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

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

gastrointestinal disease, myocardial involvement

Nail fold capillary dilatation and drop out

Antitopoisomerase-l (Scl-70) antibodies (30% of patients)

Limited cutaneous SSc

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 (1015%) late incidence of pulmonary
hypertension, with or without interstitial lung disease, primary
biliary cirrhosis may occur.
High prevalence (7080%) of anti-centromere antibodies
(ACA)

Scleroderma sine scleroderma

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

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

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 Raynauds 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 Raynauds

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

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.
The hands provide valuable clues to the diagnosis: the fingers
are spindle-shaped, 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

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 Raynauds in the limited cutaneous form of the
disease. Isolated Raynauds phenomenon without any
underlying disorder (Raynauds 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

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

Gastro-esophageal reflux disease from lower gastroesophageal 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

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

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

Pericardial effusions
Cor pulmonale may occur as a result of long-standing
pulmonary fibrosis.
Left ventricular failure from severe hypertension.
Conduction abnormalities and arrythmias.
Infiltrative cardiomyopathy

Musculoskeletal system

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

Trigeminal neuralgia (uncommon) and carpal tunnel

symptoms
may
result
from
peripheral
entrapment
neuropathies.
The central nervous system (CNS) is spared.

Obstetrics and gynecology

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:

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:

Antinuclear antibodies are present in about 95% of the

patients A nucleolar pattern is more specific than other
patterns.
Antibodies to Topoisomerase I (formerly Scl70) is present in
about one-fourth 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 SScpolymyositis overlap.

Imaging
X-rays:

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:

Pulmonary function testing

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.
Raynauds phenomenon:

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 Raynauds

Skin fibrosis:

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:

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 :

Pulmonary fibrosis may be treated with systemic steroid and

cyclophosphamide.
Sever pulmonary hypertension may be benefitted by
intravenous or aerosolized prostacyclin.
Prompt treatment of infections.

Renal disease

Early management of hypertension with calcium channel

blocker.
Management of renal failure, Dialysis.

Cardiovascular disease

Treatment of heart failure.

Pericarditis may respond to systemic steroids.

Musculoskeletal symptoms:

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:

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

Raynaud's disease blood vessel spasms that interrupt blood

flow to the fingers, toes, ears and nose

Fatigue

General feeling of being unwell (malaise)

Muscle pains / weakness

Joint pains

Mild fever

Joint swelling

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

Pulmonary hypertension. Pulmonary hypertension is the most

common cause of death in people with mixed connective tissue
disease.

Heart disease including myocarditis and pericarditis.

Side effects of long-term corticosteroid use.

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

Small dose of corticosteroids. These are the most common

treatment for moderate mixed connective tissue disease.

NSAIDS. Nonsteroidal anti-inflammatory drugs (NSAIDs) can

relieve pain and reduce inflammation.

Other immunosuppressants. Same indications for SLE.