2774 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

■ ANIMAL MODELS OF DISEASE

There is no single animal model of SSc that fully reproduces the

three cardinal processes that underlie pathogenesis. Tight-skin mice

(Tsk1/+) spontaneously develop skin (hypodermal) fibrosis due to a

duplication mutation in the fibrillin-1 gene. Mutant fibrillin-1 protein

disrupts extracellular matrix assembly, leading to aberrant activation

of the profibrotic transforming growth factor β (TGF-β). In humans,

fibrillin-1 mutations are associated with Marfan’s disease and stiff skin

syndrome but have not been reported in SSc. In mice, skin and lung

fibrosis accompanied by variable vasculopathy and autoimmunity can

be elicited by repeated injection of bleomycin or angiotensin II or by

transplantation of HLA-mismatched bone marrow or spleen cells. Targeted genetic modifications in mice give rise to new disease models for

investigating the pathogenetic roles of individual molecules, pathways,

and cell types. For example, mice lacking IRF5, the ciliary proteins

SPAG17, tenascin-C, or peroxisome proliferator-activated receptor

(PPAR)-γ, or constitutively overexpressing β-catenin, Wnt10b, sirtuin

3, Fra2, PDGFRα, or adiponectin are either resistant or hypersensitive

to experimental scleroderma or spontaneously develop multiple-organ

fibrosis. These disease models can be useful as experimental tools to

understand SSc pathogenesis and discover and validate novel targets

for therapy.

■ MICROANGIOPATHY

In a progressive model of disease pathogenesis (Fig. 360-4), vascular

injury is an early and possibly primary pathogenic event that underlies

protean manifestations of small vessel vasculopathy.

Prominent microangiopathy in multiple vascular beds is a hallmark

of SSc with important clinical sequelae including mucocutaneous

telangiectasia, Raynaud’s phenomenon, ischemic digital ulcers, scleroderma renal crisis, myocardial involvement, and PAH. Raynaud’s

phenomenon, commonly the initial manifestation of SSc, is characterized by altered blood-flow response to cold challenge in small

digital arteries. This reversible functional abnormality is associated

with autonomic and peripheral nervous system alterations, including

impaired production of the neuropeptide calcitonin gene–related

peptide from sensory afferent nerves and heightened sensitivity of α2

-

adrenergic receptors on vascular smooth-muscle cells. Isolated (primary)

Raynaud’s disease is common, generally benign, and nonprogressive.

In contrast, SSc-associated secondary Raynaud’s phenomenon often

progresses to irreversible structural changes in the small blood vessels,

culminating in ischemic digital tip ulcers, necrosis, and amputation.

Viruses, cytotoxic factors, chemokines, thrombogenic microparticles, alternate complement pathway activation, and autoantibodies targeting endothelial cells, phospholipids, and β2

-glycoprotein I (β2

GPI)

have all been implicated as putative triggers of endothelial cell injury in

SSc. Endothelial damage disrupts the production of vasodilatory (nitric

oxide and prostacyclin) and vasoconstricting (endothelin-1) substances, while causing upregulation of intercellular adhesion molecule

1 (ICAM-1) and other surface adhesion molecules. Microvessels show

enhanced permeability and transendothelial leukocyte diapedesis,

activation of coagulation cascades, elevated thrombin production,

and impaired fibrinolysis. Spontaneous platelet aggregation causes

release of serotonin, platelet-derived growth factor (PDGF), and platelet alpha granules including thromboxane, a potent vasoconstrictor.

Smooth-muscle cell–like myointimal cells accumulate in the media,

potentially arising through a process called endothelial-mesenchymal

transition (EndoMT). The basement membrane is thickened and

reduplicated, and perivascular adventitial fibrosis develops. The vasculopathic process primarily affects capillaries, arterioles, and less commonly even large vessels in many organs, resulting in impaired blood

flow and tissue ischemia. Progressive luminal occlusion due to intimal

and medial hypertrophy, combined with persistent endothelial cell

damage and adventitial fibrosis, establish a vicious cycle that underlies

fibroproliferative vasculopathy and culminates in the striking absence

of small blood vessels (rarefaction) in late-stage disease. Recurrent

ischemia-reperfusion generates reactive oxygen species (ROS) that

further damage the endothelium through peroxidation of membrane

lipids. Paradoxically, the process of revascularization that normally

reestablishes blood flow to ischemic tissue is defective in SSc despite

elevated levels of other angiogenic factors. Moreover, bone marrow–

derived circulating endothelial progenitor cells are reduced in number

and impaired in function.

There is increasing evidence implicating EndoMT in the pathogenesis of SSc vasculopathy. The process of EndoMT is characterized

by transition of endothelial cells into myofibroblasts accompanied

by loss of endothelial cell markers and acquisition of myofibroblast

markers associated with nuclear localization of the transcription factor

Snail1. In arterioles and small arteries, EndoMT leads to accumulation

of endothelial cell–derived myofibroblasts in the intima and media,

resulting in fibroproliferative vasculopathy and luminal occlusion. In

contrast, EndoMT affecting the capillary vessels leads to a destructive

vasculopathy characterized by loss of endothelial cells and accumulation of interstitial myofibroblasts derived from endothelial cells,

resulting in interstitial fibrosis and microvessel rarefaction, as can be

observed by nailfold capillaroscopy. Widespread capillary loss combined with fibroproliferative vasculopathy affecting arterioles and

arteries and impaired ability to repair and replace damaged vessels are

hallmarks of SSc.

■ INFLAMMATION AND AUTOIMMUNITY

Cellular Immunity While the initial events triggering the activation of innate and adaptive autoimmunity in SSc are unknown, a

number of observations support the inflammatory/autoimmune nature

of SSc: near-universal presence of circulating autoantibodies with

defined specificities; clustering of SSc with other autoimmune diseases;

activated immune cells, including autoreactive T cells with oligoclonal

antigen receptors, within target organs; prominent type I interferon

(IFN) signatures, characterized by elevated expression of IFN-regulated

genes, in a variety of immune cell types in circulation and in skin

biopsies; elevated circulating levels and spontaneous mononuclear

cell secretion of cytokines and chemokines such as interleukin (IL) 6,

tumor necrosis factor, IL-4, IL-10, IL-17, IL-33, CCL2, and CXCL4;

genetic association of SSc (shared with other autoimmune diseases)

with variants of MHC and other immune response genes; and the

rapid clinical response, fibrosis resolution, and vascular regeneration

observed in some SSc patients treated with immunomodulatory or

immunoablative therapies.

Circulating monocytes from SSc patients overexpress IFN-regulated

genes such as Siglec-1, have reduced levels of caveolin-1, and exhibit

a profibrotic phenotype. In early (edematous) stage SSc, mononuclear

cell infiltrates composed of activated T cells, monocytes/macrophages,

and dendritic cells can be detected in skin, lungs, and other affected

organs even prior to fibrosis or vascular damage. Dendritic cells in

close proximity to activated fibroblasts and myofibroblasts express

toll-like receptors (TLRs) that are activated by self-nucleic acids and

other endogenous ligands. TLR stimulation induces the secretion

Microvasculopathy

Immune dysregulation

Fibrosis

Systemic

sclerosis

FIGURE 360-3 The pathogenic systemic sclerosis (SSc) triad. The characteristic

constellation of synchronously occurring vasculopathy, autoimmunity/inflammation,

and fibrosis distinguishes SSc and underlies its protean clinical manifestations.

Systemic Sclerosis (Scleroderma) and Related Disorders

2775CHAPTER 360

of mediators including IFN, IL-10, thymic stromal lymphopoietin

(TSLP), and CXCL4, shaping the adaptive immune response and contributing to loss of immune tolerance. Tissue-infiltrating T cells express

CD45 and HLA-DR activation markers and display restricted T-cell

receptor signatures indicative of oligoclonal expansion in response to

recognition of as-yet-unknown antigen. Of note, in patients diagnosed

with SSc in close temporal association with cancer who are positive for

RNA polymerase III antibody, the tumor commonly harbors genetic

alterations in RNApol3, which results in the generation of autoantigen-specific T-cell immunity and cross-reactive antibodies.

Circulating T cells in SSc express chemokine receptors and α1 integrin, accounting for their enhanced binding to endothelium and to

fibroblasts, while endothelial cells express ICAM-1 and other adhesion

molecules that facilitate leukocyte diapedesis. Activated T cells show

a TH2-polarized immune response driven by dendritic cells. The TH2

cytokines IL-4, IL-13, IL-33, and TSLP induce fibroblast activation,

whereas the TH1 cytokine interferon γ (IFN-γ) blocks cytokinemediated fibroblast activation and exhibits antifibrotic properties. Evidence for altered TH17 and regulatory T-cell function in SSc has been

reported. Type 2 innate lymphoid cells (iLCs), a recently discovered

distinct lymphoid cell population implicated in type 2 immunity and

tissue remodeling, are also elevated in SSc skin biopsies. Alternately

activated macrophages expressing CD163, which produce TGF-β and

promote angiogenesis and tissue remodeling, are increased in the skin

and lung in SSc. Regulatory T cells (Tregs) enforce immune tolerance,

and although their frequency is elevated in the circulation and tissues

in SSc patients, their immunosuppressive function appears to be defective. A recent report demonstrated that Tregs play a critical role in

preventing spontaneous fibrosis in the skin, possibly by sequestering

activated TGF-β. Some evidence implicates altered B-cell homeostasis and function in SSc. Circulating B cells show elevated CD19 and

co-stimulatory molecules CD80 and CD86, suggesting B-cell chronic

activation. Serum levels of a proliferation-inducing ligand (APRIL) and

B-cell activating factor (BAFF), members of the TNF superfamily with

potent effects on B-cell activation, are elevated in SSc and associated

with extent of skin and lung involvement. B cells secrete IL-6, TGF-β,

and other profibrotic cytokines implicated in pathogenesis. Thus,

B-cell hyperactivity might directly contribute to the inflammatory and

fibrotic processes in SSc, as well as generation of autoantibodies.

Humoral Autoimmunity Circulating antinuclear antibodies

(ANAs) can be detected in virtually all patients with SSc, even in

Endothelial cell injury

Pericyte loss, EndoMT

Platelet activation

Complement pathway

Coagulation cascade

Leaky small blood vessels

Fibroproliferative arteriolar

lesions

Capillary dissolution

Vascular rarefaction

Microangiopathy

Impaired

vasculogenesis

Vascular injury

Anticentromere

Anti-topo 1

Anti-RNApol III

Anti-receptor Ab

Innate and adaptive immune responses Autoantibodies

CD4 and CD8+ T cells

Activated B cells

Monocyte/macrophages

TLR signaling, dendritic cells

Mast cells, eosinophils

Immune system responses

TH2 cytokines

Type I IFN; chemokines

TGF-β, IL-6, IL-11, IL-13

CTGF/CCN2, PDGF, Wnt

Proinflammatory/fibrotic signals

Myofibroblasts originating from stromal progenitor cells

Myofibroblast heterogeneity (CD26 profibrotic subsets)

Epigenetic reprogramming and memory

(fibroblasts, pericytes, adipocytes, endothelial cells, monocytes)

Focal adhesion, mechanosensing, mechanotransduction

Accelerated cellular aging/senescence, metabolic collapse

Apoptosis evasion

Fibrotic cellular responses

Deposition and remodeling of ECM

(collagens, COMP, osteopontin, fibulin,

fibrillin, tenascin, fibronectin, etc.)

Matrix rigidity, contraction

Tissue fibrosis

Organ failure

Pulmonary fibrosis, renal fibrosis, heart failure

GIT dysmotility, tendon friction rubs, joint contractures

Architectural disruption

Tissue hypoxia

FIGURE 360-4 Integrated progressive model of systemic sclerosis (SSc) pathogenesis. Initial vascular insult in a genetically predisposed individual triggers a cascade

of functional and structural vascular alterations associated with inflammation and autoimmunity. Early immune responses elicit fibroblast activation and differentiation,

resulting in sustained pathologic fibrogenesis, irreversible tissue damage, and failure of affected organs. Vascular damage also leads to tissue ischemia that further

contributes to progressive fibrosis and atrophy. Ab, antibody; CTGF, connective tissue growth factor; ECM, extracellular matrix; EndoMT, endothelial-mesenchymal

transition; GIT, gastrointestinal tract; IFN, interferon; IL, interleukin; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; TLR, toll-like receptor.

2776 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

early and possibly preclinical stages of disease. In addition, several

SSc-specific autoantibodies with distinct patterns of immunofluorescence show strong associations with unique disease phenotypes as well

as HLA haplotype (Table 360-4). Owing to their specificity, mutual

exclusivity, and association with unique disease manifestations, SScassociated autoantibodies have substantial utility in clinical practice for

diagnosis and risk stratification, while their role in monitoring disease

activity or response to therapy remains uncertain. Recently, antibodies

directed against fibrillin-1, matrix metalloproteinases, cell surface

markers, angiotensin II receptor, endothelin-1 receptor, or the PDGF

receptor have been identified in patients with SSc, although their clinical relevance is not yet established. These antibodies have functional

receptor agonist activity and might have direct pathogenic roles.

A variety of mechanisms have been proposed to account for the

generation of SSc-associated autoantibodies. Proteolytic cleavage,

increased expression or altered subcellular localization of normal proteins, or their alterations due to mutation in the case of certain tumors

could lead to their immune recognition as neoepitopes, resulting in a

break of immune tolerance.

■ FIBROSIS

Fibrosis synchronously affecting multiple organs is a distinguishing

feature of SSc. The process is characterized by replacement of normal tissue architecture with rigid, avascular, and relatively acellular

connective tissue. Fibrosis in SSc follows, and is a consequence of,

inflammation and microvascular damage (Fig. 360-4). Fibroblasts are

mesenchymal cells primarily responsible for the functional and structural integrity of connective tissue. Upon their activation by extracellular cues, fibroblasts proliferate; migrate; secrete collagens and other

matrix molecules, growth factors, chemokines, and cytokines; and

transdifferentiate into contractile myofibroblasts. Under normal conditions, these are responses self-limited to accomplish tissue regulated

repair and regeneration. In contrast, when these responses become

TABLE 360-4 Major Systemic Sclerosis (SSc)–Specific Autoantibodies

and Principal Associated Features

TARGET ANTIGEN SSc SUBSET

PROMINENT CHARACTERISTIC

CLINICAL ASSOCIATION

Topoisomerase I (Scl-70)

Speckled pattern

dcSSc Tendon friction rubs, digital ischemic

ulcers, scleroderma, extensive skin

involvement, early ILD, cardiac

involvement, scleroderma renal

crisis

Centromere proteins

Discrete speckled

(centromere) pattern

lcSSc Digital ischemic ulcers, calcinosis

cutis, isolated PAH; renal crisis rare

RNA polymerase III

Speckled pattern

dcSSc Rapidly progressive skin

involvement, tendon friction rubs,

joint contractures, GAVE, renal

crisis, contemporaneous cancers;

digital ulcers rare

U3-RNP (fibrillarin)

Nucleolar pattern

dc/lcSSc PAH, ILD, scleroderma renal crisis,

GI tract involvement, myositis

Th/T0

Nucleolar pattern

lcSSc ILD, PAH

PM/Scl

Nucleolar pattern

lcSSc Calcinosis cutis, ILD, myositis

overlap

Ku

Speckled pattern

Overlap SLE, myositis overlap

U1-RNP

Speckled pattern

MCTD PAH, inflammatory arthritis, myositis

overlap

U11/U12 RNP

Speckled pattern

dc/lcSSc ILD

Abbreviations: dcSSc, diffuse cutaneous SSc; GAVE, gastric antral vascular ectasia;

GI, gastrointestinal; ILD, interstitial lung disease; lcSSc, limited cutaneous SSc;

MCTD, mixed connective tissue disease; PAH, pulmonary arterial hypertension; SLE,

systemic lupus erythematosus.

sustained and amplified, pathologic fibrosis results. A panoply of stimulatory signals are potentially implicated in SSc pathogenesis. In addition to TGF-β, these include paracrine mediators IL-6, IL-11, IL-13,

and IL-23, morphogens and Wnt ligands, connective tissue growth

factor (CTGF), PDGF, lysophosphatidic acid, endothelin-1, hypoxia,

ROS, thrombin, and mechanical forces; these signals might contribute

to sustained fibroblast activation underlying maladaptive repair in SSc.

Buildup of damage-associated endogenous ligands for TLR4 (EDAfibronectin and tenascin-C) and TLR9 (mitochondrial DNA) within

the microenvironment further contributes to nonresolving fibrosis via

unchecked TLR activation and innate immune signaling.

In addition to tissue-resident fibroblasts and transformed myofibroblasts, bone marrow–derived circulating mesenchymal progenitor

cells also contribute to fibrosis. The factors that regulate the differentiation of mesenchymal progenitor cells and their trafficking from

the circulation into lesional tissue are unknown. Endothelial cells in

injured arterioles and small arteries undergo EndoMT, giving rise to

myofibroblasts that drive perivascular fibrosis. Epithelial cells, preadipocytes, and tissue fibroblasts are all putative sources of pathogenic

myofibroblasts. Although myofibroblasts are transiently found in normal wound healing, their persistence in fibrotic tissue, possibly due to

their ability to evade apoptosis, contributes to scar formation.

Explanted SSc fibroblasts display an abnormally activated phenotype

ex vivo, characterized by increased collagen production, spontaneous

ROS generation, prominent stress fibers, and constitutive expression

of alpha smooth-muscle actin. Persistence of the “scleroderma phenotype” during serial ex vivo passage of SSc fibroblasts may reflect autocrine TGF-β stimulatory loops, deregulated microRNA expressions,

cell-autonomous metabolic changes, or stable acquired epigenetic

modifications. More recently, tools such as single-cell RNA sequencing

have revealed functional heterogeneity among fibrotic fibroblasts.

PATHOLOGY

While pathologic findings vary across anatomic sites, the distinguishing hallmarks of SSc irrespective of the organ system are widespread

microangiopathy (fibroproliferative vasculopathy), capillary loss and

obliteration, and fibrosis. In early-stage disease, perivascular inflammatory cell infiltrates composed of T and B lymphocytes, activated

monocytes and macrophages, and mast cells may be detected in

multiple organs. A noninflammatory obliterative microangiopathy in

the heart, lungs, kidneys, and gastrointestinal tract is a prominent late

finding. Fibrosis most prominently affects the skin, lungs, cardiovascular system, gastrointestinal tract, tendon sheaths, perifascicular tissue

surrounding skeletal muscle, and some endocrine organs such as the

thyroid gland. Excessive accumulation of collagens and other structural

matrix macromolecules progressively disrupts normal architecture,

resulting in impaired function and failure of affected organs.

■ SKIN

In the skin, the dermis is thickened due to accumulation of broad

bundles of homogenized collagen oriented parallel to the epithelium

(Fig. 360-5A). Adnexal glands are atrophic, and loss of periadnexal

and intradermal white adipose tissue and its replacement with collagen

can be striking. While perivascular mononuclear cell infiltrates may

be seen early, established skin fibrosis shows absence of inflammation.

■ LUNGS

Autopsy studies universally show evidence of lung involvement in

both limited and diffuse cutaneous subsets of SSc. Most common is

the nonspecific interstitial pneumonia (NSIP) pattern characterized

variable interstitial fibrosis and mild chronic inflammation with T lymphocytes, macrophages, and eosinophils. With progression, interstitial

fibrosis and vascular damage dominate, often coexisting within the

same biopsy. The usual interstitial pneumonia (UIP) pattern of spatial

and temporal heterogeneity of inflammation and fibrosis and fibrotic

foci, a hallmark of idiopathic pulmonary fibrosis, is less common in SSc

(Fig. 360-5B). Fibrosis of the alveolar septae results in obliteration of

the airspaces and loss of pulmonary blood vessels. This process impairs

gas exchange and contributes to pulmonary hypertension. Intimal

Systemic Sclerosis (Scleroderma) and Related Disorders

2777CHAPTER 360

thickening of the pulmonary arteries, best seen with elastin stain,

underlies SSc-associated PAH (Fig. 360-5C) and, at autopsy, is often

associated with pulmonary emboli and myocardial fibrosis. Patients

with SSc-associated PAH also show fibrosis and intimal proliferation in

preseptal venules and veins in the lung, accounting for veno-occlusive

disease. Lymphocytic bronchiolitis involving the submucosa of the

terminal bronchioles is occasionally seen.

FIGURE 360-5 Pathologic findings in multiple organs in systemic sclerosis (SSc).

A. Left panel: The skin is thickened due to fibrotic expansion of the dermis. Inset,

higher magnification showing thick hyalinized collagen bundles replacing skin

appendages. Right panel: Mononuclear inflammatory cells in the dermis and

intradermal adipose tissue. B. Early SSc interstitial lung disease. Diffuse fibrosis

of the alveolar septae and a chronic inflammatory cell infiltrate. Trichrome stain.

C. Pulmonary arterial obliterative vasculopathy. Striking intimal hyperplasia and

luminal narrowing of small artery, with little inflammation and minimal interstitial

lung fibrosis, in a patient with SSc pulmonary arterial hypertension.

A

Epidermis

Papillary dermis

Reticular dermis

Reticular dermis

■ GASTROINTESTINAL TRACT

Pathologic changes can be found at any level from the mouth to the

rectum. Atrophy and fibrosis of the muscularis propria and characteristic vascular lesions are prominent in the lower esophagus, while

striated muscle in the upper third of the esophagus is generally spared.

Collagenous replacement of the intestinal tract architecture results

in impaired smooth-muscle contractility and diminished peristaltic

activity, underlying gut dysmotility, bacterial overgrowth, small-bowel

pseudo-obstruction, and perforation. Chronic gastroesophageal reflux

is associated with esophageal inflammation, mucosal ulceration, and

stricture formation and may lead to Barrett’s metaplasia with attendant

risk of adenocarcinoma. Esophageal dilatation and reflux may aggravate ILD due to chronic microaspiration.

■ KIDNEYS

In the kidneys, vascular lesions affecting the interlobular and

arcuate arteries predominate. Chronic renal ischemia is associated

with shrunken glomeruli. Patients with scleroderma renal crisis, a

life-threatening acute complication of SSc, show acute fibrinoid necrosis of afferent arterioles, followed by intimal proliferation (onion-skin

pattern) and ischemic collapse of glomeruli. These changes are reminiscent of thrombotic microangiopathies such as atypical hemolytic-uremic syndrome (Chap. 115) and are accompanied by thrombosis,

thrombocytopenia due to platelet consumption, and intravascular

hemolysis. Evidence of complement activation may be seen in kidney

biopsies. Extensive vascular thrombosis, glomerular collapse, and peritubular capillary deposits predict irreversible renal failure.

■ HEART

Subclinical cardiac pathology is common in SSc and may affect the

myocardium and pericardium. The characteristic arteriolar lesions

in the heart are concentric intimal hypertrophy and luminal narrowing, patchy contraction band necrosis, loss of cardiac myocytes, and myocardial fibrosis due to microvascular involvement

and ischemia-reperfusion injury. Fibrosis of the conduction system

is also common, especially at the sinoatrial node. The frequency of

epicardial atherosclerotic coronary artery disease may be increased

in SSc compared to the general population, similar to other systemic

inflammatory diseases. Pericardial involvement with chronic inflammatory infiltrates and fibrinous exudates is common and is sometimes

associated with pericardial effusions.

■ PATHOLOGY IN OTHER ORGANS

Synovitis of the hands may occur in SSc; with disease progression, the

synovium becomes fibrotic, and in contrast to rheumatoid disease,

pannus formation and bone resorption are uncommon. Fibrosis of

tendon sheaths and fascia, sometimes accompanied by calcifications, produces palpable and sometimes audible tendon friction rubs.

Inflammation and, in later stages, atrophy and fibrosis of skeletal

muscles are common findings and are similar to those in polymyositis.

Fibrosis of the thyroid and of the minor salivary glands may be seen

and underlie hypothyroidism and the sicca syndrome. Placentas from

SSc pregnancies show decidual vasculopathy, which is associated with

poor perinatal outcomes and fetal death.

CLINICAL FEATURES

■ OVERVIEW

SSc is truly a systemic disease that can affect virtually any organ

(Fig. 360-1 and Table 360-5). Although a dichotomous stratification

into diffuse and limited cutaneous subsets (Table 360-2) is useful, SSc

is far more complex, and multiple distinct clusters or endophenotypes

of SSc with characteristic manifestations and trajectories and outcomes can be recognized within each subset. Unique endophenotypes

associate with autoantibodies with distinct and mutually exclusive

specificities (Table 360-4). Moreover, patients with “overlap” have typical features of SSc coexisting with clinical and laboratory evidence of

another autoimmune disease, most commonly polymyositis, Sjögren’s

syndrome, polyarthritis, autoimmune liver disease, or SLE.

2778 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

■ INITIAL CLINICAL PRESENTATION

Characteristic initial presentation is quite different in patients with the

diffuse (dcSSc) versus limited (lcSSc) cutaneous forms of the disease.

In dcSSc, the interval between Raynaud’s phenomenon and onset

of other disease manifestations is typically brief (weeks to months).

Soft tissue swelling, puffy fingers, and pruritus are signs of the early

inflammatory “edematous” phase. The fingers, distal limbs, and face

are usually affected first. Diffuse hyperpigmentation of the skin, carpal

tunnel syndrome, arthralgias, muscle weakness, fatigue, and decreased

joint mobility are common. During the ensuing weeks to months, the

inflammatory edematous phase evolves into the “fibrotic” phase, with

skin induration associated with hair loss, reduced production of skin

oils, and decline in sweating capacity. Progressive flexion contractures

of the fingers ensue. The wrists, elbows, knees, and ankles become stiff

due to fibrosis of the supporting joint structures. While advancing skin

involvement is the most visible manifestation of early dcSSc, important and clinically silent internal organ involvement can occur during

this stage. The initial 4 years from disease onset is the period of most

rapidly evolving and potentially irreversible lung and renal damage. If

organ failure does not occur during this phase of dcSSc, the systemic

process may plateau and stabilize.

Compared to dcSSc, the course of lcSSc tends to be more indolent.

The interval between onset of Raynaud’s phenomenon and disease

manifestations such as gastroesophageal reflux disease (GERD), cutaneous telangiectasia, ischemic digital ulcers, or soft tissue calcifications

can be as long as years. Scleroderma renal crisis, significant ILD, and

tendon friction rubs occur rarely in lcSSc, whereas PAH and overlap

with keratoconjunctivitis sicca, polyarthritis, cutaneous vasculitis, and

biliary cirrhosis can develop even many years after disease onset.

ORGAN INVOLVEMENT

■ RAYNAUD’S PHENOMENON

Raynaud’s phenomenon, the most frequent extracutaneous complication of SSc, is characterized by episodic vasoconstriction in the

fingers and toes, sometimes also affecting the tip of the nose and

earlobes. Attacks are reversible, and can be triggered by a decrease in

temperature, as well as emotional stress and vibration. Attacks typically start with pallor of the fingers, followed by cyanosis of variable

duration. Hyperemia ensues spontaneously or with rewarming of the

digit. The progression of the three color phases reflects the underlying

vasoconstriction, ischemia, and reperfusion. It is important to note

that up to 5% of the general population has Raynaud’s phenomenon.

In the absence of signs or symptoms of an underlying condition,

Raynaud’s phenomenon is classified as primary (Raynaud’s disease),

which represents an exaggerated physiologic vasomotor response

to cold. Secondary Raynaud’s phenomenon occurs in SSc and other

connective tissue diseases, hematologic and endocrine conditions, and

TABLE 360-5 Frequency of Clinical Organ Involvement in Limited

Cutaneous and Diffuse Cutaneous Systemic Sclerosis (SSc)

FEATURES

LIMITED CUTANEOUS

SSc (%)

DIFFUSE CUTANEOUS

SSc (%)

Skin involvement 90a 100

Raynaud’s phenomenon 99 98

Ischemic digital ulcers 50 25

Esophageal involvement 90 80

Interstitial lung disease 35 65

Pulmonary arterial

hypertension

15 15

Myopathy 11 23

Clinical cardiac

involvement

9 12

Scleroderma renal crisis 2 15

Calcinosis cutis 40 35

a

Approximately 10% of patients have SSc sine scleroderma.

occupational disorders, and can complicate treatment with beta blockers and anticancer drugs such as cisplatin and bleomycin. Distinguishing primary Raynaud’s disease from secondary Raynaud’s phenomenon

can present a diagnostic challenge. Raynaud’s disease is supported by

the following: absence of an underlying cause; a family history of Raynaud’s phenomenon; absence of digital tissue necrosis or ulceration;

and a negative ANA test. Secondary Raynaud’s phenomenon tends to

occur at an older age, is more severe (episodes are more frequent, prolonged, and painful), and is frequently complicated by ischemic digital

ulcers and loss of digits (Fig. 360-6).

Nailfold capillaroscopy using a low-power stereoscopic microscope

or ophthalmoscope permits visualization of nailbed cutaneous capillaries under immersion oil (Fig. 360-7). Raynaud’s disease is associated with evenly spaced parallel vascular loops, whereas in secondary

Raynaud’s phenomenon, nailfold capillaries are distorted with widened

and irregular loops, dilated lumen, microhemorrhages, and areas of

vascular “dropout.” Thus, nailfold capillaroscopy can be helpful for

both differentiating primary from secondary Raynaud’s phenomenon

and for establishing the early diagnosis of SSc.

FIGURE 360-6 Digital necrosis. Sharply demarcated necrosis of the fingertip

secondary to ischemia in a patient with limited cutaneous systemic sclerosis (SSc)

associated with severe Raynaud’s phenomenon.

FIGURE 360-7 Systemic sclerosis–associated nailfold capillary alterations. In

healthy subjects, note regularly arrayed and uniform-size “hairpin” microvessels.

In early pattern, note dilations of microvessels and symmetrically increased

microvessels (giant capillaries). In active pattern, note giant capillaries, collapse

with microhemorrhages, and loss of capillaries. In late pattern, note massive loss

of capillaries, fibrosis, and neoangiogenesis with secondary dilations (nailfold

videocapillaroscopy; magnification 220×). (Courtesy Professor Maurizio Cutolo,

University of Genoa, Italy.)

Systemic Sclerosis (Scleroderma) and Related Disorders

2779CHAPTER 360

■ SKIN FEATURES

Bilateral symmetrical skin thickening is the hallmark that distinguishes

SSc from other connective tissue diseases. Skin involvement starts in

the fingers and characteristically advances from distal to proximal

extremities in an ascending fashion. Some patients note diffuse tanning in the absence of sun exposure as a very early manifestation. In

dark-skinned individuals, vitiligo-like hypopigmentation may occur.

Pigment loss sparing the perifollicular areas gives rise to a “salt-andpepper” appearance of the skin, most prominently on the scalp, upper

back, and chest. Dermal sclerosis obliterating hair follicles, sweat

glands, and eccrine and sebaceous glands causes hair loss, decreased

sweating, and xerosis and itching in affected areas of the skin. Transverse creases on the dorsum of the fingers disappear (Fig. 360-8). Fixed

flexion contractures of the fingers cause reduced hand mobility and

lead to muscle atrophy. Skin and subjacent tendon fibrosis accounts for

fixed contractures of the wrists, elbows, and knees. Thick ridges at the

neck due to firm adherence of skin to the underlying platysma muscle

interfere with neck extension.

Patients with established SSc may show a characteristic “mauskopf ”

facial appearance with taut and shiny skin, loss of wrinkles, and occasionally an expressionless facies due to reduced mobility of the eyelids,

cheeks, and mouth. Thinning of the lips with accentuation of the central incisor teeth and prominent perioral radial furrowing (rhytides)

complete the picture. Reduced oral aperture (microstomia) interferes

with eating and oral hygiene. The nose assumes a pinched, beak-like

appearance. In late-stage disease, the skin becomes thin and atrophic

and is firmly bound to the subcutaneous fat (tethering). Dilated skin

capillaries 2–20 mm in diameter (telangiectasia), reminiscent of hereditary hemorrhagic telangiectasia, are frequently on the face, hands, lips,

and oral mucosa (Fig. 360-9). The number of telangiectasias correlates

with the severity of microvascular disease, including PAH. Breakdown

of atrophic skin leads to chronic ulcerations at the extensor surfaces

of the proximal interphalangeal joints, the volar pads of the fingertips,

and bony prominences such as elbows and malleoli. Ulcers are often

painful, heal slowly, and become secondarily infected, resulting in

osteomyelitis. Healing of ischemic fingertip ulcerations leaves characteristic fixed digital “pits.” Loss of soft tissue at the fingertips due to

ischemia may be associated with striking resorption of the terminal

phalanges (acro-osteolysis) (Fig. 360-10).

Dystrophic calcifications in the skin, subcutaneous, and soft tissues (calcinosis cutis) in the presence of normal serum calcium and

phosphate levels occur in up to 40% of patients, most commonly in

those with long-standing anti-centromere antibody–positive lcSSc.

Calcific deposits, composed of calcium hydroxyapatite crystals, vary

in size from tiny punctate lesions to large conglomerate masses, and

can be readily visualized on plain radiographs or dual-energy CT.

These deposits occur when calcium precipitates in tissue damaged by

FIGURE 360-8 Sclerodactyly. Note skin induration on the fingers and fixed flexion

contractures of proximal interphalangeal joints in a patient with limited cutaneous

systemic sclerosis (lcSSc).

inflammation, hypoxia, or local trauma. Common locations include

the finger pads, palms, extensor surfaces of the forearms, and the

olecranon and prepatellar bursae (Fig. 360-11). Large calcific deposits

can cause pain and nerve compression and may ulcerate through the

FIGURE 360-9 Cutaneous vascular changes in systemic sclerosis. A. Vascular

changes at the nailfold in a patient with lcSSc. B. Telangiectasia on the face.

A

B

FIGURE 360-10 Acro-osteolysis. Note dissolution of distal terminal phalanges

(arrows). Acro-osteolysis is associated with digital ischemia and is seen in patients

with long-standing limited cutaneous systemic sclerosis (lcSSc) and Raynaud’s

phenomenon.