SYSTEMIC SCLEROSIS (SSc)
Systemic sclerosis is a chronic disease of unknown cause characterized by
affection of small blood vessels and excessive synthesis and accumulation of
extracellular matrix proteins (collagens, glycosaminoglycans, fibronectin) resulting in
fibrosis and obliteration of vessels and tissue ischemia. Vascular endothelial damage
and autoimmunity are thought to be important in the pathogenesis of this condition.
The disease most characteristically involves the skin which becomes thick and tightly
bound to underlying structures. The internal organs commonly involved are
gastrointestinal tract, lungs, kidneys, and heart. The prognosis of the disease largely
depends on the degree and extent of visceral involvement, particularly the lung and
the kidney. Apart from the multisystemic, progressive and often fatal form of the
disease known also as systemic sclerosis (systemic scleroderma, SSc), scleroderma
may also occur as localized and circumscribed forms (like morphea and linear
scleroderma) in which the internal organs are spared.
Epidemiology
This disorder is relatively rare. The peak age of onset is in the fourth and fifth
decades, and overall prevalence is 10-20 per 100 000 with a 4:1 female
preponderance. The mortality is highly variable and depends upon the extent and
location of disease.
Classification
The extent of skin involvement bears close correlation with the degree and extent
of internal organ disease. Based mainly on the extent of skin change, SSc can be
classified into two subsets even though there is some overlap One subset is called
diffuse cutaneous SSC and is characterized by the rapid development of symmetric
skin thickening of proximal and distal extremities, face, and trunk and early
involvement of kidney and other internal organs The other subset is called limited
cutaneous SSC , typified by symmetric skin thickening limited to distal extremities
and face. This subset may show features of the CREST syndrome, (calcinosis,
Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.)
The prognosis in limited cutaneous is generally better. Systemic sclerosis sine
scleroderma refers to visceral disease in absence of skin manifestations. Prognosis
depends on the severity of involvement of internal organs, particularly the lungs,
heart, and kidneys.
The following types are recognized:
Diffuse cutaneous SSc
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Onset of skin changes within 1 year of onset of Raynaud's phenomenon
Truncal and acral skin involvement
Tendon friction rubs
Visceral disease : interstitial lung disease, renal failure, diffuse
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gastrointestinal disease, myocardial involvement
Nail fold capillary dilatation and drop out
Antitopoisomerase-l (Scl-70) antibodies (30% of patients)
Limited cutaneous SSc
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Raynaud's phenomenon for years (occasionally decades)
Skin involvement limited to hands, face, feet, and forearms (acral)
Skin calcification, telangiectasia, and gastrointestinal involvement
Dilated nail fold capillary loops, usually without capillary dropout
A significant (10–15%) late incidence of pulmonary hypertension, with or
without interstitial lung disease, primary biliary cirrhosis may occur.
High prevalence (70–80%) of anti-centromere antibodies (ACA)
Scleroderma sine scleroderma
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Raynaud's phenomenon
No skin involvement
Presentation with pulmonary fibrosis, renal crisis, cardiac or gastrointestinal
disease
Antibodies may be present (Scl-70, ACA, nucleolar)
Overlap syndrome
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Systemic sclerosis occurring in association with features of other connective
tissue diseases like SLE or rheumatoid arthritis. Mixed connective tissue
disease (MCTD) is a syndrome showing features of SSc, systemic lupus
erythematosus (SLE), , polymyositis, and rheumatoid arthritis and very high
titers of circulating antibody to nuclear ribonucleoprotein (RNP) antigen.
Undifferentiated connective tissue disease
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Patients who do not fulfill diagnostic criteria of any one particular connective
tissue disease are classified in this group.
Scleroderma-Like Disorders
Cutaneous changes similar to scleroderma with or without other features like
Raynaud’s phenomenon or pulmonary fibrosis may be observed in a number of
patients who have been exposed to certain environmental toxins or drugs.
Underground coal and gold miners are more likely to develop SSc owing to exposure
to silica dust. An unusual form of scleroderma featuring Raynaud's phenomenon,
skin changes, capillary abnormalities of the nail fold), osteolysis of the distal
phalanges, and hepatic and pulmonary fibrosis may occur in workers exposed to
polyvinyl chloride. Other agents connected with sclerodermatous disease include
epoxy resins, industrial solvents, bleomycin, pentazocine, cocaine and denatured
rapeseed oil. Scleroderma-like skin changes may be associated with
scleromyxedema, porphyria cutanea tarda, and graft-versus-host (GVH) disease.
Similar skin changes, primarily in the legs, may occur in the carcinoid
Pathogenesis
CD4 T-cells accumulate in the skin, release cytokines which in turn recruit various
inflammatory cells. These in turn release various mediators(TGF-beta, IL-4, platelet
derived growth factor) which upregulate genes encoding extracellular matrix
proteins and collagen. Consequently, there is collagen deposition in the affected
tissue. Another feature is microvascular disease induced by various mediators,
presumably causing endothelial injury, and all patients with this disorder have
intimal fibrosis in digital arteries.
Pathology
Characterized by excess collagen deposition in various tissues. In the skin the
process begins with edema, which is followed by fibrosis and then atrophy. In the
esophagus this causes fibrosis and impaired esophageal motility. Interstitial fibrosis
can occur in the lung and intimal proliferation of blood vessels occurs in the kidney in
some patients.
Clinical features
The patients most commonly present with Raynaud’s phenomenon on cold
exposure. Some patients develop swelling of the hands which remain for a variable
time before developing skin thickening. Symmetric joint pain and features of
gastroesophageal reflux disease are other common presentations.
Skin
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The skin changes on the hands may start with a non-pitting edema which is
followed by induration and thickening of the skin which is bound tightly to
the underlying structures. A long interval between the onset of edema and
development of sclerosis carries a favorable prognosis. Rapid progression of
sclerosis is often associated with extensive and severe internal organ
involvement.
Once sclerosis develops, the skin appears thick and tight with loss of hair and
diminished sweating. It becomes difficult to raise a fold of skin. Thickening of
the skin starts in the fingers and progresses proximally. Limited cutaneous
scleroderma involves areas distal to the elbow and knee but may involve the
face and neck. In the diffuse cutaneous variety of SSc ,the skin thickening
affects the trunk and proximal aspects of the extremities in addition to the
face and acral portions of the body.
The face of the patients acquires a characteristics look: the skin is shiny and
tightly bound, resulting in a loss of the facial expression lines. The skin over
the nose sits tightly on the bone giving rise to a beak-like appearance. The lip
becomes thin and the opening of the mouth gets smaller (microstomia).
Linear furrows radiate from the angles of the mouth. Tightening of the skin
makes it difficult for depressing the lower eyelid with fingers.
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The hands provide valuable clues to the diagnosis: the fingers are spindleshaped, with flexion contractures. Loss of substance from the finger pulp
with small ulcers which heal with stellate-shaper scars are characteristic.
There may be dilated nail-fold capillaries and ragged cuticles.
Pigmentary changes include a mottled hypo- and hyperpigmentation (salt
and pepper appearance)
Telangiectasias are persistently dilated small blood vessels located on any
skin area, but they are most obvious in the face (perioral area) and the neck.
Calcification may occur on the fingertips and extremities, however, any area
involved with scleroderma can be affected These calcifications may ulcerate,
extrude calcified material, and heals very slowly.
Vascular changes
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Raynaud phenomenon results from abnormal vasomotor control secondary
to the microvascular damage of SSc and is characterized by sequential color
changes of pallor, cyanosis, and then erythema (white, blue, red)
accompanied by numbness, tingling, or pain. These events may be triggered
by cold, smoking, vibration or emotional stress. Raynaud phenomenon may
precede sclerosis of skin by months or even years. In diffuse cutaneous SSc,
this time interval is usually less than a year, while sclerosis may occur years
after the onset of Raynaud’s in the limited cutaneous form of the disease.
Isolated Raynaud’s phenomenon without any underlying disorder (Raynaud’s
disease ) carries excellent prognosis. A small minority of this population may
eventually develop scleroderma.
Severe vasospasm may lead to infarction and dry gangrene of the digits.
Nail fold capillary microscopy (done with an ophthalmoscope) shows dilated
capillary loops. In diffuse cutaneous SSc, some loops are destroyed giving rise
to fewer than normal number of capillaries (capillary drop-out).
Musculoskeletal system
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Pain, swelling, and stiffness of the fingers and knees is a common complaint
Generalized arthralgias and morning stiffness may mimic rheumatoid
arthritis.
Thickening and tightening of overlying skin may impair mobility of joints.
Palpable tendon friction rubs may be detected over moving joints as the
tendon is moved actively or passively,
Muscle weakness in advanced cases due to disuse atrophy.
A proximal myopathy with muscle enzyme elevations may also occur.
Acro-osteolysis (ie, resorption or dissolution of the distal end of the phalanx)
may occur. . In addition to terminal phalanges, resorption of bone may
involve ribs, clavicle, and angle of mandible.
Any joint may be affected with flexion contracture.
Gastrointestinal system
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Gastro-esophageal reflux disease from lower gastro-esophageal sphincter
tone.
Dysphagia due to atony of esophagus
Esophagitis
Barrett metaplasia
Watermelon stomach (streaks of dilated submucosal capillaries seen with
endoscope)
Malabsorption
Wide-mouth diverticula of the colon
Decreased peristalsis throughout the GI tract leading to constipation and
pseudoobstruction.
Anal sphincter incompetence
Primary biliary cirrhosis associated with antimitochondrial antibodies
Respiratory system
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Pulmonary involvement is very common and is the leading cause of mortality.
Interstitial fibrosis is the predominant pathology and occur more commonly
with the diffuse cutaneous SSc.
The most common symptom is exertional dyspnea, often accompanied by a
dry cough.
Bilateral basilar rales may be present.
Pulmonary arterial hypertension some patients with limited cutaneous SSc.
Aspiration pneumonia resulting from gastric reflux
Chest movement may be restricted by severe sclerotic changes of the skin
over the thorax.
Superimposed bacterial or viral infection
Increased frequency of alveolar cell and bronchogenic carcinoma
Kidney
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Scleroderma renal disease is commoner in diffuse cutaneous SSC.
Patients with rapidly developing diffuse scleroderma are at high risk of
developing renal crisis
Renal crisis presents as malignant hypertension with encephalopathy,
retinopathy, severe headache, seizure and a rapidly rising serum creatinine. If
untreated, this may lead to renal failure.
In some patients , renal crisis may occur in the absence of hypertension.
Renal crisis carries a high mortality if not treated appropriately.
Heart
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Pericardial effusions
Cor pulmonale may occur as a result of long-standing pulmonary fibrosis.
Left ventricular failure from severe hypertension.
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Conduction abnormalities and arrythmias.
Infiltrative cardiomyopathy
Musculoskeletal system
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Pain, swelling, and stiffness of the fingers and knees is a common complaint
Generalized arthralgias and morning stiffness may mimic rheumatoid
arthritis.
Thickening and tightening of overlying skin may impair mobility of joints.
Palpable tendon friction rubs may be detected over moving joints as the
tendon is moved actively or passively,
Muscle weakness in advanced cases due to disuse atrophy.
A proximal myopathy with muscle enzyme elevations may also occur.
Acro-osteolysis (ie, resorption or dissolution of the distal end of the phalanx)
may occur. . In addition to terminal phalanges, resorption of bone may
involve ribs, clavicle, and angle of mandible.
Any joint may be affected with flexion contracture.
Nervous system
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Trigeminal neuralgia (uncommon) and carpal tunnel symptoms may result
from peripheral entrapment neuropathies.
The central nervous system (CNS) is spared.
Obstetrics and gynecology
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Vaginal dryness, dyspareunia, and menstrual irregularities.
Higher pregnancy loss and complication rates, but a diagnosis of scleroderma
is not an absolute contraindication for pregnancy.
During pregnancy, some symptoms may increase (eg, edema, arthralgias,
reflux disease).
Other manifestations:
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Hypothyroidism from fibrosis and autoantibodies.
Erectile dysfunction in males.
Loosening of teeth due to thickening of periodontal membrane and alteration
of tooth suspensory ligament.
Dry mouth and eyes (sicca syndrome)
Constitutional features: weakness and weight loss.
Investigations
Routine haemogram: May reveal anemia.
Urinalysis: For proteinuria , hematuria, casts .
Biochemical : Blood urea ,creatinine, Liver function tests. Thyroid function tests,
Muscle enzymes
Immunological:
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Antinuclear antibodies are present in about 95% of the patients A nucleolar
pattern is more specific than other patterns.
Antibodies to Topoisomerase I (formerly Scl–70) is present in about onefourth of patients with diffuse cutaneous SSc (negative in limited disease )
and has an increased association with pulmonary fibrosis.
Anticentromere antibodies : present in about 60-90% of patients with limited
disease and 10-15% with diffuse disease.
Fibrillarin antibodies (antibody to U3 ribonucleoprotein) are also relatively
specific findings in diffuse disease.
Antibodies to U3-ribonucleoprotein( U3 RNP) is present mostly in patients
with diffuse disease and overlap syndromes.
Anti-PM-Scl is present in limited and disease with SSc-polymyositis overlap.
Imaging
X-rays:
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Chest: May show evidence of pulmonary fibrosis: linear shadows, mottling or
honeycombing particularly involving the basilar areas of lung.
Extremities: soft tissue calcinosis and bony changes like absorption of
terminal digits may be demonstrated.
Barium studies
CT scan
High-resolution CT scan may reveal a ground-glass appearance indicative of active
alveolitis.
Echocardiogram
For evaluation of pulmonary arterial pressure and pericardial effusion.
Other Tests:
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Pulmonary function testing
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Examination of bronchoalveolar lavage: the cellular pattern may indicate
active alveolitis.
Cardiac rhythm monitoring.24-hour ambulatory Hotter monitoring to
evaluate arrhythmias.
Esophagogastroduodenoscopy, esophageal manometry
Treatment:
There is no cure for scleroderma. Treatment is aimed at relieving symptoms
improving functions.
Reassurance and explanations of the nature and course of the disease should be
undertaken with a sympathetic attitude.
Regular monitoring of blood pressure, blood count, urinalysis, and renal and
pulmonary functions is indicated.
Raynaud’s phenomenon:
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Avoidance of cold exposure and smoking cessation, warm clothing.
Calcium channel blockers (Nifedipine, diltiazem)
Aspirin and dipyridamole, pentoxifylline
Losartan, Ketanserin, Fluoxetine
Topical nitroglycerine paste over digits
Intravenous alprostadil, and prostaglandin in sever Raynaud’s
Skin fibrosis:
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A number of agents are used but few have been properly evaluated for
efficacy.
Penicillamine
Colchicine, paraaminobenzoate,
Relaxin
Gamma interferon
Cyclosporine
Extracorporeal photochemotherapy
GI symptoms:
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Antacids, H2-blockers, proton-pump inhibitors
Prokinetic agents, octreotide
Reflux precautions: frequent small meals, elevation of head end of the bed,
not lying after meals, avoidance of tea, coffee, alcohol, spicy and fatty meals.
Antibiotics for treatment of bacterial overgrowth and malabsorption.
Pulmonary disease :
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Pulmonary
fibrosis
may
be
treated
with
systemic
steroid
and
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cyclophosphamide.
Sever pulmonary hypertension may be benefitted by intravenous or
aerosolized prostacyclin.
Prompt treatment of infections.
Renal disease
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Early management of hypertension with calcium channel blocker.
Management of renal failure, Dialysis.
Cardiovascular disease
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Treatment of heart failure.
Pericarditis may respond to systemic steroids.
Musculoskeletal symptoms:
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NSAIDs and paracetamol for arthralgia
Myositis may be treated with steroids, methotrexate and azathioprine.
Course and prognosis
Course of the disease is variable, the prognosis largely dependant of the severity
and extent of internal organ involvement particularly pulmonary and renal disease .
Indicators for poor prognosis include:
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Advanced age at presentation
Male sex
Black American race
Diffuse cutaneous involvement. Patients with diffuse disease has a 10 year
survival rate of about 20%
Rapidity of development of skin involvement.
Presence of significant renal of pulmonary disease .
Presence of anti-Scl 70 antibodies.
MIXED CONNECTIVE TISSUE DISEASE (MCTD)
Mixed connective tissue disease (MCTD) is an uncommon autoimmune disorder
that causes overlapping features of primarily three connective tissue diseases —
lupus, scleroderma and polymyositis. Mixed connective tissue disease also may have
features of rheumatoid arthritis.
Mixed connective tissue disease occurs most often in women and is usually
diagnosed in their 20s and 30s. Occasionally children are diagnosed with mixed
connective tissue disease.
Clinical features
Early indications of mixed connective tissue disease typically are nonspecific and
may be mistaken for any of the three connective tissue diseases — lupus,
scleroderma and polymyositis. Signs and symptoms include:
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Raynaud's disease — blood vessel spasms that interrupt blood flow to the fingers,
toes, ears and nose
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Fatigue
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General feeling of being unwell (malaise)
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Muscle pains / weakness
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Joint pains
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Mild fever
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Joint swelling
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Swollen hands and puffy fingers
Raynaud's phenomenon may begin years before other symptoms. As the disease
progresses, it can affect any of the major organ systems, including skin, joints,
muscles, heart, lungs, gastrointestinal tract, kidneys, central nervous system and
blood cells.
Mixed connective tissue disease and its treatment can lead to serious
complications, including:
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Pulmonary hypertension. Pulmonary hypertension is the most common cause of
death in people with mixed connective tissue disease.
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Heart disease including myocarditis and pericarditis.
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Side effects of long-term corticosteroid use.
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Pregnancy complications. There are conflicting studies, some of which suggest that
women with mixed connective tissue disease may experience flares during
pregnancy. Babies born to women with mixed connective tissue disease are at risk of
being born with a low birth weight.
Investigations
The presence of this specific antibody, U1-RNP can help confirm the diagnosis of
MCTD.
Treatments and drugs
There's no cure for mixed connective tissue disease, but medication can help
manage the signs and symptoms of the disease. Mild forms of mixed connective
tissue disease may not require treatment. Patients may require treatment only
during flares or, if they have a more serious form of the disease, they may require
continuous medication.
Medications may include:
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Small dose of corticosteroids. These are the most common treatment for moderate
mixed connective tissue disease.
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NSAIDS. Nonsteroidal anti-inflammatory drugs (NSAIDs) can relieve pain and reduce
inflammation.
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Other immunosuppressants. Same indications for SLE.