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

2. 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.

4. 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

5. Raynaud’s Phenomenon

6. 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.

7. Phases of skin thickening
Edematous

8. 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

9. Indurative Phase

11. 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

13. Facial changes Pinched nose (“mauskopf”) Pursed lips
Cannot evert eyelids
Lip thinning and retraction

15. Atrophic phase
Thick dermis reverts to normal or even becomes thinner (atrophy)

16. telangiectasia

18. LOCALIZED FORMS OF SCLERODERMA
Morphea
Generalized/pansclerotic morphea
Linear scleroderma En coup de saber
Progressive hemifacial atrophy

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

22. Nailfold capillaroscopy

23. Nailfold capillaroscopy
Dilated capillaries
Avascular area
Skin of finger

24. Digital ulcers – evidence of vascular disease

25. Digital necrosis

26. calcinosis

27. 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 ??

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

30. B: profound dermal inflammation
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
Varga, J. et al. J. Clin. Invest. 2007;117:
Copyright ©2007 American Society for Clinical Investigation

31. Skin of the face and neck is usually next involved and associated with an immobile and pinched facies.

32. Skin

33. Telangiectasias

34. CLINICAL FEATURES 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.

35. 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

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

38. CLINICAL FEATURES - 2 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.

40. CLINICAL FEATURES - 3 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

42. CLINICAL FEATURES - 4 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

43. CLINICAL FEATURES - 5 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

44. CLINICAL FEATURES - 6
Interstitial thickening and fibrosis and continuing evidence of interstitial inflammation.

45. CLINICAL FEATURES - 7 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

46. 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

47. CLINICAL FEATURES - 8 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

48. CLINICAL FEATURES - 9 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

50. 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.

52. Diffuse ANA

53. Nucleolar ANA

54. 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

55. Anti-DNA Topoisomerase I (Sc1-70)
20 and 40 percent of patients
intracellular enzyme involved in the initial uncoiling of supercoiled DNA before transcription

56. TREATMENTS 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

57. 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