DERMATOLOGY AND GENERAL HEALTH
Skin manifestations of
systemic disease
Ruth C Lamb
Abstract
Skin changes can be the rst sign of an underlying medical condition,
and thus the skin can act as a window to a patients general health and
guide practitioners to identifying a diagnosis. Other patients may
already have a pre-existing diagnosis and go on to develop skin
changes as part of multisystem disease.
Keywords Acquired perforating disorders; calciphylaxis; dermato-
myositis; erythema nodosum; pyoderma gangrenosum; sarcoidosis;
systemic lupus erythematosus; systemic sclerosis
Introduction
Dermatoses can form part of a multisystem disease. Other skin
changes, for example paraneoplastic eruptions, have an associ-
ation with an internal disease and thus act to aid diagnosis of an
as yet undiagnosed condition. Therefore the importance of full
examination of the skin, nails and mucosal surfaces cannot be
underestimated in ensuring that diagnostic clues are not missed.
In addition, medications given for the treatment of other diseases
can produce skin changes.
Here, the skin manifestations of systemic disease are reviewed
by system, focusing on dermatological clinical features, differ-
ential diagnoses, investigations and possible treatments. Skin
problems associated with infection or resulting from medica-
tions, and genodermatoses, are not reviewed.
Skin problems in rheumatology
Many autoimmune systemic conditions, for example lupus
erythematosus (LE), dermatomyositis (DM) and scleroderma,
have skin manifestations. Other rheumatological conditions,
such as rheumatoid arthritis (nodules), cutaneous vasculitis,
panniculitis and pyoderma gangrenosum (PG), also demon-
strate skin changes.
Lupus erythematosus
LE is a group of chronic inflammatory conditions with skin
involvement. Systemic LE (SLE) affects several systems including
renal, neuropsychiatric, haematological and musculoskeletal. It
usually occurs in female patients aged 15e45, with an incidence
of around 6.5 per 100,000 per year in the UK depending on the
sex and racial group studied. The disease is characterized by
remissions and relapses. Diagnostic criteria help diagnosis.1 The
aetiology is not fully understood, but clinical features may result
from antibody production and resulting immune complexes.
Ruth C Lamb MBCHB BMedSci (Hons) MRCP UK (Dermatology) is a
Consultant Dermatologist at St Georges NHS University Hospital
Trust, London, UK. She has a special interest in medical
dermatology. Competing interests: she has undertaken sponsored
lectures and previously sat on an advisory board for Abbvie.
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Key points
C Changes in the skin can be the first sign of an underlying
medical condition
C Some patients will have a known multisystem disease with
skin changes
C Complete examination of the skin, mucous membranes, hair
and nails, including paraneoplastic eruptions, can provide vital
clues to an as yet undiagnosed condition
Skin clinical features: skin manifestations are variable in SLE;
most common is a facial eruption known as a malar or butterfly
rash presenting as erythema over the cheeks and nasal bridge
after exposure to sun. Generalized photosensitivity, mucosal ul-
cers and non-scarring and scarring alopecia also occur.
Other subtypes of LE: other subtypes exist and can occur as a
manifestation of SLE or in isolation. They can be divided into
subacute cutaneous LE (SCLE) and chronic cutaneous LE. Of
patients with SCLE, 15% develop SLE. Chronic cutaneous LE
includes discoid LE (DLE; Figure 1) which is associated with
scarring in the skin. SLE develops in less than 5% of individuals
with DLE.
Investigations: skin biopsy is needed to confirm the diagnosis.
Cutaneous LE subtypes share some histopathological features
including hyperkeratosis, basement membrane thickening and a
superficial and perivascular inflammatory infiltrate. Direct
immunofluorescence may show the lupus band, and baseline
blood tests including antinuclear antibody (ANA) can be useful.
Differential diagnoses: these reflect the LE subtype. The facial
rash in SLE can be mistaken for acne rosacea, seborrhoeic
dermatitis, erysipelas or DM. Psoriasis and eczema should be
considered with SCL, and granuloma faciale, sarcoidosis and
cutaneous infections including tuberculosis with DLE.
Treatment: management of SLE can require systemic immuno-
suppression. Photoprotection is the mainstay of management for
skin manifestations of all LE subtypes. Topical corticosteroids or
calcineurin inhibitors can be useful.
Dermatomyositis
DM is an idiopathic inflammatory myopathy characterized by
skin changes and proximal muscle weakness. Its incidence is
estimated at 2 per 100,000 annually, and it is twice as common in
female patients. Cutaneous changes can precede muscle changes
but are seen in around 60% of patients presenting with muscle
symptoms. The pathogenesis is incompletely understood, but it
is known that myofibres and capillaries are injured by an un-
known mechanism.
Skin clinical manifestations: patients are often photosensitive.
Characteristic findings include Gottrons papules (violaceous
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 DERMATOLOGY AND GENERAL HEALTH
Figure 1 Chronic discoid lupus erythematosus left scalp.
papules on the dorsal metacarpo- and intercarpo-phalangeal
joints), a heliotrope eruption (erythematous eruption on the
upper eyelids) and the shawl sign (poikiloderma and pigmen-
tary change in photoexposed sites, e.g. upper back, V of the
neck). Nail fold changes include periungual erythema, ragged
cuticles, haemorrhagic infarcts and abnormal capillaries at the
proximal nail fold. Cutaneous calcium deposits may be seen in
juvenile DM.
Investigations: skin biopsy and serology including ANA and
extractable nuclear antigen (ENA) can be useful. Myositis-
specific autoantibodies such as antisynthetase antibodies
including anti-Jo 1 may be detected. Diagnosis of muscle disease
is by imaging, electromyography, muscle biopsy and blood tests
including creatinine kinase and inflammatory markers. Adults
with DM can have up to a sevenfold increased risk of malig-
nancy, so adult patients should undergo targeted investigation to
exclude this.2
Differential diagnoses: these include other inflammatory skin
conditions such as LE, psoriasis and eczema.
Management: this depends on the degree of muscle involve-
ment. Skin disease can be managed with topical corticosteroids
or systemic medications such as hydroxycholoroquine or
methotrexate.
Scleroderma and systemic sclerosis (SSc)
Scleroderma describes thickened skin. It can be localized to a
limited area of skin (morphoea) or be part of a systemic
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condition with internal organ involvement, known as SSc. SSc is
further characterized as diffuse or limited cutaneous SSc. The
incidence of SSc is 0.6e122 per 100,000 per year. Pathogenesis
involves immune activation, vascular damage and increased
collagen deposition.
Clinical features: systemic symptoms including Raynauds
phenomenon, arthralgia, myalgia, fatigue, breathlessness and
weight loss can occur in SSc. Gastrointestinal, cardiac, renal and
lung involvement can also be seen. Skin changes typically affect
the digits, hands and face, and include changes in pigment,
sclerodactyly, ulceration and telangiectasia. Calcium deposits
can be seen later in the disease. Localized scleroderma (mor-
phoea), not associated with internal organ involvement, can be
subdivided by extent (generalized, localized) and clinical
appearance (e.g. en coup de Sabre), which appears in a linear
formation affecting the scalp or face.
Investigations: diagnosis is made on the basis of suggestive
symptoms or clinical findings. Bloods should be checked for
ANA/ENA, including antitopoisomerase (anti Scl-70) and/or
anti-RNA polymerase III antibody.
Differential diagnosis of SSc: this includes other scleroderma-
like disorders such as morphoea, scleromyxoedema and scle-
roedema. Alternative diagnoses to consider in morphoea alone
include erythema chronicum migrans.
Treatment: SSc can require systemic immunosuppression and
agents to promote systemic vasodilatation. Morphoea can be
treated with topical corticosteroids or ultraviolet light treatment,
usually UVA.
Skin problems in gastroenterology
Several hepatic and bowel disorders, such as pruritus resulting
from deranged liver function or primary biliary cirrhosis, can
affect the skin non-specifically. Dermatitis herpetiformis, asso-
ciated with gluten-sensitive enteropathy, is characterized by skin
changes in addition to bowel manifestations. Inflammatory
bowel disease (IBD) is associated with skin changes in approxi-
mately 15% of patients; these include erythema nodosum (EN),
mucosal surface changes such as episcleritis, PG and psoriasis.
Some cutaneous manifestations, for example EN and episcleritis,
mirror bowel disease activity, but others, such as PG, can occur
independently of this. Additionally, patients with IBD can be
affected by cutaneous problems surrounding their stoma site
such as PG, or by irritant dermatitis from stoma bags or bowel
contents.
Erythema nodosum
EN occurs in around 10% of individuals with IBD. It is also
associated with other systemic conditions including sarcoidosis,
infections such as tuberculosis or streptococcal infections and
drugs such as the oral contraceptive pill. An episode can last
from 3 weeks but rarely up to 6 months. Pathogenesis is not fully
understood, but EN may be a delayed hypersensitivity reaction
after exposure to unknown antigens.
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 DERMATOLOGY AND GENERAL HEALTH

Clinical features: raised painful inflammatory nodules can
occur, classically on the anterior shins.
Investigations: the diagnosis is usually clinical, but biopsy may
demonstrate septal panniculitis. Other investigations, for
example antistreptolysin O titres, are directed at ruling out un-
derlying causes.
Treatment: management of the underlying cause, rest,
compression hosiery and anti-inflammatory medications can be
required.
Pyoderma gangrenosum
PG associated with IBD is thought to be the second most common
skin manifestation of IBD, although it remains rare. It can also be
associated with other medical conditions including haemato-
logical malignancy. PG is a neutrophilic dermatosis, and patho-
genesis can relate to neutrophil dysfunction and systemic
inflammation.
Clinical features: lesions begin as painful pustules or nodules
that ulcerate with a characteristic purple undermined edge
(Figure 2), most commonly on the legs but also around stoma
sites.
Investigations: clinical appearances are characteristic, but swabs
may reveal coexistent infection. Biopsy is often non-specific or
shows a neutrophilic infiltrate.
transplant and rarely in patients without ESRD. A cross-sectional
study of 242 outpatient haemodialysis patients showed a preva-
lence of 4%.3 The pathogenesis is unclear but it may result from
vascular and soft tissue calcification that produces reduced
arteriolar blood flow.
Clinical features: these depend on the stage of evolution of the
lesion and range from painful purple nodules to necrotic ulcer-
ation with a central black eschar in keeping with thrombosis and
ischaemia.
Investigations: skin biopsy shows arteriolar calcification and
thrombosis. A blood profile, for example parathyroid hormone
concentrations and phosphate, should be performed to examine
calcium haemostasis.
Differential diagnosis: this includes warfarin necrosis, athero-
sclerosis and cholesterol emboli.
Treatment: management includes wound care, maintenance of
calcium homeostasis and sodium thiosulphate (unlicensed indi-
cation), although evidence for the latter is scanty. The prognosis
is poor.
Acquired perforating disorders
These encompass a group of conditions seen in up to 11% of
ESRD patients on renal replacement therapy,4 or with diabetes

Treatment: management is challenging but includes potent

topical or oral corticosteroids, azathioprine (unlicensed indica-
tion) or ciclosporin (unlicensed indication).

Skin problems in renal disease

Patients with end-stage renal disease (ESRD) can experience non-
specific skin complaints including generalized itch, prurigo
nodularis and xerosis. In addition, conditions such as calciphy-
laxis and acquired perforating disorders can be seen.

Calciphylaxis
This presents with necrosis and ischaemia of the skin in patients
with ESRD on dialysis, in those who have recently had a renal

Figure 3 Acquired reactive perforating collagenosis in a patient with

Figure 2 Pyoderma gangrenosum affecting the anterior shin. diabetes mellitus.

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 DERMATOLOGY AND GENERAL HEALTH

Treatment: management is challenging but includes treatment of

Skin manifestations seen in diabetes mellitus the underlying disease (e.g. to improve glycaemic disease in
Skin change Clinical features diabetic individuals), symptomatic treatment with emollient,
topical corticosteroids and ultraviolet light therapy.
Acanthosis nigricans Velvety hyperpigmentation of the flexural
surfaces Skin problems in endocrine and metabolic disorders
Bullous diabeticorum Non-inflammatory blistering of acral skin,
Thyroid disease, both hyperthyroidism and hypothyroidism, can
(diabetic bullae) possibly associated with poor glycaemic
affect the skin, hair and nails non-specifically. This includes
control
changes in texture and pigment, such as fine, smooth or hyper-
Diabetic dermopathy Asymptomatic, circular, redepink papules or
pigmented skin in hyperthyroidism, and dry, coarse, pale skin in
plaques on pretibial skin, evolving to brown
hypothyroidism. More specific skin findings such as pretibial
atrophic patches
myxoedema are also seen.
Neuropathic Ulceration in areas susceptible to trauma,
Diabetes mellitus has multiple skin manifestations (Table 1)
ulceration including weight-bearing areas and sites of
including:
friction from footwear
 necrobiosis lipoidica e yellow atrophic patches, often on
Perforating disorders Multiple small keratotic papules sometimes
the shins and sometimes with an erythematous rim. Ul-
with an erythematous border
ceration can occur, and treatment is challenging
Necrobiosis lipoidica Redebrown papules/nodules affecting the
 acanthosis nigricans e a velvety hyperpigmentation of
shins and evolving to yellowebrown atrophic
the flexural surfaces, usually around the neck and axillae,
plaques that can ulcerate
that is seen in obese patients and in diabetes mellitus. It is
Table 1 rarely associated with malignancy. This should be
considered when the condition is rapid in onset and/or
widespread. Strict glycaemic control may produce only
mellitus (Figure 3). The pathogenesis is unclear, but it is postu- mild improvement.
lated that abnormal keratinization may result in extrusion of Other metabolic disorders with skin manifestations include
dermal material. those of the adrenal glands, for example pigmentation in Addi-
sons disease, and nutritional deficiencies such as zinc deficiency
Clinical features: these are characteristic and include multiple resulting in acrodermatitis enteropathica.
erythematous papules with central keratotic plugging. Patients
describe intense itch. The diagnosis is clinical, but biopsy can be Skin problems in malignancy and haematological disease
supportive. Skin changes can be seen in association with internal malignancy
as a paraneoplastic phenomenon and are detailed in Table 2.
Differential diagnosis: this includes nodular prurigo, folliculitis Malignancy can also occur in the skin (e.g. cutaneous T cell
and atypical infections. lymphoma), but this is not covered here. Some conditions are

Paraneoplastic skin changes

Clinical features Most commonly associated malignancy

Leser-Tr
elat disorder Multiple rapidly appearing seborrhoeic Gastrointestinal adenocarcinoma
keratoses
Necrolytic migratory erythema Erosions affecting flexural sites Glucagon-secreting tumour of the pancreas
Acanthosis palmaris and acquired Velvety appearance to the palms with ridging Gastric or lung cancer
pachydermatoglyphia (tripe palms)
Erythema gyratum repens Concentric erythematous migrating rings in Bronchial carcinoma
plaques
Acrokeratosis paraneoplastica (Bazex Psoriasiform plaques affecting acral sites Squamous cell carcinoma of the upper
syndrome) including the nose and ears aerodigestive tract, e.g. oesophagus, pharynx
Ectopic Cushings syndrome Generalized hyperpigmentation of skin and Small cell lung carcinoma
mucous membranes, often in addition to other
features of Cushings syndrome
Acanthosis nigricans Velvety, hyperpigmented, thickened flexural Gastric cancer
surfaces
Hypertrichosis lanuginosa Widespread fine hair growth commonly Adenocarcinoma of lung, bowel, breast or
affecting the head and neck kidney

Table 2

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 DERMATOLOGY AND GENERAL HEALTH

strongly associated with underlying malignancy in a small subset

of patients, for example DM, acanthosis nigricans, Sweets syn-
drome and PG, so clinicians should give consideration to
screening for underlying malignancy.

Necrolytic migratory erythema is a dermatosis associated with

a rare glucagon-secreting tumour of the pancreas; it rarely pre-
sents as glucagonoma syndrome, which includes necrolytic
migratory erythema, weight loss, new-onset diabetes mellitus
and glossitis. Treatment of the underlying tumour resolves the
symptoms, although the prognosis is often poor. Necrolytic
migratory erythema is also seen in association with some nutri-
tional deficiencies, such as of zinc.

Sweets syndrome, or acute febrile neutrophilic dermatosis, de-

scribes the appearance of erythematous, tender, firm nodules and
plaques, usually on the head, neck and/or upper extremities. The
patient can also have a fever and/or leucocytosis. It can occur with
infection (commonly upper respiratory or gastrointestinal), after
exposure to drugs (e.g. granulocyte colony-stimulating factor),
malignancy (usually haematological) or conditions such as IBD.
The pathogenesis is poorly understood, but cytokine dysre-
gulation or a hypersensitivity reaction and a possible genetic
predisposition are sometimes implicated.
Investigations e biopsy demonstrates a dense neutrophilic
dermal infiltrate with no vasculitis. Blood tests may reveal neu-
trophilia and/or elevated inflammatory markers. Investigation
for possible underlying malignancy should be directed towards
positive symptoms or signs uncovered by a general history and
examination.
Treatment e this may not be required as the condition may Figure 4 Cutaneous sarcoid affecting skin in the deltoid region of the
resolve over a few weeks. Otherwise, oral glucocorticoids are the arm.
mainstay.

Investigation: biopsy shows naked non-caseating granulomas

Skin problems in respiratory disease
Cutaneous changes can be seen in association with other lung
disorders (e.g. eczema in atopic patients with asthma) or in as-
sociation with a multisystem disorder such as sarcoid.
Sarcoid
Sarcoidosis is a multisystem disease known to affect the skin,
lung, nervous system, eyes, lymph nodes, heart, kidneys and
joints. Non-caseating granulomas are, however, seen on histol-
ogy. Clinically, skin signs are divided into papules, nodules,
plaques and infiltration of scars. It is estimated that 25% of pa-
tients with sarcoidosis have skin signs. Other skin changes, such
as EN and Sweets syndrome, can be seen in addition to the non-
caseating granulomatous changes.
Clinical manifestations in skin: papular sarcoid presents as
numerous non-scaly, 1e10-mm papules that vary in colour from
red, purple and skin colour to brown. It can involve the face and
be mistaken for acne rosacea. Subcutaneous sarcoid (Figure 4)
appears as skin-coloured plaques, often on the arms, and can be
confused with granuloma annulare. Lupus pernio describes
sarcoid affecting the face; it can resolve with scarring. Sarcoid
can also have a predilection for scars and tattoos.
surrounded by a sparse lymphocytic infiltrate. The apple jelly
appearance on diascopy is not specific for sarcoid but can be
seen in granulomatous conditions. A full physical examination,
including a chest X-ray, electrocardiogram and ophthalmology
examination, should be undertaken to assess for involvement of
other systems. Blood testing should include full blood count,
liver and renal function tests and serum calcium. Serum
angiotensin-converting enzyme concentrations can be elevated,
but this has poor sensitivity and specificity as a diagnostic test.
Differential diagnoses: these include other granulomatous dis-
orders such as foreign body granuloma, mycobacterial infection,
deep fungal infection and leprosy.
Treatment: skin changes can be treated with topical corticoste-
roids. Systemic treatment with oral glucocorticoids or immuno-
suppression with methotrexate may be required. A
KEY REFERENCES
1 Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the
classication of systemic lupus erythematosus. Arthritis Rheum
1982; 25: 1271e7.

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 DERMATOLOGY AND GENERAL HEALTH

2 Barnes BE, Mawr B. Dermatomyositis and malignancy. A review of 4 Zelger B, Hintner H, Aubock J, et al. Acquired perforating derma-
the literature. Ann Intern Med 1976; 84: 68e76. tosis. Transepidermal elimination of DNA material and possible role
3 Angelis M, Wong LL, Myers SA, et al. Calciphylaxis in patients on of leucocyte in pathogenesis. Arch Dermatol 1991; 127: 695e700.
haemodialysis: a prevalence study. Surgery 1997; 122: 1083e9.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 What is the most likely co-morbidity in this patient?

A. Coeliac disease
A 38-year-old man presented with a painful ulcerated area on his
B. Sarcoidosis
right shin. He said that it might have developed after some mild
C. Chronic renal failure
trauma from playing football with his son the previous week. He
D. Diabetes mellitus
had a history of inflammatory bowel disease.
E. Underlying malignancy
On clinical examination, he appeared well and his temperature
was 37 C. There was a 7 cm  10 cm ulcerated area with an Question 3
undermined edge on the shin.
A 45-year-old man presented with an area of scaling, erythema
and scarring affecting his right temple, and some patches of al-
What is the most appropriate initial management action?
opecia with a shiny, thin appearance of the skin in these areas.
A. Colonoscopy
He was otherwise well.
B. Biopsy of the ulcer
C. Intravenous antibiotics
Investigations
D. Oral corticosteroids
Biopsy showed hyperkeratosis, basement membrane thickening
E. Potent topical corticosteroids
and superficial and perivascular inflammatory infiltrate

What is the most likely diagnosis?

Question 2
A. Discoid lupus erythematosus
A 25-year-old woman presented with bilateral atrophic yellow B. Acne rosacea
patches affecting both shins that had been gradually C. Seborrhoeic dermatitis
enlarging over several years. The edge of the patches appeared D. Dermatomyositis
slightly red. E. Sarcoidosis

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