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CHAPTER 353

Systemic Sclerosis (Scleroderma) and Related Disorders

MASTER MODERN MEDICINE

P R I N C I P L E S O F

I N T E R N A LM E D I C I N E

HARRISON’S20th Edition

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2546 clinicalandlaboratoryfeatures,andnaturalhistory(Table 353-3).Dif-fusecutaneousSSc (dcSSc) is typicallyassociatedwithextensiveskininduration starting in the fingers (sclerodactyly) and ascending fromdistaltoproximallimbsandthetrunk.Inthesepatients,interstitiallungdisease (ILD) and acute renal involvement develop relatively early.Incontrast, inpatientswith limitedcutaneousSSc (lcSSc),Raynaud’sphenomenon generally precedes other diseasemanifestations, some-timesbyyears. In thesepatients, skin involvement remains confinedto the fingers, distal limbs, and face,while the trunk is spared. Theconstellation of calcinosis cutis, Raynaud’s phenomenon, esophagealdysmotility, sclerodactyly, and telangiectasia,washistorically termedthe CREST syndrome. In lcSSc, visceral organ involvement tends toshow insidious progression, and digital ischemic ulcers, pulmonaryarterial hypertension (PAH), hypothyroidism, and primary biliarycirrhosismayoccuraslatecomplications.Insomepatients,Raynaud’sphenomenonandcharacteristicclinicalandlaboratoryfeaturesofSScoccurintheabsenceofdetectableskinthickening.ThissyndromehasbeentermedSSc sine scleroderma.

INCIDENCE AND PREVALENCESScisanacquiredsporadicdiseasewithaworldwidedistributionandaffectingallraces.IntheUnitedStates,theincidenceis9–46casespermillionperyear.Thereareanestimated100,000U.S. cases,althoughthisnumbermaybesignificantlyhigher ifpatientswhodonotmeetclassification criteria are also included.There are large regionalvari-ations in incidence rates, potentially reflecting differences in casedefinition, environmental exposures or susceptibility genes in popu-

lations with different ancestries. Prevalence ratesinEngland,Europe,andJapanappeartobelowerthan in North America and Australia. Age, sex,andethnicity influencedisease susceptibility, andblackshavehigherage-specificincidencerates.Incommonwithotherconnectivetissuediseases,SScshowsastrongfemalepredominance(4.6:1),whichismostpronouncedinthechildbearingyearsanddeclinesaftermenopause.Anadditionalriskfactoris having an affected first-degree familymember,whichincreasesdiseaserisk13-fold.AlthoughSSccan present at any age, the peak age of onset inwomenwithboth lcSScanddcSSc is65–74years,although in blacks, disease onset occurs at anearlierage.Furthermore,blackswithSScaremorelikelytohavedcSSc,ILD,andaworseprognosis.

■■ GENETIC CONTRIBUTION TO DISEASE PATHOGENESIS

SSc is a polygenic disease. In general, thegenetic associations of SSc identified to datemake only a small contribution to disease

susceptibility. Disease concordance rates are low(4.7%) in monozygotic twins, although concor-danceforantinuclearantibody(ANA)positivityissignificantly higher. On the other hand, evidenceforgeneticcontributiontodiseasesusceptibility isprovided by the observation that 1.6% of SScpatients have a first-degree relative with SSc, aprevalence rate markedly increased compared tothegeneralpopulation.TheriskofRaynaud’sphe-nomenon, ILD, and other autoimmune diseases,including systemic lupus erythematosus (SLE)(Chap. 349),rheumatoidarthritis(Chap. 351),andautoimmune thyroiditis (Chap. 375), is alsoincreased in first-degree relatives. CurrentapproachestouncovergeneticfactorsinSScincludeDNA sequencing and single nucleotide polymor-phism(SNP)analysisofcandidategenes,andSNPanalysisof theentiregenome inahypothesis-freemanner.Genome-wideassociationstudies(GWASs)involve large multi-center and multi-national

353 Systemic Sclerosis (Scleroderma) and Related DisordersJohn Varga

DEFINITION AND CLASSIFICATIONSystemic sclerosis (SSc) is a complex and clinically heterogeneousorphan disease with protean clinical manifestations, a chronic andfrequentlyprogressivecourse,andsignificantdisability,disfigurementandmortality.Virtuallyeveryorgancanbeaffected(Fig. 353-1).

There ismarked variability among SSc patients in patterns of skininvolvement,organcomplications,ratesofdiseaseprogression,responseto treatment,andsurvival.TheearlystagesofSScareassociatedwithprominentinflammatoryfeatures;however,overtime,structuralaltera-tionsinmultiplevascularbedsandprogressivevisceralorgandysfunc-tionduetofibrosisandatrophycometodominatetheclinicalpicture.ClassificationcriteriafordiagnosisofSScareshowninTable 353-1.

Althoughthickandinduratedskin(scleroderma) is thedistinguish-inghallmarkofSSc,skinchangesalsooccurinlocalizedformsofscle-roderma, alongwithmultiplemetabolic, inherited and autoimmunedisorders (Table 353-2). Patientswith SSc can be broadly segregatedinto twomajor subsets defined by the pattern of skin involvement,

Pulmonary:Interstitial lung diseasePulmonary arteryhypertension

Cardiac:PericarditisDiastolic dysfunctionCardiomyopathyArrhythmia

Skin:IndurationCalcinosis cutisTelangiectasiaHyperpigmentationXerosis

Muscloskeletal:Joint contracturesTendon friction rubsMyositis

Upper GI:GERDGAVEBarrett’sGastroparesis

Oral: XerostomiaReduced apertureMucocutaneoustelangiectasia

Lower GI:HypomotilityBacterial overgrowthPseudo-obstruction

Vasular:Raynaud’sDigital ischemic ulcers

Renal:Sclerodermarenal crisis

FIGURE 353-1 Multi-organ involvement in systemic sclerosis. Prominent complications more common in diffuse cutaneous SSc are shown in red; more common in limited cutaneous SSc in blue; and common in both forms of SSc shown in black.

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isorders 2547TABLE 353-1 Classification Criteria for Diagnosis of Systemic

SclerosisITEM SUB-ITEM WEIGHT/SCORESkin thickening (bilateral)—fingers extending proximal to MCP joints

9

Skin thickening of fingers only

Puffy fingersSclerodactyly (skin thickened distal to MCP joints)

24

Fingertip lesions Digital tip ulcer or pitting scar

23

Mucocutaneous telangiectasia

2

Abnormal nails capillary pattern

2

Lung involvement PAHInterstitial lung disease

22

Raynaud’s phenomenon 3SSc-specific autoantibodies

ACAScl-70RNA polymerase III

3

Abbreviations: ACA, anterior cerebral artery; MCP, metacarpophalangeal joint; PAH, pulmonary arterial hypertension.

TABLE 353-2 Conditions Associated with Skin IndurationSystemic sclerosis (SSc) Limited cutaneous SSc Diffuse cutaneous SScLocalized scleroderma Guttate (plaque) morphea, bullous morphea Linear scleroderma, coup de sabre, hemifacial atrophyPansclerotic morpheaOverlap syndromes Mixed connective tissue disease SSc/polymyositisDiabetic scleredema and scleredema of BuschkeScleromyxedema (papular mucinosis)Chronic graft-versus-host diseaseDiffuse fasciitis with eosinophilia (Shulman’s disease, eosinophilic fasciitis)Stiff skin syndromePachydermatoperiostosis (Primary hypertrophic osteoarthropathy)Chemically induced and drug-associated scleroderma-like conditions Vinyl chloride–induced disease Eosinophilia-myalgia syndrome (associated with L-tryptophan contaminant

exposure) Nephrogenic systemic fibrosis (associated with gadolinium exposure)Paraneoplastic syndrome

TABLE 353-3 Subsets of Systemic Sclerosis (SSc): Features of Limited Cutaneous SSc versus Diffuse Cutaneous DiseaseCHARACTERISTIC FEATURE

LIMITED CUTANEOUS SSc DIFFUSE CUTANEOUS SSc

Skin involvement Indolent onset. Limited to fingers, distal to elbows, face; slow progression

Rapid onset. Diffuse: fingers, extremities, face, trunk; rapid progression

Raynaud’s phenomenon

Antedates skin involvement, sometimes by years; may be associated with critical ischemia in the digits

Onset coincident with skin involvement; critical ischemia less common

Musculoskeletal Mild arthralgia Severe arthralgia, carpal tunnel syndrome, tendon friction rubs; small and large joint contractures

Interstitial lung disease

Slowly progressive, generally mild

Frequent, early onset and progression, can be severe

Pulmonary arterial hypertension

Frequent, late, may occur as an isolated complication

Often occurs in association with interstitial lung disease

Scleroderma renal crisis

Very rare Occurs in 15%; onset may be fulminant; generally early (<4 years from disease onset)

Calcinosis cutis Frequent, prominent Less common, mildCharacteristic autoantibodies

Anti-centromere Anti–topoisomerase I (Scl-70), anti-RNA polymerase III

cohorts.AmajorityoftherobustlyvalidatedsusceptibilitylociforSScare genes involved in innate and adaptive immune responses, high-lighting the importanceofautoimmunityas the initial trigger for thedisease.Geneticstudieshaveshownassociationswithcommon(smalleffectsize)variantsrelatedtoBandTlymphocyteactivationandsig-naling (BANK1, BLK, CD247, STAT4, IL2RA, CCR6, IDO1, TNFSF4/OX40L,PTPN22,andTNIP1).Inaddition,candidategenestudiesandGWASsidentifiedastrongassociationwithhumanleukocyteantigen(HLA)-Class II haplotypes on chromosome 6, including HLA- DRB1*11:04, DQA1*05:01, and DQB1*03:01, and the non-HLA geneshistocompatibility complex (MHC) genes NOTCH4 and PSORSC1.Other genetic variants associated with SSc are involved in innateimmunityandthe interferonpathways(IRF5, IRF7,STAT4,TNFAIP3/A20, GSDMA, PRDM1 (BLIMP1), TNFAIP3, and TLR2). Additionalassociations with IL12RB2, IL-21, the apoptosis-related genes DNA-SE1L3 andSOX5, and the fibrosis-relatedgenesCSK, CAV1, PPARG,

andGRB10 have been reported. In addition to disease susceptibility,someofthesegeneticlociareassociatedwithparticulardiseasemani-festations or serologic subsets, including ILD (CTGF, CD226), PAH(TNIP1), and scleroderma renal crisis (HLA-DRB1*).While the func-tionalconsequencesofthesegenevariantsandtheirpotentialrolesinpathogenesisarecurrentlynotwellunderstood,itseemslikelythatincombinationtheycauseastateofalteredimmuneregulation,leadingtoincreasedsusceptibilitytoautoimmunityandpersistentinflammation.Ofnote,manyofthegeneticvariantsassociatedwithSScarealsoimpli-cated in other autoimmune disorders, including SLE, rheumatoidarthritis, and psoriasis, suggesting common pathogenic pathwayssharedamongthesephenotypicallydissimilarconditions.ThegeneticassociationsidentifiedtodateonlyexplainafractionoftheheritabilityofSSc,andGWASs,andwholeexomesequencingtoidentifyadditionalgenetic susceptibility factors inSSc,particularly rare (andpotentiallycausal)variants,arecurrentlyongoing.

ENVIRONMENTAL AND OCCUPATIONAL RISK FACTORSGiventherelativelymodestgeneticcontributiontodiseasesusceptibil-ity inSSc,environmental factors, suchas infectiousagents, intestinalmicrobiota, and occupational, dietary, lifestyle, and drug exposures,arelikelytoplayamajorrole.SomeevidencesuggestspotentialrolesforparvovirusB19,Epstein-Barrvirus(EBV),cytomegalovirus(CMV),andRhodotorula glutinisandothermicroorganisms.Anepidemicofanovelsyndromewith featuressuggestiveofSScoccurred inSpain inthe1980s.Theoutbreak, termed toxic oil syndrome,was linked touseofcontaminatedrapeseedoilforcooking.Anotherepidemicoutbreak,termedeosinophilia-myalgia syndrome(EMS),waslinkedtoconsumptionofl-tryptophan-containingdietarysupplements.Exposuretogadolin-iumcontrastmaterial inpatientswith renal compromiseundergoingmagnetic resonance scanning has been associated with nephrogenicsystemicfibrosis.Whileeachofthesenoveltoxic-epidemicsyndromeswas characterized by chronic indurative skin changes and variablevisceral organ involvement, the constellation of associated clinical,pathologic, and laboratory features distinguishes them from SSc.OccupationalexposurestentativelylinkedwithSScincludeparticulatesilica (quartz), polyvinyl chloride, epoxy resins,welding fumes, andorganicsolventsandaromatichydrocarbons includingpain thinners,toluene, xylene, and trichloroethylene. These exposures might elicit


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2548 stable and heritable epigenetic changes such as DNA methylationand histone modification underlying pathogenic alterations in geneexpression.Drugs implicated in SSc-like illnesses includebleomycin,pentazocine,andcocaine,andappetitesuppressantslinkedwithPAH.Radiationtherapyforcancerhasbeenlinkedwithde novoonsetofSScaswell aswith exacerbation of pre-existing SSc. In contrast to rheu-matoid arthritis, cigarette smokingdoes not increase the risk of SSc.AlthoughcasereportsandseriesofSScinwomenwithsiliconebreastimplantshadraisedconcernregardingapossiblecausalroleofsiliconeinSSc, large-scaleepidemiologic investigations foundnoevidenceofincreasedprevalenceofSSc.

PATHOGENESISThreecardinalpathomechanisticprocessesunderlietheproteanclinicalmanifestations of SSc: (1) diffuse microangiopathy, (2) inflammationand autoimmunity, and (3) visceral andvascular fibrosis inmultipleorgans(Fig. 353-2).WhileallthreeprocessesareconcurrentlyoperativeinSScpatients,theiractivity,relativeseverity,andcontributiontotheoverallclinicalpicturevaryamongindividualpatientsandovertime.Ingeneral, autoimmunityandalteredvascular reactivityoccur early,while fibrosis and atrophy occur later in the disease. Complex anddynamic interplay among these processes initiates and sustains thefibroticprocessandtissuedamage.

■■ ANIMAL MODELS OF DISEASENo single animal model of SSc fully reproduces the three cardinalprocesses that underlie pathogenesis, but some recapitulate selectedaspectsofthehumandisease.Tight-skinmice(Tsk1/+)spontaneouslydevelopskinfibrosisduetoamutationinthefibrillin-1gene.Mutantfibrillin-1 protein disrupts extracellular matrix assembly and causesaberrantactivationoftransforminggrowthfactorβ(TGF-β).Fibrillin-1mutations in humans are associatedwithMarfan’s disease and stiffskin syndrome, but have not been reported in SSc. Skin and lungfibrosis accompanied by variable vasculopathy and autoimmunitycanbeelicitedinmicebyinjectionofbleomycinorAngiotensinII,orby transplantationofHLA-mismatchedbonemarroworspleencells.Targetedgeneticmodificationsinmicegiverisetonewdiseasemodelsforinvestigatingthepathogeneticrolesofindividualmolecules,path-ways,andcelltypes.Forexample,micelackingIRF5,Smad3,uPAR,orperoxisomeproliferator-activated receptor (PPAR)-γ, or constitutivelyoverexpressingβ-catenin,Wnt10b, sirtuin 3, Fra-2, TGFB1, PDGFRα,or adiponectin are either resistant or hypersensitive to experimentalscleroderma,orspontaneouslydevelopfibrosis.Thesediseasemodelscancontribute tounderstandingspecificaspectsofSScpathogenesis,andtodiscoveryandvalidationofnoveltargetsfortherapy.

■■ MICROANGIOPATHYVascular injury isanearlyandpossiblyprimarypathogenicevent inSScthatleadstoproteanclinicalmanifestationsofsmallvesselvascu-lopathy(Fig. 353-3).

Mic

rova

scul

opathy Immune dysregulation

Fibrosis

Systemicsclerosis

FIGURE 353-2 The characteristic constellation of vasculopathy, autoimmunity/inflammation and fibrosis underlies the protean clinical manifestations of systemic sclerosis.

Prominentmicroangiopathyinmultiplevascularbedshasimportantclinicalsequelaeincludingmucocutaneoustelangiectasiae,Raynaud’sphenomenon,ischemicdigitalulcers,sclerodermarenalcrisis,myocar-dialinvolvement,andPAH.Raynaud’sphenomenonischaracterizedbyalteredblood-flowresponsetocoldchallenge insmalldigitalarteries.Thisinitiallyreversiblefunctionalabnormalityisassociatedwithauto-nomic andperipheral nervous systemalterations, including impairedproduction of the neuropeptide calcitonin gene-related peptide fromsensory afferent nerves and heightened sensitivity of α2-adrenergicreceptors on vascular smooth-muscle cells. Isolated (primary) Ray-naud’sdisease is common,generallybenignandnon-progressive. Incontrast,secondaryRaynaud’sphenomenoninSScisoftenprogressiveand complicated by irreversible structural changes, culminating inischemicdigitalulcers,necrosis,andamputation.

Viruses,cytotoxicfactors,andchemokinesthrombogenicmicropar-ticles, alternate complement pathway activation and autoantibodiestargeting endothelial cells, phospholipids, and β2 glycoprotein I(β2GPI)are implicatedaspotential triggersof endothelial cell injury.Endothelialdamageresultsindysregulatedproductionofvasodilatory(nitric oxide and prostacyclin) and vasoconstricting (endothelin-1)substances,aswellasupregulationofintercellularadhesionmolecule1(ICAM-1)andothersurfaceadhesionmolecules.Microvesselsshowenhanced permeability and transendothelial leukocyte diapedesis,abnormal activation of coagulation cascades, elevated thrombin pro-duction, and impaired fibrinolysis. Spontaneous platelet aggregationcausesreleaseofserotonin,platelet-derivedgrowthfactor(PDGF),andplateletalphagranulesincludingthromboxane,apotentvasoconstric-tor.Smooth-musclecell–likemyointimalcellsinthemediaproliferate,thebasementmembrane is thickenedand reduplicated, andperivas-cular adventitial fibrosis develops. The vasculopathic process affectscapillaries,aswellasarterioles,andlesscommonlyevenlargevesselsinmanyorgans,resultinginreducedbloodflowandtissueischemia.Progressiveluminalocclusionduetointimalandmedialhypertrophy,combined with persistent endothelial cell damage and adventitialfibrosis,establishaviciouscyclethatculminatesinthestrikingabsenceof small blood vessels (rarefaction) in late-stage disease. Recurrentischemia-reperfusion generates reactive oxygen species (ROS) thatfurtherdamagestheendotheliumthroughperoxidationofmembranelipids. Paradoxically, the process of revascularization that normallyreestablishesbloodflowto ischemic tissue isdefective inSScdespiteelevated levels of other angiogenic factors.Moreover, bonemarrow–derivedcirculatingendothelialprogenitorcellsarereducedinnumberandimpairedinfunction.Widespreadcapillaryloss,obliterativevas-culopathyofsmallandmedium-sizedarteries,andimpairedabilitytorepairandreplacedamagedvesselsarehallmarksofSSc.

■■ INFLAMMATION AND AUTOIMMUNITY

Cellular Immunity The following observations provide supportfor the inflammatory/autoimmune nature of SSc: near-universal pres-ence of circulating autoantibodieswith defined specificities; familialclustering of SScwith other autoimmune diseases; detection of acti-vated immunecells, includingTcellswitholigoclonalantigenrecep-torsandTfollicularhelper-likecells,intargetorgans;prominenttypeI interferon (IFN) signatures, characterizedbyelevatedexpressionofIFN-regulated genes, in a variety of cell types; elevated circulatinglevelsandspontaneoussecretionfrommononuclearcellsofcytokinesand chemokines such as interleukin-6 (IL-6); tumor necrosis factor,IL-4,IL-10,IL-17,IL-33,CCL2,andCXCL4;geneticassociationofSScwithvariantsofMHCandothergenesfunctionallyimplicatedintheimmuneresponse;andtherapidclinicalresponse,fibrosisresolution,andvascularregenerationobservedinsomeSScpatientstreatedwithimmunomodulatory or immunoablative therapies. Genetic studiesrevealstrongassociationswithMHClocusalleles,aswellasnon-HLA-linkedgenesencodingmediatorsofbothadaptiveandinnateimmuneresponses(CD247,STAT4,IRF5,CD226,TNFAIP3/A20,andTNFSF4).

CirculatingmonocytesfromSScpatientsoverexpressIFN-regulatedgenessuchasSiglec-1,havereducedlevelsofcaveolin-1,andexhibitan inherently profibrotic phenotype. In early (edematous) stage SSc,


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mononuclearcellinfiltratescomprisedofactivatedTcells,monocytes/macrophages,anddendriticcellscanbeseeninskin,lungs,andotheraffectedorganspriortoappearanceoffibrosisorvasculardamage.Den-driticcellscanbefoundincloseproximitytoactivatedfibroblastsandmyofibroblasts andexpress toll-like receptors (TLR)andsecrete IFN,IL-10,thymicstromallymphopoietin(TSLP),andCXCL4,shapingtheadaptiveimmuneresponseandcontributingtolossofimmunetolerance.Tissue-infiltratingTcellsexpressCD45andHLA-DRactivationmark-ersanddisplayrestrictedTcellreceptorsignaturesindicativeofoligo-clonalexpansioninresponsetorecognitionofas-yetunknownantigen.Ofnote, inpatientsdiagnosedwithSSc inclosetemporalassociationwithcancerwhoareRNApolymeraseIIIantibody-positive,thetumormay showmutations in RNApol3 autoantigen, which results in thegenerationofmutant-specificTcellimmunityandcross-reactiveanti-bodies.ThesefindingssupportthepremisethatanabnormalantigenmightactasinitialtriggerfortheautoimmuneresponseinSSc.

CirculatingTcellsinSScexpresschemokinereceptorsandα1inte-grin, accounting for their enhanced binding to endothelium and to

fibroblasts,whileendothelialcellsexpressICAM-1andotheradhesionmolecules that facilitate leukocyte diapedesis.Activated T cells showa TH2-polarized immune response driven by dendritic cells. The TH2cytokines IL-4, IL-13, IL-33, and TSLP induce fibroblast activation,whereastheTH1cytokineinterferonγ (IFN-γ)blockscytokine-mediatedfibroblast activationandexhibits anti-fibroticproperties.Evidence foralteredTh17andregulatoryTcell(Treg)numbersandfunctioninSSchasbeenreported.Type2innatelymphoidcells(iLCs),arecentlydis-coveredlymphoidcellpopulation implicated intype2 immunityandtissue remodeling, are also elevated in SSc skin biopsies.AlternatelyactivatedM2macrophages,whichproduceTGF-βandpromoteangio-genesisandtissueremodeling,areincreasedintheskininSSc.AlthoughthefrequencyofregulatoryTcellsthatenforceimmunetoleranceisele-vatedinthecirculationandtissues,theirimmunosuppressivefunctionappearstobedefective.SomeevidenceimplicatesalteredBcellhomeo-stasisandfunctioninSSc.CirculatingBcellsshowelevatedCD19andco-stimulatorymolecules CD80 and CD86, suggesting B cell chronicactivation.Serumlevelsofaproliferation-inducingligand(APRIL)and

Innate and adaptive immuneresponsesRecruitment and/or activation ofCD4+ and CD8+ T cells, type 2 ILCsmonocytes/macrophages, B cells,TLRs, plasmacytoid dendritic cells

Proinflammatory andprofibrotic mediatorsTh2 cytokines, type 1 IFN, TGF-β,CTGF, Wnt, PDGF, chemokines

Fibrotic responseFibroblast activation, myofibroblastdifferentiation, mesenchymalprogenitor cell impairment, epithelial/endothelial cell to mesenchymaltransition, apoptosis resistance

Extracellular matrix remodelingDeposition and accumulation ofcollagen, fibronectin, proteoglycans,tenascin, COMP; ECM reorganization,stiffness, contraction

Tissue hypoxia

Tissue fibrosis

Obliterativevasculopathy

Impairedangiogenesis/

vasculogenesis

Autoantibodies

Vascular injuryActivation of endothelial cells,platelets, alternative complementpathway, coagulation cascade;ET-1 and ROS expression

FIGURE 353-3 Initial vascular injury in a genetically susceptible individual triggers functional and structural vascular alterations, inflammation and autoimmunity, culminating in fibrosis. 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. COMP, cartilage oligomeric matrix protein; CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TGF-β, transforming growth factor β; TLR, toll-like receptor.



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2550 Bcellactivatingfactor(BAFF),membersoftheTNFsuperfamilywithpotent effects on B cell activation, are elevated in SSc, and associatewithextentofskinandlunginvolvement.BcellssecreteIL-6,TGF-β,andotherprofibroticcytokinesimplicatedinpathogenesis.Thus,BcellhyperactivityinSScmightdirectlycontributetotheinflammatoryandfibroticprocesses,aswellasgenerationofautoantibodies.MicroarrayanalysisidentifiesadistinctsubsetofSScskinbiopsieswithelevatedexpressionofinflammation-relatedgenes.EvidenceofinnateimmuneandTLRsignaling,reflectingactivationbytype1IFNfromplasmacy-toiddendritic cells, isprominent inperipheralbloodcellsand targetorgans.

Humoral Autoimmunity CirculatingANAs can bedetected byindirectimmunofluorescenceinvirtuallyallpatientswithSSc,eveninearlystagesofdisease.Inaddition,severalSSc-specificautoantibodieswithdistinctpatternsofimmunofluorescenceshowstrongassociationswith unique disease endophenotypes (Table 353-4). These antibod-ies are directed mostly against intracellular proteins associated withtranscription,DNA repair, andRNAprocessing.Owing to their highspecificity, mutual exclusivity and association with unique diseasemanifestations, SSc-associated autoantibodies have substantial utilityin clinical practice asdiagnostic andprognosticmarkers,while theirrole in monitoring disease activity remains uncertain. Moreover,antibodies directed against fibrillin-1,matrixmetalloproteinases, cellsurfacemarkersAngiotensinIIreceptor,endothelin-1receptor,muscar-inic3receptor,orthePDGFreceptor,havebeendescribedinpatientswithSSc,althoughtheirclinicalrelevanceisnotyetestablished.Theseantibodiesmanifestfunctionalreceptoragonistactivityandmighthavedirectpathogenicroles.

A variety of mechanisms have been proposed to account for thegeneration of SSc-associated autoantibodies. Proteolytic cleavage,increasedexpressionoralteredsubcellularlocalizationofnormalpro-teins,ortheiralterationsduetomutationinthecaseofcertaintumors,could lead to immune recognition as neoepitopes, resulting in thebreakingofimmunetolerance.

■■ FIBROSISFibrosisaffectingmultipleorgansisadistinguishingfeatureofSSc.Theprocess is characterizedby replacementofnormal tissuearchitecturewithdense,rigid,avascular,andrelativelyacellularconnectivetissue.FibrosisinSScfollows,andisaconsequenceof,inflammation,autoim-munity, andmicrovascular damage (Fig. 353-3). Fibroblasts aremes-enchymalcellsprimarilyresponsibleforthefunctionalandstructuralintegrity of connective tissue. Upon their activation by extracellularcues,fibroblastsproliferate,migrate,secretecollagensandothermatrixmolecules,growthfactors,chemokines,andcytokines,andtransdiffer-entiateintocontractilemyofibroblasts.Undernormalconditions,theseself-limitedresponsesaccomplishphysiologicrepairandregenerationof tissue. In contrast, when these responses become sustained andamplified,pathologicfibrosisresults.Stimulatorysignalingbyendoge-nousTGF-βandparacrinefibroticmediatorsincludingIL-6,IL-13,Wntligands,connectivetissuegrowthfactor(CTGF),PDGF,lysophosphat-idicacid,endothelin-1,hypoxia,ROS,thrombin,andmechanicalforcesare responsible for sustained fibroblast activation underlying non-resolvingfibrosisinSSc.Buildupofdamage-associatedendogenouslig-andsforTLR4(EDA-fibronectin,highmobilitygroupB1[HMGB1]andTenascin-C) and for TLR9 (mitochondrial DNA) within the fibroticmicroenvironmentfurthercontributestonon-resolvingfibrosis.

In addition to tissue-resident fibroblasts and transformed myofi-broblasts, bonemarrow–derived circulatingmesenchymalprogenitorcellsalsocontribute to fibrosis.Thefactors thatregulate thedifferen-tiationofmesenchymalprogenitorcellsandtheirtraffickingfromthecirculationintolesionaltissueareunknown.Epithelialandendothelialcells,mesenchymalprogenitor cells,preadipocytes and tissue fibrob-lastshaveall beenproposedas sourcesofmyofibroblasts in fibrosis.Although myofibroblasts are transiently found in normal woundhealing,theirpersistenceinfibrotictissue,possiblyduetoresistancetoapoptosis,contributestoscarformation.

Explanted SSc fibroblasts display an abnormally activated pheno-type ex vivo, with variably increased rates of collagen production,spontaneousROSgeneration,prominentstressfibers,andconstitutiveexpression of alpha smooth-muscle actin. Persistence of the “sclero-derma phenotype” during serial ex vivo passage of SSc fibroblastsmayreflectautocrineTGF-βstimulatoryloops,deregulatedmicroRNAexpressions,orstableacquiredepigeneticmodificationsinthesecells.

PATHOLOGYWhilepathologicalfindingsinSScvaryacrossanatomicsites,thedistin-guishinghallmarkofSScirrespectiveoftheorgansystemisthetriadofwidespreadcapillarylossandobliterativemicroangiopathy,combinedwith fibrosis in the skin and internal organs. In early-stage disease,perivascular inflammatory cell infiltrates composed of T and B lym-phocytes,activatedmonocytesandmacrophagesandmastcellsmaybedetectedinmultipleorgans.Anon-inflammatoryobliterativemicroan-giopathy isaprominent late finding in theheart, lungs,kidneys,andgastrointestinaltract.Fibrosisisfoundintheskin,lungs,cardiovascu-larandgastrointestinal systems, tendonsheaths,perifascicular tissuesurrounding skeletal muscle, and some endocrine organs. Excessiveaccumulationofcollagens,proteoglycans,COMPandotherstructuralmatrix macromolecules progressively disrupts normal architecture,resultinginimpairedfunctionandfailureofaffectedorgans.

■■ SKINThedermisisthickened,andaccumulationofbroadbundlesofhomog-enizedcollagenorientedparalleltotheepitheliumisseen(Fig. 353-4A).Adnexalglandsareatrophic,andlossofperiadnexalandintradermalwhiteadiposetissueanditsreplacementwithcollagencanbestriking.While perivascular mononuclear cell infiltrates may be seen early,established skin fibrosis generally shows absence of inflammation.Thesefindingsarehistologicallyindistinguishablefromthoseinlocal-izedscleroderma.

■■ LUNGSAutopsy studies in SSc universally show evidence of lung involve-ment. Most common is a nonspecific interstitial pneumonia (NSIP)

TABLE 353-4 Major Systemic Sclerosis-Specific Autoantibodies and Principal Associated Features

TARGET ANTIGEN SSc SUBSETPROMINENT CHARACTERISTIC CLINICAL ASSOCIATION

DNA Topoisomerase I (Scl-70)Speckled pattern

dcSSc Tendon friction rubs, digital ischemic ulcers, scleroderma, extensive skin involvement, early ILD, cardiac involvement, scleroderma renal crisis

Centromere proteinsDiscreet speckled (centromere) pattern

lcSSc Digital ischemic ulcers, calcinosis cutis, isolated PAH; renal crisis rare

RNA polymerase IIISpeckled pattern

dcSSc Rapidly progressive skin, tendon friction rubs, joint contractures, GAVE, renal crisis, contemporaneous cancers; digital ulcers rare

U3-RNP (fibrillarin)Nucleolar pattern

dc/lcSSc PAH, ILD, scleroderma renal crisis, GI tract involvement, myositis

Th/T0

Nucleolar patternlcSSc ILD, PAH

PM/SclNucleolar pattern

lcSSc Calcinosis cutis, ILD, myositis overlap

KuSpeckled pattern

Overlap SLE, myositis overlap

U1-RNPSpeckled pattern

MCTD PAH, inflammatory arthritis, myositis overlap

U11/U12 RNPSpeckled pattern

dc/lcSSc ILD

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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A

Epidermis

Papillary dermis

Reticular dermis

Reticular dermis

FIGURE 353-4 Pathologic findings in systemic sclerosis (SSc). A. Left panel: The skin is thickened due to expansion of the dermis. Inset, higher magnification showing thick hyalinized collagen bundles replacing skin appendages. Right panel: Mononuclear inflammatory cells within the intradermal adipose tissue. Black arrow, collagen; red arrow, dermal adipocytes. B. Early SSc-ILD. Diffuse fibrosis of the alveolar septae and a chronic inflammatory cell infiltrate. Trichrome stain. C. Pulmonary arterial obliterative vasculopathy. Striking intimal hyperplasia and luminal narrowing of small pulmonary artery, with little inflammation and minimal interstitial fibrosis, in a patient with SSc-PAH.

patterncharacterizedbyvariableinterstitialfibrosisandmildchronicinflammation.PatchyinfiltrationofthealveolarwallswithTlympho-cytes,macrophages,andeosinophilsmayoccurinearlydisease.Withprogression, interstitialfibrosisandvasculardamagedominate,oftencoexisting within the same biopsy. The usual interstitial pneumonia(UIP) pattern of spatial/temporal heterogeneity of inflammation,fibrosis and fibrotic foci seen in idiopathicpulmonary fibrosis is less

common in SSc (Fig. 353-4B). Fibrosis of the alveolar septae resultsin obliterationof the airspaces and loss of pulmonarybloodvessels.This process impairs gas exchange and contributes to pulmonaryhypertension. Intimal thickening of the pulmonary arteries, bestseen with elastin stain, underlies SSc-associated PAH (Fig. 353-4C)and, at autopsy, is often associatedwithmultiplepulmonary emboliandmyocardial fibrosis.Patientsmayalso show fibrosis and intimalproliferation in preseptal venules and veins in the lung, accountingfor veno-occlusive disease. Lymphocytic bronchiolitis involving thesubmucosaoftheterminalbronchiolesmayalsobeseen.

■■ GASTROINTESTINAL TRACTPathologic changes canbe foundat any level from themouth to therectum.Atrophy and fibrosis of the muscularis propria and charac-teristicvascular lesionsareprominent in the loweresophagus,whilestriatedmuscleintheupperthirdoftheesophagusisgenerallyspared.Collagenous replacement of the normal intestinal tract architectureresults in impaired smoothmuscle contractility anddiminishedper-istaltic activity, with dysmotility, bacterial overgrowth, small-bowelobstruction,andperforation.Chronicgastroesophagealrefluxisasso-ciatedwithesophagealinflammation,mucosalulceration,andstrictureformationandmayleadtoBarrett’smetaplasiawithattendantriskofadenocarcinoma. Esophageal dilation and reflux are associatedwithILDduetochronicmicroaspiration.

■■ KIDNEYSIn the kidneys, vascular lesions affecting the interlobular and arcu-ate arteries predominate. Chronic renal ischemia is associated withshrunkenglomeruli.Patientswithsclerodermarenalcrisisshowacutefibrinoid necrosis of afferent arterioles, followed by intimal prolifer-ation (onion-skin pattern), and ischemic collapse of glomeruli. Thesechangesarereminiscentofthromboticmicroangiopathiessuchasatyp-icalhemolytic-uremicsyndrome(see Chap. 304),andareaccompaniedby complement deposition, thrombosis, thrombocytopenia due toplateletconsumption,andintravascularhemolysis.Extensivevascularthrombosis,glomerularcollapseandsclerosis,andperitubularcapillarydepositsinrenalbiopsyareassociatedwithirreversiblerenalfailure.

■■ HEARTSubclinicalcardiacpathologyiscommon,withprominentinvolvementof the myocardium and pericardium. The characteristic arteriolarlesions are concentric intimal hypertrophy and luminal narrowing,accompanied by patchy contraction band necrosis, loss of cardiacmyocytes,andmyocardial fibrosisduetomicrovascular involvementand ischemia-reperfusion injury.Fibrosisof theconductionsystem iscommon,especiallyatthesinoatrialnode.Thefrequencyofepicardialatheroscleroticcoronaryarterydiseasemaybeincreasedcomparedtothe general population, similar to other systemic inflammatory dis-eases. Pericardial involvement with chronic inflammatory infiltratesand fibrinousexudates is commonandmaybeassociatedwithperi-cardialeffusions.

■■ PATHOLOGY IN OTHER ORGANSSynovitis may be found in early SSc; with disease progression, thesynoviumbecomesfibrotic,andincontrasttorheumatoiddisease,pan-nus formationor bone resorption areuncommon. Fibrosis of tendonsheathsandfascia,sometimesaccompaniedbycalcifications,producespalpable and sometimes audible tendon friction rubs. Inflammationand, inlaterstages,atrophyandfibrosisofskeletalmusclesarecom-monfindings,andaresimilartothoseinpolymyositis.Fibrosisofthethyroidglandandoftheminorsalivaryglandsmaybeseen.PlacentasfromSScpregnanciesshowdecidualvasculopathy,whichisassociatedwithpoorperinataloutcomesandfetaldeath.

CLINICAL FEATURES

■■ OVERVIEWSSc can affect virtually any organ (Fig. 353-1 and Table 353-5).AlthoughadichotomousapproachstratifyingSScintodiffuseandlim-itedcutaneoussubsets(Table353-2)isuseful,diseaseexpressionisfar



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FEATURESLIMITED CUTANEOUS SSc (%)

DIFFUSE CUTANEOUS SSc (%)

Skin involvement 90a 100Raynaud’s phenomenon 99 98Ischemic digital ulcers 50 25Esophageal involvement 90 80Interstitial lung disease 35 65Pulmonary arterial hypertension

15 15

Myopathy 11 23Clinical cardiac involvement

9 12

Scleroderma renal crisis 2 15Calcinosis cutis — —

aApproximately 10% of patients have SSc sine scleroderma.

morecomplex,andmultipledistinctendophenotypeswithuniquepat-ternsofmanifestationscanberecognizedwithineachsubset.Uniqueendophenotypesassociatewithautoantibodieswithdistinctandmutu-ally exclusive specificities (Table 353-4). Patients with SSc “overlap”havetypicalfeaturescoexistingwithclinicalandlaboratoryevidenceofanotherautoimmunedisease,mostcommonlypolymyositis,Sjögren’ssyndrome,polyarthritis,autoimmuneliverdisease,orSLE.

■■ INITIAL CLINICAL PRESENTATIONCharacteristicinitialpresentationisquitedifferentinpatientswiththediffuse(dcSSc)versuslimited(lcSSc)cutaneousformsofthedisease.IndcSSc,theintervalbetweenRaynaud’sphenomenonandonsetofotherdiseasemanifestationsisbrief(weekstomonths).Softtissueswelling,puffyfingers,andintensepruritusaresignsoftheearlyinflammatory“edematous” phase. The fingers, distal limbs, and face are usuallyaffected first. Diffuse hyperpigmentation of the skin, carpal tunnelsyndrome arthralgias,muscleweakness, fatigue, anddecreased jointmobilityarecommon.Duringtheensuingweekstomonths,theinflam-matoryedematousphaseevolves into the“fibrotic”phase,with skinindurationassociatedwithhair loss, reducedproductionofskinoils,and decline in sweating capacity. Progressive flexion contractures ofthefingersensue.Thewrists,elbows,shoulders,hipgirdles,knees,andanklesbecome stiffdue to fibrosisof the supporting joint structures.WhileadvancingskininvolvementisthemostvisiblemanifestationofearlydcSSc,importantandclinicallysilentinternalorganinvolvementcommonly occurs during this stage. The initial 4 years fromdiseaseonset is the period of most rapidly evolving pulmonary and renaldamage.IforganfailuredoesnotoccurduringthisphaseofdcSSc,thesystemicprocessmaystabilize.

ComparedtodcSSc,thecourseoflcSSctendstobemoreindolent.The interval between onset of Raynaud’s phenomenon and diseasemanifestationssuchasGERD,cutaneous telangiectasia,or soft tissuecalcificationscanbeaslongasyears.Sclerodermarenalcrisis,signifi-cantILD,andtendonfrictionrubsoccurrarelyinlcSSc,whilePAH,andoverlapwithkeratoconjunctivitissicca,polyarthritis,cutaneousvascu-litis,andbiliarycirrhosiscandevelopmanyyearsafterdiseaseonset.

ORGAN INVOLVEMENT

■■ RAYNAUD’S PHENOMENONRaynaud’sphenomenon, themost frequentextracutaneouscomplica-tionofSSc,ischaracterizedbyepisodesofreversiblevasoconstrictionin the fingers and toes, sometimes also affecting the tip of the noseandearlobes.Attacks,triggeredbyadecreaseintemperature,aswellasemotionalstressandvibration,typicallystartwithpallor,followedbycyanosisofvariableduration.Hyperemiaensuesspontaneouslyorwithrewarmingofthedigit.Theprogressionofthethreecolorphasesreflectstheunderlyingvasoconstriction,ischemia,andreperfusion.Upto 5% of the general population hasRaynaud’s phenomenon. In theabsenceofsignsorsymptomsofanunderlyingcondition,Raynaud’s

phenomenon is classified as primary (Raynaud’s disease), whichrepresents an exaggerated physiologic response to cold. SecondaryRaynaud’s phenomenon occurs in SSc and other connective tissuediseases, hematologic and endocrine conditions, and occupationaldisorders,andcancomplicate treatmentwithbetablockersandanti-cancerdrugssuchascisplatinandbleomycin.DistinguishingprimaryRaynaud’sdiseasefromsecondaryRaynaud’sphenomenoncanpres-entadiagnosticchallenge.Raynaud’sdiseaseissupportedbythefol-lowing:absenceofanunderlyingcause,afamilyhistoryofRaynaud’sphenomenon, absence of digital tissue necrosis or ulceration, and anegativeANAtest.SecondaryRaynaud’sphenomenontendstooccurat an older age (>30 years), ismore severe (episodesmore frequent,prolonged,andpainful),andisassociatedwithischemicdigitalulcersandlossofdigits(Fig. 353-5).

Nailfoldcapillaroscopyusingalow-powerstereoscopicmicroscopeoropthalmoscopepermitsvisualizationofnailbedcutaneouscapillar-iesunder immersionoil (Fig. 353-6).Raynaud’sdisease is associatedwith evenly spaced parallel vascular loops, whereas in secondary

FIGURE 353-5 Digital necrosis. Sharply demarcated necrosis of the fingertip secondary to ischemia in a patient with limited cutaneous systemic sclerosis (SSc) associated with severe Raynaud’s phenomenon.

FIGURE 353-6 SSc-associated nailfold capillary alterations. Normal nailfold pattern in healthy subjects. Note regularly-arrayed and uniform-size “hairpin” microvessels; “early pattern” showing dilations of microvessels and symmetrically increased microvessels (giant capillaries) representing the first morphological sign of systemic sclerosis; “active pattern” with giant capillaries, collapse with microhemorrages and loss of capillaries; “late pattern” showing massive loss of capillaries, fibrosis (white/yellow background) and neoangogenesis with secondary dilations (nailfold videocapillaroscope VIDEOCAP; magnification 220×). (Courtesy of Professor Maurizio Cutolo, University of Genoa.)


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FIGURE 353-7 Sclerodactyly. Note skin induration on the fingers, and fixed flexion contractures of proximal interphalangeal joints, in a patient with limited cutaneous systemic sclerosis (lcSSc).

A

B

FIGURE 353-8 Cutaneous vascular changes. A. Vascular changes at the nailfold in lcSSc. B. Telangiectasia on the face.

FIGURE 353-9 Acro-osteolysis. Note dissolution of distal terminal phalanges, commonly associated with ischemia, in a patient with long-standing limited cutaneous systemic sclerosis (lcSSc) and Raynaud’s phenomenon.

Raynaud’s phenomenon, nailfold capillaries are distorted with wid-enedandirregularloops,dilatedlumen,microhemorrhages,andareasofvascular“dropout.”Thus,nailfoldcapillaroscopycanbehelpfulindifferentiatingprimaryfromsecondaryRaynaud’sphenomenonandinestablishingtheearlydiagnosisofSSc.

■■ SKIN FEATURESBilateral symmetrical skin thickening is thehallmarkofSSc thatdis-tinguishes it fromotherconnective tissuediseases.Skin involvementstartsinthefingersandcharacteristicallyadvancesfromdistaltoprox-imal extremities in an ascending fashion. Somepatients note diffusetanningintheabsenceofsunexposureasaveryearlymanifestation.Indark-skinned individuals, vitiligo-like hypopigmentationmay occur.Because pigment loss spares the perifollicular areas, the skin mayhavea“salt-and-pepper”appearance,mostprominentlyonthescalp,upperback,andchest.Dermalsclerosisobliteratinghairfollicles,sweatglands, and eccrine and sebaceous glands cause hair loss, decreasedsweating,anddryanditchyskinontheextremities.Transversecreaseson the dorsum of the fingers disappear (Fig. 353-7). Fixed flexioncontractures of the fingers cause reduced handmobility and lead tomuscleatrophy.Skinandsubjacenttendonfibrosisaccountsforfixedcontracturesofthewrists,elbows,andknees.Thickridgesattheneckduetofirmadherenceofskintotheunderlyingplatysmamuscleinter-ferewithneckextension.

In established SSc, the face assumes a characteristic “mauskopf”appearancewithtautandshinyskin,lossofwrinkles,andoccasionallyanexpressionlessfaciesduetoreducedmobilityoftheeyelids,cheeks,andmouth.Thinningofthelipswithaccentuationofthecentralincisorteethandprominentperioralradialfurrowing(rhytides)completethepicture. Reduced oral aperture (microstomia) interferes with eatingandoralhygiene.Thenoseassumesapinched,beak-likeappearance.Inlate-stagedisease,theskinbecomesthinandatrophic,andisfirmlybound to the subcutaneous fat (tethering). Dilated skin capillaries2–20mmindiameter(telangiectasiae),reminiscentofhereditaryhem-orrhagictelangiectasia,arefrequentlyseenontheface,hands,lips,andoralmucosa(Fig. 353-8).Thenumberoftelangiectasiascorrelateswiththe severity ofmicrovascular disease, including PAH. Breakdown ofatrophicskinleadstochroniculcerationsattheextensorsurfacesoftheproximal interphalangeal joints, thevolarpadsof the fingertips, andbonyprominencessuchaselbowsandmalleoli.Ulcersareoftenpain-ful, heal slowly, andbecome secondarily infected, resulting inosteo-myelitis.Healingofischemicfingertipulcerationsleavescharacteristicfixeddigital“pits.”Lossofsofttissueatthefingertipsduetoischemiamaybeassociatedwithstrikingresorptionof the terminalphalanges(acro-osteolysis)(Fig. 353-9).

Dystrophiccalcificationsintheskin,subcutaneous,andsofttissues(calcinosis cutis) in thepresenceofnormal serumcalciumandphos-phate levelsoccur inupto40%ofpatients,mostcommonly in those

with long-standing anti-centromere antibody-positive lcSSc. Calcificdeposits, composed of calcium hydroxyapatite crystals, vary in sizefromtinypunctatelesionstolargeconglomeratemassescanbereadilyvisualized on plain radiographs, or dual-energy CT. These depositsoccurwhencalciumprecipitates in tissuedamagedby inflammation,



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FIGURE 353-10 Calcinosis cutis. Note soft tissue calcific deposit breaking through the skin in a patient with limited cutaneous systemic sclerosis (lcSSc).

FIGURE 353-11 Chest CT in systemic sclerosis. Top panel: Early interstitial lung disease with subpleural reticulations and ground glass opacities in the lower lobes. Patient in supine position. Bottom panel: Extensive lung fibrosis with coarse reticular honeycombing, and traction bronchiectasis. Note dilated esophagus. (Courtesy of Rishi Agrawal, Northwestern University.)

hypoxia,or local trauma.Commonlocations includethefingerpads,palms, extensor surfaces of the forearms, and the olecranon andprepatellarbursae(Fig. 353-10).Theycancausepainandnervecom-pression,ulceratethroughtheoverlyingskinwithdrainageofchalkywhite material, and secondary infections. Paraspinal sheet calcifica-tionsmaycauseneurologiccomplications.

■■ PULMONARY FEATURESThe two principal forms of lung involvement in SSc, ILD, and pul-monary vascular disease are frequent and account for amajority ofSSc-relateddeaths. Survival is particularlypoor in SScpatientswithconcurrentpresenceofthesetwoprocesses.Lesscommonpulmonarycomplications of SSc include aspiration pneumonitis complicatingchronicgastroesophagealreflux,pulmonaryhemorrhageduetoendo-bronchial telangiectasia, obliterative bronchiolitis, pleural reactions,restrictivephysiologyduetochestwallfibrosis,spontaneouspneumot-horax,anddrug-inducedlungtoxicity.TheincidenceoflungcancerisincreasedinSSc.

Interstitial Lung Disease WhileevidenceofILDcanbefoundinupto65%ofSScpatientsbyhigh-resolutioncomputedtomography(HRCT), clinically significant ILDdevelops in16–43%; the frequencyvariesdependingonthedetectionmethodused.Riskfactors for ILDinclude male sex, African-American race, diffuse skin involvement,severe gastroesophageal reflux, and the presence of topoisomerase Iautoantibodies;incontrast,anti-centromereantibody-positivepatientshaveareducedriskofILD.Additionalriskfactorsincludelowforcedvitalcapacity(FVC)orsingle-breathdiffusingcapacityofthelungforcarbonmonoxide (DLco) at initial presentation. Esophageal dilationwithchronicacidrefluxinSSccausemicro-aspiration,ariskfactorforthedevelopmentandprogressionofILD.Themostrapidprogressionin ILD generally occurs early in the disease course (within the first3years),whentheFVCcandeclineby30%peryear.

Pulmonary involvement can remain asymptomatic until it isadvanced.Themostcommonpresentingrespiratorysymptoms—exer-tional dyspnea, fatigue, and reduced exercise tolerance—are subtleand slowly progressive.A chronic dry coughmay be present. Phys-ical examinationmay reveal fine inspiratory “Velcro” crackles at thelung bases. Pulmonary function testing (PFT) is relatively sensitivefor detecting early pulmonary involvement, and typically shows arestrictive ventilatory defect (FV<70% predicted and/or FEV1/FVCratio>0.8), reduced total lung capacity (TLC) anddiffusing capacity(DLco).AreductioninDLcothatissignificantlyoutofproportiontothe reduction in lungvolumesshould raise suspicion forpulmonaryvasculardisease,butmayalsobeduetoanemia.Oxygendesaturationwithexerciseiscommon.

Chestradiographycanbeusedasaninitialscreeningtooltoruleoutinfectionandothercausesofpulmonaryinvolvement;however,com-paredtoHRCT,itisrelativelyinsensitivefordetectionofearlyILD.Itmaydemonstrate lowerlobesubpleuralreticular linearopacitiesandground-glassopacifications,eveninasymptomaticpatientswithnor-malPFTs(Fig. 353-11).AdditionalHRCTfindingsincludemediastinallymphadenopathy, pulmonary nodules, traction bronchiectasis, and

uncommonly,honeycombchanges.TheextentofinterstitialchangesonchestHRCTisapredictorofILDprogressionandmortality.Broncho-alveolarlavage(BAL)candemonstrateinflammatorycellsinthelowerrespiratory tract, andmay be useful for ruling out tuberculosis andother infections.However,BALdoesnot appear tobeuseful forSScdiagnosisorforidentifyingreversiblealveolitis,andisusedprimarilyfor research. Lung biopsy is indicated only in patientswith atypicalfindingsonchest radiographs.Thehistologicpatternon lungbiopsymaypredicttheriskofprogressionofILD,withNSIP,carryingabetterprognosisthanUIP.

Pulmonary Arterial Hypertension PAH resulting from vas-cular remodelingof small (<500μm)pulmonaryarteriesdevelops in8–12%ofpatientswithSSc,andoccursasanisolatedabnormalityorinassociationwithILD.PAHisdefinedhemodynamicallyasameanpul-monaryarterypressure≥25mmHgwithapulmonarycapillarywedgepressure≤15mmHgandpulmonaryvascularresistance>3Woodunits.ThenaturalhistoryofSSc-associatedPAHisvariable,butoftenfollowsadownhillcoursewithonsetofrightheartfailure.The3-yearsurvivalof SSc patients with untreated PAH is <50%. Risk factors includelcSSc,highnumbersof cutaneous telangiectasia,olderageatdiseaseonset,andthepresenceofantibodiestocentromere,U1-RNP,U3-RNP(fibrillarin), and B23.Mutations in the BMPR2 gene associatedwithidiopathicPAHarenotfoundinpatientswithSSc-PAH.

Although patients with PAH are often asymptomatic in earlystages, they may present with nonspecific symptoms of exertionaldyspnea and reduced exercise capacity. With progression, angina,near-syncope, and symptoms and signs of right-sided heart failureappear.Physicalexaminationmayshowtachypnea,a loudpulmoniccomponent of the S2 heart sound, pulmonic/tricuspid regurgitationmurmur, palpable right ventricular heave, elevated jugular venouspressure,anddependentedema.Dopplerechocardiographyprovidesanoninvasivescreeningmethodforestimatingthepulmonaryarterialpressure. In lightof thepoorprognosisofuntreatedPAHandbettertherapeuticresponseinpatientswithearlydiagnosis,allSScpatientsshouldbescreenedforPAHat initialevaluation, followedbyannualevaluation.Estimatedpulmonaryarterysystolicpressure>40mmHgatrestortricuspidregurgitationjetvelocities>3m/secsuggestPAH.PFTmayshowareducedDLcoinisolationoroutofproportionwith


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underestimate pulmonary artery pressures, cardiac catheterization isthegoldstandardrequiredtoconfirmthediagnosisofsuspectedPAH,toassess itsseverity, including thedegreeof rightheartdysfunction,to rule out veno-occlusive disease and other cardiac (post-capillary)causesofpulmonaryhypertension,andtoprovideprognosticparam-eters.YearlyechocardiographicscreeningforPAHisrecommendedinmostpatients; an isolateddecline inDLcomayalsobe indicativeofdevelopingPAH.DistinguishingPAH frompulmonaryhypertensionsecondary topulmonary fibrosisandhypoxia inSSc canbedifficult.SerumlevelsofN-terminalpro-brainnatriureticpeptide(NTproBNP)correlate with the presence and severity of PAH in SSc, as well assurvival.WhileNTproBNPmeasurementscanbeusefulinscreeningforPAHandinmonitoringtheresponsetotreatment,elevatedlevelsarenotspecificforPAHandalsooccurinotherformsofrightandleftheartdisease.Despitemorefavorablehemodynamics,theprognosisofSSc-associatedPAHisworse,andtreatmentresponsepoorer,thanthatofidiopathicPAH,mostlikelyduetofrequentconcurrenceofILDandcardiaccomplicationsinthesepatients.

■■ GASTROINTESTINAL INVOLVEMENTInvolvement of the gastrointestinal tract,which can affect any level,occursinupto90%ofSScpatientswithbothlcSScanddcSScdisease(Table 353-6).Thepathologicfindingsoffibrosis,smoothmuscleatro-phy,andobliterativesmall-vesselvasculopathyaresimilarthroughoutthelengthofthegastrointestinaltract,andcontributetoreducedqual-ityoflife,malnutrition,andincreasedmortality.

Upper Gastrointestinal Tract Involvement. Decreased oralaperture interferes with regular dental hygiene. Teeth are looseneddue to loss of periodontal ligament attaching teeth to the alveolarbone.Additionaloropharyngealmanifestationsduetoacombinationofxerostomia,shortenedfrenulum,andresorptionofthemandibularcondyles are frequent and cause much distress. Most patients havesymptoms of gastroesophageal reflux disease (GERD): heartburn,regurgitation,anddysphagia.Acombinationofreducedloweresoph-ageal sphincter pressure resulting in reflux, impaired esophagealclearanceofrefluxedgastriccontentsduetodiminishedmotility,anddelayedgastricemptyingaccountsforGERD.Calciumchannelantag-onistsandphosphodiesteraseinhibitorsusedtotreatRaynaud’sphe-nomenoncanfurtheraggravatereflux.Esophagealmanometryshowsabnormalmotilityinmostpatients,evenintheabsenceofsymptoms.Extra-esophagealmanifestationsofGERDincludehoarseness,chroniccough, andmicroaspiration, which can result in infections andmay

aggravateunderlyingILD.ChestCTcharacteristicallyshowsadilatedpatulous esophaguswith intraluminal air. Endoscopymaybeneces-sary to rule out opportunistic infections with Candida, herpes virus,andCMV.Severeerosiveesophagitismaybe foundonendoscopy inpatientswithminimalsymptoms.EsophagealstricturesandBarrett’sesophagusmaycomplicatechronicGERD.BecauseBarrett’smetapla-sia is associatedwith increased risk of adenocarcinoma, SScpatientswithBarrett’srequireregularsurveillanceendoscopywithbiopsy.

Gastroparesiswith early satiety, abdominal distention, and aggra-vatedrefluxsymptomsarecommon.Bariumcontraststudiesarenei-thersensitivenorspecificforevaluationofgastricinvolvementinSSc.Gastricantralvascularectasia(GAVE)intheantrummayoccur.Thesesubepithelial lesions, reflecting the diffuse small-vessel vasculopathyofSSc,aredescribedas“watermelonstomach”duetotheirendoscopicappearance.PatientswithGAVEcanhaverecurrentepisodesofgastro-intestinalbleeding,resultinginchronicunexplainedanemia.

Lower Gastrointestinal Tract and Anorectal Involvement Weight loss andmalnutritiondue to impaired intestinalmotility,mal-absorption,andchronicdiarrheasecondarytobacterialovergrowtharecommon.FatandproteinmalabsorptionandvitaminB12andvitaminDdeficienciesensue,andmaybefurtherexacerbatedbypancreaticinsuf-ficiency.Disturbedintestinalmotorfunctioncanalsoleadtointestinalpseudo-obstruction, with symptoms that are indistinguishable fromthoseofdelayedgastricemptying.Patientspresentwithrecurrentepi-sodesofacuteabdominalpain,nausea,andvomiting,andradiographicstudiesshowacuteintestinalobstruction.Amajordiagnosticchallengeis differentiating pseudo-obstruction, which responds to supportivecare and intravenous nutritional supplementation, from mechanicalobstruction. Colonic involvement may result in severe constipation,occasionally complicated by sigmoid volvulus. Fecal incontinence,gastrointestinalbleeding fromtelangiectasia,andrectalprolapse, canoccur. In late-stageSSc,wide-mouthsacculationsordiverticulaoccurin thecolon,occasionallycausingperforationandbleeding.Anocca-sionalradiologicfindingispneumatosiscystoidesintestinalisduetoairtrappinginthebowelwallthatmayrarelyruptureandcausebenignpneumoperitoneum.Althoughtheliverisrarelyaffected,primarybil-iarycirrhosismaycoexistwithSSc.

■■ RENAL INVOLVEMENT: SCLERODERMA RENAL CRISISSclerodermarenalcrisispresentswithacceleratedhypertensionaccom-panied by acute kidney injury and progressive failure. This acutelife-threateningcomplicationofSScoccursin10–15%ofpatients,gen-erallywithin4yearsofdiseaseonset.Rarely,sclerodermarenalcrisiscanbetheinitialpresentingmanifestationofSSc.Priortotheadventofangiotensin-converting enzyme (ACE) inhibitors, short-term survivalinsclerodermarenalcrisiswas<10%.Thepathogenesisinvolvesoblit-erativevasculopathyandluminalnarrowingoftherenalarcuateandinterlobular arteries,with consequent intravascular hemolysis, alongwithevidenceofactivationofthecomplementpathways(Fig. 353-12).Progressivereduction inrenalblood flow,aggravatedbyvasospasm,leadstojuxtaglomerularreninsecretionandactivationofAngiotensinII,withfurtherrenalvasoconstrictionresultinginaviciouscyclethatculminates in accelerated hypertension. Risk factors for sclerodermarenal crisis includeAfrican-American race, male sex, and diffuse orprogressiveskininvolvement.Upto50%ofpatientswithsclerodermarenalcrisishaveanti-RNApolymeraseIIIantibodies,whereaspatientswith anti-centromere antibodies appear to be protected from thiscomplication.Palpabletendonfrictionrubs,pericardialeffusion,newunexplained anemia, and thrombocytopenia may be harbingers ofimpendingsclerodermarenalcrisis.High-riskpatientswithearlySScshouldmonitortheirbloodpressuredaily.Becauseglucocorticoiduseisassociatedwithsclerodermarenalcrisis,prednisoneinhigh-riskSScpatients should be taken onlywhen absolutely required and at lowdoses(<10mg/d).

Patients characteristically present with accelerated hypertension(generally >150/90 mmHg) and progressive oliguric renal insuffi-ciency.However,~10%ofpatientswithsclerodermarenalcrisispresent

TABLE 353-6 Prominent Gastrointestinal Manifestations of SSc and Their ManagementSITE PRINCIPAL MANIFESTATION MANAGEMENTOropharynx Diminished oral aperture

Dry mouthPeriodontitis, gingivitis swallowing

Periodontal careArtificial salivaSwallowing therapy

Esophagus RefluxDysphagiaStricturesBarret’s metaplasia

Lifestyle modificationsProkinetic drugs proton pump inhibitorsEndoscopic procedures

Stomach GastroparesisGastric antral vascular ectasia (GAVE, watermelon stomach)

Prokinetic agentsEndoscopic laser cryotherapy

Small and large intestines

Bacterial overgrowthDiarrhea/constipationPseudo-obstructionPneumatosis intestinalisMalabsorptionColonic pseudodiverticula

LaxativesProkinetic agentsRotating antibioticsOctreotideParenteral nutritional support

Anorectum Sphincter incompetence Biofeedback, sacral nerve stimulation, surgery



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a

FIGURE 353-12 Renal changes in scleroderma renal crisis. A. Renal biopsy demonstrating intimal proliferation and myxoid changes in medium-sized renal arteries (arrows). B. Fragmentation of red blood cells due to intravascular hemolysis in scleroderma renal crisis. (Courtesy of Drs. Edward Stern and Christopher Denton, Royal Free Hospital, London, UK.)

with normal blood pressure. Normotensive renal crisis is generallyassociatedwithapooroutcome.Headache,blurredvision,congestiveheart failure, and pulmonary edema may accompany elevation ofbloodpressure.Urinalysistypicallyshowsmildproteinuria,granularcasts, and microscopic hematuria; moderate thrombocytopenia andmicroangiopathic hemolysiswith fragmented red blood cells can beseen. Progressive oliguric renal failure over several days generallyfollows. Scleroderma renal crisis is occasionally misdiagnosed asthromboticthrombocytopenicpurpura(TTP)orotherformsofthrom-botic microangiopathy. In such cases, renal biopsy and measuringvWF-cleavingproteaseactivitymaybeofsomebenefit.Oliguriaoracreatinine >3mg/dL at presentation predicts poor outcome (perma-nent hemodialysis andmortality), as do biopsy findings of vascularthrombosis and glomerular ischemic collapse. Rarely, crescentic glo-merulonephritis occurs in the setting of SSc and may be associatedwithmyeloperoxidase-specific antineutrophil cytoplasmicantibodies.Membranous glomerulonephritismay occur in patients treatedwithd-penicillamine.Asymptomatic renal function impairment occurs inuptohalfofSScpatients.Suchsubclinicalrenalinvolvementisasso-ciatedwithothervascularmanifestationsofSScandrarelyprogresses.

■■ CARDIAC INVOLVEMENTAlthough it is often silent, variable cardiac involvement in SSc isdetectedin10–50%ofpatientsscreenedwithsensitivediagnostictools.Clinical cardiac involvement, more frequent in dcSSc than in lcSSc,maybeprimaryorsecondarytoPAH,ILD,orrenalinvolvement,andis associated with poor outcomes. The endocardium, myocardium,andpericardiummayeachbeaffectedseparatelyortogether.Pericar-dial involvement is manifested as pericarditis, pericardial effusions,constrictive pericarditis, and rarely, cardiac tamponade. Conductionsystemfibrosisoccurscommonlyandmaybesilentormanifestedbyheartblock.Arrythmiasincludingprematureventricularcontractions,atrial fibrillation, and supraventricular tachycardia are common.Microvascularinvolvement,recurrentvasospasm,andischemia-reper-fusion injury contribute to patchy myocardial fibrosis, resulting inasymptomaticsystolicordiastolicleftventriculardysfunctionthatmayprogresstoovertheartfailure.Acuteorsubacutemyocarditisleadingtoleftventriculardysfunctionmayoccur,anddiagnosisrequirescar-diac magnetic resonance imaging (MRI) or endomyocardial biopsy.Whileconventionalechocardiographyhaslowsensitivityfordetectingpreclinicalheart involvement inSSc,newermodalities suchas tissueDopplerechocardiography(TDE),cMRI,andnuclear imaging(singlephoton emissionCT [SPECT]) reveal a high prevalence of abnormalmyocardialfunctionorperfusion.TheserumlevelsofN-terminalpro-BNP,aventricularhormoneelevatedinSSc-PAH,mayalsohaveutilityasmarkersofprimarycardiacinvolvement.

Musculoskeletal Complications Musculoskeletal complications are verycommoninSSc.Carpaltunnelsyndromemaybeapresentingdiseasemanifesta-tion.Generalizedarthralgiaandstiffnessareprominentinearlydisease.Mobilityofbothsmallandlargejointsisprogres-sively impaired, and fixed contracturesdevelopattheproximalinterphalangealjoints and wrists. Large joint contrac-tures, seen in patients with dcSSc, arefrequentlyaccompaniedbytendonfric-tion rubscharacterizedbycoarse leath-ery crepitation heard or palpateduponpassivejointmovement,thatareduetoextensive fibrosis and adhesion of thetendonsheathsandfascialplanesattheaffected joint. Tendon friction rubs areassociatedwith increased risk for renaland cardiac complications and reducedsurvival. Synovitis detected by ultra-soundorMRIiscommon;occasionalSScpatientsdeveloperosivepolyarthritisin

thehands,andsomehaveaseropositiverheumatoidarthritisoverlap.Muscleweakness is commonandmultifactorial:deconditioning,dis-useatrophy,malnutrition,inflammation,andfibrosismayallcontrib-ute.Achronicnon-inflammatorymyopathycharacterizedbyatrophyandfibrosiswithmildlyelevatedmuscleenzymescanbeseeninlate-stageSSc.Boneresorptionintheterminalphalangescauseslossofthedistaltufts(acro-osteolysis)(Fig.353-9).Resorptionofthemandibularcondylescanleadtobitedifficulties.Osteolysiscanalsoaffecttheribsanddistalclavicles.

■■ LESS RECOGNIZED DISEASE MANIFESTATIONSDryeyesanddrymouth(siccacomplex)arecommoninSSc.Biopsyoftheminorsalivaryglandsshowsfibrosisratherthanfocallymphocyticinfiltration characteristicofprimarySjögren’s syndrome (Chap. 354).Hypothyroidism resulting from Graves’ or Hashimoto’s disease iscommon,particularlyinlcSSc,andmaybeunder-recognized.Whereasthecentralnervoussystem isgenerally spared,unilateralorbilateralsensorytrigeminalneuropathycanoccur.Erectiledysfunctionisafre-quent,andoccasionallyinitial,diseasemanifestation.Inabilitytoattainormaintainpenileerectionisduetovascularinsufficiencyandfibrosisof corporeal smooth muscle. Sexual performance is also adverselyaffected inwomen.While fertility is not impaired in SSc, pregnancyisassociatedwithhigherriskofadversefetaloutcomes.Furthermore,cardiopulmonary involvement may worsen during pregnancy, andnewonsetofsclerodermarenalcrisishasbeendescribed.

Cancer Epidemiologic studies indicate an increased cancer riskin SSc. Lung cancer and esophageal adenocarcinoma typically occurin the setting of long-standing ILDorGERDandmaybe causedbychronicinflammationandrepair.Incontrast,breast,lung,andovariancarcinomasandlymphomastendtooccurinclosetemporalassociationwiththeonsetofSSc,particularlyinpatientswhohaveautoantibodiestoRNApolymeraseIII.Inthisscenario,SScmayrepresentaparaneo-plasticsyndrometriggeredbytheanti-tumorimmuneresponse.

■■ LABORATORY EVALUATION AND BIOMARKERSMildmicrocyticanemiaisfrequentandmayindicategastrointestinalbleedingcausedbyGAVEorchronicesophagitis.Macrocyticanemiamay be caused by folate and vitamin B12 deficiency due to small-bowel bacterial overgrowth andmalabsorption or by drugs such asmethotrexate.Microangiopathichemolyticanemiacausedbymechan-ical fragmentation of red blood cells during their passage throughmicrovessels coatedwith fibrin or platelet thrombi is a hallmark ofscleroderma renal crisis. The erythrocyte sedimentation rate (ESR)is generally normal; an elevationmay signal coexistingmyositis ormalignancy.


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AntinuclearautoantibodiesaredetectedinalmostallpatientswithSSc.Anti-topoisomeraseI(Scl-70)andanti-centromereantibodiesaremutuallyexclusiveandeachishighlyspecificforSSc.TopoisomeraseIantibodiesare associated with increased risk of ILD and poor outcomes.Anti-centromereantibodiesareassociatedwithPAH,butonlyinfrequentlywith significant cardiac, pulmonary, or renal involvement.Nucleolarimmunofluorescence pattern may indicate antibodies to U3-RNP(fibrillarin),Th/To,orPM/Scl,whereasspeckledimmunofluorescenceindicatesantibodiestoRNApolymeraseIII(Fig. 353-13).

■■ DIAGNOSIS, STAGING, AND MONITORINGThe diagnosis of SSc is made primarily on clinical grounds and isgenerally straightforward in patients with established disease. Thepresence of skin induration with a characteristic symmetric distri-bution pattern associated with typical visceral organ manifestationsestablishes the diagnosiswith a high degree of certainty. In lcSSc, ahistory of Raynaud’s phenomenon and GERD symptoms, coupledwithsclerodactylyandnailfoldcapillarychanges,oftenincombinationwith cutaneous telangiectasia and calcinosis cutis, help to establishthe diagnosis. Primary Raynaud’s disease is a benign condition thatmustbedifferentiatedfromearlyorlimitedSSc.Nailfoldmicroscopyisparticularlyhelpfulinthissituation,becauseincontrasttoSSc,nail-foldcapillariesarenormal.DiagnosingSScatanearlystagemaybeachallenge.IndcSSc,initialsymptomsareoftennonspecific,Raynaud’sphenomenonmaybeabsent,andphysicalexaminationmayonlyshowupperextremityedemaandpuffyfingers.PatientswithearlySScmight

bediagnosedasarthritis,SLE,myositis,or,mostcommonly,undiffer-entiatedconnectivetissuedisease.Withinweekstomonths,Raynaud’sphenomenonandadvancingskinindurationappear.SSc-specificauto-antibodies provide a high degree of diagnostic certainty. Raynaud’sphenomenon with fingertip ulcerations or other evidence of digitalischemia, coupled with telangiectasia, distal esophageal dysmotility,unexplainedILDorPAH,oracceleratedhypertensionwithrenalfail-ure in the absence of clinically evident skin induration, suggests thediagnosisofSScsinescleroderma.

APPROACH TO THE PATIENT

Management of Systemic SclerosisOVERVIEW: GENERAL PRINCIPLESTodate,withthepossibleexceptionofhematopoieticstemcellther-apy (HSCT),no therapyhasbeenshown to significantlyalter thenaturalhistoryofSSc.Incontrast,multipleinterventionsarehighlyeffective in alleviating the symptoms, slowing the progression ofthecumulativeorgandamage,andreducingdisability.Asignificantreduction in disease-relatedmortality has been noted during thepast25years.Inlightofthemarkedheterogeneityindiseaseman-ifestations, andnaturalhistory, themanagementof SScmandatesa“personalizedmedicine”approachthatisspecificallytailoredtoeachindividualpatient’suniqueneeds.

A B

C D

E F

FIGURE 353-13 SSc-associated autoantibodies: immunofluorescence patterns. Indirect immunofluorescence on HEp-2 substrate shows distinct patterns: A. anti-centromere; B. anti-Scl-70/topoisomerase I; C. anti-PM/Scl; D. anti-Th/To; E. anti-RNA polymerase III; F. anti-fibrillarin/U3RNP antibodies. Except for anti-centromere (discrete dots in metaphase nucleus), variations of nucleolar staining are clues to autoantibody specificity. However, immunoassays employing purified autoantigens are recommended to confirm specificity of these autoantibodies. (Courtesy of Marvin Fritzler and Susan Copple, Inova Diagnostics Inc., San Diego, California.)



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The following general principles should guide management(Table 353-7):promptandaccuratediagnosis;classificationandriskstratificationbasedonclinicalandlaboratoryevaluation,includingprognostic andpredictivebiomarkers; early recognitionof organ-based complications and assessment of their extent, severity, andlikelihoodofdeterioration;regularmonitoringfordiseaseprogres-sion,newcomplications, and response to therapy; adjusting ther-apy;andpatienteducation.Inordertominimizeirreversibleorgandamage,managementshouldbeproactive,withregularscreeningand initiation of appropriate, intervention at the earliest possibleopportunity.InlightofthecomplexandmultisystemicnatureoftheSSc,ateam-orientedmanagementapproachintegratingappropriatespecialists should be pursued.Generally, a combination of drugsthatimpactdifferentaspectsofthediseaseisused.Patientsshouldbe encouraged to become familiar with potential complicationsandunderstandtherapeuticoptions,includinginterventionaltrials,andnaturalhistory,andempoweredtopartnerwiththeirtreatingphysicians.Thisrequiresalong-termrelationshipbetweenpatientandphysician,withongoingcounseling,encouragement,andtwo-waydialogue.

DISEASE-MODIFYING THERAPY: IMMUNOSUPPRESSIVE AGENTSImmuno-suppressiveagentsusedinotherautoimmunediseaseshavegenerallyshownmodestornobenefitinSSc.Glucocorticoidsalleviatestiffness and aching in early inflammatory-stage dcSSc, but do notinfluencetheprogressionofskinorinternalorganinvolvement.Sincetheiruseisassociatedwithanincreasedriskofsclerodermarenalcri-sis,glucocorticoidsshouldbegivenonlywhenabsolutelynecessary,atthelowestdosepossible,andforbriefperiodsonly.

Cyclophosphamidehasbeenextensivelystudiedinlightofitseffi-cacyinthetreatmentofvasculitis(Chap. 356),SLE(Chap. 349),andotherautoimmunediseases(Chap. 348).Bothoralandintravenouscyclophosphamide have been shown to reduce the progression ofSSc-associated ILD,withstabilizationand, rarely,modest improve-mentofpulmonaryfunction,HRCTfindings,respiratorysymptoms,andskin induration.Thebenefitsof cyclophosphamideneed tobebalancedagainst itspotential toxicity, includingbonemarrowsup-pression,opportunisticinfections,hemorrhagiccystitisandbladdercancer,prematureovarianfailure,andlatesecondarymalignancies.

Methotrexate had modest effect on SSc skin involvement insmall studies.Mycophenolatemofetilwasevaluated inbothopenlabelandrandomizedcontrol trials.Bothskin indurationandILDimproved in patients treated with MMF, and the drug was welltolerated. Tocilizumab, a monoclonal antibody directed againsttheIL-6receptorthatblocksIL-6signaling,alsoshowedbenefit inrandomizedSSc trials.Open-labelstudiesandsmall trialsprovidesupport for the use of rituximab, amonoclonal antibodydirectedagainst thematureBcellmarkerCD20,alongwithextracorporealphotopheresis and IV immunoglobulin. Randomized trials in SScevaluating the efficacy of abatacept, a fusion protein that inhibitsTcell co-stimulationand function,areon-going.Theuseofcyclo-sporine, azathioprine, plaquenil, thalidomide, and rapamycin iscurrently not well supported by the literature. Intensive immuneablation using high-dose chemotherapy, (myeloablation) alone, orcombinedwithtotalbodyirradiation,followedbyautologousstemcellreconstitutionhasbeenevaluated inpatientswith severeearly-stageSSc. In selected patients this intensive intervention was associ-atedwith durable remission and improved long-term survival in

TABLE 353-7 Key Principles in Management• Establish early and accurate diagnosis.• Detect and evaluate internal organ involvement.• Define clinical disease stage and activity.• Tailor individualized therapy to each patient’s unique needs.• Assess treatment response, and adjust therapy as needed; monitor for

disease activity, progression and new complications.

multiple small randomized clinical trials. Since this regimen hasbeen associated with significant morbidity and even treatment-related mortality, its use currently should be restricted to SScpatientswithsevere,ortreatment-refractory,disease.

Antifibrotic Therapy Because tissue fibrosisunderliesorgandam-age in SSc,drugs that interferewith the fibroticprocess representa rational therapeutic approach. In older retrospective studies,d-penicillamine was shown to stabilize skin induration, preventnew internal organ involvement, and improve survival.However,a randomized-controlled clinical trial in early active SSc foundno difference in the extent of skin involvement between patientstreatedwith standard-dose (750mg/d) or very low-dose (125mgeveryotherday)d-penicillamine.Recentclinicaltrialsshowbenefitofpirfenidoneandofnintedanibinpatientswithidiopathicpulmo-naryfibrosis,withsignificantslowingof the lossof lungfunction.Whether these anti-fibrotic drugs have comparable efficacy andtolerability in patients with SSc-associated ILD and other fibroticmanifestationsofthediseaseisunderinvestigation.

Vascular Therapy The goal of Raynaud’s therapy is to control episodes, prevent and enhance the healing of ischemic complica-tions,andslowtheprogressionofobliterativevasculopathy.Patientsshoulddresswarmly,minimizecoldexposure,andavoiddrugsthatprecipitate or exacerbate vasospastic episodes. Extended-releasedihydropyridinecalciumchannelblockerssuchasamlodipineanddiltiazemameliorateRaynaud’sphenomenon,buttheiruseisoftenlimitedbysideeffects(palpitations,dependentedema,worseninggastroesophageal reflux).WhileACE inhibitorsdonot reduce thefrequencyorseverityofepisodes,AngiotensinIIreceptorblockerssuchaslosartanareeffectiveandwelltolerated.PatientswithRay-naud’sphenomenonunresponsive to these therapiesmay requirethe addition of α1-adrenergic receptor blockers (e.g., prazosin),5-phosphodiesterase inhibitors (e.g., sildenafil), topical nitroglyc-erine, and intermittent IV infusions of prostaglandins. Low-doseaspirin and dipyridamole prevent platelet aggregation and mayhavearoleasadjunctiveagents.Inpatientswithischemicdigitaltipulcerations,theendothelin-1receptorantagonistbosentanreducestheriskofnewulcers.Digitalsympathectomyandintradigitalinjec-tions of botulinum typeA (Botox)may be considered in patientswith severeon-going ischemia.Empirical long-term therapywithstatins and antioxidants may retard the progression of vasculardamageandobliteration.Thereislimitedevidence-basedinforma-tionforthetreatmentofcardiaccomplicationsofSSc,whichshouldbe guidedby specialists experienced in their diagnosis andman-agement.Whileselectivebetablockerssuchasmetoprololcanpre-cipitatevasospasm,non-dihydropyridinecalciumchannelblockerscanbeusedforratecontrolinatrialarrhythmias,andnon-selectivealpha/beta blockers such as carvedilol for improvingmyocardialperfusionandleftventricularsystolicfunction.

TREATMENT

TREATMENT OF SSc-ASSOCIATED ILDILD is a leading causeofdeath inpatientswithSSc.However, asSSc-associated ILD is not necessarily progressive, it is importantto identify patients who are at high risk for disease progressionin the absence of treatment. The extent of ILD onHRCT and theFVCatinitialevaluation,anddeclineinPFTsduringthepreceding12-monthperiod,arehelpfulinidentifyingthesepatients.PatientsathighriskforILDshouldbemonitoredbyperformingPFTsevery6months; serialHRCT imaging is not recommended.Cyclophos-phamide,givenIVororallyfor6to12months,andmycophenolatemofetil slow thedecline in lung functionand improverespiratorysymptoms; however, cyclophosphamide is associated with morefrequent side effects.The safety and efficacyof anti-fibroticdrugsrecently approved for idiopathic pulmonary fibrosis in the treat-ment of SSc-associated ILD are currently under investigation. Incertain patients who show continued progression of ILD despite


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prolonging procedure, although significant GERD is a concern inSSc.RecurrenceofSSc-ILD in transplanted lungallograftshasnotbeenreported.

TREATMENT OF GASTROINTESTINAL COMPLICATIONSBecauseoralproblemsincludingdecreasedoralaperture,decreasedsaliva production, gum recession, periodontal disease, and teethlossarecommon,regulardentalcareisrecommended.Gastroesoph-ageal reflux is very common and may occur in the absence ofsymptoms. Patients should be instructed to elevate the head ofthe bed, eat frequent small meals, and avoid alcohol, caffeine,and known reflux exacerbants, or meals before bedtime. Protonpump inhibitors reduce acid reflux and in patientswith SScmayneed to be given in relatively high doses. Prokinetic agents suchas metoclopramide, erythromycin (a motilin agonist), and domp-eridonemayoccasionallybehelpful,butare frequentlyassociatedwithsideeffects.Botulinumtoxin injectionsometimesamelioratesimpairedgastric emptying.Anti-refluxprocedures such asNissenfundoplication can result in secondary achalasia and generallyshould be avoided. Episodic bleeding from GAVE (watermelonstomach)maybeamenable to treatmentwithendoscopicablationusing laser or argon plasma photocoagulation, although bleedingfrequentlyrecurs.Somepatientsmayrequireenteralfeedingand/or decompression via percutaneous gastrostomy or jejunostomy.Smallbowelbacterialovergrowthsecondary todysmotilitycausesabdominal bloating anddiarrhea, andmay lead tomalabsorptionand severemalnutrition. Treatmentwith short courses of rotatingbroad-spectrum antibiotics such as metronidazole, erythromycin,andrifaximincaneradicatebacterialovergrowth.Smallbowelhypo-motilitymayrespondtooctreotide;however,pseudo-obstructionisdifficulttotreat.Fecalincontinence,afrequentandunder-reportedcomplication, may respond to anti-diarrheal medication, biofeed-backtherapy,sphincteraugmentation,andsacralneuromodulation.Potentialmalnutritionshouldberoutinelyassessed.

TREATMENT OF PAHIn SSc, PAH carries an extremely poor prognosis and accountsfor 30%of deaths. Because PAH is asymptomatic until advanced,patients with SSc should be screened at initial evaluation, andregularly thereafter. Treatment is generally started with an oralendothelin-1receptorantagonistsuchasbosentanoraphosphodi-esterase5inhibitorsuchassildenafil.Recently,thesolubleguanylatecyclasestimulatorriociugat,whichactsbyincreasingtheproductionof nitric oxide, and the selective IP prostacyclin receptor agonistselexipag, were shown to improve PAH symptoms and survival.Patients may also require diuretics and digoxin. If hypoxemia isdocumented, supplemental oxygen should be prescribed in orderto avoid secondarypulmonary vasoconstriction. Prostacyclin ana-loguessuchasepoprostenolortreprostinilcanbegivenbycontin-uous IV or SC infusion, or via intermittent nebulized inhalations.Combination therapywith different classes of agents acting addi-tively or synergistically is often necessary. Lung transplantationremainsanoptionforselectedSScpatientswithPAHwhofailmed-icaltherapy,and2-yearsurvivalrates(64%)arecomparabletothoseofidiopathicILDorPAH.

MANAGEMENT OF RENAL CRISISSclerodermarenalcrisisisamedicalemergency.Sincetheoutcomeislargelydeterminedbytheextentofrenaldamageatthetimethataggressive therapy is initiated, prompt recognition of impendingorearlysclerodermarenalcrisis isessential,andeffortsshouldbemadetoavoiditsoccurrence.High-riskSScpatientswithearlydis-ease, extensive and progressive skin involvement, tendon frictionrubs,andanti-RNApolymeraseIIIantibodiesshouldbeinstructedtomonitortheirbloodpressuredailyandreportsignificantaltera-tionsimmediately.Potentiallynephrotoxicdrugsshouldbeavoided,andglucocorticoidsshouldbeusedonlywhenabsolutelynecessaryandatlowdoses.Patientspresentingwithsclerodermarenalcrisisshould be immediately hospitalized. Once other causes of renal

disease are excluded, treatment should be started promptly withtitrationofshort-actingACEinhibitors,with thegoalofachievingrapid normalization of the blood pressure. In patients with per-sistent hypertension, addition of angiotensin II receptor blockers,calciumchannelblockers,endothelin-1receptorblockers,prostacy-clins,anddirectrenininhibitorsshouldbeconsidered.Uptotwo-thirdsofpatientswithsclerodermarenalcrisiswillrequiredialysis.Substantialrenalrecoverycanoccur,anddialysiscanbediscontin-uedin30–50%ofthepatients.Kidneytransplantationisappropriateforpatientsunabletodiscontinuedialysisafter2years.SurvivaloftransplantedSScpatientsiscomparabletothatofotherdiseases,andrecurrenceofrenalcrisisisrare.

SKIN CAREBecause skin involvement in SSc is never life-threatening and itstabilizes and may even regress spontaneously, disease manage-ment should not be dictated by its cutaneousmanifestations. Theinflammatorysymptomsofearlyskininvolvementcanbecontrolledwithantihistaminesandshort-termuseoflow-doseglucocorticoids(<5 mg/d of prednisone). Cyclophosphamide and methotrexatehavemodesteffectsonskininduration.Becausetheskinisdry,theuseofhydrophilicointmentsandbathoilsisencouraged,andregu-larskinmassageishelpful.Telangiectasia,whichpresentsacosmeticproblem,especiallyontheface,canbetreatedwithpulseddyelaser.Ischemicdigitalulcerationsshouldbeprotectedbyocclusivedress-ing topromotehealingandprevent infection. Infected skinulcersaretreatedwithtopicalantibioticsandsurgicaldebridement.Whilenotherapyhasbeenshowntobeeffectiveinpreventingsofttissuecalcificdepositsorpromotingtheirdissolution,reportssupporttheuse of diltiazem,minocycline, bisphosphonates, and topical or IVsodium thiosulfate (STS).Other therapies thathavebeenused forcalcinosis includecarbondioxide laser, extracorporeal shock-wavelithotripsy,andsurgicalhigh-speedmicrodrilling.

TREATMENT OF MUSCULOSKELETAL COMPLICATIONSArthralgia and joint stiffness are very common and distressingmanifestationsinearly-stagedisease.Shortcoursesofnonsteroidalanti-inflammatory agents,methotrexate, and cautious use of low-doseglucocorticoidsalleviatesymptoms.Physicalandoccupationaltherapycanbeeffectiveforpreventinglossofmusculoskeletalfunc-tionandjointcontractures,andshouldbeinitiatedearly.

COURSEThenatural history of SSc is highly variable anddifficult to predict,especially in early stages of the disease. Patientswith dcSSc tend tohave a more rapidly progressive course and worse prognosis thanthose with lcSSc. Inflammatory symptoms of early dcSSc, such asfatigue, edema, joint pain and pruritus subside, and skin thickeningreachaplateauat2–4yearsafterdiseaseonset. It isduringtheearlyedematous/inflammatory stage that life-threatening visceral organinvolvementmaydevelop.Whileexistingvisceralorganinvolvement,such as ILD,may progress even after skin involvement peaks, neworgan involvement is rare. Scleroderma renal crisis generally occurswithinthefirst4yearsofdisease.Inlate-stagedisease(>6years),theskin is usually soft and atrophic. Skin regression characteristicallyoccursinanorderthatisthereverseofinitialinvolvement,withsoft-eningonthetrunksfollowedbyproximalandfinallydistalextremities;however,sclerodactylyandfixedfingercontracturesgenerallypersist.Relapseorrecurrenceofskin thickeningafterpeakskin involvementhas been reached is uncommon.Patientswith lcSSc follow a clinicalcourse that ismarkedlydifferent than thatofdcSSc.Raynaud’sphe-nomenon typicallyprecedesotherdiseasemanifestationsbyyearsoreven decades. Visceral organ complications such as PAH generallydeveloplateandprogressslowly.

PROGNOSISSScconfersasubstantialincreaseintheriskofprematuredeath.Age-and gender-adjusted mortality rates are fivefold to eightfold highercomparedtothegeneralpopulation,andmorethanhalfofallpatients



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2560 withSScdiefromtheirdisease.Inonepopulation-basedstudyofSSc,themediansurvivalwas11years.InpatientswithdcSSc,5-and10-yearsurvivalratesare70%and55%,respectively,whereasinpatientswithlcSSc,5-and10-yearsurvivalratesare90%and75%,respectively.Theprognosiscorrelateswiththeextentofskininvolvement,whichitselfisasurrogateforvisceralorganinvolvement.MajorcausesofdeatharePAH, pulmonary fibrosis, gastrointestinal involvement, and cardiacdisease.Sclerodermarenalcrisisisassociatedwitha30%3-yearmor-tality.Lungcancerandexcesscardiovasculardeathsalsocontributetoincreasedmortality.Markers of poorprognosis includemale gender,African-American race, older age at disease onset, extensive skinthickening with truncal involvement, palpable tendon friction rubs,andevidenceofsignificantorprogressivevisceralorganinvolvement.Laboratory predictors of increased mortality at initial evaluationincludeanelevatedESR,anemia,proteinuria,andanti–topoisomeraseIantibodies.Inonestudy,SScpatientswithextensiveskininvolvement,vitalcapacity<55%predicted,significantgastrointestinalinvolvement(pseudo-obstruction or malabsorption), clinical evidence of cardiacinvolvement,orsclerodermarenalcrisishada9-yearsurvivalof<40%.The severityofPAHpredictsmortality, andpatientswithmeanpul-monary arterial pressure ≥45mmHghad a 33%3-year survival. Theadvent ofACE inhibitors in scleroderma renal crisis had a dramaticimpact on survival, increasing from <10% at 1 year in the pre–ACEinhibitor era to >70% 3-year survival at the present time.Moreover,10-year survival in SSc has improved from <60% in the 1970s to>66–78% in the1990s,a trend that reflectsbothearlierdetectionandbettermanagementofcomplications.

LOCALIZED SCLERODERMAThe term scleroderma describes a group of localized skin disorders(Table353-1).Theseoccurmorecommonlyinchildrenthaninadults,and in marked contrast to SSc, are generally not complicated byRaynaud’s phenomenon or significant internal organ involvement.Morpheapresentsassolitaryormultiplecircularpatchesofthickskinor,rarely,aswidespreadinduration(generalizedorpanscleroticmor-phea);thefingersaregenerallyspared.Linearsclerodermamayaffectsubcutaneous tissues, leading to fibrosis and atrophy of supportingstructures,tendons,muscle,andevenbone.Inchildren,thegrowthofaffectedlongbonescanberetarded.Whenlinearsclerodermacrosseslargejoints,significantcontracturescandevelop.

MIXED CONNECTIVE TISSUE DISEASEPatientswhohavelcSSccoexistingwithfeaturesofSLE,polymyositis,and rheumatoid arthritis may have mixed connective tissue disease(MCTD). This overlap syndrome is generally associated with thepresenceofhightitersofautoantibodiestoU1-RNP.Thecharacteristicinitial presentation is Raynaud’s phenomenon associatedwith puffyfingers and myalgia. Over time, sclerodactyly, soft tissue calcinosis,andcutaneoustelangiectasiamayappear.SkinrashsuggestiveofSLE(malarerythema,photosensitivity)ordermatomyositis(heliotroperashon the eyelids, erythematous rash on knuckles) occur. Arthralgia iscommon,andsomepatientsdeveloperosivepolyarthritis.PulmonaryfibrosisandisolatedorsecondaryPAHmaydevelop.Othermanifesta-tionsincludeesophagealdysmotility,pericarditis,Sjögren’ssyndrome,and renal disease, especiallymembranous glomerulonephritis. Labo-ratoryevaluationshowselevatedESRandhypergammaglobulinemia.While anti-U1RNPantibodies aredetected inhigh titers, SSc-specificautoantibodiesareabsent.IncontrasttoSSc,MCTDoftenrespondstoglucocorticoids,andthelong-termprognosisisbetterthanthatofSSc.WhetherMCTDis trulyadistinctentityor isasubsetofSLEorSSc,remainscontroversial.

■■ EOSINOPHILIC FASCIITIS (DIFFUSE FASCIITIS WITH EOSINOPHILIA)Eosinophilicfasciitis isarare idiopathicdisorderofadultsassociatedwithabruptskininduration.Theskincharacteristicallyshowsacoarsecobblestone“peaud’orange”appearance.IncontrasttoSSc,Raynaud’sphenomenon and SSc-associated internal organ involvement andautoantibodies are absent. Furthermore, skin involvement spares the

fingers.Full-thicknessbiopsyofthelesionalskinrevealsfibrosisofthesubcutaneousfascia,withvariableinflammationandeosinophil infil-tration.Intheacutephaseoftheillness,peripheralbloodeosinophiliamaybeprominent.MRIappearstobeasensitivetoolforthediagnosisofeosinophilic fasciitis.Eosinophilic fasciitis canoccur inassociationwith, or preceding, various myelodysplastic syndromes or multiplemyeloma.Althoughglucocorticoidscausepromptresolutionofeosin-ophilia,theskinshowsslowandvariableimprovement.Theprognosisofpatientswitheosinophilicfasciitiswhodonotdevelophematologi-calcomplicationsisgenerallygood.

■■ FURTHER READINGAllanore Y et al: Systemic sclerosis. Nat Rev Dis Primers 1:15002,2015.

Herzog EL et al: Interstitial lung disease associated with systemicsclerosisandidiopathicpulmonaryfibrosis:Howsimilarordistinct?ArthritisRheum66:1967,2014.

JosephCGetal:Associationof theautoimmunediseasesclerodermawithanimmunologicresponsetocancer.Science343:152,2014.

MartyanovV,WhitfieldML:Molecularstratificationandprecisionmedicine in systemic sclerosis from genomic and proteomic data.CurrOpinRheumatol28:83,2016.

Tashkin DP et al: Mycophenolate mofetil versus oral cyclophos-phamide in scleroderma-related interstitial lung disease (SLS II):Arandomised controlled, double-blind, parallel group trial. LancetRespirMed4:708,2016.

354 Sjögren’s SyndromeHaralampos M. Moutsopoulos

■■ DEFINITION, INCIDENCE, AND PREVALENCESjögren’ssyndromeisachronic,slowlyprogressingautoimmunedis-ease characterizedby lymphocytic infiltration of the exocrine glandsresulting inxerostomiaanddryeyes (keratoconjunctivitis sicca).Thesyndrome has unique features since it presents with a wide clinicalspectrumfromorgan-specificautoimmuneexocrinopathytosystemicdisease.Asmallbutsignificantnumberofpatientsdevelopmalignantlymphoma.Thediseasecanpresentasanentityaloneorinassociationwithotherautoimmunediseases(Table 354-1).Finally,thehistopatho-logiclesioninthelabialminorsalivaryglandsiseasilyaccessibleaid-ingthediagnosis,prognosisanddiseasepathogenesis.

Middle-aged women (female-to-male ratio, 9:1) are primarilyaffected,althoughSjögren’ssyndromemayoccuratanyage,includingchildhood.TheprevalenceofprimarySjögren’ssyndromeis~0.5–1%,while5–20%ofpatientswithotherautoimmunediseasessuffer fromSjögren’ssyndrome(secondary).

■■ PATHOGENESISSjögren’ssyndromeischaracterizedbybothlymphocyticinfiltrationoftheexocrineglandsandBlymphocytehyperreactivity.Anoligomono-clonal B cell process, which is characterized by cryoprecipitable

TABLE 354-1 Association of Sjögren’s Syndrome with Other Autoimmune DiseasesRheumatoid arthritisSystemic lupus erythematosusSclerodermaMixed connective tissue diseasePrimary biliary cirrhosisAutoimmune thyroid diseaseChronic active hepatitis




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