Skin Manifestations of Systemic Diseases

Do you know when skin findings are a result systemic disease? Board-certified dermatologist Azeen Sadeghian shows us how to recognize these important skin manifestations. This blog post has been adapted from a VisualDx webinar on multiple skin findings of important systemic diseases and some key differences among skin colors. This content is geared toward non-dermatologist physicians and clinicians.


Cutaneous findings are not common; however, several manifestations have been described.

Skin manifestations:

  • Pernio-like lesions
    • Found on acral surfaces.
    • Look for erythema, edema, vesiculation, and purpura of the hands and feet.
    • Lesions may be painful, itchy, or asymptomatic.
    • Lesions seen more often on feet (aka COVID toes) than on hands.
    • Younger individuals late in disease course usually experience milder illness.
  • Vesicular eruption
    • Lesions occur at the same stage (which differs from chicken pox).
    • Can coalesce and become hemorrhagic.
    • Seen more in middle-aged patients with moderate disease severity.
    • Itch is common.
  • Urticarial eruption
  • A macular or papulosquamous eruption
  • Livedo or retiform purpura
    • Transient livedo has been seen in milder illness.
    • Retiform purpura that may be complicated by skin necrosis may be seen in individuals with severe disease.

Measles / Rubeola / “First Disease”

Transmission is respiratory.

Infection begins in nasopharynx or conjunctiva then spreads to lymph nodes / blood.

There is a 1- to 2-week incubation period, fever/prodrome of the 3C’s:

  • Cough
  • Coryza: mucous discharge (Catarrhal) of the mucous membrane in the nose.
  • Conjunctivitis

Skin manifestations:

  • Enanthem: Koplik spots are gray / white papules on the buccal mucosa that resolve before the exanthem.
  • Exanthem: morbilliform (maculopapular) begins at the frontal hairline and post auricular; spreads from the head down (cephalocaudal).

Complications may include thrombocytopenia, encephalitis, myocarditis, subacute sclerosing panencephalitis, secondary respiratory infections / pneumonia.

Serology for diagnosis:

  • Polymerase chain reaction (PCR) is an option (nasopharyngeal or urine).
  • IgM may be delayed up to 3 days after rash.

Diabetes Mellitus

Acanthosis Nigricans

  • Consists of hyperpigmented, velvety plaques typically in the flexural and intertriginous regions.
  • Often associated with diabetes, insulin resistance, and metabolic syndrome.
  • May be associated with other diseases such as paraneoplastic acanthosis nigricans.
  • Paraneoplastic AN is most commonly associated with gastric carcinoma.
  • Elderly nonobese patients with new AN should have malignancy considered as a cause.
  • Atypical (palmar, perioral, or mucosal) distributions or acute-onset AN may be more associated with malignancy.

Bullous Diabeticorum

This is a diagnosis of exclusion.

Skin manifestations:

  • Tense, noninflammatory vesicles or bullae on acral sites.
  • The lower extremities, including the toes, are most commonly affected, although the hands and forearms can also be involved. Lesions are rarely present on the trunk.
  • Lesions are typically self-limited and will resolve with supportive measures within 2-6 weeks. In some cases, a topical antibiotic can be used to prevent secondary infection and provide a barrier protection to the wound.

Diabetic Foot Ulcer

Check for this, particularly in patients with calluses. Neurogenic ulcers are difficult to treat, frequently recur, and result in significant morbidity from loss of function or loss of limb.

Skin manifestations:

  • Ulcerations are often seen on weightbearing areas of the foot such as the heel and plantar metatarsal heads.
  • Ulcerations are also encountered on the tips of prominent toes and hammer toes and over the malleoli.
  • The ulcers are surrounded by a thick callus.

Necrobiosis Lipoidica Diabeticorum

Only 0.3% of diabetic patients get this; but 30% of necrobiosis lipoidica patients have diabetes.

 Skin manifestations:

  • NLD begins as yellow-brown or red-brown papules or nodules, the lesions progress over time into yellow-brown-red colored atrophic plaques with elevated violaceous borders.
  • Plaques are atrophic and shiny in appearance, often with prominent telangiectasias.
  • Disease may be unilateral or bilateral; it is common on the lower extremities, particularly on the pretibial surface.
  • Approximately one-third of cases will develop ulcerations, often in the setting of trauma.


Seen in chronic renal failure, hemodialysis, and secondary hyperparathyroidism. Nontraditional causes are less common.

Skin manifestations:

  • Early: painful, violaceous retiform patches and plaques.
  • Late: necrosis, ulcers, eschar formation, and possibly gangrene.
  • Found in fatty areas such as the thighs, buttocks, or abdomen.

High mortality rate (60%-87%), secondary to sepsis from large, nonhealing ulcers.

There are also many cases of “nonuremic” or “nontraditional” calciphylaxis, which can occur in the setting of liver disease, diabetes, warfarin use, use of calcium-based phosphate binders, systemic corticosteroid use, solid organ malignancies, systemic lupus erythematosus, and Crohn disease.

Erythema Nodosum

Most common type of inflammatory panniculitis. Triggers include infection, pregnancy, medications, connective tissue disease, or malignancy. Autoinflammatory associations include sarcoidosis, inflammatory bowel disease, Sjögren syndrome, reactive arthritis, Behçet syndrome, and Sweet syndrome.

Skin manifestations:

  • Inflammation is typically symmetrical, bilateral, and involves the pretibial region.
  • Clues: tender, smooth nodules that are “deep-seated” in appearance. Nodules do not ulcerate.
  • The presence of nodules in sites other than the legs, ulceration, or scarring should prompt skin biopsy, tissue culture, and laboratory investigation of other etiologies of panniculitis.
  • Arthralgias are common.

Lyme Disease (Erythema Migrans)

Early localized (days to weeks following tick bite):

  • EM occurs at the site of the tick bite in 60%-90% of instances.
  • Occurs with or without systemic symptoms.
  • False negative serological testing. 

Early disseminated (weeks to months following tick bite):

  • Multiple widespread lesions represent dissemination.
  • 10% have neurologic features: meningitis, cranial or peripheral neuropathies.
  • Facial nerve palsy (Bell palsy) is the most common cranial nerve neuropathy.
  • 5% have cardiac manifestations such as AV block, myocarditis.
  • Serological testing is usually positive.

Late (months to few years):

  • Untreated cases may have chronic arthritis (typically knees), mild encephalopathy with subtle cognitive deficits, and axonal polyneuropathies.
  • Serological testing is virtually always positive.

Reactive Arthritis

A type of spondyloarthropathy; joint fluid is sterile.

This syndrome occurs 1-4 weeks after gastrointestinal or genitourinary infection with specific bacteria. Patients occasionally have systemic features, including fever, weight loss, and fatigue. Rarely there may be cardiac conduction abnormalities, aortic insufficiency, pericarditis, pleuritis, or nephropathy. For many patients, reactive arthritis is a self-limited disease, and they recover completely within 2-6 months.

A minority of patients present with the full “classic” triad of arthritis, urethritis (or cervicitis), and conjunctivitis.

Skin manifestations:

  • Conjunctivitis is bilateral and mucopurulent.
  • Balanitis circinata or circinate vulvitis.
  • Keratoderma blenorrhagicum.
  • Oral ulcers / geographic tongue.
  • Paronychia.


A systemic granulomatous inflammatory disorder with a bimodal age distribution, observed more frequently in Black women in the fourth decade. Symptoms include fever, night sweats, and weight loss.

Skin manifestations:

  • Asymptomatic red-brown dermal papules and/or plaques. However, lesions may be nonspecific.
  • Lesions favor the face, neck, upper extremities, and upper trunk are the most common specific cutaneous sarcoid lesions. A yellow-brown “apple jelly” color can be seen when a lesion is compressed with a glass slide (diascopy).
  • Less common manifestations include sarcoid lesions with epidermal change such as scale, hypopigmentation, subcutaneous nodules, cicatricial alopecia, ulceration, and scar. May occur in tattoos.

Check for enlarged lacrimal glands by everting the upper eyelid.


There are several variants of lupus.

Systemic Lupus Erythematosus (SLE)

Four of the former criteria for SLE are visible/cutaneous findings of:

  • Photosensitivity
  • Discoid rash
    • Raised or scarred, atrophic, erythematous plaques.
    • Favors scalp, ears, sun-exposed areas of the face and arms.
    • Adherent scales.
    • Look for atrophy, telangiectasia, follicular keratotic plugs, depigmentation in the center, and hyperpigmentation at the periphery.
  • Malar rash aka butterfly rash
    • Erythema covering the nose and medial cheeks. Exacerbated after sun exposure. Can precede systemic symptoms by weeks.
    • Look for fine, scaling, coalesced papules/plaques.
  • Oral ulcers

Discoid Lupus Erythematosus (DLE)

Most common form of chronic cutaneous lupus erythematosus. Can occur in isolation or with SLE.

Skin manifestations:

  • Raised or scarred, atrophic, erythematous plaques.
  • Favors scalp, ears, sun-exposed areas of the face and arms.
  • Adherent scale.
  • Look for atrophy, telangiectasia, follicular keratotic plugs, depigmentation in the center, and hyperpigmentation at the periphery.
  • Alopecia associated with DLE is scarring; permanent hair loss may be seen.

Bullous Systemic Lupus Erythematosus

Occurs due to intense inflammation; has different locations and history than diabetic bulla.

Skin manifestations:

  • Purpura may be secondary to vasculitis or thrombocytopenia.

Subacute Cutaneous Lupus Erythematosus

Skin manifestations:

  • Psoriasiform or annular lesions in a photodistributed pattern.
  • Livedo reticularis: persistent mottling of blood vessels of the skin. This is a possible clue of lupus or cryoglobulins (although it can be associated with multiple other things such as collagen disorder, other autoimmune disorder, medications, hypercoagulation disorder).
  • Telangiectasias around nail folds.

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