CUTANEOUS MANIFESTATIONS of SYSTEMIC DISEASE Kayla Bliton, DO Mclaren Macomb Family Medicine PGY-3

1/21/2016

CUTANEOUS MANIFESTATIONS OF SYSTEMIC DISEASE Kayla Bliton, DO McLaren Macomb Family Medicine PGY-3

SCOPE OF PRESENTATION

 Common Derm Terminology

 Reveal associations between internal disease and the skin  Diabetes Mellitus  Thyroid Disorders  Rheumatological Disorders  Vasculitis  Renal Disease  Pulmonary Disease  Gastrointestinal Disease

 Recognize the Lesion

 Not on Treatment

1 1/21/2016

REVIEW DERM TERMINOLOGY

PRIMARY LESIONS

 Definition – a lesion that is directly associated with a disease process

 Measured in maximum diameter

 Macule – flat lesion < 1cm

 Patch – flat lesion ≥ 1cm

 Papule – palpable lesion < 1cm

 Nodule – palpable lesion ≥ 1cm – generally round

 Plaque – palpable lesion ≥ 1cm – generally flat

 Tumor – mass ≥ 2cm

 Morbiliform – macules and papules together – NOT Maculopapular

2 1/21/2016

PRIMARY LESIONS

 Vesicle – fluid filled blister ≤ 1cm

 Bulla – fluid filled blister > 1cm

 Pustule – small elevations in the skin filled with purulent material

SECONDARY LESIONS

 Definition – modification of a primary lesion that results from evolution of the primary lesion or is caused by mechanical means

 Scales – masses of keratin

 Crusts – dried serum, pus or blood

 Excoriations – punctate or linear abrasion made by mechanical means

 Fissures – linear cleft

 Erosions – loss of part or all of the epidermis

 Ulcers – complete loss of epidermis and part of dermis

 Scars – new connective tissue replacing the dermis or deeper

3 1/21/2016

DIABETES MELLITUS

 Prevalence in US: ~9%  30% will have a cutaneous manifestation at some point  Type 1 – more AI associated lesions  Type 2 – more cutaneous infections  Overall prevalence of skin disorders is the same between types 1 and 2  Skin lesion usually follow the diagnosis but may be seen first

4 1/21/2016

DIABETES MELLITUS OUTLINE

 Diabetic Dermopathy  Acanthosis Nigricans  Tripe Palms  Necrobiosis Lipoidica  Diabetic Bullae  Eruptive Xanthomas  Granuloma Annulare

DIABETIC DERMOPATHY

 Characteristics  #1 cutaneous manifestation of DM  40% prevalence in DM pts

 M:F = 2:1  70% of diabetic men over 60 yo

 Does occur in people without DM – if ≥4 lesions – specificity is high for DM

5 1/21/2016

 Lesion  Asymptomatic

 Start as small, dull- red papules  atrophic, hyperpigmented scars

 Found mainly on the shins

ACANTHOSIS NIGRICANS

 Lesion  Hyperpigmented, velvety plaques, symmetric, grey/brown/black  Body folds – neck and axilla  Blacks and Hispanics > Whites

6 1/21/2016

 3 different types  Type 1

 Extensive and sudden onset

 Adenocarcinoma of the GI tract

 Suspect if many lesions in different body areas in non- obese male over 40 yo

 Type 2

 Familial AN

 AD – seen at birth or early childhood

 Not assoc. with cancer

 Type 3  Most common type of AN  Overall prevalence unknown  ~20% of all pts  Neck, axilla and groin  Obese pts  Most have clinical or subclinical IR

 Also assoc. with other disease states that have atypical glucose metabolism

 PCOS, Acromegaly, Gigantism, Cushing syndrome, DM, Addison’s disease, Prader-Willi Syn, Hypothyroidism, Insulin resistance

 10% of Renal transplant pts

7 1/21/2016

TRIPE PALMS

 Characteristics  AKA acanthosis palmaris  Thick, velvety palms  Can occur with AN, DM

 Associations  95% of pts with tripe palms have cancer

 77% also involve AN – gastric cancer  If only on palms – lung cancer

 Presenting symptom in 40% of pts with cancer

NECROBIOSIS LIPOIDICA

 Characteristics  Assoc with DM  3X more common in women  20-40 yo  Can be seen in elderly or kids  Not painful

 Lesion  Small, well-circumscribed and elevated red papules +/- scale  Does not disappear under pressure  Usually anterior shin

8 1/21/2016

 Evolves into irregularly oval lesions  Well defined boarders and a smooth, glistening surface  Center is depressed and sulfur yellow

 Central area atrophies and telangiectasias can be seen  1/3 will develop ulcerations  Spontaneously resolves in ~15% with scarring

 Necrobiosis Lipoidica Diabeticorum

 60% are found in patients with Insulin Dependent DM  20% occur in patients at risk for DM

 IDDM – onset avg 22 yo  NIDDM – onset avg 49 yo

9 1/21/2016

DIABETIC BULLAE

 Characteristics  Rare  Appear after relative hypoglycemia  Most heal in 4-5 weeks without scarring  Can result in chronic ulceration

 Lesions  Noninflammatory, painless blistering usually in acral areas  Lower legs - ≥ 10cm

ERUPTIVE XANTHOMAS

 Characteristics  Most common causes

 Uncontrolled type 2 diabetes and hypertriglyceridemia  May also be seen in

 Hypothyroidism and chronic renal failure  Meds

 Estrogens, steroids, systemic retinoids  +/- pruritus

10 1/21/2016

 Lesion  Seen all over body

 Extensor areas (elbows, thighs, knees), intertriginous areas (axilla, groin), oral mucosa  Sudden crops of non-tender yellow, red or brown papules with a red rim

GRANULOMA ANNULARE

 Characteristics  M:F = 1:2  Usually will spontaneously resolve, usually 3-4 years, w/o scars  Idiopathic Localized GA  Lesions  Diffuse and symmetric, papular or annular  Neck, upper trunk and proximal UE, back of hands  Asymptomatic to severe pruritus

11 1/21/2016

 Localized GA  Usually found on dorsal or lateral hands and feet  Children and young adults  Can be assoc. with AI thyroiditis

 Generalized GA Examples of  > 10 lesions Generalized GA  Women in 50s and 60s  May be assoc. with DM, dyslipidemia, HIV

SCLEREDEMA

 Characteristics  Late onset, long duration IDDM  M:F = 10:1, obese  Control of DM doesn’t control Scleredema

 Lesion  Insidious onset of woody (stiff) induration and thickening of the skin and the mid-upper back, neck and shoulders  Sharp step-off from involved to normal skin.  Skin looks thickened – dermis expanded 2-3x

 NOT SCLERODERMA – no hyalinization (change in skin to glassy appearance)

12 1/21/2016

THYROID DISEASE

Thyroid

THYROID DISEASE OUTLINE

 Hyperthyroidism  Graves’ Disease  Pretibial Myxedema  Scleroderma  Hypothyroidism  Vitiligo

13 1/21/2016

Thyroid

HYPERTHYROIDISM

 Skin surface  Warm, moist, smooth  Bronzed appearance  Palmar Erythema  Facial Flushing Pre-treatment Post-treatment

 Hair Texture  Thin  Downy  Non-scarring diffuse alopecia

Thyroid

 Nail Changes ~5% pts  Plummer Nail

 Concave nail

 Distal separation

 Not specific

14 1/21/2016

Thyroid

GRAVES’ DISEASE

 Characterized by:  20-30 years  M:F ratio – 1:7  #1 cause of non-iatrogenic hyperthyroidism

 Skin manifestations almost only associated with Graves’ Disease (Diamond Triad)  Ophthalmopathy  Pretibial Myxedema  Thyroid Acropachy

Thyroid

THYROID ACROPACHY

 Characteristics  1% of Graves pts  Triad:

 Digital clubbing

 Soft tissue swelling of hands and feet

 New periosteal bone formation in distal long bones

15 1/21/2016

Thyroid

PRETIBIAL MYXEDEMA

 Characteristics  4% of Graves pts  AKA Graves Dermopathy  Late manifestation, seen with ophthalmopathy in 99%

 Lesion:  Soft tissue swelling and new bone formation  Bilateral shins  Nodules and plaques  Thick, hyperpigmented, firm skin

Thyroid

SCLEROMYXEDEMA

 Characteristics  Affects middle aged adults  Not common  AKA papular mucinosis

 Lesions  Many, waxy papules in pink, white or yellow  Found on face, trunk, axillae, extremities

 Lesion are due to hyaluronic acid accumulation in the dermis

16 1/21/2016

Thyroid

HYPOTHYROIDISM

 Middle aged women  Diffuse hair loss, coarse / brittle hair  Myxedema - swelling of face and underlying tissues

Pre-treatment Post-treatment

Thyroid

 Cutis verticis gyratum  Folds and furrows on the scalp

Onycholysis

17 1/21/2016

Thyroid

 Loss of lateral third of eyebrows  Chronic periorbital infiltration

 Carotenemia  Yellow tint to skin  Palms / soles  Decreased hepatic conversion of beta- carotene to Vitamin A

Thyroid

VITILIGO

 Characteristics  Onset 10-30 yo  Prevalence .5-1% in most countries  India >8%  Women

 Autoimmune related  #1 - thyroid disease  IDDM

 Lesion  Acquired depigmentation through destruction of melanocytes surrounded by normal border  Hair loses pigmentation

 Ocular abnormalities more common

18 1/21/2016

Thyroid

 Generalized pattern

 Most common of 6 different types of vitiligo

 Symmetric involvement

 Most common areas – face, upper chest, axilla, groin, dorsal hands

 Skin around orifices commonly affected

 Trauma can cause lesions – elbows, knees

RHEUMATOLOGY

19 1/21/2016

Rheum

RHEUMATOLOGY OUTLINE

 Dermatomyositis  Lupus  SLE  Acute cutaneous  Subacute cutaneous  Discoid  Rheumatoid Arthritis

Rheum

DERMATOMYOSITIS

 Inflammatory connective tissue disease that classically involves the skin (dermato-) with muscle inflammation (- myositis)

 Symmetric proximal muscle weakness

 Amyopathic Dermatomyositis – only skin disease

 M:F = 1:2 Black:White = 4:1

 Painless, intense pruritus

20 1/21/2016

Rheum

 Pathognomonic features

Heliotrope Rash

Gottron Papules

Heliotrope Flower

Rheum Shawl Sign

Holster Sign

21 1/21/2016

Rheum

Mechanic Hands Periungual Hyperkeratotic scale on lateral Telangiectasias digits or palms

Rheum

 20-25% are assoc with malignancy

 Increased risk for developing malignancy within 3 years after the diagnosis  Increased risk if > 40 yo

 Usually Adenocarcinoma  Women – Ovarian and Breast Cancer  Men – Gastric Cancer and Lymphoma

22 1/21/2016

Rheum

LUPUS

 Characteristics  Autoimmune disorder  Young adult women. M:F = 1:2  Fever and arthralgia  Cutaneous lesions in 80%

 Can be systemic (Systemic Lupus Erythematosus) or cutaneous (Discoid Lupus Erythematosus)

 Can be acute (Acute Cutaneous Lupus Erythematosus or Subacute Cutaneous Lupus Erythematosus) or chronic (Discoid Lupus Erythematosus)

Rheum

SYSTEMIC LUPUS ERYTHEMATOSUS

 Diagnostic Criteria by the American College of Rheumatology  Need 4/11

 1. Malar Rash*  2. Discoid Rash*  3. Photosensitivity*  4. Oral Ulcers – 21%*  5. Arthritis  6. Proteinuria >.5g/day or casts  7. Neurologic disorders – seizures or psychosis  8. Pleuritis / pericarditis  9. Blood abnormality –hemolytic anemia, leukopenia, thrombocytopenia  10. Immunologic disorders  11. Positive ANA

 Can have at different times or at the same time

23 1/21/2016

Rheum

ACUTE CUTANEOUS LUPUS ERYTHEMATOSUS

 Malar rash  Butterfly rash  Transient erythematous patch on cheeks and bridge of nose – can be on the ears and chest  Typically avoids the nasolabial fold

 Lasts days to weeks  Resolves without scarring

 Seen in ~60% of systemic lupus  Rarely occurs in patients without systemic disease

Rheum

 Bullous lesions  Single or group of vesicles or bullae  Sun-exposed areas  Usually meets criteria for SLE

 Vascular lesions  Seen in 50% of SLE pts  Fingers or toes

 telangiectasias, edema, erythema

24 1/21/2016

Rheum

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS (SCLE)

 Characteristics  White woman 15-40 yo  30% of pts with lesion will have systemic disease

 20% will also have discoid lupus  Present in ~15% of the SLE pts

 Can be drug induced

 Most likely HCTZ

 Anti-histone antibodies – non-specific

Rheum

 Lesion  Annular, scaly, erythematous patches  Photosensitivity – 50% - face, neck, chest, back, arms  Resolves without scarring

25 1/21/2016

Rheum

DISCOID LUPUS ERYTHEMATOSUS

 Characteristics  Chronic lesion  Above the neck

 face, scalp, concha or the ear and external canal  May see periorbital edema or erythema  Seen in ~20% of SLE pts  5% of pts with lesion will have systemic disease  Mucosal involvement seen in 25%

Rheum

 Lesions  Erythematous patch or thin plaque  Face, scalp, conchal bowl of the ear  Leads to atrophic or hyperkeratotic, hairless patches, scarring

 Patients with scarring due to lupus lesion need to be monitored for any changes or indications of skin cancer

26 1/21/2016

Rheum

RHEUMATOID ARTHRITIS

 Many patients have skin involvement from the disease or medications to treat RA

 Lesions - Rheumatoid Nodules  #1 cutaneous manifestation ~30%  Firm, asymptomatic subcutaneous nodules over extensor joints  Side effect of Methotrexate - accelerated nodulosis

VASCULITIS

27 1/21/2016

Vasc

VASCULITIS OUTLINE

 Definitions  Cutaneous Small Vessel Vasculitis  Urticarial Vasculitis  Henoch-Schönlein Purpura

Vasc

DEFINITIONS

 Petechiae  Pinpoint areas of RBCs – nonblanching red macules  Abnormal platelet quantity or function, infectious process or abnormal vasculature

 Purpura  Presence of extravascular RBCs in the dermis  Cause by vascular inflammation, external injury

 Vasculitis  Clinical and pathological process characterized by inflammation and necrosis of blood vessels

28 1/21/2016

Vasc

 Palpable purpura  Active, inflammatory process

 small vessel vasculitis  injury to the capillary beds

 Palpable

 damaged blood vessel  Purpura

 secondary bleeding into the dermis

 May be a primary process or may occur secondary to another disease

Vasc

CUTANEOUS SMALL VESSEL VASCULITIS

 Characteristics  AKA leukocytoclastic vasculitis  Fever, malaise, arthralgia

 Lesion  Palpable purpura is hallmark  Single group of lesions  +/- edematous papules and wheals  Dependent areas  Asymptomatic +/- itching or burning  Derm referral for complete workup  Resolve in 3-4 weeks

29 1/21/2016

Vasc

 Causes:

 Idiopathic 50%

 Infection  β - hemolytic Group A Strep, Mycoplasma, Mycobacterium tuberculosis

 Exposure to new medication  Meds in every class  Can be hours to years after exposure  β-lactam antibiotics, NSAIDs, diuretics

 Connective tissue disease

 Malignancy  Lymphoproliferative neoplasms  Solid tumors – Lung, Colon, GU, Breast

Vasc

URTICARIAL VASCULITIS

 Lesion  Persistent urticarial plaques lasting >24 hours  Urticaria presenting with tingling pain  Resolves with blue hyperpigmentation

 50% underlying autoimmune condition

30 1/21/2016

Vasc

HENOCH-SCHÖNLEIN PURPURA

 Characteristics  Subtype of leukoclastic vasculitis  Children or young adults  Typically follows an infection  IgA found in affected vessels on biopsy

Vasc

 Lesion  Palpable purpura on lower legs and buttocks

 Assoc with arthritis, arthralgia, abdominal pain

 Risk of renal disease – higher risk if lesions are above the waist

31 1/21/2016

NEPHROLOGY

Nephro

NEPHROLOGY OUTLINE

 Pruritus  Calciphylaxis

32 1/21/2016

Nephro

PRURITUS

 Characteristics  End Stage Renal Disease  Intense, unremitting itch  chronic scratching  secondary lesion (excoriations, lichenification, hyperpigmentation)

 Secondary Lesions  Prurigo Nodularis

 hyperkeratotic hyperpigmented papules and nodules

Nephro

Lichen Simplex Chronicus Thickened, chronic eczematous, scaly patches

Kyrle’s Disease Umbilicated, hyperpigmented papules with a central keratin core

33 1/21/2016

Nephro

CALCIPHYLAXIS

 Characteristics

 ESRD  abnormal calcium and phosphorus balance

  calcification in the lumen of arterial vessels

  decreased circulation to the skin leading to ischemia and necrosis

 <5% with ESRD will have calciphylaxis

 Poor prognosis – 60-80% die within 6 months

Nephro

 Lesions  Painful lacy purpuric patches

  bullae, ulcerations with a tough eschar

 Center is dusky and may have black necrotic areas

 Lower extremities

 More proximal may relate to worse disease

34 1/21/2016

PULMONOLOGY

Pulm

PULMONOLOGY OUTLINE

 Sarcoidosis  Erythema Nodosum  Erythema Gyratum Repens

35 1/21/2016

Pulm

SARCOIDOSIS

 Characteristics  Chronic, multisystem inflammatory disease  Pts form granulomatous tissue in affected area  Black women in 30s  25-30% have skin involvement  AKA “The great imitator”  20% of pts will have skin disease before other symptoms

 Lesions  White pts  Erythema nodosum is as common as specific cutaneous signs  10% have both types of cutaneous sarcoidosis  Black pts  Erythema nodosum much less common  50% have specific cutaneous manifestations

Pulm

 Papular sarcoid  Most common specific cutaneous lesion  <1cm  Small papules – AKA miliary sarcoid  Face, eyelids, neck, shoulder

 Lupus pernio  Thickened, purple, hyperpigmented nodules  Around the nose  Chronic, refractory

36 1/21/2016

Pulm

 Annular Sarcoid  Papular lesion arranged in annular pattern  Central clearing with possible atrophy and scarring  alopecia  Head and neck  Sun exposed area

 Classic cutaneous sarcoidosis  Purple papules or palpable plaques  Granulomatous lesions – sites of trauma (scars or tattoos)

Pulm

ERYTHEMA NODOSUM

 Characteristics  Reactive process from the inflammation of the septa in fat lobules (panniculitis)  #1 form of panniculitis

 Pt may have low grade fever, malaise, arthralgia before skin lesions  Any age, most common – young adult women  Lesions come and go  Most resolve over 4-6 weeks – typically self limiting

37 1/21/2016

Pulm

 Lesions  Tender, subcutaneous nodules  Convex appearance  Slightly red in the acute phase  Bilateral and symmetrical  Distal lower extremities

 can also appear on the trunk, thigh, or upper extremities

Pulm

 Associations  Most common nongranulomatous lesion in Sarcoidosis, usually seen in the acute phase

 Infections, Meds, Systemic diseases, Idiopathic

 #1 infection – Streptococcal

 Meds – Antibiotics, OCPs, Hormone therapy

 Pregnancy

 Systemic – Sarcoidosis, IBD

38 1/21/2016

Pulm

ERYTHEMA GYRATUM REPENS

 Lesion appearance  wavy, erythematous bands with scale  concentric pattern  woodgrain pattern  migrates quickly – up to 1cm / day

 Characteristics  Severe pruritus  Eosinophilia on lab test

Pulm

 Malignancy  70% have malignancy  Most likely lung cancer  Also breast, cervical, GI  May also be caused by medications or TB

 Skin manifestation appear ~9mo before cancer is detected

39 1/21/2016

GASTROENTEROLOGY

GASTROENTEROLOGY OUTLINE

 Inflammatory Bowel Disease  Pyoderma Gangrenosum  Porphyria Cutanea Tarda  Cryoglobulinemia

40 1/21/2016

INFLAMMATORY BOWEL DISEASE

 Erythema nodosum  #1 skin manifestation  20%  Women  Ulcerative colitis

 Can also have cutaneous Crohn’s disease  Oral involvement

 20% - mucosal hypertrophy and fissuring

 Granulomas on biopsy

 Young men

 Pyostomatitis vegetans

 intraoral pustules and ulcerations

41 1/21/2016

PYODERMA GANGRENOSUM

 Characteristics  Intense neutrophilic inflammation and invasion  Adults 40-60 yo  When active may develop new sites at areas of trauma  Needle sticks  Diagnosis of exclusion

 Lesions  Lower extremities and trunk  Presents as:  Painful ulcers – classically  Bullae  Pustulonodules  Vegetative plaques  Ulcers expand with edematous, rolled border  Violet hue  Annular rings

 Associated with underlying disease in 50-75% of patients  IBD is most common UC > Crohn’s

 Lesions are pustular lesions that do not ulcerate  May be autoimmune or hematologic (AML)

42 1/21/2016

PORPHYRIA CUTANEA TARDA

 Characteristics  Accumulation of porphyrins due to an enzyme deficiency that is essential in heme production

 Uroporphyrinogen decarboxylase  Affects CNS, skin and other organs

 Most common is a sporadic, non-familial form ~80%  Most common porphyria  Onset in 40s  Photosensitivity on sun exposed areas

 Lesions  Bullae in sun exposed areas (dorsal hands)

 Rupture easily and leave small ulcers  Skin heals leaving milia, hyperpigmentation or small scars  Hypertrichosis on dorsal hands or lateral face

43 1/21/2016

 Associations  ESLD are at risk of PCT

 Alcohol abuse, hemochromatosis, ~50% HCV infection

 3.5x increased risk of developing Hepatocellular Carcinoma

 ~15% pts with adult onset type 2 DM will have PCT

 10 years after dx of PCT  HIV infection  Estrogen treatment

 Increasing seen in women after the invention of OCPs

 60% men and 40% woman

CRYOGLOBULINEMIA

 Characteristics  Cryoglobulins - cold precipitating immunoglobulins that are soluble at body temp but precipitate peripherally under 37˚C causing disease

 Side effects due to hyperviscosity  Glomerulonephritis, neuropathy, arthritis, pulmonary inflammation

 Lesions  Palpable purpura – lower extremities or dependent areas  Most common sign of mixed cryoglobulinemia

44 1/21/2016

 Associations  >50% of pts with HCV infection

 only 10-15% will develop clinical disease

 SLE

 Lymphoproliferative disorder

 multiple myeloma or macroglobulinemia Purpura, Acrocyanosis, Skin necrosis

BIBLIOGRAPHY

 James WD, Berger TG, Elston DM. (2016) Andrew’s Diseases of the Skin: Clinical Dermatology 12th Edition.

 Schwarzenberger K, Ende J, et al (2012) MKSAP 16

 Van Linthoudt D, et al. (July 1996) “Scleromyxedema with myopathy and hyperthyroidism”. J Rheumatology (7):1299-301.

 Marinella MA. (July 2004) “Henoch-Schönlein Purpura”. N Engl J Med 351-278.

 Satish I, et al. (2016) “Rare presentation of a Rare Side Effect”. Am J Gastroenterol. 2009, 848.

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 Grandinetti LM, Tomcki KJ. (Aug 2010) “Dermatologic Signs of Systemic Disease”. Retrieved on 12/16/15 from www.clevelandclinicmeded.com/medicalpubs

 Miller-Keane, O’Toole MT. (2003) Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, 7th Edition.

 National Organization for Rare Disorders, (2015) Acanthosis Nigricans. Retrieved on 1/5/16 from rarediseases.org/rarediseases/acanthosis-nigricans.com

 Douglas RS, (2015) “Graves’ Eye Disease or Thyroid Eye Disease”. Retrieved on 1/10/16 from http://www.kellogg.umich.edu/patientcare/conditions/graves.di sease.html

 American Diabetes Association, (1995-2016). Diabetes Statistics. Retrieved on 12/27/15 from http://www.diabetes.org/diabetes- basics/statistics/?referrer=https://www.google.com/

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