InternalMed_Harrison

InternalMed_Harrison. Once the acute episode has resolved, the priority in management is to ensure long-term clinical follow-up and adherence to a regimen of secondary prophylaxis. Patients should be entered onto the local ARF registry (if present) and contact made with primary care practitioners to ensure a plan for follow-up and administration of secondary prophylaxis before the patient is discharged. Patients and their families should also be educated about their disease, emphasizing the importance of adherence to secondary prophylaxis. Ideally, primary prevention would entail elimination of the major risk factors for streptococcal infection, particularly overcrowded housing. This is difficult to achieve in most places where ARF is common.


InternalMed_Harrison

InternalMed_Harrison. Therefore, the mainstay of primary prevention for ARF remains primary prophylaxis (i.e., the timely and complete treatment of group A streptococcal sore throat with antibiotics). If commenced within 9 days of sore throat onset, a course of penicillin (as outlined above for treatment of ARF) will prevent almost all cases of ARF that would otherwisehavedeveloped.InsettingswhereARFandRHDarecommonbut microbiologic diagnosis of group A streptococcal pharyngitis is not available, such as in resource-poor countries, primary care guidelines often recommend that all patients with sore throat be treated with penicillin or, alternatively, that a clinical algorithm be used to identify patients with a higher likelihood of group A streptococcal pharyngitis. Although imperfect, such approaches recognize the importance of ARF prevention at the expense of overtreating many cases of sore throat that are not caused by group A streptococcus.


InternalMed_Harrison

InternalMed_Harrison. The mainstay of controlling ARF and RHD is secondary prevention. Because patients with ARF are at dramatically higher risk than the generalpopulationofdevelopingafurtherepisodeofARFafteragroupA streptococcal infection, they should receive long-term penicillin prophylaxis to prevent recurrences. The best antibiotic for secondary prophylaxis is benzathine penicillin G (1.2 million units, or 600,000 units if ≤27 kg) delivered every 4 weeks. It can be given every 3 weeks, or even every 2 weeks, to persons considered to be at particularly high risk, although in settings where good compliance with an every- 4-week dosing schedule can be achieved, more frequent dosing is rarely needed. Oral penicillin V (250 mg) can be given twice daily instead but is less effective than benzathine penicillin G. Penicillin-allergic patients can receive erythromycin (250 mg) twice daily.


InternalMed_Harrison

InternalMed_Harrison. The duration of secondary prophylaxis is determined by many factors, in particular the duration since the last episode of ARF Category of Patient Duration of Prophylaxis Rheumatic fever without carditis For 5 years after the last attack or 21 years of age (whichever is longer) Rheumatic fever with carditis but no For 10 years after the last attack, or residual valvular disease 21 years of age (whichever is longer) Rheumatic fever with persistent val-For 10 years after the last attack, or vular disease, evident clinically or on 40 years of age (whichever is longer); echocardiography sometimes lifelong prophylaxis aThese are only recommendations and must be modified by individual circumstances as warranted. Note that some organizations recommend a minimum of 10 years of prophylaxis after the most recent episode, or until 21 years of age (whichever is longer), regardless of the presence of carditis with the initial episode.


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InternalMed_Harrison. Source: Adapted from AHA Scientific Statement Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis. Circulation 119:1541, 2009. (recurrences become less likely with increasing time), age (recurrences are less likely with increasing age), and the severity of RHD (if severe, it may be prudent to avoid even a very small risk of recurrence because of the potentially serious consequences) (Table 381-4). Secondary prophylaxisisbestdeliveredaspartofacoordinatedRHDcontrolprogram,basedaroundaregistryofpatients.Registriesimprovetheability to follow patients and identify those who default from prophylaxis and to institute strategies to improve adherence.


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InternalMed_Harrison. VIDEO 381-1a Transthoracic echocardiographic images of a 9-year-old girl with first episode of acute rheumatic fever. Images demonstrate the typical echocardiographic findings of acute rheumatic carditis. The valve leaflets are relatively thin and highly mobile. The failure of coaptation of the mitral valve leaflets is the result of chordal elongation and annular dilatation. The mitral valve regurgitation is moderate with a typical posterolaterally directed regurgitant jet of rheumatic carditis. A. Acute rheumatic carditis (apical four-chamber view echocardiogram).


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InternalMed_Harrison. VIDEO 381-1B Transthoracic echocardiographic images of a 9-year-old girl with first episode of acute rheumatic fever. Images demonstrate the typical echocardiographic findings of acute rheumatic carditis. The valve leaflets are relatively thin and highly mobile. The failure of coaptation of the mitral valve leaflets is the result of chordal elongation and annular dilatation. The mitral valve regurgitation is moderate with a typical posterolaterally directed regurgitant jet of rheumatic carditis. B. Acute rheumatic carditis (apical four-chamber view color Doppler echocardiogram).


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InternalMed_Harrison. VIDEO 381-1C Transthoracic echocardiographic images of a 9-year-old girl with first episode of acute rheumatic fever. Images demonstrate the typical echocardiographic findings of acute rheumatic carditis. The valve leaflets are relatively thin and highly mobile. The failure of coaptation of the mitral valve leaflets is the result of chordal elongation and annular dilatation. The mitral valve regurgitation is moderate with a typical posterolaterally directed regurgitant jet of rheumatic carditis. C. Acute rheumatic carditis (parasternal long-axis view echocardiogram).


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InternalMed_Harrison. VIDEO 381-1D Transthoracic echocardiographic images of a 9-year-old girl with first episode of acute rheumatic fever. Images demonstrate the typical echocardiographic findings of acute rheumatic carditis. The valve leaflets are relatively thin and highly mobile. The failure of coaptation of the mitral valve leaflets is the result of chordal elongation and annular dilatation. The mitral valve regurgitation is moderate with a typical posterolaterally directed regurgitant jet of rheumatic carditis. D. Acute rheumatic carditis (parasternal long-axis view color Doppler echocardiogram). VIDEO 381-2a Transthoracic echocardiographic images are from a 5-year-old boy with chronic rheumatic heart disease with severe mitral valve regurgitation and moderate mitral valve stenosis.


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InternalMed_Harrison. VIDEO 381-2a Transthoracic echocardiographic images are from a 5-year-old boy with chronic rheumatic heart disease with severe mitral valve regurgitation and moderate mitral valve stenosis. Images demonstrate the typical echocardiographic findings in advanced chronic rheumatic heart disease. Both the anterior and posterior mitral valve leaflets are markedly thickened. During diastole, the motion of the anterior mitral valve leaflet tip is restricted with doming of the body of the leaflet toward the interventricular septum. This appearance is commonly described as a “hockey stick” or an “elbow” deformity. A. Chronic rheumatic heart disease (parasternal long-axis view).


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InternalMed_Harrison. A. Chronic rheumatic heart disease (parasternal long-axis view). VIDEO 381-2B Transthoracic echocardiographic images are from a 5-year-old boy with chronic rheumatic heart disease with severe mitral valve regurgitation and moderate mitral valve stenosis. Images demonstrate the typical echocardiographic findings in advanced chronic rheumatic heart disease. Both the anterior and posterior mitral valve leaflets are markedly thickened. During diastole, the motion of the anterior mitral valve leaflet tip is restricted with doming of the body of the leaflet toward the interventricular septum. This appearance is commonly described as a “hockey stick” or an “elbow” deformity. B. Chronic rheumatic heart disease (apical two-chamber view echocardiogram).


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InternalMed_Harrison. Systemic sclerosis (SSc) is an uncommon connective tissue disorder characterized by multisystem involvement, heterogeneous clinical manifestations, a chronic and often progressive course, and significant disability and mortality. Multiple genes contribute to disease susceptibility; however, environmental exposures are likely to play a major role in causing SSc. The early stage of the disease is associated with prominent inflammatory features. Over time, functional and structural alterations in multiple vascular beds and progressive visceral organ dysfunction due to fibrosis dominate the clinical picture. Although thickened skin (scleroderma) isthe distinguishing hallmark of SSc, skin induration can occur in localized forms of scleroderma and other disorders (Table 382-1). Patients with SSc can be broadly Guttate (plaque) morphea, diffuse (pansclerotic) morphea, bullous morphea Linear scleroderma, coup de sabre, hemifacial atrophy


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InternalMed_Harrison. Guttate (plaque) morphea, diffuse (pansclerotic) morphea, bullous morphea Linear scleroderma, coup de sabre, hemifacial atrophy Stiff skin syndrome Diabetic scleredema and scleredema of Buschke Scleromyxedema (papular mucinosis) Chronic graft-versus-host disease Diffuse fasciitis with eosinophilia (Shulman’s disease, eosinophilic fasciitis) Chemically induced and drug-associated scleroderma-like conditions Vinyl chloride–induced disease Eosinophilia-myalgia syndrome (associated with L-tryptophan) Nephrogenic systemic fibrosis (associated with gadolinium) Skin involvement Indolent onset. Limited to fingers, distal to elbows, face; slow progression phenomenon ment, sometimes by years; may be associated with critical ischemia in the digits Interstitial lung Slowly progressive, disease generally mild Rapid onset. Diffuse: fingers, extremities, face, trunk; rapid progression Onset coincident with skin involvement; critical ischemia less common


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InternalMed_Harrison. Onset coincident with skin involvement; critical ischemia less common Severe arthralgia, carpal tunnel syndrome, tendon friction rubs


InternalMed_Harrison

InternalMed_Harrison. Frequent, early onset and progression, can be severe grouped into diffuse cutaneous andlimitedcutaneous subsets defined by the pattern of skin involvement, as well as clinical and laboratory features (Table 382-2). Diffuse cutaneous SSc (dcSSc) is associated with extensive skin induration, starting in the fingers and ascending from distal to proximal limbs and the trunk. These patients often have early interstitial lung disease and acute renal involvement. In contrast, in patients with limited cutaneous SSc (lcSSc), Raynaud’s phenomenon may precede other manifestations of SSc by years. In these patients, skin involvement remains limited to the fingers (sclerodactyly), distal limbs, and face, and the trunk is not affected. The constellation of calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia, seen in some lcSSc patients, is termed the CREST syndrome. Visceral organ involvement in lcSSc tends to show insidious progression, and pulmonary


InternalMed_Harrison

InternalMed_Harrison. dysmotility, sclerodactyly, and telangiectasia, seen in some lcSSc patients, is termed the CREST syndrome. Visceral organ involvement in lcSSc tends to show insidious progression, and pulmonary arterial hypertension (PAH), interstitial lung disease, hypothyroidism, and primary biliary cirrhosis may occur as late complications. In some patients, Raynaud’s phenomenon and other characteristic features of SSc occur in the absence of skin thickening. This syndrome has been termed SSc sine scleroderma.


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InternalMed_Harrison. SSc is an acquired sporadic disease with a worldwide distribution and affecting all races. In the United States, the incidence is estimated at 9–19 cases per million per year. The only community-based survey of SSc yielded a prevalence of 286 cases per million. There are an estimated 100,000 cases in the United States, although this number may be significantly higher if patients who do not meet strict classification criteria are also included. Rates of SSc in England, Australia, and Japan appear to be lower. Age, gender, and ethnicity are important in disease susceptibility. In common with other connective tissue diseases, SSc shows a strong female predominance (4.6:1), which is most pronounced in the childbearing years and declines after menopause. Although SSc can present at any age, the peak age of onset for both limited and diffuse cutaneous forms is 30–50 years. The incidence is higher in blacks than whites, and disease onset occurs at an earlier age. Furthermore, blacks with SSc


InternalMed_Harrison

InternalMed_Harrison. peak age of onset for both limited and diffuse cutaneous forms is 30–50 years. The incidence is higher in blacks than whites, and disease onset occurs at an earlier age. Furthermore, blacks with SSc are more likely to have diffuse cutaneous disease associated with interstitial lung involvement and a worse prognosis.


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InternalMed_Harrison. In general, SSc shows modest heritability, and the genetic associations identified to date make only a small contribution to disease susceptibility. Concordance rates for SSc are low (4.7%) in monozygotic twins, although concordance for antinuclear antibody (ANA) positivity is significantly higher. On the other hand, evidence for genetic contribution to disease susceptibility is provided by the observation that 1.6% of SSc patients have a first-degree relative with SSc, a prevalence rate markedly increased compared to the general population. The risk of Raynaud’s phenomenon, interstitial lung disease, and other autoimmune diseases, including systemic lupus erythematosus (SLE) (Chap. 378), rheumatoid arthritis (Chap. 380), andautoimmunethyroiditis(Chap. 405),isalsoincreased.Approaches to study therole of geneticsin SScuse candidategenesingle nucleotide polymorphism (SNP) analysis and genome-wide association studies (GWASs). Candidate gene studies in SSc have shown associations with


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InternalMed_Harrison. study therole of geneticsin SScuse candidategenesingle nucleotide polymorphism (SNP) analysis and genome-wide association studies (GWASs). Candidate gene studies in SSc have shown associations with multiple gene variants, many related to B and T lymphocyte activation and signaling (BANK1, BLK, CD247, CSK, IRAK1, IL2RA, PTPN22, and TNIP1). IRAK1, which codes for a gene involved in both innate and adaptive immunity, is the first X-linked gene associated with SSc and may contribute to female predominance. Other gene variants associatedwithSScareinvolved ininnateimmunityand the interferon pathways (IRF5, IRF7, STAT4, TNFAIP3, and TLR2). In addition, candidate gene studies and GWAS both identified association with genes in the major histocompatibility complex (MHC), including NOTCH4 and PSORSC1. In addition to disease susceptibility, some of these geneticloci are associated with particularSSc diseasemanifestations or serologic subsets, including interstitial lung disease (ILD) (CTGF,


InternalMed_Harrison

InternalMed_Harrison. In addition to disease susceptibility, some of these geneticloci are associated with particularSSc diseasemanifestations or serologic subsets, including interstitial lung disease (ILD) (CTGF, CD226), PAH (TNIP1), and scleroderma renal crisis (HLA-DRB1*). Although the functional consequences of these gene variants are currentlynotwellunderstood,theymayresultinalteredimmunefunction, leading to increased susceptibility to autoimmunity and inflammation. Of note, many of the genetic variants associated with SSc are also seen in other autoimmune disorders, including SLE, rheumatoid arthritis, and psoriasis, suggesting common pathways shared among these conditions. The genetic associations identified to date only explain a fraction of the heritability of SSc, and GWASs, fine mapping, and resequencing of DNA regions of interest to identify additional genetic susceptibility factors in SSc, particularly rare variants, are currently ongoing.


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InternalMed_Harrison. Given the relatively modest geneticcontribution to diseasesusceptibility, environmental factors, such as infectious agents, intestinal microbiota, and occupational, dietary, and drug exposures, are likely to play amajor roleincausingSSc.Patientswith SSc showevidenceofchronic infection of lesional tissue with Epstein-Barr virus (EBV). They also have increased antibodies to human cytomegalovirus (hCMV), and anti–topoisomerase I (Scl-70) autoantibodies recognize hCMV-associated antigenic epitopes, suggesting molecular mimicry as a possible mechanistic link between hCMV infection and SSc. An epidemic of a novel syndrome with features suggestive of SSc occurred in Spain in the 1980s. The outbreak, termed toxic oil syndrome, was linked to contaminated rapeseed oils used for cooking. Another epidemic outbreak, termed eosinophilia-myalgia syndrome (EMS), occurred a decade later andwaslinkedtotheconsumptionof l-tryptophan-containingdietary supplements. Although both of these novel


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InternalMed_Harrison. Another epidemic outbreak, termed eosinophilia-myalgia syndrome (EMS), occurred a decade later andwaslinkedtotheconsumptionof l-tryptophan-containingdietary supplements. Although both of these novel toxic-epidemic syndromes were characterized by scleroderma-like chronic skin changes and variable visceral organ involvement, they were associated with clinical, pathologic, and laboratory features distinguishing them from SSc. Occupational exposures tentatively linked with SSc include silica dust in miners, polyvinyl chloride, epoxy resins, and aromatic hydrocarbons including toluene and trichloroethylene. Drugs implicated in SSc-like illnesses include bleomycin, pentazocine, and cocaine, and appetite suppressants linked with pulmonary hypertension. Although case reports and series describing SSc in women with silicone breast implants had raisedconcern regarding a possiblecausal roleofsilicone 2156 in SSc, large-scale epidemiologic investigations found no evidence of increased prevalence


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InternalMed_Harrison. SSc in women with silicone breast implants had raisedconcern regarding a possiblecausal roleofsilicone 2156 in SSc, large-scale epidemiologic investigations found no evidence of increased prevalence of SSc.


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InternalMed_Harrison. The following three cardinal pathophysiologic processes account for theproteanclinicalmanifestationsofSSc:(1)diffusemicroangiopathy, (2) inflammation and autoimmunity, and (3) visceral and vascular fibrosis in multiple organs (Fig. 382-1). Autoimmunity and altered vascular reactivity are early manifestations. Complex and dynamic interplay between these processes initiates and then amplifies the fibrotic process.


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InternalMed_Harrison. No single animal model of SSc fully reproduces the three cardinal processes that underlie the pathogenesis, but some recapitulate selected aspects of the human disease, including fibrosis, microvascular involvement, and autoimmunity. Tight-skin mice (Tsk1) develop spontaneous skin thickening due to a mutation in the fibrillin-1 gene. The mutant fibrillin-1 protein disrupts extracellular matrix assembly and causes aberrant activation of transforming growth factor β (TGF-β). Fibrillin-1 mutations are associated with Marfan’s disease as well as the stiff skin syndrome but not SSc. Skin and lung fibrosis can be induced in mice by injection of bleomycin, HOCl, or double-stranded RNA or by transplantation of human leukocyte antigen (HLA)–mismatched bone marrow or spleen cells. Targeted genetic modifications in mice give rise to new disease models for dissecting the pathogenetic roles of individual molecules, cell types, and networks. For example, mice lacking Smad3, an intracellular TGF-β


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InternalMed_Harrison. modifications in mice give rise to new disease models for dissecting the pathogenetic roles of individual molecules, cell types, and networks. For example, mice lacking Smad3, an intracellular TGF-β signal transducer, adiponectin, or the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ or overexpressing Wnt10b


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InternalMed_Harrison. Vascular Injury Endothelial cell activation Platelet activation; ROS Leukocyte Recruitment CD4+ CD8+ T cells Activated monocytes/macrophages Activated B cells; innate immunity Th2 Cytokines TGF-˜, CTGF, PDGF Chemokines Fibroblast Activation Fibrocyte differentiation Myofibroblast differentiation Impaired mesencymal cell Epithelial cell/endothelial cell to mesenchyme transaction apoptosis Collagen, connective tissue accumulation Extracellular matrix reorganization, contraction Impaired matrix degradation Autoantibodies Endothelin-1 Obliterative Vasculopathy Tissue Hypoxia


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InternalMed_Harrison. FIGUrE 382-1 Initial vascular injury in a genetically susceptible individual leads to functional and structural vascular alterations, inflammation, and autoimmunity. The inflammatory and immune responses initiate and sustain fibroblast activation and differentiation, resulting in pathologic fibrogenesis and irreversible tissue damage. Vascular damage results in tissue ischemia that further contributes to progressive fibrosis and atrophy. CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β. or adiponectin were either resistant or hypersensitive to chemically induced experimental scleroderma. These mouse models have potential utility in preclinical evaluation of potential therapies.


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InternalMed_Harrison. Involvement of small blood vessels in SSc affects multiple vascular beds and has important clinical sequelae including Raynaud’s phenomenon, ischemic digital ulcers, scleroderma renal crisis, and PAH. Raynaud’s phenomenon,anearlydiseasemanifestation,ischaracterizedbyanaltered blood-flow response to cold challenge. This initially 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 receptorsonvascular smooth-muscle cells. Isolated (primary) Raynaud’s phenomenon is extremely common and generally benign and nonprogressive. In contrast, SSc-associated Raynaud’s phenomenon is often progressive and complicated by irreversible structural changes, culminating in ischemic digital ulcers and loss of digits. Viruses, vascularcytotoxicfactors, thrombogenicmicroparticles, complementand


InternalMed_Harrison

InternalMed_Harrison. progressive and complicated by irreversible structural changes, culminating in ischemic digital ulcers and loss of digits. Viruses, vascularcytotoxicfactors, thrombogenicmicroparticles, complementand autoantibodiestophospholipids,β2glycoproteinI(β2GPI),andendothelialcellsaresuspectedtriggersofendothelialcellinjuryinSSc.Endothelial injury results in dysregulated production of endothelium-derived vasodilatory(nitricoxideandprostacyclin)andvasoconstricting(endothelin-1) substances, as well as increased expression of intercellular adhesion molecule1(ICAM-1)andothersurfaceadhesionmolecules.Microvessels show enhanced permeability and transendothelial leukocyte diapedesis, abnormal activation of coagulation cascades, elevated thrombin production, and impaired fibrinolysis. Spontaneous platelet aggregation causes release of serotonin, platelet-derived growth factor (PDGF), and platelet alphagranulesincludingthromboxane,apotentvasoconstrictor.Smoothmuscle cell–like myointimal cells


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InternalMed_Harrison. platelet aggregation causes release of serotonin, platelet-derived growth factor (PDGF), and platelet alphagranulesincludingthromboxane,apotentvasoconstrictor.Smoothmuscle cell–like myointimal cells proliferate, the basement membrane is thickenedand reduplicated,and fibrosis oftheadventitial layers develops. The vasculopathic process affects capillaries, as well as arterioles, and even large vessels in many organs, resulting in reduced 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 culminates in the striking absence of blood vessels (rarefaction) in late-stage disease. Recurrent ischemia-reperfusiongeneratesreactiveoxygenspecies(ROS)thatfurther damage the endothelium through peroxidation of membrane lipids. Paradoxically, the process of revascularization that normally reestablishes blood flow to ischemic tissue is defective in


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InternalMed_Harrison. 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 vascular endothelial growth factor (VEGF) and other angiogenic factors. Moreover, the number of bone marrow–derived circulating endothelial progenitor cells is reduced. Thus, widespread capillary loss, obliterative vasculopathy of small and medium-sized arteries, and failure to repair damaged vessels are hallmarks of SSc.


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InternalMed_Harrison. IMMUNE DYSrEGULaTION Cellular Immunity The following observations highlight the autoimmune nature of SSc: presence of circulating autoantibodies; familial clustering of SSc with other autoimmune diseases; detection of immune cells, including T cells with oligoclonal antigen receptors, in target organs; elevated circulating levels and spontaneous secretion from blood mononuclear cells of inflammatory cytokines and chemokines such as interleukin (IL) 1, IL-4, IL-10, IL-17, IL-33, CCL2, and CXCL4; and the association with variants in genes functionally implicated in immune responses. Genetic studies in SSc reveal strong and consistent associations with major histocompatibility locus alleles, as well as non-HLA-linked genes encoding mediators of both adaptive and innate immune responses (CD247, STAT4, IRF5, CD226, and TNFSF4). In early SSc, mononuclear inflammatory cell infiltrates comprised of activated T cells, monocytes/macrophages, and dendritic cells can be seen in skin, lungs, and


InternalMed_Harrison

InternalMed_Harrison. STAT4, IRF5, CD226, and TNFSF4). In early SSc, mononuclear inflammatory cell infiltrates comprised of activated T cells, monocytes/macrophages, and dendritic cells can be seen in skin, lungs, and other affected organs prior to appearance of fibrosis or vascular damage. Dendritic cells and T cells can often be found in close proximity to activated fibroblasts and myofibroblasts. 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 (unknown) antigen.


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InternalMed_Harrison. Abbreviations: dcSSc, diffuse cutaneous SSc; GAVE, gastric antral vascular ectasia; ILD, interstitial lung disease; lcSSc, limited cutaneous SSc; MCTD, mixed connective tissue disease; PAH, pulmonary arterial hypertension; SLE, systemic lupus erythematosus.


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InternalMed_Harrison. Circulating T cells have elevated levels of chemokine receptors and α1 integrin adhesion molecules, accounting for their enhanced binding to endothelium and to fibroblasts. Endothelial cells express ICAM-1 and otheradhesionmoleculesthatfacilitateleukocytediapedesis.Activated macrophages and T cells show a TH2-polarized type 2 immune response driven by dendritic cells and thymic stromal lymphopoietin. TH2 cytokines such as IL-4 and IL-13 induce fibroblast activation and alternate M2 macrophage polarization, whereas the TH1 cytokine interferon γ (IFN-γ) blocks cytokine-mediated fibroblast activation. Alternately activated M2 macrophages produce TGF-β and promote fibrosis. Although the frequency of circulating regulatory T cells that enforce immune tolerance is elevated in SSc, their immunosuppressive function is defective. Molecular characterization of SSc skin biopsies using DNA microarrays identifies a subset showing markedly elevated expression of inflammation-associated genes,


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InternalMed_Harrison. function is defective. Molecular characterization of SSc skin biopsies using DNA microarrays identifies a subset showing markedly elevated expression of inflammation-associated genes, particularly chemokines andtheirreceptors,interferonresponsegenes,andmediators of innate immunity. Evidence of activated innate immunity and toll-like receptor signaling, indicative of activation by type 1 interferon produced by plasmacytoid dendritic cells, is prominent in peripheral blood cells.


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InternalMed_Harrison. Humoral autoimmunity Circulating ANAs can be detected in virtually all patients with SSc. In addition, a number of SSc-specific autoantibodies have been described. These SSc-specific antibodies show strong association with distinct disease endophenotypes (Table 382-3). While most are directed against intracellular proteins associated with cell proliferation, such as topoisomerase I and RNA polymerases I, II, and III, others are directed against cell-surface antigens, receptors, or secreted proteins. Autoantibodieshaveclinicalutilityasdiagnosticandprognosticbiomarkers in SSc, and some, such as antibodies directed against the angiotensin II receptor or the PDGF receptor, may have a direct pathogenic role.


InternalMed_Harrison

InternalMed_Harrison. A variety of mechanisms have been proposed for the development of autoantibodies in SSc. Proteolytic cleavage, increased expression, or altered subcellular localization of certain cellular proteins in SSc could lead to their recognition as neoepitopes by the immune system, resulting in breakdown of immune tolerance. B cells are implicated in both the autoimmune and fibrotic process in SSc. In addition to antibody production, B cells also present antigen, secrete IL-6 and TGF-β, and modulate T cell and dendritic cell function.


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InternalMed_Harrison. Fibrosis affecting multiple organs, a distinguishing feature of SSc, is characterized by progressive replacement of normal tissue architecture with dense, stiff, and acellular connective tissue. Fibrosis characteristically follows, and is thought to be a consequence of, inflammation, autoimmunity,andmicrovasculardamage.Fibroblastsaremesenchymal 2157 cells responsible for maintaining the functional and structural integrity of connective tissue. Upon activation by TGF-β and other extracellular cues, fibroblasts proliferate; migrate; secrete collagens, growth factors, chemokines, and cytokines; and transdifferentiate into contractile myofibroblasts. Under normal conditions,these fibroticresponses constitute self-limited physiologic remodeling necessary for tissue repair and regeneration. When these responses become sustained and amplified, pathologic fibrosis results. Autocrine stimulatory signaling by endogenously produced TGF-β and fibrotic mediators such as hypoxia, ROS, thrombin, Wnt


InternalMed_Harrison

InternalMed_Harrison. these responses become sustained and amplified, pathologic fibrosis results. Autocrine stimulatory signaling by endogenously produced TGF-β and fibrotic mediators such as hypoxia, ROS, thrombin, Wnt ligands, connective tissue growth factor (CTGF), PDGF, lysophosphatidicacid,endothelin-1,mechanicalforces,andendogenous ligands for toll-like receptors are responsible for maintaining sustained fibroblast activation underlying progressive fibrosis in SSc.


InternalMed_Harrison

InternalMed_Harrison. In addition to tissue-resident fibroblasts and transformation of epithelial cells into fibroblasts, 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. Epithelial and endothelial cells, mesenchymal progenitor cells, and tissuefibroblastscandifferentiateintosmooth-muscle-likemyofibroblasts. Although myofibroblasts can be detected transiently during normal wound healing, they persist in fibrotic tissue, possibly due to resistance toapoptosis,andcontributetoscarformationviaproductionofcollagen and TGF-β and contraction of the surrounding extracellular matrix.


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InternalMed_Harrison. Explanted SSc fibroblasts may display an abnormally activated phenotype ex vivo, with variably increased rates of collagen gene tran scription, spontaneous ROS generation, and constitutive expression of alpha smooth-muscle actin stress fibers. The persistence of the “sclerodermaphenotype”ofthesecellsduringtheirserialpassageinvitromay reflect autocrine TGF-β stimulatory loops, deregulated microRNA expressions, histone acetylation, and other epigenetic modifications.


InternalMed_Harrison

InternalMed_Harrison. The distinguishing pathologic hallmark of SSc is the combination of widespread capillary loss and obliterative microangiopathy, together with fibrosis in the skin and internal organs. In early disease, perivascular inflammatory cell infiltrates composed of T lymphocytes, monocytes/macrophages, plasma cells, mast cells, and occasionally B cells may be detected in multiple organs. A bland noninflammatory obliterative vasculopathy as a late finding is prominent in the heart, lungs, kidneys, and intestinal tract. Fibrosis is found in the skin, lungs, gastrointestinal tract, heart, tendon sheaths, perifascicular tissue surrounding skeletal muscle, and some endocrine organs. In these tissues, accumulation of collagens, fibronectin, proteoglycans, tenascin, cartilage oligomeric matrix protein (COMP), and other structural macromolecules progressively disrupts normal architecture, resulting in impaired function of affected organs.


InternalMed_Harrison

InternalMed_Harrison. In the skin, fibrosis causes dermal expansion and obliteration of the hair follicles, eccrine glands, and other appendages (Fig. 382-2A). Collagen fiber accumulation is most prominent in the reticular dermis, and the fibrotic process invades the subjacent adipose layer with entrapment of adipocytes. With disease progression, the intradermal adipose layer is diminished and may completely disappear. The epidermis is atrophic, and the rete pegs are effaced.


InternalMed_Harrison

InternalMed_Harrison. Patchy infiltration of the alveolar walls with T lymphocytes, macrophages, and eosinophils occurs in early disease. With progression, interstitial fibrosis and vascular damage dominate the pathologic picture, often coexisting within the same lesions in patients with dcSSc. Pulmonaryfibrosis is characterizedbyexpansionofthe alveolar interstitium, with accumulation of collagen and other matrix proteins. The most common histologic pattern in SSc-associated ILD is nonspecific interstitial pneumonia (NSIP), distinct from the usual interstitial pneumonia (UIP) pattern characteristically seen in patients with FIGUrE 382-2 Pathologic findings in systemic sclerosis (SSc).


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InternalMed_Harrison. FIGUrE 382-2 Pathologic findings in systemic sclerosis (SSc). A. Left panel: The skin is thickened due the marked expansion of the dermis. Inset, higher magnification showing thick hyalinized collagen bundles replace skin appendages. Right panel: Inflammation in the reticular dermis. Mononuclear inflammatory cells infiltrating the dermis and intradermal adipose tissue. B. Early 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 narrowing of the lumen of a small pulmonary artery, with minimal interstitial fibrosis, in a patient with limited cutaneous SSc.


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InternalMed_Harrison. idiopathic pulmonary fibrosis (Fig. 382-2B). Progressive thickening 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 thickening of the pulmonary arteries, best seen with elastin stain, underlies pulmonary hypertension (Fig. 382-2C) and, at autopsy, is often associated with multiple pulmonary emboli and evidence of myocardial fibrosis.


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InternalMed_Harrison. Pathologicchangescanbefoundatanylevelfromthemouthtotherectum. The lower esophagus shows prominent atrophy of the muscular layers and characteristic vascular lesions; striated muscle in the upper third of the esophagus is generally spared. Replacement of the normal intestinal tract architecture results in diminished peristaltic activity, withgastroesophagealreflux,dysmotility, andsmall-bowel obstruction. Chronic reflux is associated with esophageal inflammation, ulcerations, and stricture formation and may lead to Barrett’s metaplasia. In the kidneys, vascular lesions affecting the interlobular and arcuate arteries predominate. Chronic renal ischemia is associated with shrunken glomeruli. Acute scleroderma renal crisis is associated with a classic thrombotic microangiopathic pathology: reduplication of elastic lamina, marked intimal proliferation, and narrowing of the lumen in small renal arteries, commonly accompanied by thrombosis and hemolysis.


InternalMed_Harrison

InternalMed_Harrison. The heart is frequently affected, with prominent involvement of the myocardium and pericardium. The characteristic arteriolar lesions are concentric intimal hypertrophy and luminal narrowing, accompanied by contraction band necrosis reflecting ischemia-reperfusion injury andmyocardialfibrosis. Fibrosisof the conduction systemis common, especially at the sinoatrial node. Despite the prominent role of ischemia in SSc, the frequency of atherosclerotic coronary artery disease is comparable to the general population. Synovitis may be found in early SSc; however, with disease progression, the synovium becomes fibrotic. Fibrosis of tendon sheaths and fascia produces palpable and sometimes audible tendon friction rubs. Inflammation and, in later stages, atrophy and fibrosis of the muscles are common findings. Fibrosis of the thyroid gland and of the minor salivary glands may be seen.


InternalMed_Harrison

InternalMed_Harrison. Virtually every organ can be clinically affected (Table 382-4). Most patients with SSc can be classified as lcSSc or dcSSc (Table 382-2). Although stratification of SSc patients into diffuse and limited cutaneous subsets is useful, disease expression is far more complex, and several distinct endophenotypes exist within each subset. For example, 10–15% of patients with lcSSc develop PAH without significant ILD. Other patients have systemic features of SSc without appreciable skin involvement (SSc sine scleroderma). Unique clinical phenotypes of SSc associate with specific autoantibodies (Table 382-3). Patients with “overlap” have typical SSc features coexisting with clinical and laboratory evidence of another autoimmune disease such as polymyositis, Sjögren’s syndrome, polyarthritis, autoimmune liver disease, or SLE. aApproximately 10% of limited cutaneous SSc patients have SSc sine scleroderma.


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InternalMed_Harrison. The initial presentation is quite different in the diffuse and the limited 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 and intense pruritus are signs of the early inflammatory “edematous” phase. The fingers, hands, distal limbs, and face are usually affected first. Diffuse skin hyperpigmentation and carpal tunnel syndrome can occur. 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 a decline in sweating capacity. Progressive flexion contractures of the fingers ensue. The wrists, elbows, shoulders, hip girdles, knees, and ankles become stiff due to fibrosis of the supporting joint structures. While advancing skin involvement is the


InternalMed_Harrison

InternalMed_Harrison. of the fingers ensue. The wrists, elbows, shoulders, hip girdles, 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 frequently clinically silent internal organ involvementdevelopsduringthisstage.Theinitial4yearsfromdisease onset is the period of rapidly evolving pulmonary and renal damage. If organ failure does not occur during this period, the systemic process may stabilize.


InternalMed_Harrison

InternalMed_Harrison. Compared to dcSSc, the course of lcSSc is characteristically more indolent. In these patients, the interval between Raynaud’s phenomenon and onset of manifestations such as gastroesophageal reflux, cutaneous telangiectasia, or soft tissue calcifications can be several years. On the other hand, scleroderma renal crisis and severe pulmonary fibrosis are uncommon in lcSSc. Clinically evident cardiac involvement and PAH develop in more than 15%. Overlap with keratoconjunctivitis sicca, polyarthritis, cutaneous vasculitis, and biliary cirrhosis is seen in some patients with lcSSc.


InternalMed_Harrison

InternalMed_Harrison. Raynaud’s phenomenon, the most frequent extracutaneous complication of SSc, is characterized by episodes of reversible vasoconstriction in the fingers and toes. Vasoconstriction may also affect the tip of the nose and earlobes. Attacks are triggered by a decrease in temperature, as well as emotional stress and vibration. Typical attacks start with pallor, 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.


InternalMed_Harrison

InternalMed_Harrison. Asmuch as3–5%ofthegeneralpopulationhas Raynaud’sphenomenon. In the absence of signs or symptoms of an underlying condition, Raynaud’s phenomenon is classified as primary and represents an exaggerated physiologic response to cold. Secondary Raynaud’s phenomenon can occur as a complication of SSc and other connective tissue diseases, hematologic and endocrine conditions, and occupational disorders, and can complicate the use of beta blockers and anticancer drugs such as cisplatin and bleomycin. Distinguishing primary versus secondary Raynaud’s phenomenon presents a diagnostic challenge. Primary Raynaud’s phenomenon is supported by the following: absence of an underlying cause; a family history of Raynaud’s phenomenon; absence of digital tissue necrosis, ulceration, or gangrene; and a negative ANA test. Secondary Raynaud’s phenomenon tends to develop at an older age (>30 years), is clinically more severe (episodes more frequent, prolonged, and painful), and is frequently associated with


InternalMed_Harrison

InternalMed_Harrison. ANA test. Secondary Raynaud’s phenomenon tends to develop at an older age (>30 years), is clinically more severe (episodes more frequent, prolonged, and painful), and is frequently associated with ischemic digital ulcers and loss of digits (Fig. 382-3). Nailfold capillaroscopy, where the cutaneous capillaries at the nail bed are viewed under a drop of grade B immersion oil using a low-power stereoscopic microscope, can be helpful in the evaluation of Raynaud’s phenomenon.Primary Raynaud’s phenomenonisassociated withnormal capillaries that appear as regularly spaced parallel vascular loops, whereas in patients with Raynaud’s associated with SSc and other connective tissue diseases, nailfold capillaries are distorted with widened and irregular loops, dilated lumen, and areas of vascular “dropout.” In addition to digits, cold-induced episodic Raynaud’s-like vasospasm has been documented in the pulmonary, renal, gastrointestinal, and coronary circulations in SSc.


InternalMed_Harrison

InternalMed_Harrison. While early-stage SSc is associated with edematous skin changes, skin thickening is the hallmark that distinguishes SSc from other connective tissue diseases. The distribution of skin thickening is invariably symmetric and bilateral. It typically starts in the fingers and then characteristically advances from distal to proximal extremities in an ascending fashion. The involved skin is firm, coarse, and thickened, and the extremities and trunk may be darkly pigmented. In some patients, diffuse tanning in the absence of sun exposure is a very early manifestation of skin involvement. In dark-skinned patients, vitiligolike hypopigmentation may occur. Because pigment loss spares the perifollicular areas, the skin may have a “salt-and-pepper” appearance, most prominently on the scalp, upper back, and chest. Dermal sclerosis due to collagen accumulation obliterates hair follicles, sweat glands, and eccrine and sebaceous glands, resulting in hair loss, decreased sweating, and dry skin.


InternalMed_Harrison

InternalMed_Harrison. back, and chest. Dermal sclerosis due to collagen accumulation obliterates hair follicles, sweat glands, and eccrine and sebaceous glands, resulting in hair loss, decreased sweating, and dry skin. Transverse creases on the dorsum of the fingers disappear (Fig. 382-4). Fixed flexion contractures of the fingers cause reduced hand mobility and lead to muscle atrophy. Skin thickening in combination with fibrosis of the subjacent tendons accounts for contractures of the wrists, elbows, and knees. Thick ridges at the neck due


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InternalMed_Harrison. FIGUrE 382-4 Sclerodactyly. Noteskinindurationonthefingers,andfixedflexioncontracturesattheproximalinterphalangealjointsinapatientwithlimitedcutaneoussystemicsclerosis(SSc). FIGUrE 382-3 Digital necrosis. Sharply demarcated necrosis of the fingertip in a patient with limited cutaneous systemic sclerosis (SSc) associated with severe Raynaud’s phenomenon. FIGUrE 382-5 Cutaneous vascular changes. A. Capillary changes at the nailfold in a patient with limited cutaneous systemic sclerosis (lcSSc). B. Telangiectasia on the face.


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InternalMed_Harrison. FIGUrE 382-5 Cutaneous vascular changes. A. Capillary changes at the nailfold in a patient with limited cutaneous systemic sclerosis (lcSSc). B. Telangiectasia on the face. to firm adherence of skin to the underlying platysma muscle interfere with neck extension. The face assumes a characteristic “mauskopf” appearance with taut and shiny skin, loss of wrinkles, and occasionally an expressionless facies due to reduced mobility of the eyelids, cheeks, andmouth.Thinningofthelipswithaccentuationofthecentralincisor teeth and fine wrinkles (radial furrowing) around the mouth complete the picture. Reduced oral aperture (microstomia) interferes with eating and oral hygiene. The nose assumes a pinched, beak-like appearance.


InternalMed_Harrison

InternalMed_Harrison. In established SSc, the skin is firmly bound to the subcutaneous fat (tethering) and undergoes thinning and atrophy. Telangiectasias are dilated skin capillaries 2–20 mm in diameter frequently seen in lcSSc. These lesions, reminiscent of hereditary hemorrhagic telangiectasia, are prominent on the face, hands, lips, and oral mucosa (Fig. 382-5).A greater number of telangiectasias correlates with the extent of microvascular complications,includingPAH.Breakdown ofatrophicskinleadsto chronic ulcerations at the extensor surfaces of the proximal interphalangealjoints,thevolarpadsofthefingertips,andbonyprominencessuchas the elbows and malleoli. Ulcers are painful and may become secondarily infected, resulting in osteomyelitis. Healing of ischemic fingertip ulcerations leaves characteristic fixed digital “pits.” Loss of soft tissue at the fingertipsdue to ischemiais frequentandmaybeassociated withstriking resorption of the terminal phalanges (acro-osteolysis) (Fig. 382-6).


InternalMed_Harrison

InternalMed_Harrison. Calcium deposits (calcinosis) in the skin and soft tissues occur in patients with lcSSc who are positive for anticentromere antibodies. The deposits, varying in size from tiny punctate lesions to large conglomerate masses, are composed of calcium hydroxyapatite crystals and can be readily visualized on plain x-rays. Frequent locations include the finger pads, palms, extensor surfaces of the forearms, and the olecranon and prepatellar bursae (Fig. 382-7). They may occasionally ulcerate through the overlying skin, producing drainage of chalky white material, pain, and local inflammation. Paraspinal soft tissue calcifications may cause neurologic complications. FIGUrE 382-6 Acro-osteolysis. Notedissolutionofterminalphalan-gesinapatientwithlong-standinglimitedcutaneoussystemicsclero-sis(lcSSc)andRaynaud’sphenomenon.


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InternalMed_Harrison. FIGUrE 382-6 Acro-osteolysis. Notedissolutionofterminalphalan-gesinapatientwithlong-standinglimitedcutaneoussystemicsclero-sis(lcSSc)andRaynaud’sphenomenon. Pulmonary involvement is frequent in SSc and is the leading cause of death. The two principal forms are ILD and pulmonary vascular disease. Patients with SSc frequently develop some degree of both complications. Less frequent pulmonary manifestations include aspiration pneumonitis complicating chronic gastroesophageal reflux, pulmonary hemorrhage due to endobronchial telangiectasia, obliterative bronchiolitis, pleural reactions, restrictive ventilatory defect due to chest wall fibrosis, spontaneous pneumothorax, and drug-induced lung toxicity. The incidence of lung cancer is increased.


InternalMed_Harrison

InternalMed_Harrison. Interstitial Lung Disease (ILD) Evidence of ILD can be found in up to 90% of patients with SSc at autopsy and 85% by thin-section high-resolution computed tomography (HRCT). In contrast, clinically significant ILD develops in 16–43%; the frequency varies depending on the detection method used. Risk factors include male gender, African-American race, diffuse skin involvement, severe gastroesophageal reflux, and the presence of topoisomerase I autoantibodies, as well as a low forced vital capacity (FVC) or single-breath diffusing capacity of the lung for carbon monoxide (DLco) at initial presentation. In these patients, the most rapid progression in lung disease occurs early in FIGUrE 382-7 Calcinosis cutis. Notelargecalcificdepositbreakingthroughtheskininapatientwithlimitedcutaneoussystemicsclerosis(lcSSc).


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InternalMed_Harrison. FIGUrE 382-7 Calcinosis cutis. Notelargecalcificdepositbreakingthroughtheskininapatientwithlimitedcutaneoussystemicsclerosis(lcSSc). FIGUrE 382-8 HRCT images of the chest from patients with systemic sclerosis. Top panel: Early interstitial lung disease. Mild changes with sub pleural reticulations and ground glass opacities in the lower lobes of the lung. Patient in supine position. Bottom panel: Extensive lung fibrosis with ground glass opacities, coarse reticular honeycombing, and traction bronchiectasis. (Courtesy of Rishi Agrawal, MD.) the course of the disease (within the first 3 years), when the FVC can decline by 30% per year.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary involvement can remain asymptomatic until it is advanced. The most common presenting respiratory symptoms— exertional dyspnea, fatigue, and reduced exercise tolerance—are subtle and slowly progressive. A chronic dry cough may be present. Physical examination may reveal “Velcro” crackles at the lung bases. Pulmonary function testing (PFT) is a sensitive method for detecting early pulmonary involvement. The most common abnormalities are reductions in FVC, total lung capacity (TLC), and DLco. A reduction in DLcothatis significantly out of proportion to the reduction in lung volumes should raise suspicion for pulmonary vascular disease, but may also be due to anemia. Oxygen desaturation with exercise is common.


InternalMed_Harrison

InternalMed_Harrison. Chest radiography can rule out infection and other causes of pulmonary involvement, but compared to HRCT, it is relatively insensitive for detection of early ILD. HRCT shows subpleural reticular linear opacities and ground-glass opacifications, predominantly in the lower lobes, even in asymptomatic patients (Fig. 382-8). Additional HRCT findings include mediastinal lymphadenopathy, pulmonary nodules, traction bronchiectasis, and uncommonly, honeycomb changes. The extent of pulmonary interstitial changes on HRCT is a predictor of mortality in SSc. Bronchoalveolar lavage (BAL) can demonstrate inflammation in the lower respiratory tract and may be useful for ruling out infection. Although an elevated proportion of neutrophils (>2%) and/or eosinophils (>3%) in the BAL fluid is correlated with more extensive lung disease on HRCT and is associated with more rapid decline in FVC and reduced survival, BAL is not useful for identifying reversible alveolitis. Lung biopsy is indicated only in


InternalMed_Harrison

InternalMed_Harrison. more extensive lung disease on HRCT and is associated with more rapid decline in FVC and reduced survival, BAL is not useful for identifying reversible alveolitis. Lung biopsy is indicated only in patients with atypical findings on chest radiographs and should be thoracoscopically guided. The histologic pattern on lung biopsy may predict theriskofprogressionofILD.ThemostcommonpatterninSSc,NSIP, carries a better prognosis than UIP.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary arterial Hypertension (PaH) PAH, defined as a mean pulmonary arterial pressure ≥25 mmHg with a pulmonary capillary wedge pressure≤15 mmHg, developsinapproximately15%ofpatientswithSSc and can occur in association with ILD or as an isolated abnormality. The natural history of SSc-associated PAH is variable, but in many patients, it follows a downhill course with development of right heart failure. The 2161 median survival of SSc patients with untreated PAH is 1 year following diagnosis. Risk factors for PAH include limited cutaneous disease, older age at disease onset, severe Raynaud’s phenomenon, and the presence of antibodies to centromere, U1-RNP, U3-RNP (fibrillarin), and B23.


InternalMed_Harrison

InternalMed_Harrison. The initial symptom of PAH is typically exertional dyspnea and reduced exercise capacity. With disease progression, angina, exertional near-syncope, and symptoms and signs of right-sided heart failure appear. Physical examination may show tachypnea, a prominent split S2heartsound,palpablerightventricularheave,elevatedjugularvenous pressure, and dependent edema. Doppler echocardiography provides a noninvasive method for estimating the pulmonary arterial pressure. In light of the poor prognosis of untreated PAH, all SSc patients should be screened for its presence at initial evaluation. Echocardiographic estimates of pulmonary arterial systolic pressures >40 mmHg at rest suggest PAH. Pulmonary function testing may show a reduced DLcoin isolation or out of proportion with the severity of restriction. Right heart catheterization is the gold standard for diagnosing PAH. Because echocardiography can result in over-or underestimation of pulmonary arterial pressures in SSc, cardiac


InternalMed_Harrison

InternalMed_Harrison. of restriction. Right heart catheterization is the gold standard for diagnosing PAH. Because echocardiography can result in over-or underestimation of pulmonary arterial pressures in SSc, cardiac catheterization is always required to confirm the presence of PAH; accurately assess its severity, including thedegreeofrightheartdysfunction;andruleoutvenoocclusivedisease and other cardiac causes of pulmonary hypertension. Yearly echocardiographic screening for PAH is recommended in most patients with SSc; an isolated decline in DLcomay also be indicative of developing PAH. Serum levels of brain natriuretic peptide (BNP) and N-terminal pro-BNPcorrelatewith the presenceandseverity of PAHinSSc,aswell as survival. While BNP measurements can be useful in screening for PAH and in monitoring the response to treatment, elevated BNP levels are not specific for PAH and also occur in other forms of right and left heart disease. The prognosis of SSc-associated PAH is worse, and treatment response


InternalMed_Harrison

InternalMed_Harrison. response to treatment, elevated BNP levels are not specific for PAH and also occur in other forms of right and left heart disease. The prognosis of SSc-associated PAH is worse, and treatment response poorer, than in idiopathic PAH


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InternalMed_Harrison. The gastrointestinal tract is affected in up to 90% of SSc patients with both limited and diffuse cutaneous forms of the disease. The pathologic features of atrophy of smooth muscle, intact mucosa, and obliterative small-vessel vasculopathy are similar throughout the length of the gastrointestinal tract.


InternalMed_Harrison

InternalMed_Harrison. Upper Gastrointestinal Tract Involvement Oropharyngeal manifestations due to a combination of xerostomia, reduced oral aperture, periodontal disease, and resorption of the mandibular condyles are frequent and cause much distress. The frenulum of the tongue may be shortened. Most patients have symptoms of gastroesophageal reflux disease (GERD): heartburn, regurgitation, and dysphagia. A combination of reduced lower esophageal sphincter pressure resulting in gastroesophageal reflux, impaired esophageal clearance of refluxed gastric contents due to diminished motility in the distal two-thirds of the esophagus, and delayed gastric emptying accounts for GERD. Manometry shows abnormal upper intestinal motility in most patients with SSc. Extraesophageal manifestations of GERD include hoarseness, chronic cough, and aspiration pneumonitis, which may aggravate underlying ILD. Chest computed tomography (CT) scan characteristically shows a dilated esophagus with intraluminal air. Endoscopy may be


InternalMed_Harrison

InternalMed_Harrison. chronic cough, and aspiration pneumonitis, which may aggravate underlying ILD. Chest computed tomography (CT) scan characteristically shows a dilated esophagus with intraluminal air. Endoscopy may be necessary to rule out opportunistic infections with Candida, herpes virus, and cytomegalovirus.Severeerosiveesophagitismay befoundonendoscopy in patients with minimal symptoms. Esophageal strictures and Barrett’s esophagus may complicate chronic GERD. Because Barrett’s esophagus isassociatedwithanincreasedriskofadenocarcinoma,SScpatientswith Barrett’s esophagus need periodic endoscopy and esophageal biopsy.


InternalMed_Harrison

InternalMed_Harrison. Gastroparesis with early satiety, abdominal distention, and aggravated reflux symptoms is common. The presence and severity of gastroparesis can be assessed by radionuclide gastric emptying studies. Gastric antral vascular ectasia (GAVE) in the antrum may occur. These subepithelial lesions, reflecting the diffuse small-vessel vasculopathy of SSc, are described as “watermelon stomach” due to their endoscopic appearance. Patients with GAVE can have recurrent episodes of gastrointestinal bleeding, resulting in chronic unexplained anemia.


InternalMed_Harrison

InternalMed_Harrison. 2162 Lower Gastrointestinal Tract Involvement Impaired intestinal motility may result in malabsorptionand chronic diarrheasecondarytobacterial overgrowth. Fat and protein malabsorption and vitamin B12 and vitamin D deficiency ensue, sometimes culminating in severe malnutrition. Disturbed intestinal motor function can also cause intestinal pseudo-obstruction, with symptoms of nausea and abdominal distension that are indistinguishable from those of delayed gastric emptying. Patients present with recurrent episodes of acute abdominal pain, nausea, and vomiting. Radiographic studies show acute intestinal obstruction, and the major diagnostic challenge is to differentiate pseudoobstruction, which responds to supportive care and intravenous nutritional supplementation, from mechanical obstruction. Colonic involvement may cause severe constipation, fecal incontinence, gastrointestinal bleeding from telangiectasia, and rectal prolapse. In late-stage SSc, wide-mouth sacculations or diverticula


InternalMed_Harrison

InternalMed_Harrison. Colonic involvement may cause severe constipation, fecal incontinence, gastrointestinal bleeding from telangiectasia, and rectal prolapse. In late-stage SSc, wide-mouth sacculations or diverticula occur in the colon, occasionally causing perforation and bleeding. An occasional radiologic finding is pneumatosis cystoides intestinalis due to airtrappinginthe bowelwall thatmayrarelyrupture andcausebenign pneumoperitoneum. Although the liver is rarely affected, primary biliary cirrhosis may coexist with SSc.


InternalMed_Harrison

InternalMed_Harrison. rENaL INVOLVEMENT: SCLErODErMa rENaL CrISIS


InternalMed_Harrison

InternalMed_Harrison. Scleroderma renal crisis occurs in 10–15% of patients and generally within4yearsoftheonsetofthedisease.Priortotheadventofangiotensin-converting enzyme (ACE) inhibitors, short-term survival in scleroderma renalcrisiswas <10%. The pathogenesis involves obliterative vasculopathy and luminal narrowing of the renal arcuate and interlobular arteries. Progressive reduction in renal blood flow, aggravated by vasospasm, leads to juxtaglomerular hyperplasia, increased renin secretion, and activation of angiotensin, with further renal vasoconstriction resulting in a vicious cycle that culminates in accelerated hypertension. Risk factors for scleroderma renal crisis include African-American race, male gender, and dcSSc with extensive and progressive skin involvement. Up to 50% of patients with scleroderma renal crisis have anti-RNA polymeraseIIIantibodies.Palpabletendonfrictionrubs,pericardialeffusion, new unexplained anemia, and thrombocytopenia may be harbingers of impending scleroderma renal


InternalMed_Harrison

InternalMed_Harrison. renal crisis have anti-RNA polymeraseIIIantibodies.Palpabletendonfrictionrubs,pericardialeffusion, new unexplained anemia, and thrombocytopenia may be harbingers of impending scleroderma renal crisis. High-risk patients with early SSc should be counseled to check their blood pressure daily. Patients with lcSSc or anticentromere antibodies rarely develop scleroderma renal crisis. Because there is an association between glucocorticoid use and scleroderma renal crisis, prednisone should be used in high-risk SSc patients only when absolutely required and at low doses (<10 mg/d).


InternalMed_Harrison

InternalMed_Harrison. Patients characteristically present with accelerated hypertension and progressive oliguric renal insufficiency. However, approximately 10% of patients with scleroderma renal crisis present with normal blood pressure. Normotensive renal crisis is generally associated with a poor outcome.Headache,blurred vision, and congestiveheartfailure mayaccompanyelevationofbloodpressure.Urinalysistypicallyshows mild proteinuria, granular casts, and microscopic hematuria; thrombocytopenia and microangiopathic hemolysis with fragmented red blood cells can be seen. Progressive oliguric renal failure over several days generally follows. In some cases, scleroderma renal crisis is misdiagnosed as thrombotic thrombocytopenic purpura or other forms of thrombotic microangiopathy. In these cases, a renal biopsy may be of some benefit. In addition, biopsy findings of vascular thrombosis and glomerular ischemic collapse predict poor renal outcomes. Oliguria or a creatinine >3 mg/dL at presentation predicts


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InternalMed_Harrison. may be of some benefit. In addition, biopsy findings of vascular thrombosis and glomerular ischemic collapse predict poor renal outcomes. Oliguria or a creatinine >3 mg/dL at presentation predicts poor outcome, with permanent hemodialysis and high mortality. Rarely, crescentic glomerulonephritis occurs in the setting of SSc and may be associated with myeloperoxidase-specific antineutrophil cytoplasmic antibodies. Membranous glomerulonephritis may occur in patients treated with d-penicillamine. Asymptomatic renal function impairment occurs in up to half of SSc patients. Such subclinical renal involvement is associated with other vascular manifestations of SSc and rarely progresses.


InternalMed_Harrison

InternalMed_Harrison. Although it is often silent, cardiac involvement in SSc is frequently detected when patients are screened with sensitive diagnostic tools. Clinically evident cardiac involvement is associated with poor outcomes. Cardiac disease in SSc may be primary or secondary to PAH, ILD, or renal involvement. It occurs more frequently in patients with dcSSc than in those with lcSSc and generally develops within 3 yearsoftheonsetofskinthickening.Clinicallyevidentcardiacinvolvement in SSc is a poor prognostic factor. The endocardium, myocardium, and pericardium may each be affected separately or together. Manifestations of pericardial involvement include acute pericarditis, pericardial effusions, constrictive pericarditis, and cardiac tamponade. Conduction system fibrosis occurs commonly and may be silent or manifested by atrial and ventricular tachycardias or heart block. Recurrent vasospasm and ischemia-reperfusion injury contribute to myocardial fibrosis, resulting in asymptomatic systolic or


InternalMed_Harrison

InternalMed_Harrison. or manifested by atrial and ventricular tachycardias or heart block. Recurrent vasospasm and ischemia-reperfusion injury contribute to myocardial fibrosis, resulting in asymptomatic systolic or diastolic left ventricular dysfunction that may progress to overt heart failure. Systemic and pulmonary hypertension and lung and renal involvement may alsoimpact ontheheart. Despitethepresenceof widespread obliterative vasculopathy, the frequency of clinical or pathologic epicardial coronary artery disease in SSc is not increased. While conventional echocardiography has low sensitivity for detecting SSc preclinical heart involvement, newer modalities such as tissue Doppler echocardiography(TDE),cardiacmagneticresonanceimaging(cMRI), thallium perfusion, and nuclear imaging (single photon emission CT [SPECT]) reveal a high prevalence of abnormal myocardial function or perfusion in SSc patients. The serum level of N-terminal pro-BNP, a ventricular hormone, is a marker for PAH in SSc, but may also


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InternalMed_Harrison. [SPECT]) reveal a high prevalence of abnormal myocardial function or perfusion in SSc patients. The serum level of N-terminal pro-BNP, a ventricular hormone, is a marker for PAH in SSc, but may also have utility as a marker of primary cardiac involvement.


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InternalMed_Harrison. Carpal tunnel syndrome occurs frequently and may be a presenting manifestation. Generalized arthralgia and stiffness are prominent in early disease. Mobility of small and large joints is progressively impaired, especially in dcSSc. Most commonly affected are the hands. Contractures develop at the proximal interphalangeal joints and wrists. Large joint contractures can be accompanied by tendon friction rubs, characterized by leathery crepitation that can be heard or palpated upon passivemovement, thataredue to extensive fibrosis and adhesion of the tendon sheaths and fascial planes at the affected joint. Presence of tendon friction rubs is associated with increased risk for renal and cardiac complications and reduced survival. True joint inflammation is uncommon; however, occasional patients develop erosive polyarthritis in the hands. Muscle weakness is common and may indicate deconditioning, disuse atrophy, and malnutrition. Less commonly, inflammatory myositis indistinguishable from


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InternalMed_Harrison. develop erosive polyarthritis in the hands. Muscle weakness is common and may indicate deconditioning, disuse atrophy, and malnutrition. Less commonly, inflammatory myositis indistinguishable from idiopathic polymyositis may occur. A chronic noninflammatory myopathy characterized by atrophy and fibrosis in the absence of elevated muscle enzyme levels can be seen in late-stage SSc. Bone resorption occurs most commonly in the terminal phalanges, where it causes loss of the distal tufts (acroosteolysis)(Fig.382-5). Resorption of themandibular condylescanlead to bite difficulties. Osteolysis can also affect the ribs and distal clavicles.


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InternalMed_Harrison. Many SSc patients develop dry eyes and dry mouth (sicca complex). Biopsy of the minor salivary glands shows fibrosis rather than focal lymphocytic infiltration characteristic of primary Sjögren’s syndrome (Chap. 383). Hypothyroidismis commonand generally due tofibrosis of the thyroid gland. The frequency of macrovascular involvement, including peripheral vascular and coronary artery disease, may be increased. Whereas the central nervous system is generally spared, sensory trigeminal neuropathy due to fibrosis or vasculopathy can occur,presentingwithgradualonsetofpainandnumbness.Pregnancy in women with SSc may be associated with an increased rate of adverse fetal outcomes. Furthermore, cardiopulmonary involvement may worsen during pregnancy, and new onset of scleroderma renal crisis has been described. Erectile dysfunction is frequent in men with SSc and may be the initial disease manifestation. Inability to attain or maintain penile erection is due to vascular insufficiency and


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InternalMed_Harrison. has been described. Erectile dysfunction is frequent in men with SSc and may be the initial disease manifestation. Inability to attain or maintain penile erection is due to vascular insufficiency and fibrosis.


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InternalMed_Harrison. Malignancy in SSc Epidemiologic studies indicate an increased risk of cancer in SSc. Lung cancer and esophageal adenocarcinoma typically occur in the setting of long-standing ILD or gastroesophageal reflux diseaseandmaybecausedbychronicinflammationandrepair.Incontrast, breast, lung, and ovarian carcinomas and lymphomas tend to occur in close temporal association with the clinical onset of SSc, particularly in patients who have autoantibodies to RNA polymerase III. In these cases, SSc may represent a paraneoplastic syndrome triggered by the anti-tumor immune response.


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InternalMed_Harrison. A mild normocytic or microcytic anemia is frequent in patients with SSc and may indicate gastrointestinal bleeding caused by GAVE or chronic esophagitis. Macrocytic anemia may be caused by folate and vitamin B12 deficiency due to small-bowel bacterial overgrowth and malabsorption or by drugs such as methotrexate or alkylating agents. Microangiopathic hemolytic anemia caused by mechanical fragmentation of red blood cells during their passage through microvessels coated withfibrin orplateletthrombi isahallmark of the thromboticmicroangiopathy associated with scleroderma renal crisis. Thrombocytopenia and leukopenia may indicate drug toxicity. In contrast to other connective tissue diseases, the erythrocyte sedimentation rate (ESR) is generally normal; an elevation may signal coexisting myositis or malignancy.


InternalMed_Harrison

InternalMed_Harrison. Antinuclear autoantibodies are present in almost all patients with SSc andcanbedetectedatdiseaseonset.Autoantibodiesagainsttopoisomerase I(Scl-70)andcentromerearemutuallyexclusiveandquitespecificforSSc (Table 382-3).Topoisomerase Iantibodies aredetectedin 31%ofpatients with dcSSc, but in only 13% of patients with lcSSc. They are associated withincreasedriskofILDandpooroutcomes.Anticentromereantibodies are detected in 38% of patients with lcSSc, but in only 2% of patients with dcSSc and rarely in patients with Raynaud’s phenomenon and Sjögren’s syndrome. Anticentromere antibodies in SSc are associated with PAH, but only infrequently with significant cardiac or renal involvement or ILD. Nucleolar immunofluorescence pattern on serologic testing reflects antibodies to U3-RNP (fibrillarin), Th/To, or PM/Scl, whereas a speckled immunofluorescencepattern indicates antibodies to RNA polymerase III. Although antibodies to β2GPI occur in antiphospholipid antibody syndrome


InternalMed_Harrison

InternalMed_Harrison. (fibrillarin), Th/To, or PM/Scl, whereas a speckled immunofluorescencepattern indicates antibodies to RNA polymerase III. Although antibodies to β2GPI occur in antiphospholipid antibody syndrome andarenotspecificforSSc,theirpresenceinSScisassociatedwith an increased risk of ischemic lesions in the fingers.


InternalMed_Harrison

DIaGNOSIS, STaGING, aND MONITOrING

InternalMed_Harrison. DIaGNOSIS, STaGING, aND MONITOrING


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InternalMed_Harrison. ThediagnosisofSScismadeprimarilyonclinicalgroundsandisgenerally straightforward in patients with established disease. The presence of skin induration,withacharacteristicsymmetricdistributionpatternassociated with typical visceral organ manifestations, establishes the diagnosis with a highdegreeofcertainty.AlthoughtheconditionslistedinTable382-1can beassociatedwithskininduration,thedistributionpatternofskinlesions, together with the absence of Raynaud’s phenomenon or typical visceral organ manifestations or SSc-specific autoantibodies, differentiates these conditions from SSc. Occasionally, full-thickness biopsy of the skin is requiredforestablishingthediagnosisofscleredema, scleromyxedema,or nephrogenic systemic fibrosis. In lcSSc, a history of antecedent Raynaud’s phenomenon and gastroesophageal reflux symptoms, coupled with the presenceofsclerodactylyandcapillarychangesonnailfoldcapillaroscopy, often in combinations with cutaneous telangiectasia and calcinosis, helps


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InternalMed_Harrison. and gastroesophageal reflux symptoms, coupled with the presenceofsclerodactylyandcapillarychangesonnailfoldcapillaroscopy, often in combinations with cutaneous telangiectasia and calcinosis, helps toestablishthediagnosis.Thefindingofdigitaltippittingscarsandradiologic evidence of pulmonary fibrosis in the lower lobes are particularly helpful diagnostically. Primary Raynaud’s phenomenon is a common benign condition that must be differentiated from early or limited SSc. Nailfoldmicroscopyisparticularlyhelpfulinthissituation,becauseinprimaryRaynaud’sphenomenon,thenailfoldcapillariesarenormal,whereas in SSc, capillary abnormalities, as well as serum autoantibodies, can be detected even before other disease manifestations.


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InternalMed_Harrison. EstablishingthediagnosisofSScatanearlystageofthediseasemaybe a challenge. In dcSSc, initial symptoms are often nonspecific and relate to inflammation. Patients complain of fatigue, swelling, aching, and stiffness, and Raynaud’s phenomenon may initially be absent. Physical examinationmayrevealdiffuseupperextremityedemaandpuffyfingers. Patientsatthisstagearesometimesdiagnosedasearlyrheumatoidarthritis, SLE, myositis, or, most commonly, undifferentiated connective tissue disease. Within weeks to months, Raynaud’s phenomenon and characteristic clinical features appear accompanied by advancing induration of the skin. The presence of antinuclear and SSc-specific autoantibodies provides a high degree of diagnostic specificity. Raynaud’s phenomenon with fingertip ulcerations or other evidence of digital ischemia, coupled 2163 with telangiectasia, distal esophageal dysmotility, unexplained ILD or PAH, or accelerated hypertension with renal failure in the absence of clinically evident skin


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InternalMed_Harrison. of digital ischemia, coupled 2163 with telangiectasia, distal esophageal dysmotility, unexplained ILD or PAH, or accelerated hypertension with renal failure in the absence of clinically evident skin induration, suggests the diagnosis of SSc sine scleroderma. These patients may have anticentromere antibodies.


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InternalMed_Harrison. OVErVIEW: MaNaGEMENT PrINCIPLES To date, no therapy has been shown to significantly alter the natural history of SSc. In contrast, multiple interventions are highly effective in alleviating the symptoms, slowing the progression of the cumulative organ damage, and reducing disability. A significant reduction in disease-related mortality has been noted during the past 25 years. In light of the marked heterogeneity in disease manifestations, organ complications, and natural history, treatment must be tailored to each individual patient’s unique needs.


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InternalMed_Harrison. A thorough investigation should be undertaken at baseline. Optimal management incorporates the following principles (Table 382-5): prompt and accurate diagnosis; classification and risk stratification based on clinical and laboratory evaluation; early recognition of organ-based complications and assessment of their extent, severity, and likelihood of deterioration; regular monitoring for disease progression, activity, new complications, and response to therapy; adjusting therapy; and continuing patient education. In order to minimize irreversible organ damage, the management of life-threatening complications must be proactive, with regular screening and initiation of appropriate intervention at the earliest possible opportunity. In light of the complex and multisystemic nature of the SSc, a team-based management approach integrating multiple specialists should be pursued whenever possible. Most patients are treated with combinations of drugs that impact different aspects of the


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InternalMed_Harrison. SSc, a team-based management approach integrating multiple specialists should be pursued whenever possible. Most patients are treated with combinations of drugs that impact different aspects of the disease. We encourage patients to become familiar with the spectrum of potential complications and understand therapeutic options and natural history, and empower them to partner with their treating physicians. This requires a long-term relationship between patient and physician, with ongoing counseling and encouragement.


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InternalMed_Harrison. DISEaSE-MODIFYING THEraPY: IMMUNOSUPPrESSIVE aGENTS Immunosuppressive agents used in the treatment of other autoimmune or connective tissue diseases have generally shown modest or no benefit in SSc. Glucocorticoids may alleviate stiffness and aching in early-stage dcSSc but do not influence the progression of skin or internal organ involvement, and their use is associated with an increased risk of scleroderma renal crisis. Therefore, glucocorticoids should be given only when absolutely necessary, at the lowest dose possible, and for brief periods only. The use of cyclophosphamide has been extensively studied in light of its efficacy in the treatment of vasculitis (Chap. 385), SLE (Chap. 378), and other autoimmune diseases (Chap. 377e).


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InternalMed_Harrison. Both oral and intermittent IV cyclophosphamide were shown to reduce the progression of SSc-associated ILD, with stabilization and, rarely, modest improvement of pulmonary function and HRCT findings after 1 year of treatment. Improvement in respiratory symptoms and skin induration was also noted. These beneficial effects wane upon discontinuation of therapy. The benefits of cyclophosphamide need to be balanced against its potential toxicity, including bone marrow suppression, opportunistic infections, hemorrhagic cystitis and bladder cancer, premature ovarian failure, and late secondary malignancies. early and accurate diagnosis. internal organ involvement. clinical disease stage and activity. individualized therapy to each patient’s unique needs. treatment response, and adjust therapy as needed; monitor for disease progression and new complications.


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InternalMed_Harrison. 2164 Methotrexate was associated with a modest skin improvement in small studies. Mycophenolate mofetil treatment was associated with improved skin induration in uncontrolled studies and was generally well tolerated. Small studies support the use of rituximab in SSc patients with skin involvement and ILD. The use of cyclosporine, azathioprine, extracorporeal photopheresis, thalidomide, rapamycin, imatinib, and IV immunoglobulin is currently not well supported by the literature. Intensive immune ablation using a conditioning regimen of high-dose chemotherapy with or without irradiation, followed by autologous stem cell reconstitution, has resulted in durable disease remission in some cases and is undergoing evaluation in randomized clinical trials. In light of its potential morbidity and mortality, as well as significant cost, autologous stem cell transplantation in SSc is still considered experimental.


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InternalMed_Harrison. antifibrotic Therapy Because widespread tissue fibrosis in SSc causes progressive organ damage, drugs that interfere with the fibrotic process represent a rational therapeutic approach. D-Penicillamine has been extensively used as an antifibrotic agent. In retrospective studies, D-penicillamine stabilized and improved skin induration, prevented new internal organ involvement, and improved survival. However, a randomized controlled clinical trial in early active SSc found no difference in the extent of skin involvement between patients treated with standard-dose (750 mg/d) or very low-dose (125 mg every other day) D-penicillamine. Recent clinical trials show benefit of pirfenidone and of nintedanib in patients with idiopathic pulmonary fibrosis, with significant slowing of the loss of lung function. Whether these two new drugs will have comparable efficacy in the treatment of SSc-associated lung disease is still under investigation.


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InternalMed_Harrison. Vascular Therapy The goal of therapy is to control Raynaud’s phenomenon, prevent the development and enhance the healing of ischemic complications, and slow the progression of obliterative vasculopathy. Patients should dress warmly, minimize cold exposure or stress, and avoid drugs that precipitate or exacerbate vasospastic episodes. Some patients with Raynaud’s may respond to biofeedback therapy. Extended-release dihydropyridine calcium channel blockers such as nifedipine, amlodipine, or diltiazem can ameliorate Raynaud’s phenomenon, but their use is often limited by side effects (palpitations, dependent edema, worsening gastroesophageal reflux). While ACE inhibitors do not reduce the frequency or severity of episodes, angiotensin II receptor blockers such as losartan are effective and generally well tolerated. Patients with Raynaud’s phenomenon unresponsive to these therapies may require the addition of α1-adrenergic receptor blockers (e.g., prazosin), 5-phosphodiesterase inhibitors


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InternalMed_Harrison. well tolerated. Patients with Raynaud’s phenomenon unresponsive to these therapies may require the addition of α1-adrenergic receptor blockers (e.g., prazosin), 5-phosphodiesterase inhibitors (e.g., sildenafil), serotonin reuptake inhibitors (e.g., fluoxetine), topical nitroglycerine, and intermittent infusions of IV prostaglandins. Low-dose aspirin and dipyridamole prevent platelet aggregation and may have a role as adjunctive agents. In patients with ischemic ulcers, the endothelin-1 receptor antagonist bosentan reduces the risk of new ulcers. Digital sympathectomy and local injections of botulinum type A (Botox) into the digits are options in patients with severe ischemia and impending loss of the digits. Empirical long-term therapy with statins and antioxidants may retard the progression of vascular damage and obliteration. Vasodilators such as ACE inhibitors, calcium channel blockers, and endothelin receptor blockers may also improve myocardial perfusion and left ventricular


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InternalMed_Harrison. of vascular damage and obliteration. Vasodilators such as ACE inhibitors, calcium channel blockers, and endothelin receptor blockers may also improve myocardial perfusion and left ventricular function.


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InternalMed_Harrison. TrEaTMENT OF GaSTrOINTESTINaL COMPLICaTIONS Because oral problems including decreased oral aperture, decreased saliva production, gum recession and periodontal disease leading to teeth loss are common, regular dental care is recommended. Gastroesophageal reflux is very common and may occur in the absence of symptoms; therefore all patients with SSc should be treated. Patients should be instructed to elevate the head of the bed, eat frequent small meals, and avoid oral intake before bedtime. Proton pump inhibitors reduce acid reflux and may need to be given in relatively high doses. Prokinetic agents such as domperidone may be helpful, especially if delayed gastric emptying is present. Episodic gastrointestinal bleeding from gastric antral vascular ectasia (watermelon stomach) may be amenable to treatment with endoscopic laser photocoagulation, although recurrence can occur. Bacterial overgrowth due to small-bowel dysmotility causes abdominal bloating and diarrhea and may lead to


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InternalMed_Harrison. amenable to treatment with endoscopic laser photocoagulation, although recurrence can occur. Bacterial overgrowth due to small-bowel dysmotility causes abdominal bloating and diarrhea and may lead to malabsorption and severe malnutrition. Treatment with short courses of rotating broad-spectrum antibiotics such as metronidazole, erythromycin, and tetracycline can eradicate bacterial overgrowth. Parenteral hyperalimentation is indicated if malnutrition develops. Chronic hypomotility of the small bowel may respond to octreotide, but pseudo-obstruction is difficult to treat. Fecal incontinence, a frequently underreported complication of SSc, may respond to anti-diarrheal medication and biofeedback therapy.


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InternalMed_Harrison. TrEaTMENT OF PULMONarY arTErIaL HYPErTENSION (PaH) In patients with SSc, PAH carries an extremely poor prognosis and accounts for 30% of deaths. Because PAH is asymptomatic until advanced, patients with SSc should be screened for its presence at initial evaluation, and on a yearly basis thereafter. Treatment is generally started with an oral endothelin-1 receptor antagonist such as bosentan or a phosphodiesterase type 5 inhibitor such as sildenafil. Patients may also require diuretics and digoxin when appropriate. If hypoxemia is documented, supplemental oxygen should be prescribed in order to avoid hypoxia-induced secondary pulmonary vasoconstriction. Prostacyclin analogues such as epoprostenol or treprostinil can be given by continuous IV or SC infusion, or via intermittent nebulized inhalations. Combination therapy with different classes of agents, such as an endothelin-1 antagonist and a phosphodiesterase inhibitor, is often necessary. Lung transplantation remains an option for


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InternalMed_Harrison. inhalations. Combination therapy with different classes of agents, such as an endothelin-1 antagonist and a phosphodiesterase inhibitor, is often necessary. Lung transplantation remains an option for selected patients who fail medical therapy.


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InternalMed_Harrison. TrEaTMENT OF rENaL CrISIS Scleroderma renal crisis is a medical emergency. Since the outcome is largely determined by the extent of renal damage present at the time that aggressive therapy is initiated, prompt recognition of impending or early scleroderma renal crisis is essential, and efforts should be made to avoid its occurrence. High-risk SSc patients with early disease, extensive and progressive skin involvement, tendon friction rubs, and anti-RNA polymerase III antibodies should be instructed to monitor their blood pressure daily and report significant alterations immediately. Potentially nephrotoxic drugs should be avoided, and glucocorticoids should be used only when absolutely necessary and at low doses. Patients presenting with scleroderma renal crisis should be immediately hospitalized. Once other causes of renal disease are excluded, treatment should be started promptly with titration of short-acting ACE inhibitors, with the goal of achieving rapid normalization of the


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InternalMed_Harrison. Once other causes of renal disease are excluded, treatment should be started promptly with titration of short-acting ACE inhibitors, with the goal of achieving rapid normalization of the blood pressure. In patients with hypertension persisting despite ACE inhibitor therapy, addition of angiotensin II receptor blockers, calcium channel blockers, and direct renin inhibitors should be considered. Anecdotal evidence indicates responses to endothelin-1 receptor blockers and prostacyclins. Up to two-thirds of patients with scleroderma renal crisis go on to dialysis. The outcome of scleroderma renal crisis is worse in patients with antibodies to topoisomerase I compared to those with antibodies to RNA polymerase III. Substantial renal recovery can occur following scleroderma renal crisis, and dialysis can be discontinued, in 30–50% of the patients. Kidney transplantation is appropriate for those unable to discontinue dialysis after 2 years. Survival of transplanted SSc patients is comparable


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InternalMed_Harrison. can be discontinued, in 30–50% of the patients. Kidney transplantation is appropriate for those unable to discontinue dialysis after 2 years. Survival of transplanted SSc patients is comparable to that of patients with other connective tissue diseases, and recurrence of renal crisis is rare.


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InternalMed_Harrison. SKIN CarE Because skin involvement in SSc is never life-threatening and because it stabilizes and may even regress spontaneously, over time, the management of SSc should not be dictated by its cutaneous manifestations. The inflammatory symptoms of early skin involvement can be controlled with antihistamines and cautious short-term use of low-dose glucocorticoids (<5 mg/d of prednisone). Retrospective studies have shown that D-penicillamine reduced the extent and progression of skin induration; however, these benefits could not be substantiated in a controlled prospective trial. Cyclophosphamide and methotrexate have modest effects on skin induration. Because the skin is dry, the use of hydrophilic ointments and bath oils is encouraged. Regular skin massage is helpful. Telangiectasia may present a cosmetic problem, especially on the face. Treatment with pulsed dye laser may have short-term benefit. Ischemic digital ulcers should be protected by occlusive dressing to promote healing and


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InternalMed_Harrison. a cosmetic problem, especially on the face. Treatment with pulsed dye laser may have short-term benefit. Ischemic digital ulcers should be protected by occlusive dressing to promote healing and prevent infection. Infected skin ulcers are treated with topical antibiotics. Surgical debridement may be indicated. No therapy has been shown to be effective in preventing the formation of calcific soft tissue deposits or promoting their dissolution.


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InternalMed_Harrison. TrEaTMENT OF MUSCULOSKELETaL COMPLICaTIONS Arthralgia and joint stiffness are common and distressing manifestations most prominent in early-stage disease. Short courses of nonsteroidal anti-inflammatory agents, weekly methotrexate, and cautious use of low-dose corticosteroids may alleviate these symptoms. Physical and occupational therapy can be effective for maintaining musculoskeletal function and improving long-term outcomes. The natural history of SSc is highly variable and difficult to predict, especially in early stages of the disease, when the specific subset— diffuse or limited cutaneous form—is not clear. Patient with dcSSc tend to have a more rapidly progressive course and worse prognosis than those with lcSSc.


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InternalMed_Harrison. In dcSSc, inflammatory symptoms such as fatigue, edema, arthralgia, and pruritus tend to subside, and the extent of skin thickening reaches a plateau at 2–4 years after disease onset, followed by slow regression.Itisduringtheearlyedematous/inflammatorystage,generally lasting <3years, that important visceralorganinvolvement occurs. While existing visceral organ involvement, such as pulmonaryfibrosis, may progress even after skin involvement peaks, new organ involvement is rare. Scleroderma renal crisis almost invariably occurs within the first 4 years of disease. In late-stage disease (>6 years), the skin is usually soft and atrophic. Skin regression characteristically occurs in an order that is the reverse of initial involvement, with softening on the trunks followed by proximal and finally distal extremities; however, sclerodactyly and finger contractures generally persist. Relapse or recurrence of skin thickening after the peak of skin involvement has been


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InternalMed_Harrison. by proximal and finally distal extremities; however, sclerodactyly and finger contractures generally persist. Relapse or recurrence of skin thickening after the peak of skin involvement has been reachedisuncommon.Patientswith lcSScfollow aclinicalcourse that is markedly different than that of dcSSc. Raynaud’s phenomenon typically precedes other disease manifestations by years or even decades. Visceral organ complications such as PAH and ILD generally develop late and progress slowly.


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InternalMed_Harrison. SSc confers a substantial increase in the risk of premature death. Age-and gender-adjusted mortality rates are fivefold to eightfold higher compared to the general population, and more than half of all patients with SSc die from their disease. In one population-based study of SSc, the median survival was 11 years. In patients with dcSSc, 5-and 10-year survival rates are 70% and 55%, respectively, whereas in patients with lcSSc, 5-and 10-year survival rates are 90% and 75%, respectively. The prognosis correlates with the extent of skin involvement, which itself is a surrogate for visceral organ involvement. Major causes of death are PAH, pulmonary fibrosis, gastrointestinal involvement, and cardiac disease. Scleroderma renal crisis is associated with a 30% 3-year mortality. Lung cancer and excess cardiovascular deaths also contribute to increased mortality. Markers of poor prognosis include male gender, African-American race, older age at disease onset, extensive skin thickening with


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InternalMed_Harrison. excess cardiovascular deaths also contribute to increased mortality. Markers of poor prognosis include male gender, African-American race, older age at disease onset, extensive skin thickening with truncal involvement, palpable tendon friction rubs, and evidence of significant or progressive visceral organ involvement. Laboratory predictors of increased mortality at initial evaluation include an elevated ESR, anemia, proteinuria and anti–topoisomerase I antibodies. In one study, SSc 2165 patients with extensive skin involvement, lung vital capacity <55% predicted, significant gastrointestinal involvement (pseudoobstruction ormalabsorption), evidenceof cardiac involvement(arrhythmias or congestive heart failure), or scleroderma renal crisis had a cumulative 9-year survival <40%. The severity of PAH is strongly associated with mortality, and SSc patients who had a mean pulmonary arterial pressure ≥45 mmHg had a 33% 3-year survival. The advent of ACE inhibitors in scleroderma renal


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InternalMed_Harrison. of PAH is strongly associated with mortality, and SSc patients who had a mean pulmonary arterial pressure ≥45 mmHg had a 33% 3-year survival. The advent of ACE inhibitors in scleroderma renal crisis had a dramatic impact on survival, increasing from <10% at 1 year in the pre–ACE inhibitor era to >70% 3-year survival at the present time. Moreover, 10-year survival inSSc has improvedfrom<60%inthe 1970s to >66–78%inthe 1990s, a trend that reflects both earlier detection and better management of complications.


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InternalMed_Harrison. The term scleroderma is commonly used to describe a group of localizedskindisorders(Table382-1).Theseoccurmorecommonlyinchildren than in adults. In contrast to SSc, localized scleroderma is rarely complicated by Raynaud’s phenomenon or significant internal organ involvement. Morphea presents as solitary or multiple circular patches of thickened skin or, rarely, as widespread induration (generalized or pansclerotic morphea); the fingers are spared. Linear scleroderma— streaks of thickened skin, typically in one or both lower extremities— may affect the subcutaneous tissues, leading to fibrosis and atrophy of supporting structures, muscle, and bone. In children, the growth of affected long bones can be retarded. When linear scleroderma lesions cross joints, significant contractures can develop.


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InternalMed_Harrison. Patients who have lcSSc coexisting with features of SLE, polymyositis, and rheumatoid arthritis may have mixed connective tissue disease (MCTD). This overlap syndrome is generally associated with the presence of high titers of autoantibodies to U1-RNP. The characteristic initial presentation is Raynaud’s phenomenon associated with puffy fingers and myalgia. Gradually, lcSSc features of sclerodactyly, calcinosis, and cutaneous telangiectasia develop. Skin rashes suggestive of SLE (malar rash, photosensitivity) or of dermatomyositis (heliotrope rash on the eyelids, erythematous rash on the knuckles) occur. Arthralgia is common, and some patients develop erosive polyarthritis. Pulmonary fibrosis and isolated or secondary PAH may develop. Other manifestations include esophageal dysmotility, pericarditis, Sjögren’s syndrome, and renal disease, especially membranous glomerulonephritis. Laboratory evaluation indicates features of inflammation with elevated ESR and hypergammaglobulinemia.


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InternalMed_Harrison. pericarditis, Sjögren’s syndrome, and renal disease, especially membranous glomerulonephritis. Laboratory evaluation indicates features of inflammation with elevated ESR and hypergammaglobulinemia. While anti-U1RNP antibodies are detected in the serum in high titers, SSc-specific autoantibodies are not found. In contrast to SSc, patients withMCTDoften show a good responseto treatmentwithglucocorticoids, and the long-term prognosis is better than that of SSc. Whether MCTD is a truly distinct entity or is, rather, a subset of SLE or SSc remains controversial.