SYSTEMIC SCLEROSIS: A Vascular Perspective

https://doi.org/10.1016/S0889-857X(05)70295-7Get rights and content

The evidence that generalized scleroderma (systemic sclerosis, SSc) is a vascular disease is compelling. Raynaud's phenomenon and subcutaneous edema are early manifestations, whereas vascular insufficiency from both arterial intimal scarring and microvessel obliteration in many organs compromises critical organ function, determines mortality and morbidity in the individual patient, and in association with fibrosis provides in the skin the fundamental pathogenetic rationale for dividing SSc into subsets that can empirically be shown to be prognostically meaningful.

Consider the extent of the clinical problem. Between 5% and 30% of adults worldwide can be shown to have the cold- and stress-induced exaggerated yet intermittent vasospasm called Raynaud's phenomenon (RP). Now well-established microscopic (nailfold capillaroscopy) and serologic (indirect immunofluorescence with rapidly dividing human cells such as HEp-2) laboratory determinations can select a small proportion of RP subjects (estimated to be 10% of all RP-positive and up to 50% of clinically referred RP-positive subjects) who, when capillary- and serology-positive, join the mild end of the spectrum of SSc with limited cutaneous systemic sclerosis. Thus, in the definable portion of adults who are Raynaud's-positive, and either capillary-positive or serology-positive, we have a group of subjects in which to study the natural history of at least limited cutaneous SSc and to interrupt the pathogenetic process when we understand how to intervene safely.7, 24, 28, 44

It follows, therefore, that a detailed understanding of the vascular pathogenesis and its relationship to the fibrosis characteristic of SSc could directly influence our management and therapy of this difficult disease. Such a premise is the basis of this article.

Section snippets

Definition

SSc is a generalized disorder of the interstitial connective tissues and vasculature with distinct abnormalities of three systems, immune and autoimmune, vascular and microvascular, and mesenchymal extracellular matrix (ECM), that lead to exuberant fibrosis. The principal target organs for vascular insufficiency and fibrosis are the skin, lungs, gastrointestinal tract, heart, and kidneys. The process can vary from aggressive and fulminating to indolent and chronic. The rate of involvement of

Raynaud's Phenomenon (RP)

As mentioned earlier, the prevalence of RP varies by as much as six-fold depending on the population surveyed, from a low of 5% to a high of 30%. Multiple factors have been proposed to explain these differences. In a US study7, 24, 28 consisting of whites and blacks, the prevalence varied from 5% to 10% and a disproportionately high prevalence noted in black men was adequately accounted for by the high proportion of heavy manual labor carried out by the study subjects. Thus occupation must be

The Physiologic Lesion

The markedly attenuated microvascular bed in SSc can be studied physiologically as well as morphologically. Exaggerated vasospasm and dramatically reduced microvascular volumes have been well documented by such notables as Sir Thomas Lewis, Grant and Bland, Coffman and Cohen, Nilsson and Lassen, Downey and Cannon, Burch et al, Maricq et al, Jablonska et al, Rowell et al, Norton et al, and most recently by Cooke et al. Cooke et al have recently demonstrated, using Doppler techniques, that

VASCULAR MANAGEMENT AND THERAPY

This article is not intended to be exhaustive in a clinical or therapeutic context. Probably the most significant change in the life of an SSc patient has been the introduction and use of ACE inhibitors to prevent renal failure, hypertension, and the direct proliferative and vasculotoxic effects of angiotensin II on blood-vessel wall cells. These may be the only class of drugs in which definite prolongation of life in SSc is well documented and generally agreed upon. They are especially helpful

SUMMARY

The horizon is bright for SSc in a vascular context. Surrogate markers can now be routinely used in the management of the active patient; new cytokines, such as VEGF, can be studied along with the known abnormalities of the cytokine cascade (TGFβ1, PDGF) for a more integrated understanding of the vascular pathogenesis of SSc (Fig. 6); and combination therapies can be applied before vascular insufficiency leads to vital organ failure. Thus, despite reimbursement and research funding constraints,

ACKNOWLEDGMENTS

The author thanks Beth Gladden and her staff for the preparation of this article.

References (54)

  • K.M. Dameron et al.

    Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1

    Science

    (1994)
  • H.F. Dvorak et al.

    Vascular permeability factor/vascular endothelial growth factor: An important mediator of angiogenesis in malignancy and inflammation

    Int Arch Allergy Immunol

    (1995)
  • E. Dwyer et al.

    The role of the trimolecular complex (αβTCR-MHC+peptide) in the pathogenesis of systemic sclerosis. In Korn J, LeRoy C (eds): The Immunopathogenesis of Systemic Sclerosis

    Int Rev Immunol

    (1995)
  • D. Fivenson et al.

    C-x-c chemokine efflux during chronic wound healing: critical role of the elr motif in angiogenesis [abstract]

    Federation Proceedings

    (1995)
  • B.L. Gruber

    Mast cells: Accessory cells which potentiate fibrosis

    Int Rev Immunol

    (1995)
  • M.S. Gruschwitz et al.

    Correlation of soluble adhesion molecules in the peripheral blood of scleroderma patients with their in situ expression and with disease activity

    Arthritis Rheum

    (1995)
  • N. Inoue et al.

    Molecular regulation of the bovine endothelial cell nitric oxide synthase by transforming growth factor-β

    Arterioscler Thromb Vasc Biol

    (1995)
  • S. Jimenez et al.

    Retroviruses and the pathogenesis of systemic sclerosis

    Int Rev Immunol

    (1995)
  • M.B. Kahaleh

    The vascular endothelium in scleroderma

    Int Rev Immunol

    (1995)
  • M.B. Kahaleh et al.

    Endothelial injury in scleroderma

    J Exp Med

    (1979)
  • G. Karsenty et al.

    Regulation of type-I collagen genes expression

    Int Rev Immunol

    (1995)
  • L.M. Khachigian et al.

    Nuclear factor-kb interacts functionally with the platelet-derived growth factor b-chain shear-stress response element in vascular endothelial cells exposed to fluid shear stress

    J Clin Invest

    (1995)
  • H. Kiener et al.

    Increased levels of circulating intercellular adhesion molecule-1 in patients with systemic sclerosis

    Clin Exp Rheumatol

    (1994)
  • J.H. Korn et al.

    The immunopathogenesis of systemic sclerosis

    Int Rev Immunol

    (1995)
  • T.S. Kupper

    Adhesion molecules in scleroderma: Collagen binding integrins

    Int Rev Immunol

    (1995)
  • B. Lee et al.

    Molecular structure and function of autoantigens in systemic sclerosis

    Int Rev Immunol

    (1995)
  • E.C. LeRoy et al.

    Raynaud's phenomenon: A proposal for classification

    Clin Exp Rheumatol

    (1992)
  • Cited by (0)

    Address reprint requests to E. Carwile LeRoy, MD, Department of Microbiology and Immunology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425

    *

    From the Medical University of South Carolina, Charleston, South Carolina

    View full text