2023
Clinical Phenotypes of Patients With Systemic Sclerosis With Distinct Molecular Signatures in Skin
Yang M, Goh V, Lee J, Espinoza M, Yuan Y, Carns M, Aren K, Chung L, Khanna D, McMahan ZH, Agrawal R, Nelson L, Shah SJ, Whitfield ML, Hinchcliff M. Clinical Phenotypes of Patients With Systemic Sclerosis With Distinct Molecular Signatures in Skin. Arthritis Care & Research 2023, 75: 1469-1480. PMID: 35997480, PMCID: PMC9947190, DOI: 10.1002/acr.24998.Peer-Reviewed Original ResearchConceptsRadiographic interstitial lung diseaseInterstitial lung diseaseHigher mRSSSSc patientsSerum autoantibodiesClinical phenotypeHealthy participantsScl-70 antibodyPresent multicenter studySimilar disease durationSystemic sclerosis patientsDistinct clinical phenotypesSkin gene expressionValuable clinical informationDcSSc patientsDisease durationIdentifies patientsSystemic sclerosisSclerosis patientsMulticenter studyLung diseaseSkin fibrosisSimilar prevalenceClinical dataMultivariable modelingThree Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients
Makinde H, Dunn JLM, Gadhvi G, Carns M, Aren K, Chung AH, Muhammad LN, Song J, Cuda CM, Dominguez S, Pandolfino JE, D'Amico J, Budinger GS, Assassi S, Frech TM, Khanna D, Shaeffer A, Perlman H, Hinchcliff M, Winter DR. Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients. Arthritis & Rheumatology 2023, 75: 595-608. PMID: 36281773, PMCID: PMC10165944, DOI: 10.1002/art.42380.Peer-Reviewed Original ResearchConceptsDiffuse cutaneous systemic sclerosisNonclassical monocytesClassical monocytesSSc patientsTranscriptional signatureSystemic sclerosisSkin diseasesCharacteristic transcriptional signaturesRNA-seq dataSSc skin diseaseWorse lung functionCutaneous systemic sclerosisEarly systemic sclerosisActivity outcome measuresDistinct transcriptional profilesTranscriptional profilingRNA sequencingTranscriptional profilesProspective registryDisease activityLung functionComplex clinical phenotypeGene expressionPeripheral bloodMinority cell populationHyperspectral imaging in systemic sclerosis-associated Raynaud phenomenon
Teaw S, Gupta A, Williams A, Wilson F, Sumpio B, Sumpio B, Hinchcliff M. Hyperspectral imaging in systemic sclerosis-associated Raynaud phenomenon. Arthritis Research & Therapy 2023, 25: 10. PMID: 36670487, PMCID: PMC9854186, DOI: 10.1186/s13075-023-02990-3.Peer-Reviewed Original ResearchConceptsRaynaud's condition scoreCochin Hand Function ScaleSSc patientsClinic settingPatient-reported outcome instrumentsResultsNinety-two percentSystemic sclerosis patientsMann-Whitney U testHealthy control participantsCHF scoreSSc durationSSc-RPDigital ulcersCutaneous SScProvocation challengeRaynaud's phenomenonSclerosis patientsClinical trialsOutcome instrumentsOxygen saturationBurden assessmentPatientsCold provocationHemoglobin concentrationDisease severity
2022
Circulating CTRP9 Is Associated With Severity of Systemic Sclerosis–Associated Interstitial Lung Disease
Yang MM, Balmert LC, Marangoni RG, Carns M, Hinchcliff M, Korman BD, Varga J. Circulating CTRP9 Is Associated With Severity of Systemic Sclerosis–Associated Interstitial Lung Disease. Arthritis Care & Research 2022, 75: 152-157. PMID: 34251759, PMCID: PMC9233895, DOI: 10.1002/acr.24749.Peer-Reviewed Original ResearchConceptsC1q/tumor necrosis factor-related protein 9Interstitial lung diseaseSystemic sclerosisLung diseaseLung functionSystemic Sclerosis-Associated Interstitial Lung DiseaseSSc-associated interstitial lung diseasePulmonary function test dataLatent trajectory analysisVital capacity percentWorse lung functionPrimary outcome measureWorse pulmonary functionCause of morbidityRetrospective longitudinal studyAdipose tissue metabolismCross-sectional analysisAdipokine homeostasisDisease stabilityPulmonary functionSSc patientsSerum levelsPatient RegistryPredictive markerCapacity percentHuman dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis
Bhandari R, Yang H, Kosarek NN, Smith AE, Garlick JA, Hinchcliff M, Whitfield ML, Pioli PA. Human dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis. Rheumatology 2022, 62: si114-si124. PMID: 35946522, PMCID: PMC9910573, DOI: 10.1093/rheumatology/keac453.Peer-Reviewed Original ResearchConceptsFibroblast-derived exosomesSSc patientsMacrophage activationGender-matched control subjectsSSc fibroblastsDonor-derived macrophagesReciprocal activationUpregulated surface expressionMHC class IICo-cultured macrophagesHealthy control fibroblastsExtracellular matrix depositionCell typesSystemic sclerosisHealthy ageIL-10Production of collagenIL-12p40IL-6Control subjectsSkin biopsiesSSc skinTherapeutic targetingClass IIFlow cytometryDifferences in symptom experience among patients with systemic sclerosis: a cluster analytic approach to identifying subgroups
Murphy SL, Chen YT, Lee YC, Carns M, Aren K, Korman B, Hinchcliff M, Varga J. Differences in symptom experience among patients with systemic sclerosis: a cluster analytic approach to identifying subgroups. Rheumatology 2022, 62: si64-si73. PMID: 35920770, PMCID: PMC9910572, DOI: 10.1093/rheumatology/keac444.Peer-Reviewed Original ResearchConceptsSleep disturbancesSymptom experienceSymptom subgroupsSymptom clustersTreatment approachesSingle US academic medical centerLarge SSc cohortPatient-reported symptomsCo-occurring painUS academic medical centersSymptoms of peopleDistinct symptom clustersAcademic medical centerMain symptom clustersSimilar disease severityDifferent symptom presentationsSSc cohortSSc patientsSystemic sclerosisPain interferencePatient subgroupsModerate symptomsMedical CenterSymptom presentationDisease severityA genomic meta-analysis of clinical variables and their association with intrinsic molecular subsets in systemic sclerosis
Franks JM, Toledo DM, Martyanov V, Wang Y, Huang S, Wood TA, Spino C, Chung L, Denton C, Derrett-Smith E, Gordon JK, Spiera R, Domsic R, Hinchcliff M, Khanna D, Whitfield ML. A genomic meta-analysis of clinical variables and their association with intrinsic molecular subsets in systemic sclerosis. Rheumatology 2022, 62: 19-28. PMID: 35751592, PMCID: PMC9788818, DOI: 10.1093/rheumatology/keac344.Peer-Reviewed Original ResearchConceptsMolecular subsetsIntrinsic subsetInflammatory subsetBaseline demographicsSSc patientsWhite/Caucasian patientsBaseline clinical demographicsAverage disease durationRodnan skin scoreAfrican American/BlackASSET trialUnique gene expression signatureDisease durationGene expression signaturesClinical demographicsParticipant seraSkin scoreSystemic sclerosisValidation cohortClinical variablesCaucasian patientsSpecific therapyAmerican/BlackSkin biopsiesDisease pathogenesis
2021
Heterogeneity of primary and secondary peristalsis in systemic sclerosis: A new model of “scleroderma esophagus”
Carlson DA, Prescott JE, Germond E, Brenner D, Carns M, Correia CS, Tetreault M, McMahan ZH, Hinchcliff M, Kou W, Kahrilas PJ, Perlman HR, Pandolfino JE. Heterogeneity of primary and secondary peristalsis in systemic sclerosis: A new model of “scleroderma esophagus”. Neurogastroenterology & Motility 2021, 34: e14284. PMID: 34709690, PMCID: PMC9046463, DOI: 10.1111/nmo.14284.Peer-Reviewed Original ResearchConceptsHigh-resolution manometryIneffective esophageal motilitySecondary peristalsisSystemic sclerosisFLIP panometryAbsent contractilityContractile responseDistensibility indexFunctional luminal imaging probe (FLIP) panometryEsophagogastric junction distensibility indexPattern of contractilityEGJ-DIScleroderma esophagusEsophageal dysmotilityReflux severitySSc patientsClinical outcomesEsophageal motilityManometric diagnosisPrimary peristalsisMotor abnormalitiesNormal peristalsisEsophageal functionChicago ClassificationPatientsComputer vision applied to dual-energy computed tomography images for precise calcinosis cutis quantification in patients with systemic sclerosis
Chandrasekaran AC, Fu Z, Kraniski R, Wilson FP, Teaw S, Cheng M, Wang A, Ren S, Omar IM, Hinchcliff ME. Computer vision applied to dual-energy computed tomography images for precise calcinosis cutis quantification in patients with systemic sclerosis. Arthritis Research & Therapy 2021, 23: 6. PMID: 33407814, PMCID: PMC7788847, DOI: 10.1186/s13075-020-02392-9.Peer-Reviewed Original ResearchConceptsSSc patientsCalcinosis cutisCC lesionsSystemic sclerosisBland-Altman plotsConcordance correlation coefficientIndependent radiologistsLin's concordance correlation coefficientConfidence intervalsValid clinical trialsExpert musculoskeletal radiologistsSpearman correlation coefficientClinical trialsMusculoskeletal radiologistsPatientsBurden quantificationLesionsMean differenceGold standardRadiologistsCorrelation coefficientLonger lengthPhalanxSpearman's rhoValidation study
2020
Mast cell activation in the systemic sclerosis esophagus
Tom K, Mehta BK, Hoffmann A, Aren K, Carns M, Lee J, Martyanov V, Popovich D, Kosarek N, Wood T, Brenner D, Carlson DA, Ostilla L, Willcocks E, Bryce P, Wechsler JB, Whitfield ML, Hinchcliff M. Mast cell activation in the systemic sclerosis esophagus. Journal Of Scleroderma And Related Disorders 2020, 6: 77-86. PMID: 34179507, PMCID: PMC8225255, DOI: 10.1177/2397198320941322.Peer-Reviewed Original ResearchMast cell numbersSSc patientsCell-directed therapiesSystemic sclerosisEsophageal biopsiesClinical parametersHealthy participantsCell numberNormal-like subsetsMast cell densityCell-targeted therapiesMast cell markersUseful therapeutic approachMast cell activationMast cell quantityRelevant clinical parametersMolecular classification systemEoE patientsEsophageal symptomsEosinophilic esophagitisUpper esophagusSkin biopsiesEntire esophagusMast cellsTherapeutic approachesCalcinosis is associated with ischemic manifestations and increased disability in patients with systemic sclerosis
Valenzuela A, Baron M, Rodriguez-Reyna TS, Proudman S, Khanna D, Young A, Hinchcliff M, Steen V, Gordon J, Hsu V, Castelino FV, Schoenfeld S, Li S, Wu JY, Fiorentino D, Chung L. Calcinosis is associated with ischemic manifestations and increased disability in patients with systemic sclerosis. Seminars In Arthritis And Rheumatism 2020, 50: 891-896. PMID: 32898758, PMCID: PMC8205269, DOI: 10.1016/j.semarthrit.2020.06.007.Peer-Reviewed Original ResearchConceptsSSc patientsSystemic sclerosisDigital ischemiaHealth Assessment Questionnaire Disability IndexCochin Hand Functional ScaleACR/EULAR criteriaSubcutaneous calcium depositionConsecutive SSc patientsSubset of patientsMedian T-scoreDisability IndexFinger/thumbCommon complicationDisease durationEULAR criteriaIschemic manifestationsAcro-osteolysisMultivariable analysisPhysical examinationHand functionClinical correlationHand dysfunctionClear historyHigh burdenBone densitometryProfibrotic Activation of Human Macrophages in Systemic Sclerosis
Bhandari R, Ball MS, Martyanov V, Popovich D, Schaafsma E, Han S, ElTanbouly M, Orzechowski NM, Carns M, Arroyo E, Aren K, Hinchcliff M, Whitfield ML, Pioli PA. Profibrotic Activation of Human Macrophages in Systemic Sclerosis. Arthritis & Rheumatology 2020, 72: 1160-1169. PMID: 32134204, PMCID: PMC7329566, DOI: 10.1002/art.41243.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntigens, CDAntigens, Differentiation, MyelomonocyticCell DifferentiationChemokine CCL2Coculture TechniquesFemaleFibroblastsFibrosisHLA-DR AntigensHumansImmunophenotypingInterleukin-6Lectins, C-TypeLeukocytes, MononuclearMacrophage ActivationMacrophagesMaleMannose ReceptorMannose-Binding LectinsMiddle AgedMonocytesPhosphorylationReceptor, Transforming Growth Factor-beta Type IReceptor, Transforming Growth Factor-beta Type IIReceptors, Cell SurfaceRNA, MessengerScleroderma, SystemicSkinSTAT3 Transcription FactorTranscriptomeTransforming Growth Factor betaConceptsPeripheral blood mononuclear cellsSystemic sclerosisSSc patientsBasal conditionsSex-matched healthy controlsSSc fibroblastsSurface markersHealthy donor monocytesBlood mononuclear cellsMediator of fibrosisInflammatory macrophage activationMonocyte-derived macrophagesActivation profilesGrowth factor βFibrotic activationGene expression signaturesDonor monocytesMononuclear cellsProfibrotic activationSkin fibrosisInterleukin-6Healthy controlsSSc skinIndependent cohortMacrophage activationPro-fibrotic Activation of Human Macrophages in Systemic Sclerosis
Bhandari R, Ball M, Martyanov V, Popovich D, Schaafsma E, Han S, Eltanbouly M, Carns M, Arroyo E, Aren K, Hinchcliff M, Whitfield M, Pioli P. Pro-fibrotic Activation of Human Macrophages in Systemic Sclerosis. The Journal Of Immunology 2020, 204: 224.33-224.33. DOI: 10.4049/jimmunol.204.supp.224.33.Peer-Reviewed Original ResearchSystemic sclerosisSSc patientsIL-6IL-6 blockadeHealthy donor monocytesMediator of fibrosisFibrotic activationSSc tissuesInflammatory signatureDonor monocytesPatient macrophagesHealthy donorsTherapeutic targetingBasal conditionsSoluble factorsHuman macrophagesSurface markersMacrophagesPatient's skinElevated levelsGene expression profilesSclerosisPatientsFibrosisImmunophenotypeCirculating classical monocytes share a common transcriptional signature with skin macrophages in Systemic Sclerosis
Makinde H, Dominguez S, Cuda C, Gadhvi G, Aren K, Zeng C, Eickelberg G, Khanna D, Assassi S, Frech T, Winter D, Perlman H, Hinchcliff M. Circulating classical monocytes share a common transcriptional signature with skin macrophages in Systemic Sclerosis. The Journal Of Immunology 2020, 204: 152.12-152.12. DOI: 10.4049/jimmunol.204.supp.152.12.Peer-Reviewed Original ResearchClassical monocytesSSc patientsSystemic sclerosisSkin macrophagesCommon transcriptional signatureEnd-organ fibrosisSystemic sclerosis cohortTranscriptional signatureSites of fibrosisPrecursors of macrophagesUpregulated genesSSc progressionProspective registryControl patientsProinflammatory moleculesSkin biopsiesPatientsMacrophage clustersMacrophagesMonocytesRespective controlsPrecursor populationSclerosisSignificant differencesFibrosis
2019
Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile
Skaug B, Khanna D, Swindell WR, Hinchcliff ME, Frech TM, Steen VD, Hant FN, Gordon JK, Shah AA, Zhu L, Zheng WJ, Browning JL, Barron AMS, Wu M, Visvanathan S, Baum P, Franks JM, Whitfield ML, Shanmugam VK, Domsic RT, Castelino FV, Bernstein EJ, Wareing N, Lyons MA, Ying J, Charles J, Mayes MD, Assassi S. Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile. Annals Of The Rheumatic Diseases 2019, 79: annrheumdis-2019-215894. PMID: 31767698, PMCID: PMC7386329, DOI: 10.1136/annrheumdis-2019-215894.Peer-Reviewed Original ResearchConceptsImmune cell signaturesEarly diffuse systemic sclerosisDiffuse systemic sclerosisLonger disease durationSystemic sclerosisDisease durationCell signatureSSc patientsT cellsEarly diffuse cutaneous systemic sclerosisScleroderma Outcome Study cohortDiffuse cutaneous systemic sclerosisShorter disease durationCutaneous systemic sclerosisRodnan skin scoreCD8 T cellsB cell signaturesCD4 T cellsSystemic sclerosis cohortImmune cell markersClinical trial designDiffuse SSc patientsBiopsy RNAProspective registryClinical course
2018
Diffuse cardiac fibrosis quantification in early systemic sclerosis by magnetic resonance imaging and correlation with skin fibrosis
Lee DC, Hinchcliff ME, Sarnari R, Stark MM, Lee J, Koloms K, Hoffmann A, Carns M, Thakrar A, Aren K, Varga J, Aquino A, Carr JC, Benefield BC, Shah SJ. Diffuse cardiac fibrosis quantification in early systemic sclerosis by magnetic resonance imaging and correlation with skin fibrosis. Journal Of Scleroderma And Related Disorders 2018, 3: 159-169. PMID: 29808171, PMCID: PMC5969530, DOI: 10.1177/2397198318762888.Peer-Reviewed Original ResearchEarly systemic sclerosisT1 mapping parametersSystemic sclerosisSSc patientsDiffuse myocardial fibrosisT1 mapping indicesSkin scoreMyocardial fibrosisSkin fibrosisCardiac structure/functionRodnan skin scoreCardiac magnetic resonance T1 mappingT1 mappingMagnetic resonance imagingMagnetic resonance T1 mappingCardiac involvementCardiovascular evaluationConsecutive patientsClinical studiesPatientsResonance imagingFibrosisFibrosis quantificationCine imagingSclerosis
2017
Abnormal esophageal acid exposure on high‐dose proton pump inhibitor therapy is common in systemic sclerosis patients
Stern EK, Carlson DA, Falmagne S, Hoffmann AD, Carns M, Pandolfino JE, Hinchcliff M, Brenner DM. Abnormal esophageal acid exposure on high‐dose proton pump inhibitor therapy is common in systemic sclerosis patients. Neurogastroenterology & Motility 2017, 30 PMID: 29110377, PMCID: PMC5771836, DOI: 10.1111/nmo.13247.Peer-Reviewed Original ResearchConceptsProton pump inhibitorsAcid exposure timeEsophageal acid exposureSystemic sclerosis patientsHigh-dose proton pump inhibitorsEsophageal pH-impedance testingGastro-esophageal reflux diseasePH-impedance testingSSc patientsSystemic sclerosisSclerosis patientsAcid exposurePPI therapyHigh-dose proton pump inhibitor therapyAbnormal esophageal acid exposureCase-control retrospective analysisHigh-dose PPI therapyHigh-resolution manometry findingsHigher acid exposure timeTotal acid exposure timeProton pump inhibitor therapyTwice-daily proton pump inhibitorsHiatal hernia sizeNon-SSc patientsRheumatology SSc criteriaBrief Report: Association of Elevated Adipsin Levels With Pulmonary Arterial Hypertension in Systemic Sclerosis
Korman BD, Marangoni RG, Hinchcliff M, Shah SJ, Carns M, Hoffmann A, Ramsey‐Goldman R, Varga J. Brief Report: Association of Elevated Adipsin Levels With Pulmonary Arterial Hypertension in Systemic Sclerosis. Arthritis & Rheumatology 2017, 69: 2062-2068. PMID: 28651038, PMCID: PMC5748338, DOI: 10.1002/art.40193.Peer-Reviewed Original ResearchMeSH KeywordsAdiponectinAdultAgedAutoantibodiesComplement Factor DCytokinesFemaleGene Expression ProfilingHumansHypertension, PulmonaryLeptinMaleMiddle AgedNatriuretic Peptide, BrainNicotinamide PhosphoribosyltransferaseOdds RatioPolymorphism, Single NucleotideResistinScleroderma, DiffuseScleroderma, LimitedConceptsSSc-related pulmonary arterial hypertensionPulmonary arterial hypertensionSystemic sclerosisAdipokine levelsComplement pathway activationAdipsin levelsArterial hypertensionLimited cutaneous systemic sclerosisB-type natriuretic peptidePathway activationSerum adipokine levelsCutaneous systemic sclerosisLevels of adiponectinGene single nucleotide polymorphismsAdipose tissue biologyTissue-derived markersAdipokine balanceAutoantibody statusPulmonary functionSSc patientsAdipocyte dysfunctionClinical featuresPathogenic linkClinical manifestationsNatriuretic peptide
2016
Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity
Lofgren S, Hinchcliff M, Carns M, Wood T, Aren K, Arroyo E, Cheung P, Kuo A, Valenzuela A, Haemel A, Wolters PJ, Gordon J, Spiera R, Assassi S, Boin F, Chung L, Fiorentino D, Utz PJ, Whitfield ML, Khatri P. Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity. JCI Insight 2016, 1: e89073. PMID: 28018971, PMCID: PMC5161207, DOI: 10.1172/jci.insight.89073.Peer-Reviewed Original ResearchSSc patientsSystemic sclerosisDisease severityMulticohort analysisHealthy controlsHigh case fatality rateLarge longitudinal trialsSkin severity scoreUnmet critical needRare autoimmune diseaseMonths of treatmentRodnan skin scoreConnective tissue diseaseCase fatality rateSkin samplesPotential clinical utilitySkin biopsy samplesRobust molecular signatureSSc cohortSkin scoreTissue diseaseAutoimmune diseasesSeverity scorePatient responseDiscovery cohortUtility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry.
Chung L, Fairchild RM, Furst DE, Li S, Alkassab F, Bolster MB, Csuka ME, Derk CT, Domsic RT, Fischer A, Frech TM, Gomberg-Maitland M, Gordon JK, Hinchcliff M, Hsu V, Hummers LK, Khanna D, Medsger TAJ, Molitor JA, Preston IR, Schiopu E, Shapiro L, Hant F, Silver R, Simms R, Varga J, Steen VD, Zamanian RT. Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clinical And Experimental Rheumatology 2016, 35 Suppl 106: 106-113. PMID: 27908301.Peer-Reviewed Original ResearchConceptsB-type natriuretic peptideNT-proBNP levelsPg/mLSSc-PHNT-proBNPPulmonary hypertensionSSc patientsSystemic sclerosisNatriuretic peptideBaseline B-type natriuretic peptideMedian B-type natriuretic peptideSystemic sclerosis-associated pulmonary hypertensionMulticenter prospective cohortNT-proBNP groupNatriuretic peptide levelsRight ventricular dysfunctionPredictors of mortalityPulmonary arterial hypertensionPredictors of progressionAssessment of patientsBaseline creatinineSSc-PAHArterial hypertensionPAH patientsVentricular dysfunction