations Symmetrically distributed Usually pruritic Incidence of around 0.5% Usually isolated but may be associated with underlying disease (UC and Crohn’s Disease)

Lichen Planus Lichen Planus

Lichen Planus Lichen Planus

Celiac Disease Celiac Disease – also known as Celiac Sprue. autoimmune disease of the small intestine Abdominal pain, discomfort, diarrhea, constipation, failure to thrive (children) May lead to vitamin deficiencies due to malabsorption Increasing in incidence due to improved screening Associated with Dermatitis Herpetiformis

Dermatitis Herpetiformis Intensely pruritic, chronic, papulovesicular eruption distributed symmetrically on extensor surfaces classically over the elbow Most patients have an associated gluten sensitive enteropathy that may be asymptomatic Universally responsive to Dapsone Most patients with DH have Celiac Disease although many are mild or asymptomatic Gluten free diet is beneficial

Dermatitis Herpetiformis

Dermatitis Herpetiformis

Cutaneous Manifestations of Hepatitis Urticaria Vasculitis Polyarteritis Nodosa Relapsing Papulovesicular Rash

Urticaria in Hepatitis

Vasculitis in Hepatitis

NEUROLOGICAL DISEASES Parkinson’s Disease Cerebrovascular Accident (Stroke)

Parkinson’s Disease Degenerative disorder of the Central Nervous System Motor symptoms result from death of Substantia Nigra cells of the Midbrain which generate Dopamine Tremor at rest, bradykinesia, rigidity, postural instability Later in disease dementia and neuropsychiatric problems may occur

Parkinson’s Disease Hyperhidrosis especially of the face and palms Peripheral sweat gland function is controlled by sympathetic nervous system which is altered in PD patients

Parkinson’s Disease Seborrheic Dermatitis Overexcretion of sebum on the face which is thought to be caused by hyperactivity of the Parasympathetic component of the Autonomic Nervous System

Parkinson’s Disease Seborrheic Dermatitis

Cerebrovascular Accident (Stroke) Changes are due to Unilateral disturbance in autonomic function - including skin temperature, turgor, xerosis and sweating Loss of motor function –including edema and ulceration (pressure ulcers)

Cerebrovascular Accident (Stroke)

Cerebrovascular Accident (Stroke)

DISEASES NOT OTHERWISE SPECIFIED Sarcoidosis

Sarcoidosis A granulomatous disease most commonly associated with lesions of the lungs and bilateral hilar lymphadenopathy Multisystem disease that can present in many ways 1/3 of pateints complain of fatigue, fever and weight loss 1/3 of patients have dyspnea, cough and chest pain Serum ACE levels raised in 60% of patients Skin lesions occur in 40 % of patients

Sarcoidosis Skin Lesions Lupus Pernio Skin Plaques Subcutaneous nodules Erythema Nodosum

Sarcoidosis Lupus Pernio – the most characteristic of all Sarcoid skin lesions Chronic, violaceous, indurated papules and plaques with a predilection for the face especially the nose May be associated with advance pulmonary disease

Sarcoidosis Lupus Pernio

Sarcoidosis Lupus Pernio

Sarcoidosis Erythema Nodosum