Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis

Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis

Sergio A. Jimenez, MD; and
Chris T. Derk, MD

From Thomas Jefferson University, Philadelphia, Pennsylvania.

PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE

Co-sponsored by the American College of Physicians and the American Physiological Society

Physiology in Medicine: Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD, Associate Editor; William J. Koopman, MD, Associate Editor

Annals of Internal Medicine: Paul Epstein, MD, Series Editor

Clinical Principles

Systemic sclerosis is an autoimmune connective tissue disorder of unknown cause.

It is clinically heterogeneous, ranging from limited skin involvement to diffuse skin sclerosis with severe internal organ involvement.

The Raynaud phenomenon, swelling of the extremities, and diffuse arthralgias often precede the onset of skin tightness and induration.

Visceral involvement with fibrosis, microvascular alterations, and mononuclear cell infiltration of the gastrointestinal tract, lungs, heart, and kidneys is present to a variable extent in most patients.

Autoantibodies, some with very high specificity, are present almost universally.

Mortality and morbidity are substantial and are directly related to the extent of the fibrotic and microvascular alterations.

A better understanding of the pathogenesis of this incurable disorder will help to design effective therapies in the future.

Physiologic Principles

The pathogenesis of systemic sclerosis is extremely complex; at present, no single unifying hypothesis explains all aspects.

Fundamental abnormalities in at least 3 types of cells are intimately involved in the development of the clinical and pathologic manifestations of the disease: 1) fibroblasts; 2) endothelial cells; and 3) cells of the immune system, in particular T and B lymphocytes.

The profound functional alterations in these cells result in the characteristic triad of pathologic changes: severe and often progressive cutaneous and visceral fibrosis; obliteration of the lumen of small arteries and arterioles; and humoral and cellular immunologic abnormalities, which include the production of autoantibodies, the chronic mononuclear cell infiltration of affected tissues, and the dysregulation of lymphokine and growth factor production.

A …

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