scleroderma overlap syndromes

C

86-1

86 Overlap SyndromesROBERT BENNETT 1

4.Dermatomyositis(DM)5.Rheumatoidarthritis(RA)6.Sjögren’ssyndromeAllsixclassicAICTDsaredescriptivesyndromeswithout

a “gold standard” for diagnosis. The diagnosis of a well-differentiated AICTD is usually readily apparent withoutrecoursetoextensiveinvestigations.However,intheearlystages,thereareoftencommonfeaturessuchasRaynaud’sphenomenon,arthralgias,myalgias,esophagealdysfunction,and positive tests for antinuclear antibodies (ANA). Insuch cases the diagnosis is not always so obvious; this isoften referred to as undifferentiated connective tissuedisease(UCTD).1About35%ofsuchpatientshaveclinicaloverlapsyndromes,whereasmostdifferentiateintoaclini-calpictureconsistentwiththetraditionaldescriptionofanAICTD. In some instances one AICTD evolves intoanotherAICTDovertime.

ThepropensityfordifferentiationintoaclassicAICTDorthemaintenanceofanoverlapstate isoftenassociatedwithdistinctiveserologicprofilesandmajorhistocompati-bility (MHC) linkages. Although most rheumatologistsgenerally feel more comfortable thinking in terms of theclassic AICTD paradigms, a case can be advanced forusing serologic profiles and HLA typing to better under-standtheclinical featuresandprognoses.Inthisrespectacarefulanalysisoftheoverlapsyndromesandtheirserologicassociations has provided insights for understanding theclinical heterogeneity of the AICTDs.2 Researchers havereported numerous clinical correlations of autoantibodies(Table86-1).

EpidEmiology

ThereportedprevalenceofAICTDsisvariable,dependingonmethodology,natureofreferralbias,andethnicity.3ItisgenerallyacceptedthatSjögren’ssyndromehasthehighestprevalence (0.5 to 3.6%), with SLE being much lower atabout15to50per100,000.Scleroderma,polymyositis,anddermatomyositis are relatively rare AICTDs, occurring infewerthan10per100,000.Expertsareincreasinglyrealizingthat overlap syndromes of scleroderma and myositis aremorecommonthanthe“pure”formsofthedisease.4Thereare no epidemiology studies of overlap syndromes, apartfrom Japan,where the reportedprevalenceofmixedcon-nective tissue disease (MCTD) was 2.7 per 100,000. Thesyndrome of MCTD usually occurs as an isolated finding,buttherearereportsofafamilialoccurrence.UnlikeSLE,precipitation by sun exposure has not been described inpatientswithMCTD.Likewise,drugexposurehasnotbeenrelatedtotheonsetofMCTD,althoughatransientappear-anceofanti-RNPantibodieshasbeenseenattheinitiation

Key Points

Diffuse connective tissue diseases (DCTDs) are usually associated with autoimmunity to spliceosomal components (U-RNPs, heterogeneous RNPs), nucleosomal components (nucleosomes, DNA, histones), and proteosomal components (HC9, LMP2).

Apoptotic modification of molecules often renders them more antigenic.

The evolution of symptoms may be associated with molecular mimicry and epitope spreading.

In their early stages most autoimmune connective tissue diseases are not clinically well differentiated; this stage of disease progression is called undifferentiated connective tissue disease (UCTD).

About 50% of UCTDs remain undifferentiated.

Important clues about the eventual direction of differentiation can be obtained from nail-fold capillary microscopy and the type of autoantibody profile combined with regular clinical evaluations.

Mixed connective tissue disease (MCTD) is the prototypical overlap disease with features of lupus, scleroderma, and inflammatory myositis. This overlap is not seen at the outset of MCTD; rather it often takes several years to develop.

The most common presentation of MCTD is Raynaud’s phenomenon.

MCTD is most commonly associated with antibodies to U1-RNP; in general this antibody predicts lack of severe renal and central nervous system (CNS) involvement.

The major cause of death in MCTD is pulmonary hypertension, and all MCTD patients should have regular echocardiograms to determine its evolution.

The management of overlap syndromes is based on the usual treatment of the constituent features of its clinical components (i.e., systemic lupus erythematosus [SLE], scleroderma, and inflammatory muscle disease).

Theclusteringofsymptomsandsignsintoreadilyrecogniz-ablegroupingshasanimportanthistoricprecedenceintheclassification of disease. With the progress of knowledge,suchgroupingsmaybecomemorepreciselydefinedintermsof distinctive pathology, specific laboratory findings, andgeneticassociations.According tocurrentnosology, therearesixautoimmuneconnectivetissuediseases(AICTDs):

1. Systemiclupuserythematosus(SLE)2.Scleroderma(Scl)3.Polymyositis(PM)

Firestein_Chapter 86_main.indd 1 5/2/2012 5:27:20 PM

To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s), editor(s), reviewer(s), Elsevier and typesetter Toppan Best-set. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication.

C

86-2 part 12 | Scleroderma, Inflammatory myopathIeS, and overlap SyndromeS

Table 86-1 correlations of autoantibodies with clinical features

Autoantigen Clinical Associations

rheumatoid factor ra, erosive arthritis, cryoglobulinemiacyclic citrullinated peptide ranucleosome Sle, Scl, mctdproteasome Sle, pm/dm, Sjögren’s syndrome, multiple sclerosisSm snrnp Slehistones h1, h2a, h2B, h3, h4 Sle, Uctd, ra, pBc, generalized morphearibosomal p Sle psychosisdsdna Sle, glomerulonephritis, vasculitisacl/β2-glycoprotein Sle, thrombosis, thrombocytopenia, miscarriagesβ2-glycoprotein–independent acl mctd (not associated with apl syndrome)68 kd peptide of U1-rnp mctd, raynaud’s, pulmonary hypertensionU1 snrnp mctd, Sle, pmhnrnp-a2 (also called ra-33) mctd, ra, erosive arthritis in Sle and Sclro/la Sjögren’s, Scle, congenital heart block, photosensitivity, pöcfodrin Sjögren’s, glaucoma, moyamoya diseaseplatelet-derived growth factor diffuse and limited Scltopoisomerase 1 (Scl-70) diffuse Scl with prominent organ involvementcentromere limited Scl, creSt, raynaud’s, pulmonary hypertension, pBcth/to limited SclU3-snrnp limited Sclhnrnp-I Scl (early diffuse and limited)rna polymerases I and III Scl (diffuse with renovascular hypertension)fibrillarin Severe generalized SclKu myositis overlap, primary pulmonary hypertension Grave’s diseaseU5-snrnp myositis overlappm/Scl myositis overlap with arthritis, skin lesions, mechanic’s handsSignal recognition particle myositis overlap (severe course with cardiac disease)antisynthetases (Jo-1, pl-7, pl-12) myositis overlap with arthritis and interstitial lung diseasemi-2 dermatomyositisproteinase-3 Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), pulmonary capillaritismyeloperoxidase churg-Straus, pauci-immune glomerulonephritisendothelial cell pulmonary hypertension, severe digital gangreneα-enolase Behçet’s, ra, mctd, Scl, takayasu’sangiotensin-converting enzyme 2 aIctds with vasculopathy

ACL, anticardiolipin; AICTDs, autoimmune connective tissue diseases; APL, antiphospholipid syndrome; CREST, syndrome of calcinosis, Raynaud’s phenom-enon, esophageal dysmotility, sclerodactyly, and telangiectasia; DM, dermatomyositis; hn, heterogeneous nuclear; MCTD, mixed connective tissue disease; PBC, primary biliary cirrhosis; PM, polymyositis; RA, rheumatoid arthritis; RNP, ribonucleo-protein particle; Scl, scleroderma; SLE, systemic lupus erythematosus; sn, small nuclear; UCTD, undifferentiated connective tissue disease.

ofprocainamidetherapy.5VinylchlorideandsilicaaretheonlyenvironmentalagentsthathavebeenassociatedwithMCTDsofar.

AuToimmuniTy in ovErlAp SyndromES

Compellingevidenceindicatesthatautoimmunityisoftenantigen driven by components of subcellular particles, inparticularspliceosomes,nucleosomes,andproteasomes.6

Autoimmunity to Spliceosomal Components

CertaincomponentsofthespliceosomearecommontargetsofautoimmunityintheAICTDs.7Furthermore,itappearsthatpost-translationalmodificationsofthesemolecules,asoccursduringapoptosis,areoftenassociatedwithincreasedimmunogenicity.8Spliceosomesarecomplexnuclearparti-cles made up of some 300 distinct proteins and 5 RNAs,whichareinvolvedintheprocessingofpremessengerRNA(pre-mRNA)intomature“splicedRNA.”9Twomajorspli-ceosomal subunits are antigenic targets in autoimmunity:(1) small nuclear ribonucleoprotein protein particles(snRNPs) and (2) heterogeneous nuclear RNP particles(hnRNPs).

ThesnRNPscontainsmallRNAspeciesranginginsizefrom 80 to 350 nucleotides that are complexed with pro-teins.6TheseRNAscontainahighcontentofuridineandare therefore called U-RNAs; 5 different U-RNAs weredefinedonthebasisofimmunoprecipitation(U1,U2,U4,U5,andU6).Autoantibodiestothesecomplexesaremainlydirected to the protein components. Anti-Sm antibodiesprecipitatefiveproteinswithmolecularweightsof28,000(B′B),16,000(D),13,000(E),12,000(F),and11,000(G);fiveofthesepolypeptidesarecommontotheU1,U2,U4,U5,andU6RNAs.Anti-RNPantibodiesprecipitatethreeproteins with molecular weights of 68,000 (70K), 33,000(A′),and22,000(C);thesepolypeptidesareuniquelyasso-ciatedwithU1RNA(Figure86-1).TheclinicalcorrelatesconsideredtobedistinctiveofMCTDareassociatedwiththe 70kD specificity with an immunodominant epitopeembracing amino acid residue 125 flanked by importantconformational residues at positions 119-126 (see Figure86-1).Ontheotherhand,SLEisassociatedwithanti-Smantibodies.

ThehnRNPsareamongthemostabundantproteinsintheeukaryoticcellnucleus.Theycontainpre-mRNAasso-ciatedwith30smallproteinsthatareallstructurallyrelatedandhavemolecularweightsof33to43kD.NinehnRNPcoreproteinshavebeendesignatedA1,A2,B1a,B1b,B1c,B2,C1,C2,andC3.Anantibodytermedanti-RA33,which



C

86-3chapter 86 | overlap SyndromeS

apoptoticallyreleasedconstituents.12Nucleosomalantibod-ies are directed to antigenic determinants on the intactnucleosome rather than its individual components, DNAandhistones. In a studyof496patientswith13differentAICTDand100patientswithhepatitisC,antinucleosomeantibodies were found in the sera of patients with SLE(71.7%),Scl(45.9%),andMCTD(45.0%).13

Autoimmunity to proteosomal Components

The26Sproteasomeisalargesubcellularparticleinvolvedinthedegradationofproteinsthathavebeentaggedwithubiquitin,resultinginthegenerationofpeptidesforpresen-tationbytheMHCclassImolecules(Figure86-3).Thereis good evidence that it is the target of an autoimmuneresponse in AICTD. Antibodies to proteasomal subunitshavebeenreportedinpatientswithautoimmunemyositis,systemic lupus erythematosus, and primary Sjögren’s syn-drome.Circulating20Sproteasomes(c20S)subunitsappeartohaveanassociationwithdiseaseactivityinMCTDandSLE.14

generation of Autoimmunity

Theantibodyresponsetojustonecomponentofanintra-cellular structure such as a spliceosome will result in theuptake of the entire particle by antigen processing cells 2

targets the 33kD hnRNP-A2, is particularly interestingbecauseitisfoundinaboutone-thirdofserafrompatientwithRA,SLE,andMCTD.10ItalsohasassociationswithpatientsubsetsoferosivearthritisinSLE,scleroderma,andMCTD and predicts the eventual development of RA inpatientswithearlypolyarthritis.11Importantly,thisassocia-tionwithanti-RA33isnotseeninscleroderma(sineero-sions),PM,oroverlapsofPM/SclorPM/DM.TheantigenicepitopesofhnRNP-A2containtwoRNAbindingregionsattheN-terminalendandaglycine-richC-terminalregion.Certain disease subsets target these two RNA bindingregionsdifferently.Forinstance,RAandSLEserapreferen-tiallyreactwiththecompletesecondRNAbindingdomain,whereasMCTDseratargetanepitopethatspansbothRNAbindingdomains.

Autoimmunity to nucleosomal Components

Nucleosomesarethecompactbuildingblocksofchromatinandconsistofanoctamerof twocopiesofhistonesH2A,H2B,H3,andH4,aroundwrappedapproximately146basepairs ofDNA(Figure86-2).During apoptosis endonucle-ases cleave chromatin with the liberation of nucleosomalparticles.Followingthereleaseintothecytoplasm,nucleo-somes migrate to the surface of the dying cell12 and thusbecomeaccessibletoBcellreceptors.Thedevelopmentofautoimmunityhasbeenlinkedtodefectivephagocytosisof

Figure 86-1 the spliceosome is made up of five small nuclear rnas (snrnas) complexed with proteins to form a small nuclear ribonucleoprotein particle (snrnp). this subcellular structure is responsible for splicing introns from pre-mrna to form mrna via a 59-splice recognition site. antibodies to various spliceosomal constituents are a common feature of autoimmune rheumatic disorders with a tendency to associate with different clinical profiles (see table 86-1). the U1 small nuclear rnp (U1-snrnp) particle of the spliceosome is composed of U1-rna, rnp proteins (70 kd, a, and c), and common Sm proteins (B′B, d, e, f, and G). the structure of U1-rna consists of single-stranded rna and double-stranded rna called stem-loops I, II, III, and Iv. an electron density map of the functional core of U1-snrnp at 5.5 a resolution (see a) has enabled the spatial visualization of the rna and placement of the seven Sm proteins, U1-c, and U1-70K into the map. a striking feature is the amino (n)-terminal polypeptide of U1-70K, which extends over a distance of 180 a from its rna binding domain, wraps around the core domain consisting of the seven Sm proteins, and finally contacts U1-c, which is crucial for 59-splice-site recognition. (Modified from Newman J: Structural studies of the spliceosome, curr opin Struct Biol 20:82–89, 201;0 and Pomeranz AD: Crystal structure of human spliceosomal U1 snRNP at 5.5 A resolution, nature 458:457–480, 2009.)

7

SL4

SL3

Sm site

H

SL2KL

SL2

SL3

5¢ end

U1-C

U1-70K

SL4U1-A

SL2

SL1



C


disorders ischaracterizedbydifferentialdegreesofepitopespreading.Thewidestrangeofantibodies,tobothsnRNPandhnRNP,isseeninSLE;amorerestrictedantispliceoso-mal antibody repertoire to snRNP and hnRNP is seen inMCTD;andinRAtheantispliceosomalantibodyrepertoireisrestrictedtohnRNP.22Ingeneraltheautoimmunerheu-maticdiseasesarecharacterizedbytheproductionofauto-antibodies that recognize evolutionarily conservedmolecules.Themechanismwherebythese“hidden” intra-cellularmoleculesbecomeautoantigensisanareaofongoingresearch. The two main theories are apoptotic modifica-tion23andmolecularmimicry.24

Proteinsmodifiedduringapoptosiscanbepresented tothe immune system in ways that bypass tolerance to self-proteins.6Althoughrheumaticdiseaseautoantigensarenotunified by common structure or function, they have thecommonfeatureofbecomingclusteredandconcentratedinthesurfaceblebsofapoptoticcells.Apopulationofsmallerblebscontainsfragmentedendoplasmicreticulumandribo-somes, as well as the ribonucleoprotein Ro. Larger blebs(apoptoticbodies)containnucleosomalDNA,Ro,La,andthesmallnuclearribonucleoproteins.25Duringtheprocessof apoptosis several enzyme systems are upregulated withresulting post-translational modifications of the cleavedproteins.Thesemodifications,whichincludecitrullination,phosphorylation, dephosphorylation, transglutamination,and conjugation to ubiquitin, render the molecules moreantigenic.For instance, theU1-70Kprotein iscleavedbythe enzyme caspase-3, converting it into a C-terminallytruncatedfragment,whichcontainsamajorBcellepitopethatispreferentiallyrecognizedbyautoimmunesera.26

(APCs).Thusalltheproteinsmakinguptheparticlewillbesubjecttoantigenprocessingwithpotentialpeptidepre-sentationlinkedtotheiraffinitytoclassIIHLAantigens.DependingonthepolymorphismsoftheindividualsHLAmolecules, there will be a diversification of the antibodyresponse to include some of these other antigens. Thisprocess iscalledepitope spreadingandisconsideredpivotalin thedevelopmentof the linkedantibody responses thatareobservedindifferentCTDs.15Forinstance,ithasbeenshown that the induction of an immune response to onecomponentofaU-RNPcomplexcan induceadiversifiedautoantibody response to other components of thecomplex.16Inthiswayanimmuneresponsebecomesmodi-fied over time, and this change has been associated withchangesintheclinicalpicture.

The interaction between T cell receptors and peptidespresentedbyHLAmoleculesisacriticaleventinthegen-erationofautoimmunity.The70kDanti-U1RNPantibodyresponsesareassociatedwiththeHLADR4andDR2phe-notype.17 In a transgenic murine model of MCTD, themajority of T cells targeted a limited number of epitopesresiding within the RNA binding domain of the 70kDantigen.18DNAsequencingofHLA-DBgeneshasrevealedthatDR2-andDR4-positivepatients shareacommonsetofaminoacidsinthebetachainatpositions26,28,30,31,32,70,and73thatformapocketforantigenbinding.ItishypothesizedthatthesetwoHLAsubtypesrepresentacriti-calgeneticspecificityforthepresentationofantigenicpep-tidestotheircognateTcellreceptors.ThesharedepitopeonHLA-DR4/DR2thatisassociatedwithananti-U1-RNPresponseisdifferentfromthesharedepitopeassociatedwithHLA-DR4/DR1 inRApatients.19The70kDpolypeptidehasseveraldifferentepitopes,themostconsistentsequencebeingKDKDRDRKRRSSRSR.20Thisregionispreferen-tially targeted by MCTD sera but not by SLE sera.21 Theautoimmune response to the spliceosome in these three

Figure 86-2 the nucleosome is the fundamental repeating unit of chro-matin. the central part of the nucleosome is composed of a tetramer composed of two molecules of histones h3 and h4, flanked by two dimers of histones h2a and h2B. this central core is surrounded by two super-helical turns, consisting of 146 base pairs of histone-free dna. histone h1 is located at the point where dna enters and exits the nucleo-some. antibodies to the nucleosome arise early in the evolution of sys-temic lupus erythematosus—before anti-dna and antihistone antibodies. thus the nucleosome is thought to be an important early autoantigen in the development of epitope spreading. nucleosome anti-bodies are also found in scleroderma and mixed connective tissue disease. (From Amoura Z, Koutouzov S, Piette C, et al: The role of nucleo-somes in lupus, curr opin rheumatol 12:369–373, 2000.)

H1

H3 H2A H2B

NH2

NH2

NH2

NH2

Figure 86-3 most proteins in the cytosol and nucleus are degraded via the proteasome-ubiquitin pathway. the 26S proteasome is a huge complex of 2.5 mega-daltons, made up of approximately 35 different subunits. It contains a proteolytic core complex, the 20S proteasome, and one or two 19S regulatory complexes that associate with the termini of the barrel-shaped 20S core. the function of proteasomes is twofold: (1) to degrade intracellular proteins that have been tagged with ubiqui-tin and (2) to generate antigenic peptides for presentation by the major histocompatibility complex class I molecules. antibodies to proteasomal subunits have been reported in several autoimmune diseases (especially systemic lupus erythematosus and polymyositis/dermatomyositis), and elevated levels of proteasomes have been correlated with disease activity.

Core particle

Regulatory particle

Regulatory particle

Ubiquitin

195 cap

205 core

195 cap

265 proteasome



C


PM/DM—0.5%).31 Certain combinations of features arepredictive for the development of an established CTD:PolyarthritisplusU1RNPantibodiespredictMCTD,siccasymptoms plus anti-SSA/SSB antibodies predict Sjögren’ssyndrome,Raynaud’s phenomenonplus anucleolarANApatternpredictScl,polyarthritisplushighlevelsofrheuma-toidfactor(RF)predictRA,andfever/serositisplusahomo-geneous ANA pattern or anti-dsDNA antibodies predictprogressionintoSLE(Table86-2).Theidentificationofapathologic nail-fold capillary pattern can provide someearly indication that theUCTDmayprogress to systemicsclerosis (SSc) or MCTD (Figure 86-5).32 Low levels ofvitaminDarealsoreportedtobeariskfactorforthedevel-opmentofUCTDsandshouldbeevaluatedandcorrectedinallsuchpatients.33

SClErodErmA ovErlApS

Theinitialstimulusforafirstantibodyresponsemaybeanon–self-proteinpossessingapeptideregionthatmimicsaself-epitope—so-called molecular mimicry. Environmentalstressors such as infection, toxins, drugs, and ultravioletlight may, under some circumstances, induce acceleratedapoptosis.Acriticallimitationtomolecularmimicryisthenecessity for theantigenicsequencetoundergoTCRrec-ognition.HelperT lymphocytes (CD4+)usually recognizepeptides of 12 to 16 amino acids in the context of HLAclassIImolecules.However,insomeinstancessmallerpep-tidesmayberecognized.Theycanbemoreimmunostimula-torythantheparentligand.ThusantigenrecognitionbyTcells is highly degenerate and expands the potential formolecular mimicry. The universe of molecules containinga pentapeptide, for example, is much greater than for12 amino residue peptide. Once an immune response toone component of an immunogenic molecular complexhas been elicited, other proteins/epitopes of the complexmay become antigenic by the same process of epitopespreading.15

undiFFErEnTiATEd ConnECTivE TiSSuE diSEASE

Key Points

Nearly all patients with a UCTD have Raynaud’s phenomenon in combination with an unexplained synovitis.

Nail-fold capillary microscopy is useful in evaluating the potential pathology.

Antibody profiles are useful in predicting the eventual clinical features: U1 RNP antibodies predict the differentiation into MCTD. DNA antibodies predict the differentiation into SLE. Nucleolar antibodies predict the differentiation into

systemic sclerosis (SSc). Synthetase and PM/Scl antibodies predict the

differentiation into a myositis overlap syndrome.

3

Rheumatologistsfrequentlyseepatientswhopresentwithaweakly positive ANA and nonspecific symptoms such asarthralgias, fatigue,andcoldsensitivity.Thecriticalques-tion in such patients is “will they develop a connectivetissuedisease?”or“dotheyhavefibromyalgia?”

Theanswertothisquestionisnotalwaysstraightforwardbecausefibromyalgiaisnotadiagnosisofexclusion27;itisacommon comorbidity with the well-defined CTDs and isoften associated with cold-induced vasospasm.28 An algo-rithmfordiagnosingUCTDsisgiveninFigure86-4.IntheearlystagesofaCTD,theremaybejustoneortwosuspi-ciousclinicalandlaboratoryfeatures,butadefinitivediag-nosis cannot always be made. In such cases a workingdiagnosis of undifferentiated connective tissue disease(UCTD) may be appropriate.29 Most patients with thisUCTD have Raynaud’s phenomena with or without anunexplainedpolyarthralgiaandapositiveANAwithusuallyjust a single autoantibody specificity, often anti-Ro andanti-RNP.30A5-year follow-upstudyof665patientswithUCTD reported that only 34% developed a well-definedCTD (RA—13.1%, Sjögren’s—6.8%, SLE—4.2%,MCTD—4%, Scl—2.8%, systemic vasculitis—3.3%, and

Table 86-2 disorders associated with Increased fibrosis

Localized

morpheaScleredemaScleromyxedemaeosinophilic fasciitispeyronie’s diseasedupuytren’s contracturepachydermoperiostitisIdiopathic pulmonary fibrosisSclerosing cholangitisprimary biliary cirrhosiscryptogenic fibrosis

Systemic

Sclerodermametastatic carcinoidretroperitoneal fibrosisGraft-versus-host diseasenephrogenic systemic fibrosisamyloidosis

Key Points

Scleroderma overlap syndromes include scleroderma variants such as calcinosis, Raynaud phenomemon, esophageal involvement, sclerodactyly, and telangiectasia (CREST), myositis associated with sclerodactyly, and MCTD.

Raynaud’s phenomenon is often the first clinical feature of SSc overlaps and must be distinguished from primary cold Raynaud’s (i.e., cold-induced vasospasm).

The finding of thickened and dilated capillaries on nail-fold microscopy and pathologic autoantibodies (e.g., Scl-70, anticentromere, PM/Scl, U1-RNP) are important clues about the development of an overlap syndrome.

CREST has a common overlap with primary biliary cirrhosis.

Pulmonary fibrosis and pulmonary hypertension are the main causes of morbidity/mortality.

Scleroderma-like disorders (e.g., eosinophilic fasciitis, scleromyxedema, nephrogenic fibrosis, scleredema) need to be considered in the differential diagnosis of scleroderma overlaps.



C


Figure 86-4 algorithm for evaluating patients with undifferentiated connective tissue disease (Uctd). creSt,calcinosis, raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; mctd, mixed connective tissue disease; Sle, systemic lupus erythematosus.

Muscle pain/weaknessInflammatory myositisVasculitisMetabolic myopathyDrug reaction (e.g., statins)HypothyroidismAcromegalyViral infectionOveruse syndromeOsteomalaciaVitamin D deficiencySarcoidosisPolymyalgia rheumaticaSjögren’s syndromePeripheral neuropathyHyperparathyroidism

Raynaud’s phenomenonPrimary Raynaud’sScleroderma/MCTD/SLECRESTMyositis overlapTakayasu’s arteritisVasculitisThoracic outlet syndromeAntiphospholipid syndromeThromboangiitis obliteransAtheroembolic diseaseCryoglobulinemiaBacterial endocarditisPolycythemia veraMedication induced

If a specific diagnosis can be made, thenmanage as per contemporary guidelines

If no specific diagnosis can be made, then consider adiagnosis of a UCTD or overlap syndrome.Are any of the following features present?

Raynaud’s phenomenon, proximal sclerodactyly,interstitial lung disease, esophageal hypomotility,

trigeminal neuropathy, puffy hands

U1-RNP, U2-RNP, U3-RNP, U4-RNP, U5-RNP,Fibrillarin, SRP, anti-trRNA synthetases,

PM/Sci, RNA polymerases, anti-Ku, anti-Th

If “YES,” then follow up and treat as apotential overlap syndrome

If “NO,” then treat conservatively andfollow for further developments

Suspect a connective tissue disease?

Rule out osteoarthritis, bursitis/tendinitis,myofascial pain, and fibromyalgia

Does the patient have evidence for anyof the following problems?

Persistent arthritisRheumatoid arthritisPsoriatic arthritisReactive arthritisRheumatic feverSLE/MCTDDrug-induced lupusEnteropathic arthritisAnkylosing spondylitisTophaceous goutLyme diseaseAcromegalyHemochromatosisSarcoidosisWhipple’s diseasePolymyalgia rheumaticaMalignancy

Episodic arthritisGoutPseudogoutViral arthritisPalindromic rheumatismSerum sicknessReactive arthritisBacterial endocarditisLyme diseaseBehçet’s diseaseRelapsing polychondritisSarcoidosisSjögren’s syndromeMalignancy

Clinical features Autoantibodies

Several fibrotic conditions may mimic scleroderma (seeTable86-2).Sclerodermaitselfhasawidespreadheteroge-neityofdiseaseexpressionrangingfromadiffusecutaneousdisease, with a poor prognosis, to a limited cutaneousinvolvement,withgenerallyagoodprognosis.Furthermore,somepatientswithSclhaveaprominentoverlapwithother

connective tissuediseases.34 Inmanycases, theseoverlapsoccurinpatientswhodonothaveprominentskininvolve-ment (sine scleroderma) or with the limited form ofthedisease—CREST.Approximately90%ofpatientswithSclhave apositiveANA.Scleroderma-related antibodiesincludetopoisomerase1(Scl-70),anticentromere(ACA),



C


Figure 86-5 nail-fold capillaroscopy in patients with systemic sclerosis and mixed connective tissue disease (mctd). A, normal capillaries. B, mctd patient showing dilated and thickened capillary loops. C, early scleroderma with irregular capillaries and mild dropout. d, advanced scleroderma with capillary dropout and neoangiogenesis. (Modified from Cutolo M, Sulli A, Pizzorni C, Smith V: Capillaroscopy as an outcome measure for clinical trials on the peripheral vasculopathy in SSc—is it useful? Int J rheumatol pii:784947, 2010.)

A B

C D

hnPNP-I,RA33,p23,p25,RNApolymeraseI(RNAP-1),RNApolymeraseIII,U1-RNP,PM/Scl,fibrillarin,histone,Ku,endothelialcell,andTh/To35(seeTable86-1).

AGermanregistryforsclerodermahasreportedonpat-terns of organ involvement in two subsets of 1483 SScpatients.36 Limited distal skin involvement (distal to thekneeandelbows)wasseenin46%(thelcSScgroup),and33%hadprogressivewidespreadscleroderma(rapidinvolve-mentoftrunk,face,andextremities—thedcSScgroup).Anoverlapsyndromewasseenin11%,and8%wereundiffer-entiated.Theextentoforganinvolvementvariedbetweensubgroups.For instance,musculoskeletal involvementwasseenin68%oftheoverlapgroupcomparedwith57%ofthedcSSc group. Pulmonary fibrosis (56%) and pulmonaryhypertension (19%) were most common in the dcSScgroup,butpulmonaryhypertensionwasseenin15%ofthedcSScgroup.

Specificantibodyprofilestendtobeassociatedwithdis-tinctive patterns of morbidity and mortality.37 Patientspossessinganticentromere,antiU3snRNP,andantiTh/Toantibodies tend to have the limited form of Scl, whereasanti- Scl-70, ACA, and anti-RNAP are associated with

diffuseskininvolvementandsystemicdisease.Anti-PM/Sclantibodiesareassociatedwithamyositis/Scloverlapandatendencytodeveloppulmonaryinterstitialdisease.38About60% of patients with scleroderma have obvious synovitis,and35%arepositiveforRF.ErosivearthritisinSclhasanassociation with anti- RA33; the Scl component in suchoverlappatients isoftenan incomplete formofCREST.39The limited form of scleroderma has a well-documentedoverlapwithprimarybiliarycirrhosis.Thedistinctiveanti-bodyassociationofsclerodermawithPBCisantimitochon-drial antibodies.40 Conversely, anticentromere antibodieshave been found in 10% to 29% of patients with PBC;approximatelyhalfdevelopedsomefeaturesoftheCRESTsyndrome.Henceaserologicoverlapbetweenthetwosyn-dromesismoreprevalentintheclinicaloverlap.Low-grademuscle involvement is not uncommon in scleroderma,being described in between 50% and 80% of patients. AEuropean review of 114 scleroderma overlap patientsreported a 95% PM-Scl antibody positivity41 with 80%havinganinflammatorymyositis.This“scleromyositis”dif-feredfromMCTDbycoexistentfeaturesofdermatomyositis(myalgia, myositis, Gottron sign, heliotrope rash,



C


cases.NSF isusuallynonresponsive tocorticosteroidsandimmunosuppressivetherapy.

Eosinophilicfasciitispresentswithlimitedscleroderma-like skin changes involving the extremities (see Figure86-6).Thecorrectdiagnosisissuggestedbyfindingaperiph-eral eosinophilia and a hyper-gammaglobulinemia.43 Thedefinitive diagnosis is established by a full-thickness skinbiopsythatshowsadiffuseinflammationofthefascia.Initialtreatment iswithcorticosteroids(prednisone0.5 to1mg/kg) tapering according to the clinical response; somepatientsneedtocontinuemoderate-dosecorticosteroidsforupto2years.Methotrexateandmycophenalatemaybeusedinrefractorycases.

Scleromyxedemaischaracterizedbycutaneousmucino-sisandisoftenassociatedwithagammopathy,usuallyIgMand light chains.44 The mucinous skin lesions appear aswaxypapuleson the face,neck, and limbs. If thepapulescoalesce, it may be mistaken for scleroderma (see Figure86-6). Systemic involvement may occur with dysphagia,proximal muscle weakness, pulmonary, cardiac, and renalcomplications.It isdifficulttomanage;corticosteroidsareusually tried initially, in refractory cases some benefit has

4

Figure 86-6 four examples of fibrosing disorders. A, Scleromyxedema (mucinous skin lesions appear as waxy papules on the face). B, eosinophilic fasciitis (induration of skin and subcutaneous tissues). C, Scleredema (diffuse subcutaneous edema with swelling over right trapezius). d, nephrogenic systemic fibrosis (coalescence of indurated nodules with joint contracture). (Modified from Boin F, Hummers LK: Scleroderma-like fibrosing disorders, rheum dis clin north am 34:199–220, 2008.)

8

A B

C D

calcinosis),butnooverlapSLEfeatures,asischaracteristicofclassicMCTD.Manyofthesepatientshadadeformingarthritisofthehands.Ingeneraltheyhadachronicbenigncourse,andmostweresteroidresponsive.Sclerodermalupusoverlapsarelesscommon.However,SclpatientsoftenhaveantinuclearotherthanACAandScl-70.

Nonsclerodermafibroticdisordermaybemistakenforasclerodermaoverlapatinitialpresentation(seeTable86-2);althoughthesedisordersmayhavesomesystemicinvolve-ment, they seldom exhibit overlap features with otherAICTDs.

Nephrogenicsystemicfibrosis(NSF)isafibroticdisorderthat develops in some patients following exposure togadolinium-containingcontrastagents;mostpatientshavepre-existingrenaldisease.42Histologicallythereisfibroblastproliferation, thickened collagen bundles, and deposits ofmucin, similar to thoseobserved in scleromyxedema.Theclinicalpresentationisarapidprogressionwithconfluenceofinitiallyfocalareasofinduratedskin(Figure86-6).Theface isusually spared,but jointcontracturesmayoccurattheelbowsandknees,andsystemicinvolvementwithpul-monaryandneurologicsymptomscandevelopinrefractory



C


ofpatientswithARSantibodies,withmyopathyoccurringmuch later. The association of myositis in patients withanti-U1-RNP antibodies is usually seen in the context ofMCTD.50 Antibodies to the signal recognition particle(SRP)havebeenreported in4%ofpatientswithScl/PMoverlap; these patients usually have a severe, rapidly pro-gressive myositis with prominent muscle fiber necrosiswithoutmuchinflammatorycellinfiltration.51

A2006clinicalandlongitudinalstudyof100consecu-tive French Canadian patients with idiopathic IIM con-cluded that the originalBohan and Peter classification ofinflammatory myopathies should be abandoned because60% of patients with IIM were found to have an overlapsyndrome.4InthisstudyanoverlapsyndromewasbasedonthepresenceofaninflammatorymyopathyaspertheBohanandPeterclassification,52plusatleastoneclinicaloverlapfeature(Table86-3),oroneofthefollowingautoantibodies:synthetases,centromere,topoI,RNA-polymerasesIorIII,Th;U1RNP,U2RNP,U3RNP,U5RNP,Pm-Scl,Ku,SRPandnucleoporins(seeTable86-3).ThedistinctionbetweenclassicPM/DMandanoverlapsyndromewasreportedtobeof prognostic/therapeutic significance because classic PMnearlyalwayspursuedchroniccoursewith50%ofpatientsbeinginitiallyunresponsivetocorticosteroidtherapy.Puredermatomyositiswasalmostalwayschronic,butmosthadan initial response to corticosteroids.On the other hand,myositisoverlap syndromes (usuallywith scleroderma fea-tures) were almost always responsive to corticosteroids(≈90%responserate).Whenoverlappatientsweredividedaccording to antibody subsets, antisynthetase, SRP, andnucleoporin aAbs were markers for treatment-resistantmyositis, whereas aAbs to U1RNP, Pm-Scl, or Ku weremarkers for corticosteroid responsiveness. Patients withautoimmune myositis, especially dermatomyositis, are atriskofdevelopingcancer,53andithasbeenproblematicastohowfarandhowoftenoneshouldpursueamalignancyworkup.Itisnowapparentthatthefindingofanantibodyagainst 155kDa and 140kDa protein specificities (anti-155/140 antibody) signifies a significant risk for theco-occurrenceofamalignancyandpointstotheneedforathoroughcancerworkup.54

mixEd ConnECTivE TiSSuE diSEASE

5

been reported for intravenous immunoglobulin andthalidomide.

Scleredema is a cutaneous mucinosis that often startswith a febrile episode and resolves spontaneously.45 Morechronic scleredema has been associated with paraprotein-emias including multiple myeloma and diabetes mellitus.Thedermis is thickenedwith increasedcollagenglycosyl-ation,asindiabeticstiffskinsyndrome.Thefaceandneckarecommonlyinvolved,andthereisrelativesparingofthehandsandfeet(seeFigure86-6).Systemicorganinvolve-ment is rare,butamonoclonalgammopathy is sometimesseen. Such cases need to be worked up for lymphoma.Refractorycaseshavebeenhelpedbylocalradiotherapy.

myoSiTiS ovErlApS

Key Points

Myositis overlap syndromes are more common than the classic descriptions of PM or DM.

Amino-acyl trRNA synthetase antibodies (ARS) are associated with myositis, arthritis, and interstitial lung disease.

Arthritis and interstitial lung disease may antedate the appearance of myositis in patients with ARS.

Antibodies to synthetases, signal recognition particle (SRP), and nucleoporin tend to be associated with corticosteroid unresponsiveness.

Antibodies to U1RNP, Pm-Scl, or Ku are associated with corticosteroid responsiveness.

Antibodies to 155 kDa and 140 kDa proteins have been associated with an increased risk of myositis-associated malignancy.

Polymyositis (PM), dermatomyositis (DM), and inclusionbodymyositis(IBM)aretheclassicidiopathicinflammatorymyopathies(IIM),yetthesameclinicalpictureandinves-tigationalfindingsmaybefoundinpatientswithSLE,Scl,MCTD,andSjögren’ssyndrome.Suchoverlaps,especiallywith scleroderma, have been reported as being morecommonintheclassicdescriptionofpolymyositis.4Whenclinical overlaps emerge, they are most commonly associ-ated with specific autoantibodies, namely anti-PM-Scl,anti-Ku,U1RNP,Jo-1,SRP,andARS.46Thearthropathyassociatedwithpolymyositis ischaracterizedbydeformingsubluxations(particularlyofthedistalinterphalangealsandthumbs)withonlyminorerosivechanges.Anothermyositisoverlapsyndromeisseeninpatientswithamino-acyltrRNAsynthetaseantibodies(ARS).47Thisisafamilyofenzymesthat catalyze the transfer of a specific amino acid to itscognate transfer RNA—the commonest association iswithanti-Jo1 (histidine-trRNAsynthetase).Theclinicalsyndromesassociatedwiththevariousantisynthetaseanti-bodies are similar, with remissions and exacerbationscharacterized by inflammatory myositis, fever, Raynaud’ssyndrome, and skin problems (mechanic’s hands).48 ThearthritisofARSmayinitiallymimicRAwithaninflamma-toryarthritisandnodules;erosions,however,donotoccur.49Interstitiallungdiseasemaybeapresentingclinicalfeature

Key Points

The clinical overlap features of MCTD (i.e., Scl, SLE, and IIM) seldom occur concurrently but develop sequentially over the course of months or years.

Raynaud’s phenomenon is seen in nearly all patients with MCTD; if Raynaud’s syndrome is absent, the diagnosis should be reconsidered.

About 25% of MCTD patients develop renal involvement—usually membranous glomerulonephritis. Proliferative glomerulonephritis is uncommon in MCTD.

Serious CNS involvement is rare in MCTD; the commonest findings are trigeminal neuropathy and sensorineural hearing loss.

Pulmonary HTN is the commonest cause of death in MCTD patients and should be screened for on an ongoing basis.



C


Clinical Features

Diagnosis

MCTD is an overlap syndrome that embraces features ofSLE, Scl, and PM/DM.57 These overlap features seldomoccur concurrently; it usually takes several years beforeenoughoverlappingfeatureshaveappearedtobeconfidentthatMCTDisthemostappropriatediagnosis.58Thecom-monest clinical associations with U1 RNP antibodies inthe early phase of the disease are hand edema, arthritis,Raynaud’s phenomenon, inflammatory muscle disease,andsclerodactyly.NoAmericanCollegeofRheumatology(ACR) criteria are available for the diagnosis of MCTD,butacomparativestudyreportedthattwocriteriasets,thoseofAlarcon-SegoviaandKahn,hadthebestsensitivityandspecificity(62.5%and86.2%,respectively)59(Table86-4).The sensitivity could be improved to 81.3% if the term“myalgia” was substituted for “myositis.”60 Some patientsinitially diagnosed as MCTD will evolve into a clinicalpicturemostconsistentwithSLEorRA;inonelong-termfollow-up, more than half of the subjects continued tosatisfy criteria for MCTD.61 A comparison of the clinicaland serologic features of MCTD with SLE, RA, Scl, andPM/DMisgiveninTable86-5.

Early Symptoms

IntheearlystagesmostpatientsdestinedtodevelopMCTDcannot be differentiated from the other classic AICTDs.

MCTDwasdescribedbySharpandcolleagues55ina1972paperreportinganoverlapofSLE,Scl,andPM.Thiswasthe first overlap syndrome defined in terms of a specificantibody—namely antibodies to a ribonuclease-sensitiveextractablenuclearantigen(ENA).Overthepast38years,many studies have explored the clinical correlates of thisantibodysystem(nowcalledU1 RNP).

Serologic Features

ThebasicpremiseoftheMCTDconceptisthatthepres-ence of high-titer anti-U1 RNP antibodies modifies theexpressionofanAICTDinwaysthatarerelevanttoprog-nosisandtreatment.56ThefirstcluetodiagnosingMCTDisusuallyapositiveANAwithahigh-titerspeckledpattern.Thetiterisoftengreaterthan1:1000andsometimesgreaterthan 1:10,000. This finding should prompt the measure-mentofantibodiestoU1-RNP,Sm,Ro,andLa.It isalsopertinent to note whether the serum contains antibodiestodsDNAandhistonesbecausepatientsdestinedtofollowacoursemostconsistentwithMCTDhaveserawithpre-dominantU1-RNPreactivity.Antibodies todsDNA,Sm,and Ro are occasionally seen as a transient phenomenoninpatientswithMCTD.Butwhentheyare foundconsis-tently, as the predominant antibody system, the clinicalpicture is usually more consistent with classic SLE. Anti-bodies to the 70kD antigen, especially in its apoptoticform,aremostcloselyassociatedwiththeclinicalcorrelatesofMCTD.8

Table 86-3 Suggested classification for Inflammatory myopathies

Abbreviation description

pm pure polymyositisdm pure dermatomyositisom overlap myositis: myositis with at least 1 clinical overlap feature and/or an overlap autoantibodycam cancer-associated myositis: with clinical paraneoplastic features and without an overlap autoantibody or anti-mi-2

Bohan and Peter’s52Definition of Myositis

1. Symmetric proximal muscle weakness.2. elevation of serum skeletal muscle enzymes.3. electromyographic triad of short, small, polyphasic motor unit potentials; fibrillations, positive sharp waves, and insertional irritability; and

bizarre, high-frequency repetitive discharges.4. muscle biopsy abnormalities of degeneration, regeneration, necrosis, phagocytosis, and an interstitial mononuclear infiltrate.5. typical skin rash of dm including the heliotrope rash, Gottron sign, and Gottron papules.

definite myositis: 4 criteria (without the rash) for pm, 3 or 4 criteria (plus the rash) for dm.probable myositis: 3 criteria (without the rash) for pm, 2 criteria (plus the rash) for dm.possible myositis: 2 criteria (without the rash) for pm, 1 criterion (plus the rash) for dm.

Definition of Clinical Overlap Features

Inflammatory myopathy plus at least 1 or more of the following clinical findings: polyarthritis, raynaud’s phenomenon, sclerodactyly, scleroderma proximal to metacarpophalangeal joints, typical SSc-type calcinosis in the fingers, lower esophageal or small-bowel hypomotility, dlco lower than 70% of the normal predicted value, interstitial lung disease on chest radiogram or computed tomography scan, discoid lupus, anti-native dna antibodies plus hypocomplementemia, 4 or more of 11 american college of rheumatology criteria for systemic lupus erythematosus, antiphospholipid syndrome.

Definition of Overlap Autoantibodies

antisynthetases (Jo-1, pl-7, pl-12, oJ, eJ, KS); scleroderma-associated autoantibodies (scleroderma-specific antibodies: centromeres, topoisomerase I, rna polymerases I or III, th; and antibodies associated with scleroderma overlap: U1-rnp, U2-rnp, U3-rnp, U5-rnp, pm-Scl, Ku, and other autoantibodies (signal recognition particle, nucleoporins).

Definition of Clinical Paraneoplastic Features

cancer within 3 yr of myositis diagnosis, plus absence of multiple clinical overlap features; plus, if cancer was cured, myositis was cured as well.

Modified from Troyanov Y, Targoff IN, Tremblay JL, et al: Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients, Medicine (Baltimore) 84:231–249, 2005.



C


Fever

FevermaybeaprominentfeatureofMCTDintheabsenceofanobviouscause.Feverofunknownoriginhasbeentheinitial presentation of MCTD; after careful evaluation,feverinMCTDcanusuallybetracedtoacoexistentmyo-sitis, aseptic meningitis, serositis, lymph adenopathy, orintercurrentinfection.

Joints

Joint pain and stiffness is an early symptom in nearly allpatientswhodeveloptheMCTDsyndrome.Overthepast2 decades it has become increasingly apparent that jointinvolvementinMCTDismorecommonandmoreseverethan in classic SLE.63 About 60% of patients eventuallydevelop an obvious arthritis, often with deformities com-monlyseeninRAsuchasulnardeviation,swanneck,andboutonnièrechanges.64Radiographsusuallyshowacharac-teristic absence of severe erosive changes; they often

TheassumptionthatadiagnosisofMCTDimpliesasimul-taneous presence of features usually seen in SLE, Scl, andPMiserroneous.Itisunusualtoseesuchanoverlapduringthe early course of MCTD, but with the progress of timethe overlapping features usually occur sequentially. Earlyinthecourseofthediseasemostpatientscomplainofeasyfatigability,poorlydefinedmyalgias,arthralgias,andRayn-aud’sphenomenon;atthispointintimeadiagnosisofRA,SLE,orundifferentiatedconnectivetissuedisease(UCTD)seemsmostappropriate.1Ifsuchapatientisfoundtohaveswollenhandsorpuffyfingers(Figure86-7)inassociationwithahigh-titerspeckledANA,heorsheshouldbecare-fully followed for the evolution of overlap features (seeTable86-3).Ahightiterofanti-RNPantibodiesinapatientwith UCTD is a powerful predictor for a later evolutioninto MCTD. Less commonly there is an acute onset ofMCTD, which gives little clue to the subsequent course;suchpresentationshaveincludedpolymyositis,acutearthri-tis, aseptic meningitis, digital gangrene, high fever, acuteabdomen,andtrigeminalneuropathy.62

Table 86-4 diagnostic criteria for mixed connective tissue disease

Alarcón-Segovia Criteria Kahn Criteria

Serologic criteria anti-rnp at hemagglutination titer of ≥1 : 1600 high-titer anti-rnp corresponding to a speckled ana of ≥1 : 1200 titer

clinical criteria 1. Swollen hands2. Synovitis3. myositis (biologically proven)4. raynaud’s phenomenon5. acrosclerosis

1. Swollen fingers2. Synovitis3. myositis4. raynaud’s phenomenon

mctd present if: Serologic criterion accompanied by 3 or more clinical criteria, one of which must include synovitis or myositis

Serologic criterion accompanied by raynaud’s phenomenon and 2 or more the 3 remaining clinical criteria

ANA, antinuclear antibody; MCTD, mixed connective tissue disease; RNP, ribonucleoprotein particle. From Alarcon-Segovia D, Cardiel MH: Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients, J Rheumatol

16(3):328–334, 1989.

Table 86-5 differential features of the classic autoimmune connective tissue diseases

Clinical Feature SlE rA Scl pm mCTd

pleurisy/pericarditis ++++ + + – +++erosive joint disease ± ++++ + ± +raynaud’s phenomenon ++ – ++++ + ++++Inflammatory myositis + + + ++++ +++Sclerodactyly ± – ++++ – ++nonacral skin thickening – – +++ – –Interstitial pulmonary fibrosis + + +++ ++ +pulmonary hypertension ++ ± + + +++Butterfly rash ++++ – – – ++oral ulcers +++ – – – ++Seizures/psychosis +++ – – – −trigeminal neuropathy + – ++ – +++peripheral neuropathy ++ ++ ± – ++transverse myelopathy +++ + – – ++aseptic meningitis +++ + – – +++diffuse proliferative glomerulonephritis ++++ – – – +membranous glomerulonephritis +++ – – – ++renovascular hypertension + – ++++ – +++Inflammatory vasculitis ++ ++ + + +noninflammatory vasculopathy – – ++++ – +++esophageal dysmotility + ± ++++ + +++

MCTD, mixed connective tissue disease; PM, polymyositis; RA, rheumatoid arthritis; Scl, scleroderma; SLE, systemic lupus erythematosus.



C


developaflexortenosynovitis,boneedema,andpericapsu-larinflammationreminiscentofaseronegativespondyloar-thropathy(Figure86-8).ApositiveRFisfoundin50%to70% of patients; indeed, patients may be diagnosed ashavingRAandfulfillACRcriteriaforRA.

Skin and Mucous Membranes

Most patients with MCTD develop mucocutaneouschangessometimeduringthecourseofthesyndrome.Rayn-aud’sphenomenon is thecommonestproblemandoneoftheearliestmanifestationsofMCTD.66Itmaybeaccompa-nied by puffy, swollen digits and sometimes total handedema.62Insomepatients,skinchangescommonlyassoci-ated with classic SLE are prominent findings, particularlymalar rash and discoid plaques. Other problems haveincludedbuccalulceration,siccacomplex,orogenitalulcer-ation, livedo vasculitis, subcutaneous nodules, and nasalseptalperforation.

Muscle

MyalgiaisacommonsymptominpatientswiththeMCTDsyndrome.Inmostpatientsthereisnodemonstrableweak-ness,EMGabnormalities,ormuscleenzymechanges. It isoften unclear whether the symptom represents a low-grade myositis, physical deconditioning, or an associated

resemble Jaccoud’s arthropathy. However, a destructivearthritisincludinganarthritismutilansisawell-establishedassociation.64 Small marginal erosions, often with a well-demarcatededge,arethemostcharacteristicradiologicfea-turesinpatientswithseverejointdisease.65Somepatients

Figure 86-8 hand magnetic resonance images of two females aged 25 and 32 with mixed connective tissue disease and hand arthritis. A, patient 1 has synovitis/effusion around the ulnar styloid (asterisk) and tenosynovitis of the flexor and extensor tendons (arrows) (t1-weighted gadolinium-enhanced sequence on axial plane). B, patient 2 has intense synovitis of the radioulnar joint (asterisk) and extensor tenosynovitis (arrows) causing thickening of the dorsum of the hand (t1-weighted short tau inversion recovery [StIr] sequence on axial plane). C, patient 1 has synovitis/effusion, and pericapsular edema is seen in the second proximal interphalangeal joint. the distended capsule is indicated by arrows. d, patient 2 has intracap-sular synovial effusion or synovitis of the third and fourth metacarpophalangeal joints (arrows). (Both C and d are t1-weighted StIr sequences in the coronal plane.) (From Cimmino MA, Lozzelli A, Garlaschi G, et al: Magnetic resonance imaging of the hand in mixed connective tissue disease, ann rheum dis 62:380–381, 2003.)

A

**

B

C D

Figure 86-7 the hand of a man with mixed connective tissue disease. the fingers have a generally puffy appearance with a fusiform proximal interphalangeal swelling of the third finger from an inflammatory arthri-tis. there is a periungual infarct at the nail fold of the third finger. (Modi-fied from Pope JE: Other manifestations of mixed connective tissue disease, rheum dis clin north am 31:519–533, 2005.)



C


pulmonaryhypertension (PAH); thisoccurs in some20%ofpatients and isoftenasymptomatic in its early stages.69Theearlydetectionofpulmonaryhypertensionis increas-inglyimportantbecausetherearenowmoreeffectivethera-peuticoptions.PAHisprobablyunderdiagnosedinitsearlystages; in a community rheumatology practice setting anelevationoftheestimatedrightventricularsystolicpressure(ERVSP),consistentwiththediagnosisofPAH,wasfoundin13%ofpreviouslyundiagnosedsubjects.70Thisdiagnosisshouldbesuspected inpatientswith increasingexertionaldyspnea.Two-dimensionalechocardiographywithDopplerflowstudiesisthemostusefulscreeningtest,withadefini-tive diagnosis requiring cardiac catheterization showing ameanrestingpulmonaryarterypressuregreaterthan25mmHgatrest.Thedevelopmentofpulmonaryhypertensionhasbeencorrelatedwithanail-foldcapillarypatternsimilartothatseeninScl,antiendothelialcellantibodies,anticardio-lipin antibodies, and anti-U1-RNP antibodies.71 Both leftandrightventriculardysfunctionappearstobeacommonfinding that is not always associated with PAH; regularechocardiographic evaluations are recommended for allMCTDpatients,especiallythosewithPAH.Elevatedlevelsofanti-U1RNPantibodies,antiendothelialcellantibodies,serumthrombomodulin,andWillebrandfactorareprognos-ticcluestothedevelopmentofPAH.72

fibromyalgiasyndrome.Theinflammatorymyopathyassoci-atedwithMCTDissimilarhistologicallytoIIM,withfea-tures of both the vascular involvement of DM and thecell-mediated changes of PM67 (Figure 86-9). In mostpatients myositis occurs as an acute flare against a back-ground of general disease activity. Such patients usuallyrespond well to a short course of high-dose corticosteroidtherapy.Anotherscenarioisthatofalow-gradeinflamma-torymyopathy,which isoften insidious in itsonset; thesepatientsoftenhaveapoortherapeuticresponsetocortico-steroids. Some patients with PM associated with MCTDdevelop an impressive fever62; other patients may give ahistoryoffebrilemyalgiasthatwerediagnosedas“flu...

Heart

AllthreelayersoftheheartmaybeinvolvedinMCTD.68An abnormal electrocardiogram (ECG) is noted in about20%ofpatients.ThemostcommonECGchangesarerightventricularhypertrophy,rightatrialenlargement,andinter-ventricularconductiondefects.Pericarditisisthecommon-estclinicalmanifestationofcardiacinvolvement,reportedin10%to30%ofpatients.Pericardial tamponade is rare.Involvementofthemyocardiumisincreasinglyrecognized.In some patients myocardial involvement is secondary to

Figure 86-9 muscle biopsy from the biceps brachii of a mixed connective tissue disease patient (h&e stain, ×300). A, moderate variation of fiber size and degenerated fibers (→) with mononuclear cell infiltration. B and C show perivascular inflammatory infiltration and thickening of vessel walls. (Modified from Vianna M, Borges MT, Borba EF, et al: Myositis in mixed connective tissue disease: a unique syndrome characterized by immuno-histopathologic elements of both polymyositis and dermatomyositis, arq neuro-psiquiatr 62:923–934, 2004.)

A B

*

*

*

*

C



C


Figure 86-10 computed tomography scans of a patient with mixed connective tissue disease and pulmonary hypertension (A, upper zones; B, lower zones). there are bilateral pleural effusions and enlarged bilateral mediastinal lymph nodes in the right paratracheal region and left perivascular areas. the pulmonary artery has a diameter greater than that of the ascending aorta—consistent with the diagnosis of pulmonary hypertension. Both hilar pulmonary arteries are also enlarged. a fairly large pericardial effusion is present. the lung windows show evidence of a diffuse abnormality with linear opacities and some areas of ground-glass attenuation in the upper zones. at the lung bases there are more confluent opacities, both reticular and ground glass, and some air-space consolidation. no honeycombing is identified, and there is no distortion of the lung architecture. (From Saito Y, Terada M, Ishida T, et al: Pulmonary involvement in mixed connective tissue disease: comparison with other collagen vascular diseases using high resolution CT, J comput assist tomogr 26:349–357, 2002.)

A B

Figure 86-11 Intimal hyperplasia and smooth muscle hypertrophy without accompanying inflammation are the characteristic features of the vasculopathy of mixed connective tissue disease. When it occurs in the lung, as shown here, it may give rise to severe pulmonary hyperten-sion. (note absence of pulmonary fibrosis.) the plexiform lesion (arrow) is a characteristic pathologic finding in this disease process. (From Bull TM, Fagan KA, Badesch DB: Pulmonary vascularmanifestations of mixed connective tissue disease, rheum dis clin north am 31:451–464, 2005.)

Lung

Lunginvolvementoccursinupto75%ofpatients.73Earlysymptomsthatshouldpromptfurtherinvestigationsaredrycough,dyspnea,andpleuriticchestpain.74Interstitiallungdisease (ILD) occurs in up to 50% of subjects. High-resolutioncomputedtomography(HRCT)isthemostsen-sitivetesttodeterminethepresenceofILD(Figure86-10).75ThecommonestHRCTfindingsareseptalthickeningandground-glassopacities.UntreatedILDisusuallyprogressivewiththedevelopmentofseverepulmonaryfibrosisin25%ofsubjectsafter4yearsoffollow-up.76Pulmonaryhyperten-sion (PAH) is prognostically the most severe form ofpulmonaryinvolvementinMCTD.UnlikeScl,wherepul-monary hypertension is often secondary to an interstitialpulmonary fibrosis, PAH in MCTD is usually caused bya bland intimal proliferation and medial hypertrophy ofpulmonaryarterioles77(Figure86-11).

Kidney

IntheinitialdescriptionofMCTD,renalinvolvementwasconsidered to be rare.57 After some 4 decades of observa-tions, it is now evident that renal involvement occurs inabout 25% of patients.78 However, high titers of anti-U1RNPantibodiesarerelativelyprotectiveagainstthedevel-opmentofdiffuseproliferativeglomerulonephritis,irrespec-tive of whether they occur in a setting of classic SLE orMCTD. When patients with MCTD do develop renalchanges,itusuallytakestheformofamembranousglomeru-lonephritis.79 This is often asymptomatic but may some-timescauseanovertnephroticsyndrome.86Thedevelopmentof diffuse proliferative glomerulonephritis or parenchymalinterstitial disease has been rarely recorded in MCTD.ThereisincreasingrecognitionthatMCTDpatientsareatriskofdevelopingarenovascularhypertensivecrisissimilartothesclerodermakidney.

Gastrointestinal

Gastrointestinal involvement is a major feature of theoverlapwithscleroderma,occurringinabout60%to80%ofpatients.63ThecommonestabdominalprobleminMCTDis disordered motility in the upper gastrointestinal tract.Therehavebeencasereportsofhemoperitoneum,hemato-bilia, duodenal bleeding, megacolon, pancreatitis, ascites,protein-losingenteropathy,primarybiliarycirrhosis,portalhypertension, pneumatosis intestinalis, and autoimmunehepatitis.80 Abdominal pain in MCTD may result frombowelhypomotility,serositis,mesentericvasculitis,colonic



C


gravis, polyradiculopathy, demyelinating disorder, andperipheralneuropathy.ElevatedCSFlevelsofanti-U1RNPantibodies,withapredominanceofanti-70kDantibodies,have been reported in both SLE and MCTD patientswithdiffusecentralneuropsychiatricinvolvement.84Manypatients with AICTDs have changes on brain magneticresonanceimagingthatarereferredtoasunspecificbrightobjects (UBOs). In many instances UBOs occur in theabsenceofneurologicsymptoms.However,thereisamodestcorrelationbetweenthedensityandpositioningofUBOs;inMCTDtheselesionstendtoclusteratthecorticomedul-laryjunctionandperiventricularregion.85

Blood Vessels

Raynaud’s phenomenon is an early feature of nearly allpatientswhoareeventuallydiagnosedashavingMCTD.66A bland intimal proliferation and medial hypertrophyaffectingmediumandsmallsizevesselsisthecharacteristicvascular lesion of MCTD86 (see Figure 86-11) and is thecharacteristic pathology in pulmonary hypertension andrenovascular crises. Both nail-fold capillary microscopy87and color Doppler88 are useful in distinguishing benignprimaryRaynaud’sfromsecondaryinvolvementinMCTDandotherAICTDs(seeFigure86-5).Fingernailcapillaros-copy is abnormal in most MCTD patients with the samepattern of capillary dilation and dropout that has beenreported in Scl.89 An angiographic study reported a highprevalence of medium-size vessel occlusions90 (Figure86-12).EndothelialcellandanticardiolipinantibodieshavebeenreportedtobeassociatedwithendothelialdysfunctionandthedevelopmentofatherosclerosisinMCTD.91

perforation,andpancreatitis.Malabsorptionsyndromecanoccur secondarily to small bowel dilation with bacterialovergrowth. Liver involvement in the form of chronicactive hepatitis and Budd-Chiari syndrome has beendescribed. Pseudodiverticulae, identical to those seen inSCC,maybeseenalongtheantimesentericborderofthecolon.

Nervous System

InkeepingwithSharp’soriginaldescription,CNSinvolve-ment has not been a conspicuous feature of MCTD. Thecommonest problem is a trigeminal neuropathy.81 In areviewof81caseoftrigeminalneuropathyseeninaneuro-logic clinic, the most frequently associated CTDs wereundifferentiated connective tissue disease (47%), mixedconnectivetissuedisease(26%),andscleroderma(19%).Asensorineuralhearinglosshasbeenreportedinnearly50%of MCTD patients.82 In contrast to CNS involvement inclassic SLE, frank psychosis and convulsions have rarelybeen reported in MCTD.81 Headaches are a relativelycommon symptom; in the majority of patients they arevascular inoriginwithmanyofthecomponentsofclassicmigraine. Inasubsetof thesepatients, signsofmeningealirritation develop and examination of the cerebral spinalfluid reveals the changes of aseptic meningitis.83 AsepticmeningitisinMCTDhasalsobeendescribedasahypersen-sitivityreactiontoNSAIDs,inparticularsulindacandibu-profen. There are isolated reports of transverse myelitis,cauda equina syndrome, cerebralhemorrhage, retinal vas-culitis, optic neuropathy, progressive multifocal leukoen-cephalopathy, cold-induced brain ischemia, myasthenia

Figure 86-12 A, digital angiogram showing multiple arterial occlusions with collateral formation. B, digital angiogram showing ulnar artery occlu-sions. (From Peller JS, Gabor GT, Porter JM, Bennett RM: Angiographic findings in mixed connective tissue disease: correlation with fingernail capillary photo-microscopy and digital photoplethysmography findings, arthritis rheum 28:768, 1985. Reprinted with permission of the American College of Rheumatology.)

A B



C


(e.g., tadalafil), and prostaglandin analogs (e.g., iloprost)should be considered in severe refractory cases.101 Pulmo-naryhypertensionisthemaincauseofdeathinMCTD,andpatients should be evaluated at regular intervals for thedevelopment of this complication because early interven-tionisthekeytoeffectivemanagement.Recentadvancesin the treatment of pulmonary hypertension have led toreduced morbidity and mortality.77 Overall effective man-agement requires anticoagulation and vasodilator therapysuchascalciumchannelblockersorprostacyclinanalogues.Long-term treatment with intravenous epoprostenol orprostacyclin improves exercise capacity, hemodynamics,and survival in many patients,102 as does therapy withinhaled iloprost.103 Evidence indicates that some patientsrespondtoaregimenofintravenouscyclophosphamideandcorticosteroids.104Bosentan,anoralendothelium-1antago-nist,hasbeenreportedtoimprovedyspneaandslowPAHprogressioninMCTD.105

Themanagementofoverlapsyndromeshasnotbeenthesubjectofcontrolledtrials.Thereforemanagementisbasedonananalysisof theclinical featuresand theapplicationofmanagementstrategiesusedintheusualtreatmentpre-senting features in terms of inflammatory arthritis, Rayn-aud’s,inflammatorymuscledisease,serositis,interstitiallungdisease, pulmonary hypertension, and the gastrointestinalfeaturesofscleroderma.Bydefinition,theclinicalfeaturesof an overlap syndrome will be quite diverse and oftenchangeovertime.Thusaconstantreappraisalofmanage-mentstrategiesisnecessaryateachpatientvisit.

Many of the problems causing morbidity in overlapsyndromes tend to be intermittent and responsive tocorticosteroids (e.g., aseptic meningitis, myositis, pleurisy,pericarditisandmyocarditis).Ontheotherhand,nephroticsyndrome,Raynaud’sphenomenon,deformingarthropathy,acrosclerosis,andperipheralneuropathiesareusuallysteroidresistant. Many of the scleroderma-like gastrointestinalproblemscanbemanagedaccording to theusualpracticein scleroderma such as management of renal crisis withACE inhibitors, Raynaud’s phenomenon with calciumchannel blockers, and gastrointestinal reflux disease withproton pump inhibitors.101 Fibrotic lung disease is notori-ously resistant to corticosteroids and immunosuppressives;thereissomeevidencethatanewclassofdrugs,thetyrosinekinaseinhibitors(e.g.,imatinib),maybeeffectiveinsomepatients.106

In patients with steroid-resistant thrombocytopenia,refractory myositis, or hemolytic anemia, it is worthconsidering the use of intravenous gammaglobulin107 ordanazol.108

Successful autologous peripheral blood stem cell trans-plantation has been reported in a patient with refractorymyositisandMCTD.109Overthelongterm,concernusuallymountsoverthetotalcorticosteroidburdenandthepossi-bilityof inducingan iatrogenicsteroidmyopathy,nosoco-mial infection, aseptic necrosis of bone, or acceleratedosteoporosis.Routineevaluationofbonemineraldensityiswarrantedtodetectearlypresymptomaticosteoporosisandinitiationoftherapywithantiresorptiveagents.Unlesscon-traindicated,allpatientsshouldtakesupplementarycalciumandvitaminD.Inpatientsrequiringlong-termcorticoste-roids it would seem reasonable to use antimalarials110 ormethotrexate111inanattempttominimizethecumulative

6

Blood

HematologicabnormalitiesareacommonfindinginMCTD.Anemiais foundin75%ofpatients,andtheusualprofileis most consistent with the anemia of chronic inflamma-tion.63 A positive Coombs test is seen in about 60% ofpatients,butanoverthemolyticanemiaisuncommon.92AsinSLE,aleukopeniaaffectingmainlythelymphocyteseriesisseeninabout75%ofpatientsandtendstocorrelatewithdisease activity. Less common associations have beenthrombocytopenia thrombotic thrombocytopenia purpuraand red cell aplasia. Hypocomplementemia has beendescribed in several studies63; it is not as prevalent as inclassicSLEandhasnotbeencorrelatedwithanyparticularclinicalsituation.PositivetestsforRFhavebeenfoundinabout50%ofpatients.93ThepresenceofRF is associatedwithmoreseveredegreesofarthritis,especiallyifanti-A2/RA33arealsopresent.11Anticardiolipinantibodiesorlupusanticoagulants, or both, have also been reported. Unlikethe anticardiolipin antibodies found in SLE, they areβ2-glycoprotein independent and tend to be associated withthrombocytopeniaratherthanthromboticevents.94

pregnancy

ReportsofmaternalandfetalmorbidityinMCTDarequitediverse.95InacomparisonstudyofpatientswithMCTDandSLE,thefertilityratesinbothanddiseaseswereunaltered,whereastheparityandfetalwastagewasincreasedinboth.96Some studies have reported an exacerbation of MCTDduring pregnancy and postpartum flares,96 whereas othershavenot.AntiendothelialantibodieshavebeenlinkedtospontaneousabortioninMCTD.97Asinglecaseofneonatal“lupus”hasbeenreported,suggestingapathogenicroleforthetransplacentalpassageofanti-U1RNPantibodies.98

Juvenile mixed Connective Tissue disease

MCTD may first become apparent in childhood. Theaverageageofonsetinonereportwas10.7years.99Polyar-thritis and Raynaud’s phenomena are the most commonpresentingfeatures.Theretendstobeaprogressionoforganinvolvement with 20% involvement at 5 years and 48%at 10 years. Significant myocarditis, glomerulonephritis,thrombocytopenia,seizures,hemolyticuremicsyndrome,anacutecoronarysyndrome,andasepticmeningitishavebeendescribedinisolatedcases.

mAnAgEmEnT oF ConnECTivE TiSSuE diSEASE ovErlApS

TherationalmanagementofoverlapCTDsisconfoundedby the absence of controlled trials. Recommendations formanagementarebasedonconventionaltreatmentsforSLE,PM/DM, RA, and Scl.100 General guidelines for treatingspecific features of the overlap CTDs are given in Table86-6.NearlyallpatientswithCTDsexperienceRaynaud’sphenomenon. Apart from advice as to minimizing coldexposure, most cases should be tried on calcium blockers(e.g., nifedipine). The use of topical nitrates, endothelinantagonists(e.g.,bosentan),phosphodiesterase-5inhibitors



C


Table 86-6 Guidelines for managing overlap Syndromes

problems Treatments

fatigue, arthralgias, myalgias nSaIds, antimalarials, low-dose prednisone (<10 mg/day); trial use of modafanilarthritis nSaIds, antimalarials, methotrexate, consider tnf inhibitiona

raynaud’s phenomenon Keep warm, avoid finger trauma, avoid β-blockers, stop smoking; dihydropyridine calcium channel blocker (e.g., nifedipine); α-sympatholytic (e.g., prazosin); consider endothelin receptor antagonist (e.g., bosentan) in recalcitrant cases

acute-onset digital gangrene local chemical sympathectomy (infiltration of lidocaine at base of involved digit), anticoagulation, topical nitrates; consider hospitalization for intra-arterial prostacyclin; start endothelin receptor antagonist therapy

pleurisy nSaId or short course of prednisone (≈20 mg/day)pericarditis nSaId or short course of prednisone (≈20 mg/day); tamponade will require percutaneous or

surgical drainageaseptic meningitis discontinue nSaIds,b short course of high-dose prednisone, about 60 mg/daymyositis acute onset, severe: prednisone 60-100 mg/day

chronic, low grade: prednisone, 10-30 mg/dayc

consider methotrexate and/or IvIG in recalcitrant casesmembranous glomerulonephropathy mild: no treatment required

progressive proteinuria: trial of ace inhibitor; trial of low-dose aspirin combined with dipyridamole

Severe: trial of prednisone 15-60 mg/day plus monthly pulse cyclophosphamide or daily chlorambucil

nephrotic syndrome Steroids alone are seldom effective. low-dose aspirin combined with dipyridamole to prevent thrombotic complications; ace inhibitor to reduce protein loss; trial of prednisone 15-60 mg/day plus monthly pulse cyclophosphamide or daily chlorambucil; dialysis or transplantation may be required

Scleroderma-like renal crisis ace inhibitormyocarditis trial of steroids and cyclophosphamided; avoid digoxine

Incomplete heart block avoid chloroquinef

asymptomatic pulmonary hypertension trial of steroids and cyclophosphamide, low-dose aspirin and angiotensin-converting enzyme inhibitors; consider endothelin receptor antagonist (oral bosentan)

Symptomatic pulmonary hypertension Intravenous prostacyclin, angiotensin-converting enzyme inhibitors, anticoagulation, endothelin receptor antagonist (oral bosentan); trial of sildenafil; heart-lung transplantation

aseptic meningitis discontinue nSads and give short course of high-dose prednisone (≈80 mg/day)vascular headache trial of propranolol and/or alternate-day aspirin, 350 mg

Symptomatic use of a triptan (e.g., sumatriptin, eletriptan)autoimmune anemia/thrombocytopenia high-dose steroids (≈prednisone 80 mg/day) with taper dependent on clinical course. consider

danazol, IvIG, and immunosuppression in recalcitrant casesthrombotic thrombocytopenic purpura Immediate infusion of fresh frozen plasma; may require plasma exchange and transfusion of

platelet depleted rBcs; consider splenectomy in recalcitrant casesdysphagia mild: no treatment

With reflux: proton pump inhibitor; consider nissen fundoplication.Severe: calcium channel antagonist, alone or in combination with an anticholinergic agent

Intestinal dysmotility prokinetic agents such as metoclopramide and erythromycinSmall bowel bacterial overgrowth: tetracycline, erythromycin

osteoporosis ca/vit d supplements, estrogen replacement or raloxifene; biphosphonatesg; nasal calcitonin; carboxyl truncated pth analogs such as hpth-(1-34).

heartburn/dyspepsia raise head of bed, discontinue smoking, lose weight and avoid caffeine; h2 antagonists, h+ proton pump blockers; trial of metoclopramide; consider Helicobacter pylori infection in recalcitrant cases

trigeminal neuropathy no effective therapy for numbness; trial of an antiepileptic (e.g., gabapentin) or tricyclic antidepressant (e.g., nortryptiline) for pain

aHas been associated with flares in MCTD and SLE.bSulindac and ibuprofen have been associated with a hypersensitivity aseptic meningitis.cRemain alert for steroid myopathy, aseptic necrosis of bone, and accelerated osteoporosis.dCardiotoxic at high doses.ePredisposes to ventricular arrhythmias.fPredisposes to complete heart block.gCannot be used if esophagus is more than mildly involved.

9

ACE, angiotensin-converting enzyme; IVIG, intravenous immunoglobulin; NSAID, nonsteroidal anti-inflammatory drug; PTH, parathyroid hormone; RBC, red blood cell; TNF, tumor necrosis factor.

steroidburden.Antimalarialsshouldbeusedwithcautioninoverlappatientswithafascicularorbundlebranchblockdue to the riskofcausingacompleteheartblock112oranidiosyncratichepatitis.113Digitalis is relatively contraindi-catedinpatientswithmyocarditisduetotheriskofinduc-ingventriculararrhythmias.AsinSLE,theTNFinhibitoretanercept has been reported to exacerbate MCTD.114Rituximabhasbeenbeneficialinsomepatientswithsevere

refractoryantisynthetasesyndrome.115Patientswithseverehanddeformitiesmaybehelpedbysofttissuereleaseopera-tionsandselectedjointfusions.

Themanagementofpregnancypresents several specialproblems in patients with overlap CTDs. Doria and col-leagues116haveprovidedthefollowinggeneraladvice:

1. Patients shouldbecorrectly informedabouttheriskofbecomingpregnant.



C


pulmonary hypertension in nine patients and two deathsunrelated to MCTD.120 It is evident that the course ofoverlapsyndromesisunpredictable;manypatientsdofollowarelativelybenigncourse,butitismajororganinvolvementthatultimatelydictatesthemorbidityandmortalityofthedisease.

references1. LeRoyEC,MaricqH,KahalehM:Undifferentiatedconnectivetissue

syndrome,Arthritis Rheum23:341–343,1980.2. RahmanA,StollarBD:Originandstructureofautoantibodiesand

antigens in autoimmune rheumatic diseases, Lupus 17(3):232–235,2008.

3. GaubitzM:Epidemiologyofconnectivetissuedisorders,Rheumatol-ogy (Oxford)45(Suppl3):iii3–iii4,2006.

4. Troyanov Y, Targoff IN, Tremblay JL, et al: Novel classification ofidiopathicinflammatorymyopathiesbasedonoverlapsyndromefea-turesandautoantibodies:analysisof100FrenchCanadianpatients,Medicine (Baltimore)84(4):231–249,2005.

5. Winfield JB,KofflerD,KunkelHG:Developmentof antibodies toribonucleoprotein followingshort termtherapywithprocainamide,Arthritis Rheum18:531,1975.

6. KattahNH,KattahMG,UtzPJ:TheU1-snRNPcomplex:structuralproperties relating to autoimmune pathogenesis in rheumatic dis-eases,Immunol Rev233(1):126–145,2010.

7. McClainMT,RamslandPA,KaufmanKM,JamesJA:Anti-smauto-antibodiesinsystemiclupustargethighlybasicsurfacestructuresofcomplexedspliceosomalautoantigens,J Immunol168(4):2054–2062,2002.

8. HoffmanRW,MaldonadoME:Immunepathogenesisofmixedcon-nective tissue disease: a short analytical review, Clin Immunol128(1):8–17,2008.

9. PomeranzKrummelDA,OubridgeC,LeungAK,etal:Crystalstruc-tureofhumanspliceosomalU1snRNPat5.5Aresolution,Nature458(7237):475–480,2009.

10. SteinerG,SkrinerK,HassfeldW,SmolenJS:Clinicalandimmuno-logicalaspectsofautoantibodies toRA33/hnRNP-A/Bproteins—alinkbetweenRA,SLEandMCTD,Mol Biol Rep23(3-4):167–171,1996.

11. Hassfeld W, Steiner G, Graninger W, et al: Autoantibody to thenuclearantigenRA33:amarkerforearlyrheumatoidarthritis,Br J Rheumatol32(3):199–203,1993.

12. RadicM,MarionT,MonestierM:Nucleosomesareexposedatthecellsurfaceinapoptosis,J Immunol172(11):6692–6700,2004.

13. AmouraZ,KoutouzovS,ChabreH, et al:Presenceof antinucleo-someautoantibodiesinarestrictedsetofconnectivetissuediseases:antinucleosomeantibodiesoftheIgG3subclassaremarkersofrenalpathogenicity in systemic lupus erythematosus, Arthritis Rheum43(1):76–84,2000.

14. MajetschakM,PerezM,SorellLT,etal:Circulating20Sproteasomelevelsinpatientswithmixedconnectivetissuediseaseandsystemiclupus erythematosus, Clin Vaccine Immunol 15(9):1489–1493,2008.

15. DeshmukhUS,BagavantH,LewisJ,etal:Epitopespreadingwithinlupus-associated ribonucleoprotein antigens, Clin Immunol 117(2):112–120,2005.

16. MonneauxF,MullerS:Keysequencesinvolvedinthespreadingofthe systemic autoimmune response to spliceosomal proteins, Scand J Immunol54(1-2):45–54,2001.

17. GenthE,ZarnowskiH,MierauR,etal:HLA-DR4andGm(1,3;5,21)are associated with U1-nRNP antibody positive connective tissuedisease,Ann Rheum Dis46:189–196,1987.

18. GreidingerEL,ZangYJ,JaimesK,etal:CD4+Tcellstargetepitopesresiding within the RNA-binding domain of the U1-70-kDa smallnuclear ribonucleoprotein autoantigen and have restricted TCRdiversityinanHLA-DR4-transgenicmurinemodelofmixedconnec-tivetissuedisease,J Immunol180(12):8444–8454,2008.

19. MerrymanPF,CrapperRM,LeeS,etal:ClassIImajorhistocompat-ibility complex gene sequences in rheumatoid arthritis: the thirddiversityregionofbothDRbeta1andDRbeta2genesintwoDR1,DRw10-positive individuals specify the same inferred amino acidsequenceas theDRbeta1andDRbeta2genesof aDR4(Dw14)haplotype,Arthritis Rheum32:251–258,1989.

2.Pregnanciesshouldbeplannedwhenthediseaseisinremissionbecause it increases theprobabilityof suc-cessfulmaternalandfetaloutcome.

3.Patients shouldbe regularlymonitoredduringgesta-tion and postpartum by a multidisciplinary teamincluding a rheumatologist, an obstetrician, and aneonatologist.

4. Inthecaseofdiseaserelapseanadequatetreatment,evenaggressiveifnecessary,shouldberecommendedbecauseactivediseasecanbemoredetrimentalforafetusthandrugs.

ThereisoftenatendencytoassumethatallpatientswithoverlapCTDsshouldbeonlong-termcorticosteroids;thismistakeiscompoundedbytheassumptionthatallmedicalproblems in these patients are related to their underlyingoverlap CTDs. For instance, apparent flares of discomfortandpain inoverlapCTDsmaybedue tomyofascialpainsyndromeorfibromyalgiaandarethusunresponsivetocor-ticosteroids.Likewise,thefeelingofmalaiseandeasyfati-gabilitymayberelatedtoareactivedepressionorthefactthatthepatienthasbecomedeconditioned.Prematureath-erosclerosis isnowwell recognizedasacauseof increasedmorbidityandmortalityinAICTDs,117andallpatientswithoverlapsyndromesneedongoingevaluationforriskfactorsand appropriate advice and therapy for hypertension andhyperlipidemia.ThemanagementofpatientswithoverlapCTDsrequirescontinuingreassessmentofanever-changingpatternofclinicalproblemsandaconstantalertnesstotheiatrogenicdisease.Aswithanydiseaseofunknownetiology,effective management of patients with the overlap CTDspresentsaconstantandever-evolvingchallenge.

prognoSiS

Theprognosisforoverlapsyndromesisoftenbetterthantheclassic AICTDs. For instance, Troyanov reported on thefollow-up of 100 patients with idiopathic inflammatorymyopathy. It was found that the long-term course aftertreatmentwithprednisone,withadose/duration that ini-tiallyresultedingoodsymptomaticimprovement,wasstrik-inglydifferent; all PM patients (100%) and most DMpatients(92%)progressedtochronicmyositis,whereasonly58% of overlap patients developed persistent muscledisease.4 The tendency for overlap patients to developchronicdiseasewasmorecommon in thosewithantisyn-thetaseandnucleoporinantibodiesandlesswithantibodiestoU1-RNP,Pm-Scl,orKu.PatientswiththreeorfourU1snRNP antibodies (i.e., anti-70kD, anti-A, anti-C, andanti-U1 snRNA) tended to have minimal renal diseasecomparedwithpatientswithjustoneortworeactivities.118Antibodiesto155kDand140kDproteinsinmyositisarea risk factor for the development of cancer.119 There isunequivocalevidencethatpatientswithhigh-titerU1-RNPantibodies have a low prevalence of serious renal diseaseand life-threatening neurologic problems; in this senseMCTD can be favorably compared with classic SLE.However, not all patients with MCTD have a favorableprognosisanddeathmayoccurfromprogressivepulmonaryhypertensionanditscardiacsequelae.A38-yearfollow-upof47MCTDpatientsattheUniversityofMissourireportedafavorablecoursein62%andcontinuingactivediseasein38%.Eleven(23%)patientshadafataloutcomerelatedto



C


45. BeersWH, InceA,MooreTL:ScleredemaadultorumofBuschke:a case report and review of the literature, Semin Arthritis Rheum35(6):355–359,2006.

46. GhirardelloA,ZampieriS,TarriconeE,etal:Clinicalimplicationsof autoantibody screening in patients with autoimmune myositis,Autoimmunity39(3):217–221,2006.

47. DugarM,CoxS,LimayeV,etal:Clinicalheterogeneityandprog-nostic features of South Australian patients with anti-synthetaseautoantibodies,Intern Med J41:674–679,2010.

48. MarguerieC,BunnCC,BeynonHL,etal:Polymyositis,pulmonaryfibrosisandautoantibodiestoaminoacyl-tRNAsynthetaseenzymes,Q J Med77(282):1019–1038,1990.

49. MummGE,McKownKM,BellCL:Antisynthetase syndromepre-sentingasrheumatoid-likepolyarthritis,J Clin Rheumatol16(7):307–312,2010.

50. BennettRM:Overlapsyndromes.In:FiresteinGS,BuddRC,HarrisED Jr, et al, editors. Textbook of rheumatology, ed 8, Philadelphia,2009,WBSaunders,pp1381–1399.

51. TakadaT,HirakataM,SuwaA,etal:ClinicalandhistopathologicalfeaturesofmyopathiesinJapanesepatientswithanti-SRPautoanti-bodies,Mod Rheumatol19(2):156–164,2009.

52. Bohan A, Peter JB, Bowman RL, Pearson CM: Computer-assistedanalysisof153patientswithpolymyositisanddermatomyositis,Medi-cine (Baltimore)56(4):255–286,1977.

53. ChenYJ,WuCY,HuangYL,etal:Cancerrisksofdermatomyositisandpolymyositis:anationwidecohortstudyinTaiwan,Arthritis Res Ther12(2):R70,2010.

54. ChinoyH,PayneD,PoultonKV,etal:HLA-DPB1associationsdifferbetweenDRB1*03positiveanti-Jo-1andanti-PM-Sclantibodyposi-tive idiopathic inflammatory myopathy, Rheumatology (Oxford)48(10):1213–1217,2009.

55. SharpGC,IrvinWS,LaRoqueRL,etal:Associationofautoantibod-iestodifferentnuclearantigenswithclinicalpatternsofrheumaticdisease and responsiveness to therapy, J Clin Invest 50:350–359,1971.

56. Aringer M, Smolen JS: Mixed connective tissue disease: what isbehindthecurtain?Best Pract Res Clin Rheumatol21(6):1037–1049,2007.

57. SharpGC,IrvinWS,TanEM,etal:Mixedconnectivetissuedisease:anapparentlydistinctrheumaticdiseasesyndromeassociatedwithaspecific antibody to an extractable nuclear antigen, Am J Med52:148–159,1972.

58. BennettRM:Mixedconnectivetissuediseaseandoverlapsyndromes.In:HarrisED,etal,editors.Textbook of rheumatology,ed7,Philadel-phia,2004,WBSaunders,pp1241–1529.

59. Alarcon-SegoviaD,CardielMH:Comparisonbetween3diagnosticcriteria for mixed connective tissue disease. Study of 593 patients,J Rheumatol16(3):328–334,1989.

60. Amigues JM, Cantagrel A, Abbal M, Mazieres B: Comparativestudy of 4 diagnosis criteria sets for mixed connective tissuedisease in patients with anti-RNP antibodies. AutoimmunityGroupoftheHospitalsofToulouse,J Rheumatol23(12):2055–2062,1996.

61. vandenHoogenFH,SpronkPE,BoerboomsAM,etal:Long-termfollow-upof46patientswithanti-(U1)snRNPantibodies,Br J Rheu-matol33:1117–1120,1994.

62. Bennett RM, O’Connell DJ: Mixed connective tisssue disease: aclinicopathologicstudyof20cases,Semin Arthritis Rheum10(1):25–51,1980.

63. Pope JE: Other manifestations of mixed connective tissue disease,Rheum Dis Clin North Am31(3):519–533,vii,2005.

64. BennettRM,O’ConnellDJ:Thearthritisofmixedconnectivetissuedisease,Ann Rheum Dis37(5):397–403,1986.

65. UdoffEJ,GenantHK,KozinF,GinsbergM:Mixedconnectivetissuedisease: the spectrum of radiographic manifestations, Radiology124(3):613–618,1977.

66. Grader-BeckT,WigleyFM:Raynaud’sphenomenoninmixedcon-nective tissue disease, Rheum Dis Clin North Am 31(3):465–481,2005.

67. ViannaMA,BorgesCT,BorbaEF,etal:Myositisinmixedconnec-tivetissuedisease:auniquesyndromecharacterizedbyimmunohis-topathologicelementsofbothpolymyositisanddermatomyositis,Arq Neuropsiquiatr62(4):923–934,2004.

68. Lundberg IE: Cardiac involvement in autoimmune myositis andmixedconnectivetissuedisease,Lupus14(9):708–712,2005.

20. JamesJA,ScofieldRH,HarleyJB:Basicaminoacidspredominateinthesequentialautoantigenicdeterminantsofthesmallnuclear70Kribonucleoprotein,Scand J Immunol39:557–566,1994.

21. Barakat S, Briand JP, Abuaf N, et al: Mapping of epitopes on U1snRNPpolypeptideAwithsyntheticpeptidesandautoimmunesera,Clin Exp Immunol86:71–78,1991.

22. Hassfeld W, Steiner G, Studnicka-Benke A, et al: Autoimmuneresponsetothespliceosome.Animmunologiclinkbetweenrheuma-toid arthritis, mixed connective tissue disease, and systemic lupuserythematosus,Arthritis Rheum38(6):777–785,1995.

23. Mahoney JA, Rosen A: Apoptosis and autoimmunity, Curr Opin Immunol17(6):583–588,2005.

24. Mihara S, Suzuki N, Takeba Y, et al: Combination of molecularmimicryandaberrantautoantigenexpressionisimportantfordevel-opmentof anti-Fas ligandautoantibodies inpatientswith systemiclupuserythematosus,Clin Exp Immunol129(2):359–369,2002.

25. Casciola-RosenLA,AnhaltG,RosenA:Autoantigenstargeted insystemic lupus erythematosus are clustered in two populations ofsurfacestructuresonapoptotickeratinocytes,J Exp Med179(4):1317–1330,1994.

26. Hof D, Cheung K, de Rooij DJ, et al: Autoantibodies specific forapoptoticU1-70Karesuperiorserologicalmarkersformixedconnec-tivetissuedisease,Arthritis Res Ther7(2):R302–R309,2005.

27. Wolfe F, Smythe HA, Yunus MB, et al: The American College ofRheumatology1990Criteria for theClassificationofFibromyalgia.Report of the Multicenter Criteria Committee, Arthritis Rheum33(2):160–172,1990.

28. Okano Y, Steen VD, Medsger TA, Jr: Autoantibody reactive withRNApolymeraseIIIinsystemicsclerosis,Ann Intern Med119:1005–1013,1993.

29. MoscaM,TaniC,NeriC,etal:Undifferentiatedconnectivetissuediseases(UCTD),Autoimmun Rev6(1):1–4,2006.

30. VazCC,CoutoM,MedeirosD,etal:Undifferentiatedconnectivetissue disease: a seven-center cross-sectional study of 184 patients,Clin Rheumatol28(8):915–921,2009.

31. Bodolay E, Csiki Z, Szekanecz Z, et al: Five-year follow-up of 665Hungarian patients with undifferentiated connective tissue disease(UCTD),Clin Exp Rheumatol21(3):313–320,2003.

32. SmithV,DeKF,PizzorniC,etal:Nailfoldcapillaroscopyforday-to-dayclinicaluse:constructionofasimplescoringmodalityasaclinicalprognostic index for digital trophic lesions, Ann Rheum Dis70(1):180–183,2011.

33. ZoldE,SzodorayP,GaalJ,etal:VitaminDdeficiencyinundifferenti-ated connective tissue disease, Arthritis Res Ther 10(5):R123,2008.

34. Pope JE: Scleroderma overlap syndromes, Curr Opin Rheumatol14(6):704–710,2002.

35. Steen VD: Autoantibodies in systemic sclerosis, Semin Arthritis Rheum35(1):35–42,2005.

36. HunzelmannN,GenthE,KriegT,etal:TheregistryoftheGermanNetworkforSystemicScleroderma:frequencyofdiseasesubsetsandpatternsoforgan involvement,Rheumatology (Oxford)47(8):1185–1192,2008.

37. Ho KT, Reveille JD: The clinical relevance of autoantibodies inscleroderma,Arthritis Res Ther5(2):80–93,2003.

38. HankeK,BrucknerCS,DahnrichC,etal:AntibodiesagainstPM/Scl-75andPM/Scl-100areindependentmarkersfordifferentsubsetsofsystemicsclerosispatients,Arthritis Res Ther11(1):R22,2009.

39. Zimmermann C, Steiner G, Skriner K, et al: The concurrence ofrheumatoid arthritis and limited systemic sclerosis: clinical andserologic characteristics of an overlap syndrome, Arthritis Rheum41(11):1938–1945,1998.

40. AkimotoS,IshikawaO,MuroY,etal:Clinicalandimmunologicalcharacterization of patients with systemic sclerosis overlappingprimary biliary cirrhosis: a comparison with patients with systemicsclerosisalone,J Dermatol26(1):18–22,1999.

41. JablonskaS,BlaszczykM:Sclerodermaoverlapsyndromes,Adv Exp Med Biol455:85–92:85-92,1999.

42. ChenAY,ZirwasMJ,HeffernanMP:Nephrogenicsystemicfibrosis:areview,J Drugs Dermatol9(7):829–834,2010.

43. Bischoff L, Derk CT: Eosinophilic fasciitis: demographics, diseasepatternandresponsetotreatment:reportof12casesandreviewoftheliterature,Int J Dermatol47(1):29–35,2008.

44. BoinF,HummersLK:Scleroderma-likefibrosingdisorders,Rheum Dis Clin North Am34(1):199–220,2008.



C


91. Soltesz P, Bereczki D, Szodoray P, et al: Endothelial cell markersreflecting endothelial cell dysfunction inpatientswithmixed con-nectivetissuedisease,Arthritis Res Ther12(3):R86,2010.

92. SegondP,YeniP,JacquotJM,MassiasP:Severeautoimmuneanemiaandthrombopeniainmixedconnectivetissuedisease,Arthritis Rheum21:995,1986.

93. Mimura Y, Ihn H, Jinnin M, et al: Rheumatoid factor isotypes inmixed connective tissue disease, Clin Rheumatol 25(4):572–574,2006.

94. KomatireddyGR,WangGS,SharpGC,HoffmanRW:Antiphospho-lipid antibodies among anti-U1-70kDa autoantibody positivepatientswithmixedconnectivetissuedisease,J Rheumatol24(2):319–322,1997.

95. KitridouRC:Pregnancyinmixedconnectivetissuedisease,Rheum Dis Clin North Am31(3):497–508,vii,2005.

96. Kaufman RL, Kitridou RC: Pregnancy in mixed connective tissuedisease:comparisonwithsystemiclupuserythematosus,J Rheumatol9(4):549–555,1982.

97. Bodolay E, Bojan F, Szegedi G, et al: Cytotoxic endothelial cellantibodies in mixed connective tissue disease, Immunol Lett20(2):163–167,1989.

98. FujiwakiT,UrashimaR,UrushidaniY,etal:Neonatallupuserythe-matosus associated with maternal mixed connective tissue disease,Pediatr Int45(2):210–213,2003.

99. TsaiYY,YangYH,YuHH,etal:Fifteen-yearexperienceofpediatric-onsetmixedconnectivetissuedisease,Clin Rheumatol29(1):53–58,2010.

100. KimP,GrossmanJM:Treatmentofmixedconnectivetissuedisease,Rheum Dis Clin North Am31(3):549–565,viii,2005.

101. LevienTL:Advances in the treatmentofRaynaud’sphenomenon,Vasc Health Risk Manag6:167–177,2010.

102. Galie N, Manes A, Branzi A: Medical therapy of pulmonaryhypertension.Theprostacyclins,Clin Chest Med22(3):529–537,x,2001.

103. Vegh J,SoosG,Csipo I, et al:Pulmonary arterialhypertension inmixedconnectivetissuedisease: successful treatmentwithIloprost,Rheumatol Int26(3):264–269,2006.

104. SanchezO,SitbonO, JaisX, et al: Immunosuppressive therapy inconnective tissue diseases-associated pulmonary arterial hyperten-sion,Chest130(1):182–189,2006.

105. NaclerioC,D’AngeloS,BaldiS,etal:Efficacyofbosentaninthetreatmentofapatientwithmixedconnectivetissuediseasecompli-cated by pulmonary arterial hypertension, Clin Rheumatol 29:687–690,2009.

106. DistlerJH,DistlerO:Tyrosinekinaseinhibitorsforthetreatmentoffibroticdiseasessuchassystemicsclerosis:towardsmoleculartargetedtherapies,Ann Rheum Dis69(Suppl1):i48–i51,2010.

107. GodeauB,ChevretS,VaretB,etal: Intravenous immunoglobulinorhigh-dosemethylprednisolone,withorwithoutoralprednisone,for adults with untreated severe autoimmune thrombocytopenicpurpura: a randomised, multicentre trial, Lancet 359(9300):23–29,2002.

108. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al:Successfultherapywithdanazolinrefractoryautoimmunethrombo-cytopenia associated with rheumatic diseases, Br J Rheumatol36(10):1095–1099,1997.

109. Myllykangas-Luosujarvi R, Jantunen E, Kaipiainen-Seppanen O,et al: Autologous peripheral blood stem cell transplantation in apatientwithseveremixedconnectivetissuedisease,Scand J Rheuma-tol29(5):326–327,2000.

110. Wallace DJ: Antimalarials—the ‘real’ advance in lupus, Lupus10(6):385–387,2001.

111. Sato EI: Methotrexate therapy in systemic lupus erythematosus,Lupus10(3):162–164,2001.

112. Nolan RJ, Shulman ST, Victorica BE: Congenital complete heartblock associated with maternal mixed connective tissue disease,J Pediatr95(3):420–422,1979.

113. GinerGalvanV,OltraMR,RuedaD,etal:Severeacutehepatitisrelated tohydroxychloroquine inawomanwithmixedconnectivetissuedisease,Clin Rheumatol26(6):971–972,2007.

114. RichezC,BlancoP,DumoulinC,SchaeverbekeT:Lupuserythema-tosusmanifestationsexacerbatedbyetanercepttherapyinapatientwithmixedconnectivetissuedisease,Clin Exp Rheumatol23(2):273,2005.

69. SullivanWD,HurstDJ,HarmonCE,etal:Aprospectiveevaluationemphasizingpulmonaryinvolvementinpatientswithmixedconnec-tivetissuedisease,Medicine (Baltimore)63(2):92–107,1984.

70. WigleyFM,LimaJA,MayesM,etal:Theprevalenceofundiagnosedpulmonary arterial hypertension in subjects with connective tissuediseaseatthesecondaryhealthcarelevelofcommunity-basedrheu-matologists (the UNCOVER study), Arthritis Rheum 52(7):2125–2132,2005.

71. VeghJ,SzodorayP,KappelmayerJ,etal:Clinicalandimmunosero-logicalcharacteristicsofmixedconnective tissuediseaseassociatedwithpulmonaryarterialhypertension,Scand J Immunol64(1):69–76,2006.

72. VeghJ,SzodorayP,KappelmayerJ,etal:Clinicalandimmunosero-logicalcharacteristicsofmixedconnective tissuediseaseassociatedwithpulmonaryarterialhypertension,Scand J Immunol64(1):69–76,2006.

73. HantFN,HerpelLB,SilverRM:Pulmonarymanifestationsofsclero-derma and mixed connective tissue disease, Clin Chest Med31(3):433–449,2010.

74. BullTM,FaganKA,BadeschDB:Pulmonaryvascularmanifestationsof mixed connective tissue disease, Rheum Dis Clin North Am31(3):451–464,vi,2005.

75. ColinG,NunesH,HatronPY, et al: [Clinical studyof interstitiallung disease in mixed connective tissue disease], Rev Mal Respir27(3):238–246,2010.

76. Vegh J,SzilasiM,SoosG,etal: [Interstitial lungdisease inmixedconnectivetissuedisease],Orv Hetil146(48):2435–2443,2005.

77. CoghlanJG,PopeJ,DentonCP:Assessmentofendpointsinpulmo-naryarterialhypertensionassociatedwithconnectivetissuedisease,Curr Opin Pulm Med16Suppl1:S27–S34,2010.

78. Kitridou RC, Akmal M, Turkel SB, et al: Renal involvement inmixed connective tissue disease: a longitudinal clinicopathologicstudy,Semin Arthritis Rheum16(2):135–145,1986.

79. BennettRM,SpargoBH: Immunecomplexnephropathy inmixedconnectivetissuedisease,Am J Med63(4):534–541,1977.

80. Takahashi A, Abe K, Yokokawa J, et al: Clinical features ofliver dysfunction in collagen diseases, Hepatol Res 40:1092–1097,2010.

81. Bennett RM, Bong DM, Spargo BH: Neuropsychiatric problemsin mixed connective tissue disease, Am J Med 65(6):955–962,1986.

82. HajasA,SzodorayP,BarathS, et al:Sensorineuralhearing loss inpatients with mixed connective tissue disease: immunologicalmarkers and cytokine levels, J Rheumatol 36(9):1930–1936,2009.

83. OkadaJ,HamanaT,KondoH:Anti-U1RNPantibodyandasepticmeningitisinconnectivetissuediseases,Scand J Rheumatol32(4):247–252,2003.

84. Sato T, Fujii T, Yokoyama T, et al: Anti-U1 RNP antibodies incerebrospinalfluidareassociatedwithcentralneuropsychiatricmani-festations in systemic lupus erythematosus and mixed connectivetissuedisease,Arthritis Rheum62:3730–3740,2010.

85. SchedelJ,KuchenbuchS,SchoelmerichJ,etal:Cerebrallesionsinpatients with connective tissue diseases and systemic vasculitides:are there specific patterns? Ann N Y Acad Sci 1193(1):167–175,2010.

86. AlpertMA,GoldbergSH,SingsenBH,etal:Cardiovascularmani-festations of mixed connective tissue disease in adults, Circulation68(6):1182–1193,1983.

87. MaricqHR,LeRoyEC,D’AngeloWA,etal:Diagnosticpotentialofin vivo capillary microscopy in scleroderma and related disorders,Arthritis Rheum23:183,1980.

88. Schmidt WA, Krause A, Schicke B, Wernicke D: Color Dopplerultrasonographyofhandandfingerarteries todifferentiateprimaryfrom secondary forms of Raynaud’s phenomenon, J Rheumatol35(8):1591–1598,2008.

89. Lambova SN, Muller-Ladner U: The role of capillaroscopy in dif-ferentiation of primary and secondary Raynaud’s phenomenon inrheumaticdiseases: a reviewof the literatureand twocase reports,Rheumatol Int29(11):1263–1271,2009.

90. PellerJS,GaborGT,PorterJM,BennettRM:Angiographicfindingsinmixedconnectivetissuedisease.Correlationwithfingernailcapil-lary photomicroscopy and digital photoplethysmography findings,Arthritis Rheum28(7):768–774,1985.



C


119. ChinoyH,FertigN,OddisCV,etal:Thediagnosticutilityofmyo-sitisautoantibodytestingforpredictingtheriskofcancer-associatedmyositis,Ann Rheum Dis66(10):1345–1349,2007.

120. BurdtMA,HoffmanRW,DeutscherSL,et al:Long-termoutcomeinmixedconnectivetissuedisease:longitudinalclinicalandserologicfindings,Arthritis Rheum42(5):899–909,1999.

referencesThe references for this chapter can also be found onwww.expertconsult.com.

115. SemM,MolbergO,LundMB,GranJT:Rituximabtreatmentoftheanti-synthetase syndrome: a retrospective case series, Rheumatology (Oxford)48(8):968–971,2009.

116. DoriaA,IaccarinoL,GhirardelloA,etal:Pregnancyinrareautoim-munerheumaticdiseases:UCTD,MCTD,myositis,systemicvascu-litisandBehçetdisease,Lupus13(9):690–695,2004.

117. HahnBH,GrossmanJ,ChenW,McMahonM:Thepathogenesisofatherosclerosisinautoimmunerheumaticdiseases:rolesofinflamma-tionanddyslipidemia,J Autoimmun28(2-3):69–75,2007.

118. Kaneko Y, Suwa A, Hirakata M, et al: Clinical associations withautoantibody reactivities to individual components of U1 smallnuclearribonucleoprotein,Lupus19(3):307–312,2010.



AUTHOR QUERY FORM

Dear Author

During the preparation of your manuscript for publication, the questions listed below have arisen. Please attend to these matters and return this form with your proof.

Many thanks for your assistance.

Query References Query Remarks

1 AU: We have your affiliations for the front matter listed as follows; pls. verify or update them if needed: Robert Bennett, MD / Professor of Medicine / Oregon Health and Science University / Portland, Oregon.

2 AU: Are antigen processing cells the same as antigen-presenting cells (APCs), which is on the style sheet?

3 AU: Is the key point that begins with “Synthetase and …” supposed to be indented like the previous three, or does it stand on its own?

4 AU: Pls. check dosage & initial it.

5 AU: Pls. clarify the semicolon after “Th”—did you intend it to be a comma? If not, is a word missing after the semicolon to explain the rest of the list?

6 AU: Do you mean “usual treatment-presenting features” (hyphenate)?

7 AU: Pls. clarify the phrase “(see A)” in Fig 86-1’s legend; delete?

8 AU: Expanded Fig 86-6’s credit line per PubMed (added 2nd author name, article title, & corrected page numbers); is it correct?

9 AU: Pls. check dosages in Table 86-6 & initial.



scleroderma overlap syndromes

Documents