Scleroderma

• derived from greek and means hard skin • Affects about 250/million = 7500 Canadians • Affects mainly women in the prime of their life 50 years) (women:men ratio 3-5:1, onset between 30-

SYSTEMIC SCLEROSIS OR SCLERODERMA

A generalized disorder of connective tissue characterized clinically by: –thickening and fibrosis of the skin (scleroderma) – distinctive forms of involvement of internal organs, notably the heart, lungs, kidneys, and gastrointestinal tract.

ACR CRITERIA

• Sclerodermatous skin change in any location proximal to the metacarpophalangeal joints • The presence of two or more of the following features contributed further as minor criteria: – sclerodactyly – pitting scars of fingertips or loss of digital finger pad substance – bibasilar pulmonary fibrosis

Raynaud’s Phenomenon

Skin thickening of systemic sclerosis begins on the fingers and hands in nearly all cases. The skin initially appears shiny and taut and may be erythematous at early stages .

Phases of skin thickening

• Edematous

Causes of this swelling

• Basically this is water in the tissues = edema • Binding of water to increased extracellular connective tissue matrix • Inflammation • Poor lymphatic return • Microvascular injury with fluid extravasation

• Indurative Phase

• Thick • Shiny • Taught • Tightly adheres to underlying tissue so cannot be easily picked up • Creases disappear • May become hyper- or hypo-pigmented • Hair loss • Decreased sweating

Facial changes

• Pinched nose (“mauskopf”) • Pursed lips • Cannot evert eyelids • Lip thinning and retraction

Atrophic phase

• Thick dermis reverts to normal or even becomes thinner (atrophy)

telangiectasia

LOCALIZED FORMS OF SCLERODERMA

• Morphea • Generalized/pansclerotic morphea • Linear scleroderma En coup de saber • Progressive hemifacial atrophy

What else can we see on, in or under the skin ?

Nailfold capillaroscopy

Nailfold capillaroscopy

Nail Skin of finger Avascular area Dilated capillaries

Digital ulcers – evidence of vascular disease

Digital necrosis

calcinosis

• Modified Rodnan skin score mRSS • Used for studies to follow patients • We collect this on all our patients • The main outcome measure of studies of “disease modifying drugs” • Surrogate of disease severity ??

• extensive hyalinization and sclerosis of the reticular dermis with loss of adnexal structures

• A: fibrosis in the upper dermis - keratinocyte hypertrophy with a flattening of the epidermis inflammatory infiltrates in the dermis • B: profound dermal inflammation • C: established fibrosis loss of microvasculature, dermal structures and dermis-subcutaneous adipose tissue interface Copyright ©2007 American Society for Clinical Investigation

Varga, J. et al. J. Clin. Invest. 2007;117:557-567

CLINICAL FEATURES

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Musculoskeletal

– Generalized arthralgia and morning stiffness – Erosive arthropathy has been demonstrated to occur in some series in as many as 29 percent of patients.

– An inexorable loss of hand function is the rule as skin thickening worsens and the underlying joints become tethered and restricted in motion.

– Insidious muscle weakness, both proximal and distal, occurs in many patients with systemic sclerosis secondary to disuse atrophy – Subcutaneous calcinosis occurs in around 40 percent of patients with long-standing limited scleroderma and less frequently in diffuse disease

Subcutaneous calcinosis occurs in around 40 percent of patients with long-standing limited scleroderma and less frequently in diffuse disease

CLINICAL FEATURES - 2

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Gastrointestinal

– Disordered peristalsis of the lower two thirds of the esophagus presents as dysphagia – Impaired function of the lower esophageal sphincter – chronic esophageal reflux include erosive esophagitis with bleeding, Barrett's esophagus, and lower esophageal stricture – Involvement of the stomach occurs in systemic sclerosis and presents clinically as ease of satiety and on occasion as either functional gastric outlet obstruction or acute gastric dilatation.

CLINICAL FEATURES - 3

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Small bowel involvement

– Intermittent bloating with abdominal cramps, intermittent or chronic diarrhea, and presentations suggestive of intestinal obstruction. – Malabsorption occurs – Bacterial overgrowth in areas of intestinal stasis occurs frequently

CLINICAL FEATURES - 4

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Colonic involvement

… – is present in the majority of patients with systemic sclerosis – is infrequently a prominent cause of clinical symptoms.

– and constipation, obstipation, and pseudo obstruction may occur and are related to abnormal colonic motility

CLINICAL FEATURES - 5

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Pulmonary manifestations

– Progressive dyspnea on exertion, limited effort tolerance, and a nonproductive cough are typical and the leading cause of mortality and a principal source of morbidity

CLINICAL FEATURES - 6

Interstitial thickening and fibrosis and continuing evidence of interstitial inflammation .

CLINICAL FEATURES - 7

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Pulmonary Hypertension

– Individuals with limited systemic sclerosis may also develop interstitial disease but are also at risk for progressive pulmonary hypertension in the absence of interstitial change, a complication most typical of long-standing disease – Detected by right-sided heart catheterization in 33 percent of all patients and 5 of 10 with limited scleroderma

• Intimal proliferation with reduplication of the internal elastic lamella and medial myxomatous change are seen in this photomicrograph of a pulmonary arteriole obtained at post mortem from a patient with long-standing limited scleroderma and severe pulmonary hypertension

CLINICAL FEATURES - 8

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Myocardial involvement

– Patchy myocardial fibrosis in as many as 81 percent of patients with systemic sclerosis. – Clinically, however, myocardial involvement is less confidently detected, – The fibrosis seems inseparable from and may be due to intermittent microvascular ischemia of the myocardium

CLINICAL FEATURES - 9

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Renal involvement

– Sudden onset of accelerated to malignant hypertension, rapidly progressive renal insufficiency, hyperreninemia, and evidence of microangiopathic hemolysis describes the syndrome of "scleroderma renal crisis." – Usually an individual with diffuse scleroderma whose disease is at an early stage

IMMUNOLOGIC FEATURES

• Antinuclear antibodies are present in the sera of more than 90 percent • When tissue culture substrates for indirect immunofluorescent study, most notably the human laryngeal carcinoma cell line HEp 2, are used, anticentromere antibodies give rise to coarse speckled patterns on interphase nuclei and appear as centromeric clustering on metaphase nuclei.

Diffuse ANA

Nucleolar ANA

• The original reports suggested that between 50 and 96 percent of patients with limited systemic sclerosis had detectable serum anticentromere antibody. • In contrast, anticentromere antibody is found in less than 10 percent of individuals with diffuse scleroderma and is infrequent in other nonsystemic sclerosis connective tissue diseases.

• anticentromere antibody confers a favorable prognosis

Anti-DNA Topoisomerase I (Sc1 70)

• 20 and 40 percent of patients • intracellular enzyme involved in the initial uncoiling of supercoiled DNA before transcription

TREATMENTS

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Disease-Modifying Therapies

– A truly "disease-modifying" therapy for systemic sclerosis should enhance survival or reduce disability and comorbidity from the disease, or both – Controlled and prospective clinical trials have been performed but with disappointingly uniformly negative results

TREATMENTS - 2

• • • • • • •

D-Penicillamine Relaxin

- pregnancy related hormone

Methotrexate

- folate antagonist

Interferon

-

gamma

- need larger trials

Interferon

-

alpha

- no benefit

Etanercept

- need controlled trials

Autologous stem cell transplant