Scleroderma - Summary
o Diffuse scleroderma (10%) – bilat symmetric fibrosis skin – face and prox + distal extremities
o CREST (90%) – skin confined to fingers and face
- Chemical induced - vincyl chloride disease
- Eosinophilic fasciitis pseudoscleroderma
- CREST syndrome
- limited form of systemic sclerosis in which there is Calcinosis, Raynaud's phenomenon, oEsophageal involvement, Sclerodactyly and Telangiectases.
Characteristically, the telangiectases are well-defined and flat (matt).
- Investigations – ANA – anticentromere antibodies (Crest) and Scl-70 (sys sclerosis)
- The diagnosis is generally made from the patient's history and the findings on examination of the skin and other organs.
- A skin biopsy is not usually necessary but characteristically shows excessive ground substance and odd-looking endothelial cells in the dermis and
later deposits of collagen. The epidermis is usually atrophic.
- Up to 90% have elevated antinuclear antibodies (ANA) but these are less frequent than in the more common connective tissue disease,
systemic lupus erythematosus. Thyroid antibodies may occur and result in an under-active thyroid gland
- Anticentromere antibodies are characteristic of CREST syndrome and may be present in Raynaud phenomenon before systemic sclerosis
appears. Scl-70 is unique to systemic sclerosis and is more likely to be associated with severe systemic sclerosis involving the lungs. Many other
less specific antibodies have been reported to be associated with different patterns of disease.
- Anaemia, raised sedimentation rate (ESR) and increased gamma globulins (hypergammaglobulinaemia) and varying immune abnormalities are quite
common especially positive rheumatoid factors.
o No overall effective therapy but penicillamine (500-1500mg/day), methotrexate cyclosporine have been tried
o Protection and treatment of ulcers
o Infection (usually staph)
o Calcinosis – no effective treatment
o Daily physical therapy
o Immune system targets – cyclophosphamide (for interstitial lung) and sildenafil - viagra (vascular lung and digits)
Systemic lupus erythematosus Spliceosomal snRNP, Ro/La (SS-A/SS-B) particle, histone and native DNA
Sjögren’s syndrome Ro/La ribonuclear particle, muscarinic receptor
Rheumatoid arthritis Citrullinated cyclic peptide, IgM
Dermatomyositis/polymyositis t-RNA synthetases
Diffuse systemic sclerosis Topoisomerase
Limited systemic sclerosis (CREST) Centromere proteins
Thickened and missing in Scleroderma DM
Tortuous in Lupus
Antinuclear antibody screening
ANA is the first test to order when collagen vascular disease is suspected (Table 17-2).
Table 17-2 -- ANA Screening Test
ANA (on Hep-2 cells) Frequency of ANA positivity (%)
Systemic lupus erythematosus 95-100
Drug-induced lupus erythematosus 100
Sjögren’s syndrome 80
Rheumatoid arthritis 40-60
Mixed connective tissue disease 100
Table 17-4 -- Diagnostic Significance of Immunologic Findings in Serum and Skin Biopsies in Connective Tissue Diseases
Disease Biopsy findings: Direct immunofluorescence Serum findings Relevance
ANA elevated titers (about 95%-99%); nDNA antibodies about 50%-75%; DNP
LE band (granular immune deposits, IgG,
antibodies <50%; Sm antibodies in about 20%; RNP antibodies in about 5%-30%; DIF, ANA, and ENA usually
and/or IgM) IgA, C3 at DEJ in lesional
Systemic LE SS-A antibodies in about 30%-40%; SS-B antibodies in about 1%-15%; phospholipid diagnostic; nDNA and Sm antibodies
and/or normal skin (over 90% in sun-
antibodies in about 30%-50%; PCNA antibodies in about 2%-10%; Ku(Ki) antibodies are diagnostic markers
in about 10%
Discoid LE LE band, mostly IgG and C in lesion ONLY Essentially negative; ANA titers usually in normal range LE band highly characteristic
DIF and anti–SS-A (Ro) highly
Subacute, cutaneous LE LE band in lesion ANA positive in 70%; SS-A (Ro) antibodies positive in more than 60%
ANA positive in 30%; antibodies to SS-A (Ro) in 100%; antibodies to SS-B (La) in DIF and anti–SS-A (Ro) highly
Neonatal LE LE band in lesion (about 50%)
about 60% characteristic
DIF and histone antibodies in
ANA positive in more than 90%; histone positive about 90%; other antibodies to
Drug-induced LE LE band in lesion (rare) absence of other nuclear antibodies
nDNA and ENA negative
Nuclear IgG or LE band in normal and/or Serology and/or DIF of nuclei
Mixed connective tissue disease Speckled ANA antibodies in more than 95% and RNP antibodies in more than 90%
lesional epidermis diagnostic for MCTD, SLE, or PSS
ANA positive in about 55%; antibodies to SS-A (Ro) in 43%-88%; SS-B (La) in 14%- Positive serum results support
Sjögren’s syndrome Negative
60%; RF positive diagnosis
Progressive systemic sclerosis Nucleolar IgG in epidermis in few cases; ANA (about 85%) speckled or nucleolar; centromere antibody in CREST (70%-90%); DIF limited value; centromere
Disease Biopsy findings: Direct immunofluorescence Serum findings Relevance
(scleroderma) most negative Scl-70 antibodies in diffuse sclerosis (45%) and in acrosclerosis (15%-20%) antibodies are diagnostic marker in
CREST; Scl-70 antibodies are
diagnostic marker in scleroderma
ANA usually positive (more than 80%); Jo-1 antibodies in 30% PM, 10% DM; SS-A
Limited value, but positive serum
Polymyositis/dermatomyositis Negative (Ro) antibodies in 55% PM/scleroderma overlap; Ku (Ki) antibodies in 10%
results support diagnosis
ANA usually negative or low titer; RF positive in about 90%; RNA positive in about Positive serum results support
Rheumatoid arthritis Negative
70%-90% and 95% of RF-negative cases diagnosis
The Connective Tissue Diseases Cascade begins with the following two tests that are done in all cases:
1. Cyclic citrullinated peptide antibodies—Serum autoantibodies to cyclic citrullinated peptide (CCP) are quite specific for rheumatoid arthritis (RA), the most common
connective tissue disease. Unlike the test for rheumatoid factor, which has poor specificity for RA, the test for CCP antibodies has proven to be reliable for differentiating
RA from other connective tissue diseases. This test is not an ideal screening test since it is positive in fewer than 80% of patients with RA and negative test results do not
conclusively exclude RA. Strongly positive tests for CCP antibodies have a very high positive predictive value for this disease.
2. Antinuclear antibodies (ANAs)—A negative ANA test result is useful for excluding lupus erythematosus and scleroderma, the two most commonly encountered
connective tissue diseases other than RA. Other disease-specific autoantibodies rarely occur in sera that test negative or have low levels of reactivity for ANA. Using a
cutoff level of 3.0 units for ANA permits detection of >90% of sera with an identifiable specific autoantibody on follow-up testing. If the screening test for ANA is >3.0 units,
second-order testing is performed for additional disease-specific autoantibodies.
The second level of testing includes the following four components:
1. Double-stranded DNA (dsDNA) antibody, IgG, serum (anti-dsDNA)—A positive test result for anti-dsDNA antibodies is found in up to 82% of patients with active lupus
erythematosus (LE). Anti-dsDNA antibodies are highly specific for LE, making this test useful for confirming the diagnosis. Low levels may account for false-positive
reactivity. The levels of anti-dsDNA correlate with disease activity. Order this as a stand-alone test to monitor disease activity. dsDNA antibodies are also found in 20% to
30% of patients with Sjögren’s syndrome, 20% to 25% of patients with mixed connective tissue disease (MCTD), and less than 5% of patients with progressive systemic
2. Antibodies to extractable nuclear antigens, serum (ENA)—The antibodies to the ENA group are comprised of six autoantibodies directed against small nuclear
ribonucleoproteins (snRNPs) and enzymes. Autoantibodies to these individual antigens are important serologic markers of particular connective tissue diseases.
A. Autoantibodies to SS-A/Ro, serum (SS-A): SS-A antibodies occur with variable frequencies in several connective tissue diseases including Sjögren’s
syndrome, LE, and RA. When present in isolation or with SS-B antibodies, the finding of this autoantibody is consistent with Sjögren’s syndrome. SS-A antibodies
are found in approximately 60% of patients with Sjögren’s syndrome and 35% of patients with LE.
B. Autoantibodies to SS-B/La, serum (SS-B): SS-B antibodies rarely occur in isolation and are most often encountered in sera that contain SS-A antibodies. SS-B
(La) antibody is seen in 50% to 60% of Sjögren’s syndrome cases and is specific if it is the only ENA antibody present; 15% to 25% of patients with systemic
lupus erythematosus and 5% to 10% of patients with progressive systemic sclerosis also have this antibody.
C. Autoantibodies to Sm, serum (Sm): Sm antibodies are highly specific for LE. The test for Sm antibodies lacks sensitivity; and this autoantibody is detectable in
only approximately 30% of patients with documented LE. The presence of antibodies to Smith (Sm) is often associated with renal disease.
D. Autoantibodies to U(1) RNP, serum (U1RNP): Antibodies to U1RNP occur in several different connective tissue diseases including mixed connective tissue
disease and LE. The finding of U1RNP antibodies in the absence of anti-dsDNA antibodies and antibodies to other ENAs is consistent with the diagnosis of mixed
connective tissue disease. U1RNP antibodies have been reported in 71% to 100% of patients with mixed connective tissue disease.
E. Autoantibodies to Scl-70, serum (Scl-70): Scl-70 antibodies react with the enzyme DNA topoisomerase I and are highly specific for scleroderma. Scl-70
antibodies have been reported in approximately 40% of patients with scleroderma. The presence of Scl-70 antibodies is consistent with the diagnosis of
scleroderma and indicates an increased risk for systemic involvement including pulmonary fibrosis.
F. Autoantibodies to Jo-1, serum (Jo-1): Jo-1 antibodies are highly specific for polymyositis but occur in only approximately 20% of polymyositis patients. The
presence of Jo-1 antibody is also found in patients with dermatomyositis, or myositis associated with another rheumatic disease. The finding of Jo-1 antibodies
indicates an increased risk for severe disease with pulmonary involvement and fibrosis.
3. Centromere antibodies, IgG, serum—Centromere antibodies demonstrate a specific ANA pattern, which is present in 80% to 90% of individuals with CREST variant
scleroderma. The pattern is also seen in 30% of patients with Raynaud’s phenomenon; 12% of patients with mixed connective tissue disease, diffuse scleroderma,
interstitial pulmonary fibrosis, and primary biliary cirrhosis; and in a smaller percent of patients with SLE and RA.
4. Ribosome P antibodies, IgG, serum—Autoantibodies reacting with cytoplasmic ribosomes are highly specific for systemic lupus erythematosus. Ribosomal P antibodies
are found in approximately 12% of patients with SLE and in 90% of patients with lupus psychosis; titers often increase more than fivefold during and before active phases of
MORPHEA (Figure 17-33)
Morphea is more common in females; it can occur at any age but is more common after age 30. Like scleroderma, morphea begins spontaneously and involves
thickening or sclerosis of the skin. The two diseases differ in appearance, in the extent of the lesions, and in evolution. Scleroderma appears as a bound-down skin
thickening with minor skin color change, progresses to involve large contiguous areas of skin, and does not improve with time. The lesions of morphea begin as
one-to-several circumscribed areas of purplish induration.
Figure 17-33 A single or few oval areas of nonpitting erythema and edema typically appear on the trunk. A violaceous border (lilac ring) surrounds the indurated area. The center of the lesion
then develops smooth, ivory-colored hairless or hyperpigmented plaques, and the ability to sweat is lost.
After weeks or months, the major portion of the central region of discoloration becomes thickened, firm, hairless, and ivory-colored. The smooth, dull, white, waxy
surface is elevated, in contrast to the diffusely bound-down skin of scleroderma. The violaceous or lilac-colored active inflammatory border is a highly characteristic
feature of morphea. During the active stage, the round-to-oval plaques slowly extend peripherally but do not increase very much in size. Active lesions persist for 1
to 25 years. Inactive lesions leave their mark. Although much of the induration and skin thickening disappear, previously involved sites may exhibit atrophy and a
mottled brown hyperpigmentation at the border and in the previously thickened plaque area. The remainder of the lesion becomes hypopigmented.
Multiple small, white plaques (guttate morphea) are a rare form of morphea. Most reported cases are probably cases of lichen sclerosis et atrophicus; in fact, the
two diseases may appear simultaneously in the same patient.
Anti-DNA antibodies have been reported in some children. The presence of antihistone antibodies (AHAs) has been demonstrated in localized scleroderma. AHAs
were detected in 42% of patients with localized scleroderma and in 87% of patients with generalized morphea. The presence of AHAs strongly correlated with the
number of morphea lesions, the total number of lesions, and the number of involved areas of the body. ANAs did not correlate with the presence or number of
linear lesions. The relationship of morphea to Borrelia infection remains undetermined.
The histopathologic features vary with the course of the disease. Early active lesions show inflammatory cells in the dermis and subcutaneous tissue. Inflammation
is most marked at the violaceous border. The collagen becomes eosinophilic and increases to occupy portions of the subcutaneous fat. Inflammation and sclerosis
diminish with time.
Asymptomatic plaques should probably be left alone to resolve spontaneously. Topical steroids and occlusion may induce slight improvement.
Inducing atrophy by infiltrating with triamcinolone acetonide (10 mg/ml diluted 1:3 saline -> 2.5mg/ml) may be useful in areas where skin thickening has resulted in
discomfort or limitation of motion. Thickened tissue offers great resistance to infiltration, and scattered pitted areas of atrophy rather than a uniform decrease in
plaque thickness may result.
Hydroxychloroquine sulfate (200 mg) may be considered for patients who have multiple lesions that on skin biopsy are shown to be in an active inflammatory
stage. The adult dosage is 200 mg of hydroxychloroquine twice a day. Induration may be markedly reduced or disappear in 2 to 4 months. The medication should
be discontinued after lesions improve. The fundi should be examined by an ophthalmologist before antimalarials are started and should be monitored periodically.
Calcipotriene cream (Dovonex) 0.005% may be an effective treatment for localized scleroderma. Calcipotriene ointment 0.005% was applied without occlusion in
the morning but with occlusion at night. The effects of the application are evident by 1 month.
Systemic sclerosis (systemic scleroderma) is a multisystem disease that results in fibrosis and vascular abnormalities in association with autoimmune
changes. These lead to breakdown of the skin, subcutaneous tissue, muscles and internal organs (e.g. digestive tract, heart, lungs and kidneys). The skin
becomes thickened and tightly bound to underlying structures.
Localised scleroderma (also known as morphoea) is an unrelated skin disease and is confined to the skin.
Features of systemic sclerosis
Calcinosis Calcinosis X-ray Sclerodactyly
CREST syndrome Ulcerated and resorbing fingertips Vasculitis
Who gets it and what is the cause?
Systemic sclerosis is a rare condition that may occur in people of any race, although it is less common in people of Asian descent. It appears to be three to
four times more common in women than men and is comparatively rare in children. It usually starts between 30-40 years in women and later in men.
Systemic sclerosis is classified as an autoimmune disease of an unknown cause. This means the immune system is reacting against one's own tissues. It
appears to involve some injury to the cells that line blood vessels (endothelial cells) and this results in excessive activation of the dermal connective tissue
cells, the fibroblasts. Fibroblasts normally produce collagen and other glycosamine proteins. Certain factors have been identified that may trigger the disease.
These include injury, drugs (e.g. vitamin K, cocaine, penicillamine, appetite suppressants and some chemotherapeutic agents), and chemicals (e.g. silica,
organic solvents, pesticides, aliphatic hydrocarbons and epoxy resin).
What are the signs and symptoms of systemic sclerosis?
Raynaud phenomenon is usually the first symptom of systemic sclerosis. Patients experience episodes of vasospasm , which causes blood vessels in the
fingers and toes to constrict. As less blood is reaching these extremities the skin changes colour to white and the fingers and toes may feel cold and numb. As
they warm up, they go blue and then red before returning to normal again.
Thermal imaging (heat sensing)
Normal hand Raynaud phenomenon
Other skin changes include:
Thickening of the skin of the fingers, then atrophy (thinned) and sclerosis (scarring). The fingers become spindle-shaped (sclerodactyly) from
resorption of the fingertips.
Fragile nails become smaller with ragged cuticles
Taut, shiny skin that may have dark or pale patches (hyper- or hypopigmentation). The tight skin may affect most parts of the body, including the
face, resulting in loss of expression and difficulty opening the mouth properly.
Visibly dilated blood vessels (telangiectases) appear on the fingers, palms, face, lips, tongue and chest.
Calcinosis (calcium deposits) develops in the skin, particularly the fingers, hands and other bony areas. These can breakdown and discharge chalky
Ulcers may follow minor injuries over the joints, or on the tips of fingers and toes where the circulation is poor. Ulceration can lead to dry gangrene
and eventual loss of the tips of the fingers (like frost bite).
Ulcers may also arise over calcinosis and on the lower legs.
Sicca symptoms (dry eyes, dry mouth) and Sjogren syndrome
In addition to the skin changes, the disease affects many other organs. Problems that may occur include:
Friction rubs over the joints and tendons, particularly the knees.
Eye changes with tightness of lids, reduced tear secretion, retinopathy
Joint pain, muscle pain and weakness and limited movement resulting in contractures.
The digestive tract may be affected throughout its length. Oesophageal reflux is common causing difficulty in swallowing solid and liquid food. This
can lead to nausea, vomiting, weight loss, stomach cramps, diarrhoea, constipation and bleeding.
Lung and heart involvement may manifest as shortness of breath, high blood pressure, chest pain, pleurisy, pneumothorax, pericarditis arrhythmias,
general heart enlargement and heart failure.
Progressive kidney disease resulting in proteinuria, high blood pressure and eventually renal failure.
What is the CREST syndrome?
CREST syndrome (also called CRST syndrome) is a limited form of systemic sclerosis in which there is Calcinosis, Raynaud's phenomenon, oEsophageal
involvement, Sclerodactyly and Telangiectases. Characteristically, the telangiectases are well-defined and flat (matt).
What tests should be done?
The diagnosis is generally made from the patient's history and the findings on examination of the skin and other organs. A skin biopsy is not usually
necessary but characteristically shows excessive ground substance and odd-looking endothelial cells in the dermis and later deposits of collagen. The
epidermis is usually atrophic.
Up to 90% have elevated antinuclear antibodies (ANA) but these are less frequent than in the more common connective tissue disease, systemic lupus
erythematosus. Thyroid antibodies may occur and result in an under-active thyroid gland
Anticentromere antibodies are characteristic of CREST syndrome and may be present in Raynaud phenomenon before systemic sclerosis appears. Scl-70 is
unique to systemic sclerosis and is more likely to be associated with severe systemic sclerosis involving the lungs. Many other less specific antibodies have
been reported to be associated with different patterns of disease.
Anaemia, raised sedimentation rate (ESR) and increased gamma globulins (hypergammaglobulinaemia) and varying immune abnormalities are quite common
especially positive rheumatoid factors.
What is the treatment of systemic sclerosis?
There is no cure for systemic sclerosis and treatment is aimed at controlling symptoms and preventing complications. Because the symptoms of systemic
sclerosis are so diverse a team of medical specialists is usually necessary.
It is absolutely essential to discontinue smoking.
Skin Topical corticosteroids and emollients for itchy skin
Avoid cold temperatures and wear warm clothing including gloves and socks to prevent Raynaud phenomenon. Medical
treatment includes calcium channel blockers, aspirin and vasodilating drugs.
Calcinosis may be treated with calcium channel blockers, anticoagulants, colchicine and intralesional steroids and possibly
excision of deposits
Research suggests intensive ultraviolet radiation treatment (phototherapy) with UVA1 (340-400nm) can soften fibrosis.
This is not yet available in New Zealand
ciclosporin may help some patients
Joint and Oral corticosteroids
Gastrointestinal Proton pump inhibitor, e.g. omeprazole
Surgery for strictures
Kidney ACE inhibitors