Scleroderma is a group of rare, progressive diseases
that involve the hardening and tightening of the skin
and connective tissues — the fibers that provide the
framework and support for your body. Localized
scleroderma affects only the skin. Systemic
scleroderma also harms internal organs, such as the
heart, lungs, kidneys and digestive tract.
Scleroderma is a chronic autoimmune disease
characterized by fibrosis (or hardening), vascular
alterations, and autoantibodies. There are two major
Limited systemic sclerosis/scleroderma's cutaneous
manifestations mainly affect the hands, arms and face.
Previously called CREST syndrome in reference to the
following complications: Calcinosis, Raynaud's
phenomenon, Esophageal dysfunction, Sclerodactyly,
and Telangiectasias. Additionally, pulmonary arterial
hypertension may occur in up to one third of patients
and is the most serious complication for this form of
Diffuse systemic sclerosis/scleroderma is rapidly
progressing and affects a large area of the skin and one
or more internal organs, frequently the kidneys,
esophagus, heart and lungs. This form of scleroderma
can be quite disabling. There are no treatments for
scleroderma itself, but individual organ system
complications are treated.Other forms of scleroderma
include Systemic sine scleroderma, which lacks skin
changes, but has systemic manifestations, and two
localized forms which affect the skin, but not the
internal organs: morphea, and linear scleroderma.
Prognosis is generally good for limited cutaneous
scleroderma patients that escape pulmonary
complications. Prognosis is worse for diffuse cutaneous
disease, particularly in older age, and for males. Death
occurs most often from pulmonary, heart and kidney
The term systemic sclerosis is used to describe a
systemic disease characterized by skin induration and
thickening accompanied by various degrees of tissue
fibrosis and chronic inflammatory infiltration in
numerous visceral organs, prominent fibroproliferative
vasculopathy, and humoral and cellular immune
The American College of Rheumatology (ACR) criteria
for the classification of systemic sclerosis require one
major criterion or two minor criteria, as follows:
- Proximal scleroderma is characterized by
symmetric thickening, tightening, and induration
of the skin of the fingers and the skin that is
proximal to the metacarpophalangeal or
metatarsophalangeal joints. These changes may
affect the entire extremity, face, neck, and trunk
(thorax and abdomen)
- Sclerodactyly is characterized by thickening,
induration, and tightening of the skin, limited to
only the fingers.
- Digital pitting scars or a loss of substance from the
finger pad: As a result of ischemia, depressed
areas of the fingertips or a loss of digital pad tissue
- Bibasilar pulmonary fibrosis includes a bilateral
reticular pattern of linear or lineonodular densities
most pronounced in basilar portions of the lungs
on standard chest roentgenography. These
densities may assume the appearance of diffuse
mottling or a honeycomb lung and are not
attributable to primary lung disease.
Pathophysiology- Systemic sclerosis is a systemic
disease that affects many organ systems. It is most
obvious in the skin; however, the GI tract; the
respiratory, renal, cardiovascular, and genitourinary
systems; and numerous vascular structures are
frequently involved. The symptoms result from
inflammation and progressive tissue fibrosis and
occlusion of the microvasculature by excessive
production and deposition of types I and III collagens.
The levels of other macromolecules (eg,
glycosaminoglycans, tenascin, fibronectin) found in the
connective tissue are also increased.
The vascular alterations show a predilection for the
small arteries and arterioles. Vascular dysfunction is
one of the earliest alterations of systemic sclerosis and
may represent the initiating event in its pathogenesis.
Severe alterations in small blood vessels of skin and
internal organs, including fibrosis and perivascular
cellular infiltration with activated T cells, are almost
always present in systemic sclerosis.
Causes- The exact etiology of systemic sclerosis is
unclear; however, the following pathogenic
mechanisms are always present:
- Endothelial cell injury
- Fibroblast activation
- Cellular and humoral immunologic derangement
Environmental factors (eg, triggers or accelerators) for
the development of systemic sclerosis include the
- Silica exposure
- Solvent exposure (vinyl chloride, trichloroethylene,
epoxy resins, benzene, carbon tetrachloride)
- Radiation exposure or radiotherapy
Cytomegalovirus, human herpesvirus 5, and parvovirus
B19 have been proposed as viral accelerating factors,
but evidence of their involvement is inconclusive.
Drugs: Bleomycin and pentazocine may be involved in
the development of systemic sclerosislike disorders.
- Skin tightness and induration
- Skin pigmentary changes (hyperpigmentation or
- Diffuse pruritus
- Sclerodactyly with digital ulceration, loss of skin
creases, joint contractures, and sparse hair.
- Raynaud phenomenon (recurrent vasospasm of
the fingers and toes and usually occurs in response
to stress or cold exposure)
- Healed pitting ulcers in fingertips
- Cutaneous and mucosal telangiectasis.
- Gastroesophageal reflux caused by lower
esophageal sphincter (LES) incompetence and
decreased or absent peristalsis in the lower two
thirds of the esophagus (may lead to hoarseness,
aspiration pneumonia, and dysphagia)
- Dyspepsia, bloating, and early satiety
- Constipation alternating with diarrhea (may lead
- Progressive dyspnea
- Chest pain (precordial) due to pulmonary artery
- Dry persistent cough due to restrictive lung
- Loss in joint range of motion and joint flexion
- Symptoms of carpal tunnel syndrome
- Muscle weakness
- Dyspnea due to pericardial effusion, congestive
heart failure, or myocardial fibrosis
- Palpitations, irregular heart beats, and syncope
due to conduction abnormalities
- Congestive heart failure
- Erectile dysfunction
- Dyspareunia (painful sexual intercourse)
Ears, nose, and throat
- Sicca syndrome
- Poor dentition due to sicca syndrome
- Loosening of dentition due to alteration in the
tooth suspensory ligament and thickening of the
- Hoarseness due to acid reflux with vocal cord
inflammation or fibrosis
Endocrine system -Hypothyroidism
- Renal crisis
- Chronic renal insufficiency
- Facial pain and decreased sensation due to
- Hand paresthesias and weakness due to carpal
tunnel sensory peripheral entrapment neuropathy
- Headache and stroke during hypertensive renal
- Weight loss
Skin- Skin pigmentary changes include a salt-and-pepper
appearance, with areas of hyperpigmentation
alternating with hypopigmentation, or an overall
appearance of tanned skin that persists long after
- Telangiectasias are dilated vessels located just
beneath the dermis on any skin area, but they are
most obvious in the face (perioral area), hands,
and anterior chest.
- The skin of the hands may be edematous or
swollen early in the disease, and the patient may
initially report this as puffy changes. This
edematous stage precedes the indurated sclerotic
stage; longer time to progression to the sclerotic
phase indicates a better prognosis. A rapid
progression of sclerosis is associated with a worse
prognosis and, often, more extensive and
aggressive visceral organ involvement with an
increased risk of renal crisis or interstitial lung
- In the sclerotic phase, the skin may appear tight
and shiny, with a characteristic loss of hair,
decreased sweating, and loss of the ability to make
a skin fold. This process of thickening generally
begins distally on the fingers. Structures such as
skin creases and dorsal veins begin to fade. The
skin induration usually progresses proximally in a
continuous symmetrical fashion.
- Calcinosis may develop on the fingers and
extremitiesusually the extensor side of the
forearms and the prepatellar areas; however, any
area can be affected.
- Limited cutaneous systemic sclerosis involves
areas distal to the elbow and knee but may involve
the face and neck. CREST (calcinosis, Raynaud
phenomenon, esophageal dysmotility,
sclerodactyly, and telangiectasias [not all are
needed to be called CREST]) syndrome is an older
term used to describe this subset of limited
cutaneous systemic sclerosis.
- Diffuse cutaneous systemic sclerosis refers to skin
thickening on the trunk and proximal aspects of
the extremities in addition to involvement of the
face and distal aspects of the extremities.
- Reduced oral aperture (microstomia) due to
perioral involvement (measure incisor-to-incisor
distance) may develop.
- Edema may be the result of hydrophilic
glycosaminoglycan deposits in the dermis. These
changes (edema) may also reflect vascular
changes, inflammation, and hydrostatic changes.
The mechanism by which the edema resolves is
not clear. Possibly, the edema becomes less
apparent owing to a reduction of the hydrophilic
glycosaminoglycan deposits as they are replaced
by the less hydrophilic fibrous collagens.
Alternatively, the edema does not resolve but
becomes clinically less apparent because of dermal
thickening. The edema usually does not improve
with the use of diuretic therapy.
Eyes, ears, nose, and throat
- Salivary production may be decreased and
spontaneous sublingual pooling of saliva may be
- Xerostomia and xerophthalmia may be part of the
examination findings. A confirmatory minor
salivary gland biopsy may show fibrosis without
the pronounced lymphocytic aggregates that
would be expected with primary Sjögren
syndrome. In addition, patients with systemic
sclerosis typically do not harbor anti-Ro and antiLa antibodies.
- Oropharyngeal and esophageal cancers are more
common in persons with diffuse systemic sclerosis.
- Raynaud phenomenon results in characteristic
color changes of pallor, cyanosis, and then redness
(white, blue, red), which are usually accompanied
by numbness, tingling, or pain. These events may
be triggered by cold, smoking, or emotional stress.
Subintimal hyperplasia, typically present in
systemic sclerosis vessels, can reduce the luminal
diameter by more than 75%, limiting blood flow.
This baseline reduction, in addition to the natural
response to cold, accounts for the exaggerated
- Raynaud phenomenon occurs in 5-15% of the
general population. The female-to-male ratio is
4:1, with onset occurring during the teenaged
- Raynaud phenomenon may precede obvious
systemic sclerosis features by months or even
years. Symptoms may last longer than 2 years. If
this occurs without the development of
characteristic connective-tissue diseases, a benign
primary Raynaud phenomenon is generally
indicated, with an excellent prognosis. However,
5-10% of this population may eventually develop
- Infarction and dry gangrene of the fingers and toes
may be due to severe vasospasm or to structural
- Nail-fold capillary microscopy demonstrates fewer
capillaries than normal (ie, capillary loop drop; see
image below) and numerous dilated capillary
- Patients may present with generalized arthralgias
and morning stiffness that may mimic other
systemic autoimmune diseases. Clinically apparent
synovitis is uncommon. Hand and joint function
may decline over time because of skin tightening
rather than arthropathy. Tendon friction rubs are
found almost exclusively in diffuse systemic
sclerosis and may be detected as the tendon is
moved actively or passively.
- The following palpable tendon friction rubs may be
1)Shoulder - Scapula
2)Elbow - Olecranon
3)Knee - Patella
4)Wrists - Flexor or extensor
5)Fingers - Flexor or extensor (rare)
6)Ankle - Anterior tibia, posterior tibia, peroneal,
- Myositis may cause weakness and muscle wasting.
Levels of serum creatine kinase (CK) and aldolase
- Acroosteolysis (ie, resorption or dissolution of the
distal end of the phalanx) may occur.
- Flexion contractures of any affected joint may
- Dry rales may be the only physical examination
finding that suggests pulmonary involvement in
- An accentuated pulmonic second heart sound (P2)
or right ventricular heave may indicate the
presence of pulmonary artery hypertension.
- Transthoracic echocardiography is a noninvasive
study for assessing pulmonary artery pressure. A
systolic pulmonary artery pressure of greater than
35 mm Hg is considered to represent pulmonary
artery hypertension. However, right-sided heart
catheterization provides the most accurate
pulmonary artery pressure
- Pulmonary function testing is important in all
patients with systemic sclerosis, although lung
volumes can correlate poorly with extent of
interstitial lung disease. Results of pulmonary
function testing are ultimately abnormal in 80% of
- Patients are at risk for aspiration pneumonia due
to lower esophageal sphincter incompetence
- Reflux due to decreased lower esophageal
- Severe esophagitis
- Barrett metaplasia (can lead to cancer)
- Candida esophagitis
- Esophageal strictures
- Gastric vascular antral ectasia (dilated submucosal
capillaries), also known as watermelon stomach
- Primary biliary cirrhosis (PBC) associated with
- Wide-mouth colonic diverticula
- Atrophy of smooth muscle and fibrotic changes
leading to decreased peristalsis throughout the GI
tract (gastroesophageal reflux disease [GERD],
gastroparesis, constipation, pseudo-obstruction;
- Anal sphincter incompetence
- Patients with diffuse, rapid skin involvement have
the highest risk (approximately 20-25%) of
developing scleroderma renal crisis. Renal crisis
occurs in about 10% of all patients with systemic
- Renal crisis presents as accelerated hypertension,
oliguria, headache, dyspnea, edema, and rapidly
rising serum creatinine levels.
- Scleroderma renal crisis that is not treated
aggressively invariably leads to renal failure,
requiring dialysis or renal transplantation, or even
- Preventing renal crisis is critical. Check blood
pressure, monitor serum creatinine, and start
angiotensin-converting enzyme (ACE) inhibitors
early in at-risk patients.
- Avoid high doses of corticosteroids since this is a
significant risk factor for renal crisis.
- Cardiac involvement indicates a worse prognosis.
Pericardial effusion is usually asymptomatic and
may develop in up to one third of patients with
systemic sclerosis. Clinically significant pericarditis
- Cor pulmonale may develop secondary to longstanding pulmonary fibrosis or pulmonary artery
- Conduction abnormalities, including complete A-V
block, may be revealed with routine ECG or, more
frequently, with 24-hour Holter monitor or
- Infiltrative cardiomyopathy with replacement of
cardiac muscle by fibrous tissue can lead to
arrhythmias, heart failure, or both.
- Contraction band necrosis results from global
ischemia and reperfusion. Patients may have
recurrent episodes of vasospasm that are caused
by the same mechanism involved in Raynaud
phenomenon. This process can lead to
cardiomyopathy and heart failure.
- Trigeminal neuralgia (uncommon) and carpal
tunnel symptoms may result from peripheral
entrapment neuropathies. Although rare, sensory
neuropathies unrelated to entrapment may be
Obstetrics and gynecology
- Women may experience vaginal dryness,
dyspareunia, and menstrual irregularities.
- Pregnancy in women with systemic sclerosis is
considered a high risk because of a higher risk of
pregnancy loss and higher complication rates, but
a diagnosis of systemic sclerosis is not an absolute
contraindication for pregnancy.
- Some symptoms may increase during pregnancy
(eg, edema, arthralgias, GERD). Skin
manifestations are not reported to worsen, but
the data on this matter are incomplete. Raynaud
symptoms may improve during pregnancy, only to
worsen after delivery.
- Certain medications, such as D-penicillamine,
cytotoxic agents, and ACE inhibitors, should be
discontinued prior to pregnancy.
- Erectile dysfunction is common in males and is the
presenting symptom in some cases.
- Urinary bladder fibrotic infiltration may cause
- Nephrogenic Systemic
- Primary Biliary Cirrhosis
-Primary Pulmonary Hypertension
- Bleomycin-induced scleroderma
-Digital sclerosis of diabetes mellitus
- Linear scleroderma
- Intestinal obstruction
- People with scleroderma usually have elevated
blood levels of certain antibodies produced by the
immune system like Topoisomerase I antibodies,
Anticentromere antibodies., Fibrillarin antibodies
and antibodies to ribonucleoprotein (RNP) & AntiRNA polymerase I and III antibodies
- Cell-mediated abnormalities involve lymphocytes,
mononuclear phagocytes, and mast cells.
- CT scan: HRCT scan is required to evaluate
pulmonary involvement. Imaging may reveal a
ground-glass appearance, possibly indicating
active alveolitis. Ground-glass appearance on
HRCT scan is the first abnormality observed during
the development of lung fibrosis and is
subsequently replaced by honeycombing and
traction bronchiectasis or bronchiolectasis.
- Radiography: Chest radiography is an insensitive
imaging procedure that shows only late findings of
pulmonary fibrosis, such as increased interstitial
markings. Extremity radiography should be
performed to reveal calcinosis and resorption of
the distal tufts of the digits.
- Echocardiography: Conduct this test to evaluate
the patient's pulmonary artery pressure and to
assess septal fibrosis or pericardial effusions.
- Right-heart catheterization: This remains the
standard criterion for diagnosing pulmonary
hypertension and is performed after an elevated
pulmonary artery pressure is found on
- Esophagraphy: Perform this test to document
- Nail-fold capillary microscopy: This study
demonstrates fewer capillaries than normal (ie,
capillary loop drop; see image below) and
numerous dilated capillary loops.
- Bronchoscopy with bronchoalveolar lavage: This is
used to assess for active lung inflammation
- Tissue sample- removal a small tissue sample
(biopsy) of affected skin to be examined in the
laboratory for abnormalities
TreatmentMedication-The goals of pharmacotherapy are to
reduce morbidity and to prevent complications.
Primary drug treatment aims at inhibiting tissue
fibrosis and vascular and immune system alterations,
which may be primarily responsible for the wide
variety of systemic morbidity.
Glucocorticosteroids-These agents are used to treat
inflammatory complications (eg, myositis,
Prednisone (Sterapred)- Immunosuppressant for
treatment of autoimmune disorders. May decrease
inflammation by reversing increased capillary
permeability and suppressing PMN activity. Prednisone
is inactive and must be metabolized to prednisolone.
Metabolism may be impaired in patients with liver
2.5-5 mg PO qam initially, titrate upward prn to control
symptoms, gradually decrease to maintain at lowest
possible dose; doses >40 mg/d can increase risk of
Immunosuppressive agents- These agents inhibit key
steps in immune reactions.
Azathioprine (Imuran)- Antagonizes purine metabolism
and inhibits synthesis of DNA, RNA, and proteins. May
decrease proliferation of immune cells, which results in
lower autoimmune activity. 50-150 mg/d PO qam
Methotrexate- Antimetabolite that inhibits DNA
synthesis and cell reproduction in malignant cells. May
suppress immune system. Satisfactory response
observed in 3-6 wk following administration.
7.5-25 mg/wk PO/IV/IM/SC; adjust dose gradually to
attain satisfactory response
Cyclophosphamide - Chemically related to nitrogen
mustards. As an alkylating agent, the mechanism of
action of the active metabolites may involve cross-
linking of DNA, which may interfere with growth of
normal and neoplastic cell
50-150 mg/d PO single am dose; fluid intake is
important (2-3 L/d); empty bladder hs
Mycophenolate Mofetil- Used to help limit collagen
formation. Potent selective, noncompetitive, and
reversible inhibitor of purine synthesis. Has cytostatic
effects on lymphocytes. 1-1.5 g PO bid
Chelating agents- These agents may improve certain
aspects of the disease.
Penicillamine-Inhibits the formation of mature collagen
crosslinks, rendering un-crosslinked molecules more
susceptible to proteolytic degradation.
mg/d PO on empty stomach divided bid/tid
Endothelin receptor antagonist- These agents bind to
endothelin receptor present in endothelium and
vascular smooth muscle. The effect can result in
Bosentan-Dual endothelin A and B receptor antagonist
for treatment of pulmonary arterial hypertension.
Decreases both pulmonary and systemic vascular
resistance and increases cardiac output without
increasing heart rate.
62.5 mg PO bid for 4 wk, then increase to 125 mg PO
Phosphodiesterase type 5 inhibitor, peripheral
vasodilator- These agents may increase vasodilation in
the pulmonary vascular bed. E.g Tadalafil
Sildenafil (Revatio)- Promotes selective smooth muscle
relaxation in lung vasculature possibly by inhibiting
PDE-5. This results in subsequent reduction of blood
pressure in pulmonary arteries and increase in cardiac
20 mg PO tid; adjust dose in liver or renal failure.
- Physical or occupational therapy. Therapists can
help you manage pain, improve your strength and
mobility, and work on performing essential daily
tasks to maintain your independence.
- Cosmetic procedures. The appearance of skin
lesions associated with scleroderma may be
helped by exposure to ultraviolet light. Laser
surgery also may help camouflage or eliminate
- Amputation. If finger ulcers caused by severe
Raynaud's disease have developed gangrene,
amputation may be necessary.
- Lung transplants. People who have developed
high blood pressure in the arteries to their lungs
(pulmonary hypertension) may be candidates for