2022
A 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 ResearchMeSH KeywordsGenomicsHumansMaleOligonucleotide Array Sequence AnalysisRNAScleroderma, SystemicSkinTranscriptomeConceptsMolecular 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
Large‐Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis
Bellocchi C, Ying J, Goldmuntz EA, Keyes‐Elstein L, Varga J, Hinchcliff ME, Lyons MA, McSweeney P, Furst DE, Nash R, Crofford LJ, Welch B, Goldin JG, Pinckney A, Mayes MD, Sullivan KM, Assassi S. Large‐Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis. Arthritis & Rheumatology 2021, 73: 660-670. PMID: 33131208, PMCID: PMC8005427, DOI: 10.1002/art.41570.Peer-Reviewed Original ResearchConceptsDiffuse cutaneous systemic sclerosisInterstitial lung diseaseSerum protein profilesHealthy control subjectsControl subjectsSex-matched healthy control subjectsRodnan skin thickness scoreSevere interstitial lung diseaseCutaneous systemic sclerosisMean disease durationDiffuse cutaneous SScWhole blood gene expression profilingSkin thickness scoreBlood gene expression profilingPeripheral blood cellsCancer antigen 15Epidermal growth factor receptorSoluble epidermal growth factor receptorSerum proteinsGrowth factor receptorDisease activityDisease durationSystemic sclerosisCutaneous SScImmunosuppressive agents
2020
Regulator combinations identify systemic sclerosis patients with more severe disease
Wang Y, Franks JM, Yang M, Toledo DM, Wood TA, Hinchcliff M, Whitfield ML. Regulator combinations identify systemic sclerosis patients with more severe disease. JCI Insight 2020, 5: e137567. PMID: 32721949, PMCID: PMC7526449, DOI: 10.1172/jci.insight.137567.Peer-Reviewed Original ResearchConceptsInterstitial lung diseaseSystemic sclerosisActivity scoreSevere diseaseSevere interstitial lung diseaseSubsets of SScVital capacity declineRodnan skin scoreSubgroup of patientsSystemic sclerosis patientsHeterogeneous autoimmune disorderInternal organ dysfunctionGene expression subsetsSkin gene expressionActivation of regulatorsIntrinsic subsetOrgan dysfunctionSclerosis patientsSkin scoreAutoantibody productionClinical outcomesAutoimmune disordersClinical variablesLung diseaseSkin fibrosisProfibrotic 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 activation
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 courseMyeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures
Assassi S, Wang X, Chen G, Goldmuntz E, Keyes-Elstein L, Ying J, Wallace PK, Turner J, Zheng WJ, Pascual V, Varga J, Hinchcliff ME, Bellocchi C, McSweeney P, Furst DE, Nash RA, Crofford LJ, Welch B, Pinckney A, Mayes MD, Sullivan KM. Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures. Annals Of The Rheumatic Diseases 2019, 78: 1371. PMID: 31391177, PMCID: PMC7167108, DOI: 10.1136/annrheumdis-2019-215770.Peer-Reviewed Original ResearchMeSH KeywordsAdultCyclophosphamideDown-RegulationFemaleHematopoietic Stem Cell TransplantationHumansInterferonsMaleMiddle AgedMultilevel AnalysisMyeloablative AgonistsNeutrophilsRandomized Controlled Trials as TopicScleroderma, SystemicTranscriptomeTransplantation ConditioningTransplantation, AutologousTreatment OutcomeUp-RegulationConceptsHaematopoietic stem cell transplantationStem cell transplantationSystemic sclerosisNeutrophil modulesCell transplantationAutologous stem cell transplantationMolecular signaturesImproved clinical outcomesSerum protein levelsDisease-related molecular signaturesCYC armMonths postrandomisationBaseline visitSkin scoreClinical outcomesCyclophosphamide treatmentVital capacityPretreatment baselineSignificant changesControl armBlood transcriptsWhole blood transcriptsConventional treatmentInterferonBaseline samplesSingle-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis
Reyfman PA, Walter JM, Joshi N, Anekalla KR, McQuattie-Pimentel AC, Chiu S, Fernandez R, Akbarpour M, Chen CI, Ren Z, Verma R, Abdala-Valencia H, Nam K, Chi M, Han S, Gonzalez-Gonzalez FJ, Soberanes S, Watanabe S, Williams KJN, Flozak AS, Nicholson TT, Morgan VK, Winter DR, Hinchcliff M, Hrusch CL, Guzy RD, Bonham CA, Sperling AI, Bag R, Hamanaka RB, Mutlu GM, Yeldandi AV, Marshall SA, Shilatifard A, Amaral LAN, Perlman H, Sznajder JI, Argento AC, Gillespie CT, Dematte J, Jain M, Singer BD, Ridge KM, Lam AP, Bharat A, Bhorade SM, Gottardi CJ, Budinger GRS, Misharin AV. Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2019, 199: 1517-1536. PMID: 30554520, PMCID: PMC6580683, DOI: 10.1164/rccm.201712-2410oc.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingRNA sequencingPulmonary fibrosisAlveolar macrophagesLung tissueSingle-cell transcriptomic analysisEpithelial cellsCell populationsNext-generation sequencing technologiesSingle-cell atlasHuman lungDiverse cell populationsExpression of genesRare cell populationsPulmonary fibrosis pathogenesisIdiopathic pulmonary fibrosisAirway stem cellsIndividual cell populationsTranscriptomic analysisSequencing technologiesWnt secretionRNA hybridizationSenescent cellsTransplant donorsDiscovery-based approach
2018
Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin
Hinchcliff M, Toledo DM, Taroni JN, Wood TA, Franks JM, Ball MS, Hoffmann A, Amin SM, Tan AU, Tom K, Nesbeth Y, Lee J, Ma M, Aren K, Carns MA, Pioli PA, Whitfield ML. Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin. Journal Of Investigative Dermatology 2018, 138: 1301-1310. PMID: 29391252, PMCID: PMC6590516, DOI: 10.1016/j.jid.2018.01.006.Peer-Reviewed Original ResearchConceptsMycophenolate mofetil treatmentMyeloid cell numbersMMF therapyMofetil treatmentSystemic sclerosisInflammatory scoreSkin biopsiesCell numberSkin myeloid cellsMyeloid dendritic cellsHalf of patientsRodnan skin scoreImmune cell numbersInflammatory gene signatureExpression of chemokinesProtein levelsCCL2 protein levelsCCL2 mRNA expressionInflammatory signatureDendritic cellsSkin scoreCCL2 mRNAEleven subjectsMonocyte migrationMyeloid cells
2017
A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis
Taroni JN, Greene CS, Martyanov V, Wood TA, Christmann RB, Farber HW, Lafyatis RA, Denton CP, Hinchcliff ME, Pioli PA, Mahoney JM, Whitfield ML. A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Medicine 2017, 9: 27. PMID: 28330499, PMCID: PMC5363043, DOI: 10.1186/s13073-017-0417-1.Peer-Reviewed Original ResearchConceptsDisease-associated signaturesFunctional genomic networksGene expression signaturesPulmonary fibrosisAutoimmune diseasesDisease processMulti-organ autoimmune diseaseDistinct underlying pathologyPro-fibrotic macrophagesInternal organ involvementPulmonary arterial hypertensionExpression signaturesSkin of patientsInnate immune systemWilcoxon rank sum testGenomic networksRank sum testBackgroundSystemic sclerosisArterial hypertensionOrgan involvementSystemic sclerosisUnderlying pathologyLung microenvironmentSkin fibrosisFibrotic genes
2015
Systems Level Analysis of Systemic Sclerosis Shows a Network of Immune and Profibrotic Pathways Connected with Genetic Polymorphisms
Mahoney JM, Taroni J, Martyanov V, Wood TA, Greene CS, Pioli PA, Hinchcliff ME, Whitfield ML. Systems Level Analysis of Systemic Sclerosis Shows a Network of Immune and Profibrotic Pathways Connected with Genetic Polymorphisms. PLOS Computational Biology 2015, 11: e1004005. PMID: 25569146, PMCID: PMC4288710, DOI: 10.1371/journal.pcbi.1004005.Peer-Reviewed Original ResearchConceptsGene-gene interaction networksGenetic risk lociInteraction networksGenome-wide gene expression datasetsRisk lociGene expression modulesSubset-specific genesExtracellular matrix remodelingGene expression datasetsExpression modulesSystemic sclerosisGene expressionGenetic polymorphismsIntrinsic subsetGenesSystem-level analysisExpression datasetsMatrix remodelingPolymorphic genesAntigen geneCell proliferationMultiple clinical cohortsOrgan fibrosisGene expression subsetsLoci
2013
Molecular Signatures in Skin Associated with Clinical Improvement during Mycophenolate Treatment in Systemic Sclerosis
Hinchcliff M, Huang CC, Wood TA, Mahoney J, Martyanov V, Bhattacharyya S, Tamaki Z, Lee J, Carns M, Podlusky S, Sirajuddin A, Shah SJ, Chang RW, Lafyatis R, Varga J, Whitfield ML. Molecular Signatures in Skin Associated with Clinical Improvement during Mycophenolate Treatment in Systemic Sclerosis. Journal Of Investigative Dermatology 2013, 133: 1979-1989. PMID: 23677167, PMCID: PMC3714324, DOI: 10.1038/jid.2013.130.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBiopsyCluster AnalysisFemaleGene Expression RegulationGenetic HeterogeneityGenetic MarkersHumansImmunosuppressive AgentsMaleMiddle AgedMycophenolic AcidPredictive Value of TestsReverse Transcriptase Polymerase Chain ReactionScleroderma, SystemicSkin Physiological PhenomenaTranscriptomeYoung AdultConceptsMRSS improvementSystemic sclerosisIntrinsic subsetMycophenolate mofetil treatmentCyclophosphamide-treated patientsGene expression changesGene expression subsetsMycophenolate treatmentTreatment biopsiesClinical improvementMMF treatmentMofetil treatmentGene expression signaturesSSc patientsSerial biopsiesClinical trialsExpression changesBaseline gene expressionGene expressionSSc skinSkin AssociatedPatientsTargeted treatmentPatient biopsiesBiopsy
2012
Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker?
Lakota K, Wei J, Carns M, Hinchcliff M, Lee J, Whitfield ML, Sodin-Semrl S, Varga J. Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker? Arthritis Research & Therapy 2012, 14: r102. PMID: 22548780, PMCID: PMC3446479, DOI: 10.1186/ar3827.Peer-Reviewed Original ResearchConceptsLevels of adiponectinPPAR-gamma activitySerum adiponectin levelsSystemic sclerosisAdiponectin levelsSkin fibrosisSSc patientsSkin scoreDiffuse cutaneous systemic sclerosisPeroxisome proliferator-activated receptor gammaCutaneous systemic sclerosisRodnan skin scoreProliferator-activated receptor gammaHuman subcutaneous preadipocytesProgression of fibrosisAdiponectin mRNA expressionAdiponectin gene expressionTransforming growth factor betaSignificant inverse correlationLongitudinal study changesGrowth factor betaProgressive fibrosisReal-time quantitative PCRAdiponectin expressionHealthy controls