FACULTY OF MEDICINE

&
HEALTH SCIENCES

SELF LEARNING PACKAGE

YEAR II MD

MM 20605
SYSTEMIC SCLEROSIS (SCLERODERMA)

STUDENT NAME: ---------------------------------------

MATRIC NUMBER: -------------------------------------

Dr Aye MM20605 SLP on Scleroderma

 SYSTEMIC SCLEROSIS (SCLERODERMA)

Introduction:

Systemic sclerosis is previously called ’scleroderma’(Greek- skleros which means hard, and
derma, which means skin). It is a generalized disorder of connective tissue affecting the skin,
internal organs and vasculature. The clinical hallmark is the presence of sclerodactyly in
combination with Raynaud’s phenomenon or digital ischemia.

It occurs most frequently in the 4th and 5th decades of life and with female: male ratio of 4:1

SS can be classified into two groups on the basis of its clinical course:
1. Diffuse cutaneous systemic sclerosis (DCSS): wide spread skin involvement at
onset, with rapid progression and early visceral involvement
2. Limited cutaneous systemic sclerosis (LCSS) : with relatively minimal skin
involvement, often confined to the fingers, forearms and face.
 Involvement of the viscera occurs late, and hence the disease in these patients
generally has a fairly benign course. Limited scleroderma is commonly referred to
by the acronym CREST syndrome, whose letters are the first initials of
characteristics that are usually found in this syndrome:

 Calcinosis. It is evident in the fingers of this patient with the CREST variant of systemic
sclerosis. The calcinosis appears as irregular, hard nodules associated with digital pulp
atrophy. In places, the overlying skin is thin, and the underlying calcific material appears as
small yellowish patches.
 Raynaud's phenomenon. In this syndrome, the fingers of both hands are very sensitive
to cold, and they remain cold and blue-colored after exposure to low temperatures.
Typically the hands turn white on exposure to cold, reflecting vasospasm, followed by a blue
color as ischemia and cyanosis supervene. Finally, the color changes to red as reactive
vasodilation occurs.
 Esophageal motility dysfunction In esophageal motility dysfunction, the muscles in the
esophagus become scarred by scleroderma and do not contract normally. This can cause
severe heartburn and other symptoms of gastroesophageal reflux disorder (GERD).
 Sclerodactylia (also called acrosclerosis). This is the stiffness and tightening of the skin of
the fingers, a classic symptom of scleroderma.
 Telangiectasia. There is widening of small blood vessels causes numerous flat red marks
to form on the hands, face, and tongue.

Usually only 2 of the 5 symptoms of the CREST syndrome are necessary to be

diagnosed with the disease.

Risk Factors:
 Scleroderma is not common.

Dr Aye MM20605 SLP on Scleroderma

 Specific risk factors

 Age. Systemic scleroderma usually develops between the ages of 35 and 55. Localized
scleroderma is more common in children than adults, but is extremely rare even in the
young age group
 Gender. Women are three to eight times more affected.
 Family History. A family history is the strongest risk factor for scleroderma, but even
among family members, the risk is very low (less than 1%).
 Genetics. Genetic factors appear to play a role in triggering the disease, but most cases
are unlikely to be inherited.
 Ethnicity. Limited data on risk by ethnic group in the United States suggests that the risk
from highest to lowest is the following: Choctaw Native Americans (highest), African-
Americans, Hispanics, Caucasians, Japanese Americans.

Etiology & Pathogenesis

 Fibroblast activation with excessive fibrosis is the hallmark of SS which may be

due to abnormal activation of immune system and microvascular injury.
 CD4 T cells responding to unidentified antigen accumulate in the skin and release
cytokines that activate mast cells and macrophages; in turn these cells release
fibrogenic cytokines such as IL-1, TNF, PDGF, TGF-beta, and fibroblast growth
factors.
 B cell activation as evidenced by presence of hyper-gammaglobulinemia and
ANAs. Two of the ANAs are more or less unique to SS and are therefore useful in
diagnosis. One of these, directed against the DNA topoisomerase I (anti-scl 70),
is highly specific; it is present in up to 70% of patients with diffuse scleroderma
and is a marker for patients likely to develop more aggressive disease with
pulmonary fibrosis and peripheral vascular pathology. The other ANA is an
anticentromere antibody, found in up to 90% of patients with limited
scleroderma (ie. CREST syndrome); it indicates a relatively benign course.
 Microvascular disease is not the primary event; rather, endothelial cells are
induced to release PDGF and fibroblast chemotactic factors in the setting of T cell
activation.There is endothelial damage followed by platelet aggregation lead to
release of platelet factors (eg. PDGF, TGF-alpha) that trigger periadventitial
fibrosis and eventual ischemic injury caused by widespread narrowing of the
microvasculature.

Dr Aye MM20605 SLP on Scleroderma

The American College of Rheumatology/European League Against Rheumatism criteria for the
classification of systemic sclerosis (SS)

Item Sub-item(s) & Weight/score

Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (sufficient criterion) = 9

Skin thickening of the fingers (only count the higher score) Puffy fingers = 2

Sclerodactyly of the fingers (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints)= 4

Fingertip lesions (only count the higher score) Digital tip ulcers = 2

Fingertip pitting scars = 3

Telangiectasia = 2

Abnormal nailfold capillaries = 2

Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2) Pulmonary arterial hypertension = 2

Interstitial lung disease = 2

Raynaud’s phenomenon = 3

SSc-related autoantibodies (anticentromere, anti–topoisomerase I [anti–Scl-70], anti–RNA polymerase III) , Anticentromere ,

Anti–topoisomerase I Anti–RNA polymerase III (maximum score is = 3)

* These criteria are applicable to any patient considered for inclusion in an SSc study.

The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of 9 are
classified as having definite SS.

Morphology

Skin Changes

 The vast majority of patients have diffuse, sclerotic atrophy of the skin, usually
beginning in the fingers and distal regions of the upper extremities and
extending proximally to involve the upper arms, shoulders, neck, and face.
 In the early stages, affected skin areas are somewhat edematous and have a
doughy consistency.
 In advanced stages the fingers take on a tapered, clawlike appearance with
limitation of motion in the joints, and the face becomes a drawn mask. Loss of
blood supply may lead to cutaneous ulcerations and to atrophic changes in the
terminal phalanges, including autoamputation.

Gastrointestinal Tract. The gastrointestinal tract is affected in approximately 90% of

patients.

Dr Aye MM20605 SLP on Scleroderma

  Progressive atrophy and collagenous fibrous replacement of the muscularis may
develop at any level of the gut but are most severe in the esophagus, with the
lower two-thirds often developing an inflexibility.
 The associated dysfunction of the lower esophageal sphincter gives rise to
gastroesophageal reflux and its complications, including Barrett metaplasia and
strictures.
 Loss of villi and microvilli in the small bowel is leads to malabsorption syndrome.

Musculoskeletal System

 Synovial hyperplasia and inflammation is common in the early stages; fibrosis

later ensues.
 Although these changes are reminiscent of RA, joint destruction is not common
in SS. In a small subset of patients (approximately 10%), inflammatory myositis
indistinguishable from polymyositis may develop.

Lungs. The lungs are affected in more than 50% of patients; this may manifest
as pulmonary hypertension and/or interstitial fibrosis.

Kidneys
 Renal abnormalities occur in two-thirds of patients with SS, most typically
associated with thickening of the vessel walls of interlobular arteries
(150-500 μm in diameter).
 Hypertension does occur in 30% of patients and in 20% of those patients
takes an ominously malignant course (malignant hypertension). In
hypertensive patients, vascular alterations are more pronounced and are
often associated with fibrinoid necrosis involving the arterioles together
with thrombosis and infarction.
 Such patients often die of renal failure, accounting for about half the
deaths in patients with SS. There are no specific glomerular changes.

Heart. Pericarditis with effusion and myocardial fibrosis occur in one third of
cases. Clinical myocardial involvement is less common

Clinical course
 SS affects women three times more often than men, with a peak incidence
in the 50- to 60-year age group.
 Raynaud phenomenon precedes other symptoms in 70% of cases.
 Progressive collagenisation of the skin leads to atrophy of the hands, with
increasing stiffness and eventually complete immobilization of the joints.
 Dysphagia results from esophageal fibrosis and resultant hypomotility.
Abdominal pain, intestinal obstruction, or malabsorption may reflect
involvement of small intestine.
 Respiratory difficulties reflect the pulmonary fibrosis; with advanced lung
involvement, secondary pulmonary hypertension may develop, leading to
right-sided cardiac failure.
 Myocardial fibrosis may cause either arrhythmias or cardiac failure

Dr Aye MM20605 SLP on Scleroderma

  Renal functional impairment with mild proteinuria occurs in up to 70% but
rarely causes nephrotic syndrome.
 Without malignant hypertension with subsequent development of renal
failure the progression of disease may be slow.
 In CREST syndrome, the initial manifestations are Raynaud phenomenon
and skin involvement. Visceral lesions occur late including esophageal
dysfunction, pulmonary hypertension and biliary cirrhosis. Prognosis is
better than those with systemic sclerosis with diffuse visceral involvement
at the outset.
 Pregnancy in systemic sclerosis may be uneventful with good maternal
and fetal outcomes. Scleroderma is a multisystem disease and
complications do occur; however, careful antenatal evaluations, discussion
of potential problems, and participation in a high-risk obstetric monitoring
program are important to optimize the best outcome. Women who have
diffuse scleroderma are at a greater risk for developing serious
cardiopulmonary and renal problems early in the disease so they should
be encouraged to delay pregnancy until the disease stabilizes.

Diagnosis:

 There are no specific tests for scleroderma. The doctor may suspect scleroderma after
taking a history of the symptoms and performing a physical examination.

Tests for Antinuclear Antibodies

Most patients are antinuclear antibodies (ANAs) positive. Detecting specific types of ANAs
may help diagnose scleroderma. ANA subtypes include the following:

 Rheumatoid factor, anti-single-stranded DNA, and antihistone antibodies are autoantibodies

associated with scleroderma, but they are also common in other autoimmune disorders,
such as rheumatoid arthritis and systemic lupus erythematosus.
 30% of patients with diffuse disease and 60% with limited disease have Anti-RNA
polymerase III, anti-topoisomerase I (also called anti-DNA topo 1) and anti-centromere
antibodies (ACA) .
 Higher-than-normal levels of autoantibodies to fibrillin 1, a protein found in muscle and
other connective tissues, is more common in patients with both systemic and localized
scleroderma
 RNA Polymerase III (Pol 3) is rarely linked to severe interstitial fibrosis, although this
autoantibody is strongly present in patients with kidney crisis.

Management and prognosis

Dr Aye MM20605 SLP on Scleroderma

 Five year survival rate is approximately 70%. Risk factors at presentation that associate with
poor prognosis are older age groups, diffuse skin involvement, proteinuria, high ESR, a low
gas transfer factor for carbon monoxide (TLCO) and pulmonary hypertension.
 Self-management to maintain core body temperature and avoid peripheral cold exposure is
important. Infection of ulcerated skin should be treated with prompt antibiotic therapy.
Antibiotics penetrate poorly into the skin lesions of systemic sclerosis and therefore need to
given at higher dose for longer periods. Calcium antagonist or angiotensin II receptor
antagonists may be effective for Raynaud’s symptoms. For severe digital ischemia,
intermittent infusions of epoprostenol may be helpful.
 Corticosteroids or cytotoxic drugs are indicated in patients with myositis or alveolitis. No
agent has been shown to arrest or improve skin changes.

References

Henness S, Wigley FM. Current drug therapy for scleroderma and secondary Raynaud's
phenomenon: evidence-based review. Curr Opin Rheumatol. 2007;19:611-618.

Kumar V, Cotran RS, Robbins SL (2005) Diseases of Immunity. In Robbins Basic Pathology; 8th
edition. Saunders. Philadelphia pg- 141-144

Rubin LJ. Treatment of Pulmonary Arterial Hypertension Due to Scleroderma: Challenges for the
Future. Rheumatic Dis Clin North Am. 2008;34(1):191-197; viii.

Steen VD. Pregnancy in scleroderma. Rheum Dis Clin North Am. 2007;33:345-358.

Tyndall A, Furst DE. Adult stem cell treatment of scleroderma. Curr Opin Rheumatol.
2007;19:604-610.

Boon NA et al. Systemic Sclerosis. In: Hunter JAA: Davidson’s Principles and Practice of
Medicine.. 20th ed. Churchill Livingstone.Elsevier, 2006. pp. 1136

Dr Aye MM20605 SLP on Scleroderma