scleroderma. in the name of god the merciful the compassionate

Scleroderma

In the name of God

the merciful

the compassionate

Iraj Salehi-Abari

Rheumatologist, Internist

[email protected]

mailto:[email protected]

Classification of Scleroderma:

Localized SclerodermaLocalized Scleroderma

• No visceral involvementNo visceral involvement

• No Typical hand involvementNo Typical hand involvement

• No Raynaud’s ph.No Raynaud’s ph.

• No Auto-Antibody positivityNo Auto-Antibody positivity

• Only sclerosisOnly sclerosis of one or more skin areaof one or more skin area

Systemic Scleroderma (SSc)Systemic Scleroderma (SSc)

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•SclerodermaScleroderma

Localized Scleroderma: Morphea:Morphea:

• Plaque morpheaPlaque morphea

• Guttate morpheaGuttate morphea

• Generalized morpheaGeneralized morphea

• Bullous morpheaBullous morphea

• Deep morpheaDeep morphea

Linear SclerodermaLinear Scleroderma

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Plaque morphea: Local sclerosis in Local sclerosis in << 2 anatomic sites 2 anatomic sites

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Plaque morphea:Local sclerosis in Local sclerosis in << 2 anatomic sites 2 anatomic sites

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Generalized morphea: Skin sclerosis in Skin sclerosis in >> 3 anatomic sites 3 anatomic sites

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Linear Scleroderma:

• ChildrenChildren

• Growth impairment of the involved Growth impairment of the involved

extremityextremity

• Dermatomal distributionDermatomal distribution

• En coup de sabreEn coup de sabre

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Systemic Sclerosis (SSc)Systemic Sclerosis (SSc)

Definition:Definition:

• Multisystem, Chronic, AutoimmuneMultisystem, Chronic, Autoimmune

• Overproduction of collagen fibersOverproduction of collagen fibers

• Thickened & sclerotic skinThickened & sclerotic skin

• Raynaud’s phenomenonRaynaud’s phenomenon

• Visceral organ involvement (fibrosis)Visceral organ involvement (fibrosis)

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Epidemiology:• Annual incidence in USA: 1-2 / 100,000Annual incidence in USA: 1-2 / 100,000

• Peak onset age: 30-50 y/oPeak onset age: 30-50 y/o

• 100 RA, 10 SLE, 1 Scl100 RA, 10 SLE, 1 Scl

• F/M ratio: 3/1F/M ratio: 3/1

• Black > other raceBlack > other race

• Rare in childrenRare in children

• Rare in men < 30 y/oRare in men < 30 y/o

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Clinical staging of SSc:Clinical staging of SSc:

Inflammatory stage:Inflammatory stage:• Early, Edematous phaseEarly, Edematous phase• Arthralgia, Soft tissue swellingArthralgia, Soft tissue swelling• Mistake for RA & other CTDMistake for RA & other CTD

Indurative stage:Indurative stage:• Intermediate fibrotic phaseIntermediate fibrotic phase• Hardness & thickness of skinHardness & thickness of skin• Typical clinical featuresTypical clinical features

Atrophic stage:Atrophic stage:• Late phaseLate phase• Very thin skinVery thin skin

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Clinical classification of SSc:

• DiffuseDiffuse Cutaneous Cutaneous SclScleroderma (dcSSc)eroderma (dcSSc)

• LimitedLimited Cutaneous Cutaneous SclScleroderma (lcSSc)eroderma (lcSSc)

• Systemic Sclerosis Systemic Sclerosis sine Sclsine Sclerodermaeroderma

• OverlapOverlap syndrome syndrome

• Pre-SclPre-Scleroderma or eroderma or Early SclEarly Sclerodermaeroderma

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Limited Cutaneous Scleroderma:

Distal portion of extremities plusHead & neck

Acrofacial

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Diffuse Cutaneous Scleroderma:Diffuse Cutaneous Scleroderma:

Distal + ProximalDistal + ProximalHead & NeckHead & NeckTrunkTrunk

TrunkalTrunkal

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Intermediate Cutaneous Scl.Intermediate Cutaneous Scl.

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Attention please:

• Almost all patients have skin Almost all patients have skin

involvement in the:involvement in the:

• FingersFingers: sclerodactyly: sclerodactyly

• HandsHands and and

• FaceFace

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Pathogenesis:Pathogenesis:• UnknownUnknown• Genetic BackgroundGenetic Background• Environmental trigger factors (Ags) Environmental trigger factors (Ags) • Vascular events:Vascular events:

• Raynaud’s ph.Raynaud’s ph.• Endothelial injuryEndothelial injury

• Immunological events (autoimmunity)Immunological events (autoimmunity)• CellularCellular• HumoralHumoral

• Activated fibrogenic fibroblastActivated fibrogenic fibroblast

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Genetic considerations:Genetic considerations:

• Non-Mendelian pattern of inheritanceNon-Mendelian pattern of inheritance

• Concordance rate of 4.7% in Monozygotic Concordance rate of 4.7% in Monozygotic

twinstwins

• Positive family history of 1.6% in First Positive family history of 1.6% in First

degree relativedegree relative

• Multiple Genetic loci Multiple Genetic loci

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Multiple Genetic loci:Multiple Genetic loci:• Genes encoding ACEGenes encoding ACE

• Genes encoding endothelin-1 Genes encoding endothelin-1

• Genes encoding NOSGenes encoding NOS

• Genes encoding CD19Genes encoding CD19

• Genes encoding monocyte chemoattractant Genes encoding monocyte chemoattractant

protein-1protein-1

• Genes encoding STAT4, IRF5, CTGF, SPARCGenes encoding STAT4, IRF5, CTGF, SPARC

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Environmental Antigenic triggers:

• Viruses:Viruses:

– Human CMV, and Parvovirus B19Human CMV, and Parvovirus B19

– Antitopoisomerase-I (Scl-70) recognize antigenic Antitopoisomerase-I (Scl-70) recognize antigenic

epitopes of the hCMV: epitopes of the hCMV: Molecular mimicryMolecular mimicry

• Silica:Silica:

– The incidence of SSc is increased among The incidence of SSc is increased among

miners exposed to silicaminers exposed to silica

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Environmental Antigenic triggers:

• Polyvinyl chloride, Epoxy resins, Polyvinyl chloride, Epoxy resins,

Aromatic hydrocarbons (toluene,…)Aromatic hydrocarbons (toluene,…)

• Cu, FeCu, Fe: :

– Treatment with D-penicillamineTreatment with D-penicillamine

• DrugsDrugs: :

– Bleomycin, Pentazocine & CocaineBleomycin, Pentazocine & Cocaine

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Vascular events:

• Upon Upon Raynaud’s phenomenonRaynaud’s phenomenon

• Viruses, superoxide radicals, auto-antibodies,…(Viruses, superoxide radicals, auto-antibodies,…(AgsAgs))

Endothelial injury Endothelial injury

• Endothelial injury Endothelial injury endothelium-derived endothelium-derived vasoconstrictorvasoconstrictor

((Endothelin-1Endothelin-1)) increases increases and endothelium-derived and endothelium-derived

vasodilators vasodilators ((NO, ProstacyclinNO, Prostacyclin)) decrease decrease

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Vascular events:• Vascular injury Vascular injury Increased expression of ICAM-1 Increased expression of ICAM-1 and other and other

AMsAMs

• Vascular injury Vascular injury Platelet aggregation Platelet aggregation release of Serotonin, release of Serotonin,

Thromboxane, and PDGF Thromboxane, and PDGF

• Defective fibrinolysisDefective fibrinolysis

• Microvessels show Microvessels show enhanced permeability enhanced permeability andand leukocyte leukocyte

diapedesis diapedesis

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Vascular events:

• Ischemia-reperfusion Ischemia-reperfusion Reactive oxygen species Reactive oxygen species

(ROS) (ROS) further damage the endothelium further damage the endothelium

• Defective revascularization Defective revascularization despite elevated levels despite elevated levels

of Vascular endothelial growth factor (VEGF) and of Vascular endothelial growth factor (VEGF) and

other angiogenic factorsother angiogenic factors

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Vascular events:

• The number of The number of endothelial progenitor cells is reducedendothelial progenitor cells is reduced

in circulation, and their differentiation into mature in circulation, and their differentiation into mature

endothelial cells is impaired endothelial cells is impaired Wide spread Wide spread capillary capillary

malformation and lossmalformation and loss, , obliterative vasculopathyobliterative vasculopathy of of

small and medium-sized arteries, and failure to repair small and medium-sized arteries, and failure to repair

damaged vessels are damaged vessels are hallmarks of SSchallmarks of SSc

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Vascular events:• Myointimal cells proliferate, Basement membrane is Myointimal cells proliferate, Basement membrane is

thickened and fibrosis of the adventitial layers developsthickened and fibrosis of the adventitial layers develops

• Occlusive vasculopathyOcclusive vasculopathy affects capillaries arterioles and affects capillaries arterioles and

even large vessels in many organs even large vessels in many organs reduced blood reduced blood

flow, flow, tissue ischemia tissue ischemia generation of generation of profibrotic factorsprofibrotic factors..

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Vascular events:

• Vascular injury Vascular injury Leukocyte Recruitment Leukocyte Recruitment

• Leukocyte Recruitment Leukocyte Recruitment Th2 cytokines Th2 cytokines

• Th2 cytokines Th2 cytokines Fibroblast activation Fibroblast activation

• Leukocyte Recruitment Leukocyte Recruitment Auto-Antibodies Auto-Antibodies

• Auto-Antibodies Auto-Antibodies Vascular injury Vascular injury

• Auto-Antibodies Auto-Antibodies Fibroblast activation Fibroblast activation

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Vascular events:

• Initial vascular injury in a genetically susceptible Initial vascular injury in a genetically susceptible

individual leads to functional and structural vascular individual leads to functional and structural vascular

alterations, inflammation and autoimmunityalterations, inflammation and autoimmunity

• Inflammatory and immune responses initiate and sustain Inflammatory and immune responses initiate and sustain

fibroblast activation and differentiation, resulting in fibroblast activation and differentiation, resulting in

pathologic fibrogenesis and irreversible tissue damagepathologic fibrogenesis and irreversible tissue damage

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Vascular events:

• Progressive luminal occlusionProgressive luminal occlusion

• Persistent endothelial cell damagePersistent endothelial cell damage

• Adventitial fibrosis Adventitial fibrosis

• Establish a Establish a vicious cyclevicious cycle

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Fibrosis events:

• Fibroblast activation & Tissue hypoxia Fibroblast activation & Tissue hypoxia

– Collagen accumulationCollagen accumulation

– Extracellular matrix reorganizationExtracellular matrix reorganization

– Impaired matrix degradationImpaired matrix degradation

Tissue fibrosisTissue fibrosis

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Fibrosis events:

• Fibrogenic phenotype fibroblasts:Fibrogenic phenotype fibroblasts:

– ““Scleroderma phenotype” Scleroderma phenotype”

• Uncontrolable production of collagenUncontrolable production of collagen

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Autoimmunity:

• Auto-antibodiesAuto-antibodies

• Animal modelsAnimal models

• Lymphocytes & AECA Lymphocytes & AECA Apoptosis of Apoptosis of

endothelial cellsendothelial cells

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Host susceptibility for SSc:

• Compatible Genetic backgroundCompatible Genetic background

• Basal Vasculopathy:Basal Vasculopathy:

• Basal Immunologic abnormalities and Basal Immunologic abnormalities and

Autoimmunity: Cellular, HumoralAutoimmunity: Cellular, Humoral

• ““Scleroderma phenotype” of fibroblastsScleroderma phenotype” of fibroblasts

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Basal Vasculopathy:Basal Vasculopathy:

• Raynaud’s phRaynaud’s ph.: highly sensitive alpha-2 adrenergic receptors on vascular smooth-.: highly sensitive alpha-2 adrenergic receptors on vascular smooth-

muscle cells muscle cells

• Vascular endothelium has potential of Vascular endothelium has potential of easy injuryeasy injury and and dysregulation dysregulation platelet platelet

aggregation aggregation

• Endothelium-derived Endothelium-derived vasoconstrictorsvasoconstrictors increasesincreases and and vasodilators decrease vasodilators decrease

luminal occlusionluminal occlusion

• Endothelial cells Endothelial cells overexpress ICAM-1overexpress ICAM-1 and other AMs and other AMs facilitate leukocyte facilitate leukocyte

diapedesisdiapedesis

• Reduced Endothelial progenitor cellsReduced Endothelial progenitor cells with impaired differentiation with impaired differentiation defective defective

revascularizationrevascularization

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Host susceptibility:

Basal Cellular Autoimmunity:Basal Cellular Autoimmunity:

• CD4(+) T cells CD4(+) T cells have elevated levels of have elevated levels of alpha-1 Integrin AMs alpha-1 Integrin AMs

enhanced ability to bind to endothelium & to fibroblastsenhanced ability to bind to endothelium & to fibroblasts

• Activated Macrophages & T cells show Activated Macrophages & T cells show Th2 immune responseTh2 immune response & &

secrete IL-4 & IL-13secrete IL-4 & IL-13

• Th2 cytokines Th2 cytokines production of production of TGF-B TGF-B collagen synthesis collagen synthesis

• TGF-B stimulates its own synthesis, as well as that of CTGF. TGF-B stimulates its own synthesis, as well as that of CTGF.

SoTGF-B establishes an autocrine/paracrine stimulatory loop that SoTGF-B establishes an autocrine/paracrine stimulatory loop that

sustains activation of fibroblastssustains activation of fibroblasts

• DefectiveDefective immunosuppressive function of immunosuppressive function of Regulatory T cells Regulatory T cells

(Tregs) (Tregs) loss of immune Tolerance loss of immune Tolerance

• B cells B cells TGF-B & Autoantibadies TGF-B & Autoantibadies

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Basal Humoral Autoimmunity:Basal Humoral Autoimmunity:

• Antinuclear antibodiesAntinuclear antibodies (ANA) in virtualy all patients: (ANA) in virtualy all patients:

Anti-topoisomerase-I (Anti-topoisomerase-I (Scl-70Scl-70))

Anti-centromere antibody (Anti-centromere antibody (ACAACA))

Anti Anti RNA polymerases RNA polymerases antibodyantibody

• Anti-fibroblasts Ab (Scl-70 ?), AECA, Anti-PDGF Anti-fibroblasts Ab (Scl-70 ?), AECA, Anti-PDGF

receptor Ab, Anti-fibrillin & Anti MMP Abreceptor Ab, Anti-fibrillin & Anti MMP Ab

• Proteolytic cleavage, increased expression, and Proteolytic cleavage, increased expression, and

altered localization of cellular proteins in SSc altered localization of cellular proteins in SSc

proteins are recognized as proteins are recognized as neoepitopesneoepitopes by B cells by B cells

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• ““Scleroderma phenotype” of fibroblasts:Scleroderma phenotype” of fibroblasts:

• In SSc in addition to resident fibroblasts, epithelial In SSc in addition to resident fibroblasts, epithelial

cells and endothelial cells can differentiate into cells and endothelial cells can differentiate into

myofibroblastsmyofibroblasts

• In SSc circulating mesanchymal progenitor cells of In SSc circulating mesanchymal progenitor cells of

bone marrow origin contribute to fibrosisbone marrow origin contribute to fibrosis

• Fibroblasts of SSc are Fibroblasts of SSc are “Scleroderma phenotype”“Scleroderma phenotype”::

Enhanced secretion Enhanced secretion of collagen, cytokines & growth factorsof collagen, cytokines & growth factors

ExpressionExpression of chemokine receptors and cell of chemokine receptors and cell surface AMssurface AMs

Resistance to apoptosisResistance to apoptosis

Autocrine TGF-B signalingAutocrine TGF-B signaling

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Senario of pathophysiology:

• In a susceptible individual, Complex In a susceptible individual, Complex

interplay between basal vasculopathy interplay between basal vasculopathy

and autoimmunity affects on fibrogenic and autoimmunity affects on fibrogenic

fibroblasts and initiate and amplify the fibroblasts and initiate and amplify the

fibrotic process fibrotic process

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Vascular involvement:Vascular involvement:

Early stage: Early stage: • Reversible vasospasm in arteriolesReversible vasospasm in arterioles

• Transient Raynaud ph.Transient Raynaud ph.

Intermediate stage:Intermediate stage:• Vasospasm + mild to moderate fixed stenosis Vasospasm + mild to moderate fixed stenosis

• Prolonged RP and digital ischemia and ulceration Prolonged RP and digital ischemia and ulceration

Late stage:Late stage:• Severe fixed stenosisSevere fixed stenosis

• Digital infarction and auto-amputation Digital infarction and auto-amputation

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Classic case of SSc:Classic case of SSc: A middle age woman with:A middle age woman with:

• Raynaud’s phRaynaud’s ph

• Skin hardness, hyper-hypopigmentationSkin hardness, hyper-hypopigmentation

• Masked face, telangiectasia, Micro-ostiaMasked face, telangiectasia, Micro-ostia

• Sclerodactyly, Pitting ulcerSclerodactyly, Pitting ulcer

• Dysphagia, Pyrosis, DiarrheaDysphagia, Pyrosis, Diarrhea

• Dyspnea on exersion, dry coughDyspnea on exersion, dry cough

• Arthralgia, myalgiaArthralgia, myalgia

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General manifestations:General manifestations:

Most frequent:

• Fatigue, Stiff joints

• Loss of strength, Pain

• Sleep difficulties

• Skin discoloration

Less frequent:

• Breathlessness, depression, sore eyes

• Upset stomach, nausea, weight loss

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Raynaud phenomenon (RP):Raynaud phenomenon (RP):

Definition:Definition: Sequential color changes in Sequential color changes in

the digits due to arterial vasoconstriction, the digits due to arterial vasoconstriction,

precipitated by cold, stress, a decrease in precipitated by cold, stress, a decrease in

temperature and vibration.temperature and vibration.

Epidemiology:Epidemiology:

• 3-5% of general population3-5% of general population

• More frequent in women More frequent in women

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Triphasic color changes:Triphasic color changes:

• PPallority = ‘’allority = ‘’WWhite’’ 2 p.hite’’ 2 p.

• CCyanosis = ‘’yanosis = ‘’BBlue’’ 1 p.lue’’ 1 p.

• RRedness = ‘’edness = ‘’RRed’’ 1 p.ed’’ 1 p.

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Active Raynaud’s phenomenon

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• Diagnosis is only made by HistoryDiagnosis is only made by History

• Definite RPDefinite RP: : repeated episodes of biphasic repeated episodes of biphasic

color changes upon exposure to coldcolor changes upon exposure to cold

• Possible RP: Uniphasic color changes + Possible RP: Uniphasic color changes +

numbness or paresthesianumbness or paresthesia

• No RP: No color changes upon exposure No RP: No color changes upon exposure

to coldto cold

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• Primary (idiopathic, isolated):Primary (idiopathic, isolated):

Without a definable underling causeWithout a definable underling cause

An exaggeration of normal vasoconstriction to An exaggeration of normal vasoconstriction to

cold exposure cold exposure

• Secondary (pathologic):Secondary (pathologic):

With an underling disease or causeWith an underling disease or cause

Raynaud syndromeRaynaud syndrome

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Secondary Raynaud ph:Secondary Raynaud ph:

• Systemic SclerosisSystemic Sclerosis

• SLE, other CTDSLE, other CTD

• Occlusive vascular diseaseOcclusive vascular disease

• Drugs/toxinsDrugs/toxins

• Hematologic abnormalitiesHematologic abnormalities

• Use of vibrating tools & vascular traumaUse of vibrating tools & vascular trauma

• FrostbiteFrostbite

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• Other Connective tissue diseases:Other Connective tissue diseases:

• MCTDMCTD

• Overlap syndromeOverlap syndrome

• PM/DMPM/DM

• RARA

• Sjogres’s syndromeSjogres’s syndrome

• UCTDUCTD

• VasculitisVasculitis

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• Occlusive vascular disease:Occlusive vascular disease:

• ArteriosclerosisArteriosclerosis

• AtheroemboliAtheroemboli

• Thromboangiitis obliteransThromboangiitis obliterans

• HypothyroidismHypothyroidism

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• Drugs/toxins cause RPDrugs/toxins cause RP

• AmphetaminesAmphetamines

• Beta blockers, ClonidineBeta blockers, Clonidine

• Interferon-alphaInterferon-alpha

• Bleomycin, Cisplatin, VinblastineBleomycin, Cisplatin, Vinblastine

• Cocaine, NicotineCocaine, Nicotine

• CyclosporineCyclosporine

• Ergot, MethysergideErgot, Methysergide

• Vinyl chlorideVinyl chloride

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• Hematologic disease:Hematologic disease:

• Cold agglutinin diseaseCold agglutinin disease

• CryofibrinogenemiaCryofibrinogenemia

• CryoglobulinemiaCryoglobulinemia

• ParaproteinemiaParaproteinemia

• PolycythemiaPolycythemia

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Primary Raynaud phenomenon:Primary Raynaud phenomenon:

• Age of onset: 15-30 yearsAge of onset: 15-30 years

• More common in femaleMore common in female

• Occur in multiple family membersOccur in multiple family members

• Spontaneous remission may occurSpontaneous remission may occur

• May be aggravated by: HTN, CVD, May be aggravated by: HTN, CVD,

atheroslerosis, and diabetes mellitusatheroslerosis, and diabetes mellitus

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Diagnostic criteria of Primary RP:Diagnostic criteria of Primary RP:

• Symmetric episodic attacksSymmetric episodic attacks

• No evidence of peripheral vascular diseaseNo evidence of peripheral vascular disease

• No tissue gangrene, tissue injury, or digital No tissue gangrene, tissue injury, or digital

pittingpitting

• Negative nailfold capillary examinationNegative nailfold capillary examination

• Negative ANA and normal ESRNegative ANA and normal ESR

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Normal nailfold Capillaroscopy

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Clinical clues to suggest secondary RP:Clinical clues to suggest secondary RP:

• Later age of onset (>30-40 years)Later age of onset (>30-40 years)

• Male genderMale gender

• Painful RPPainful RP

• RP with digital ulceration and gangrene RP with digital ulceration and gangrene

• Asymmetric attacksAsymmetric attacks

• RP associated with other signs or symptomsRP associated with other signs or symptoms

• Abnormal lab. data: Abnormal lab. data: CBC, ESR, auto-antibodies,… CBC, ESR, auto-antibodies,…

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Nailfold capillary microscopy:Nailfold capillary microscopy:

• Enlarged capillary loops orEnlarged capillary loops or

• Distorted capillary loops andDistorted capillary loops and

• Relative paucity of loops Relative paucity of loops

Suggest an underlying CTDSuggest an underlying CTD

• Enlargement associated with loss of Enlargement associated with loss of

capillariescapillaries

More suggestion of SSc More suggestion of SSc

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‘’Slow’’ phase nailfold capillaries in lcSSc:Capillary dilatation

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‘’Active’’ phase nailfold capillaries in dcSSc:Capillary dilatation and avascular areas

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Approach to Raynaud phenomenon:Approach to Raynaud phenomenon:

• Step I: History and physical examination by GP Step I: History and physical examination by GP

• Step II: Nailfold capillary microscopy by GPStep II: Nailfold capillary microscopy by GP

If they are normal, then Primary RP is made by a GP, and no need If they are normal, then Primary RP is made by a GP, and no need

for laboratory tests. But if there are any abnormality or nailfold for laboratory tests. But if there are any abnormality or nailfold

capillary microscopy cannot perform capillary microscopy cannot perform

• Step III: Hx., Ph. Exam. and Nailfold capillary Step III: Hx., Ph. Exam. and Nailfold capillary

microscopy by Rheumatologistmicroscopy by Rheumatologist

• Step IV: Laboratory testsStep IV: Laboratory tests

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Skin involvement:Skin involvement:• Universal feature of SSc Characterized by:Universal feature of SSc Characterized by:

– Skin thickening, hardness, and fixation Skin thickening, hardness, and fixation

• The fingers, hands and face are at firstThe fingers, hands and face are at first

• Prominent skin manifestation:Prominent skin manifestation: . Pruritus and edema in the early stages. Pruritus and edema in the early stages

. Sclerodactyly. Sclerodactyly

. Digital ulcers & pitting of fingertips. Digital ulcers & pitting of fingertips

. Telangiectasia. Telangiectasia

. Calcinosis cutis . Calcinosis cutis

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Skin involvement:Skin involvement:• Diffuse tanningDiffuse tanning in the absence of sun in the absence of sun

exposureexposure

• VitiligoVitiligo-like hypopigmentation-like hypopigmentation

• ““Salt-and-pepper” appearance: Salt-and-pepper” appearance: – In scalp, upper back, chestIn scalp, upper back, chest

– Pigment loss spares the perifollicular areasPigment loss spares the perifollicular areas

• Dry skin, hair loss:Dry skin, hair loss:– Collagen accumulation causes oblitration of hair Collagen accumulation causes oblitration of hair

follicles, sweat & sebaceous glands follicles, sweat & sebaceous glands

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The assessment of skin involvement:The assessment of skin involvement:

Estimation of:Estimation of:• Skin Skin thicknessthickness

• Pliability (Pliability (hardnesshardness))

• Fixation to underling structures (Fixation to underling structures (tetheringtethering))

The The modified Rodnan skin scoremodified Rodnan skin score::• In 17 distinct areas of the bodyIn 17 distinct areas of the body

• Score from 0 (nl) to 3 (most severe)Score from 0 (nl) to 3 (most severe)

Gold standard is skin palpation by RheumatologistGold standard is skin palpation by Rheumatologist

Ultrasonography & Durometer ?Ultrasonography & Durometer ?

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Face:Face:• ““Mauskopf” faceMauskopf” face

– Shiny taut skinShiny taut skin

– Masklike & expressionlessMasklike & expressionless

– Decreased skin foldsDecreased skin folds

• MicrostomiaMicrostomia (fish mouth)(fish mouth)

• Perioral radial furrowingPerioral radial furrowing

• ““Beak-like” noseBeak-like” nose– Small sharp nose:Small sharp nose:

• Omega signOmega sign

• Matlike telangiectasesMatlike telangiectases

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Hand involvement:Hand involvement:

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• Sclerodactyly Sclerodactyly ::

– Thickening of finger skinThickening of finger skin

– Fibrosis of tendonsFibrosis of tendons

• Tapered fingersTapered fingers

• Transverse creases on the dorsum of Transverse creases on the dorsum of

the fingers disappearthe fingers disappear

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• Digital ulcerationsDigital ulcerations

– SuperinfectionSuperinfection

– OsteomyelitisOsteomyelitis

• ““Digital pits” Digital pits” = Pitting ulcers= Pitting ulcers

– Healing of ischemic fingertip ulcerationsHealing of ischemic fingertip ulcerations

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• Dissolution of terminal phalangesDissolution of terminal phalanges

– Loss of volar pads of the fingertips Loss of volar pads of the fingertips

– Resorption of the terminal phalangs:Resorption of the terminal phalangs:

– Acro-osteolysisAcro-osteolysis

• Periungual telangiectasiaPeriungual telangiectasia

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Calcinosis cutis:Calcinosis cutis:

• Most common in patients with Most common in patients with lcSSc & positive ACAlcSSc & positive ACA

• CPPD depositionCPPD deposition

• Visualized on plain X-RaysVisualized on plain X-Rays

• Typical locations: finger pads, palms, extensor surfaces of Typical locations: finger pads, palms, extensor surfaces of

the forearms, olecranon & prepatellar bursaethe forearms, olecranon & prepatellar bursae

• Persistent firm, nontender subcutaneous lumpsPersistent firm, nontender subcutaneous lumps

• If ulcerate If ulcerate drainage of chalky white material drainage of chalky white material

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Skin involvement:Skin involvement:

Neck sign

Barnett’s sign: Vertical striations in the skin with neck extension

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Organ involvement:Organ involvement:• GastrointestinalGastrointestinal

• PulmonaryPulmonary

• RenalRenal

• CardiacCardiac

• MusculoskeletalMusculoskeletal

• OphthalmicOphthalmic

• OthersOthers

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Gastrointestinal involvement:Gastrointestinal involvement:

• In In 90%90% of cases of cases

• Any part of GIAny part of GI

• About 50% symptomaticAbout 50% symptomatic

• Esophageal: most commonEsophageal: most common

• Pathology:Pathology:

. . Smooth muscle atrophySmooth muscle atrophy

. . Gut wall fibrosisGut wall fibrosis

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Oral involvement:Oral involvement: Micro-ostia (Micro-ostia (fish mouthfish mouth))

Rigidity of tongue with short frenulumRigidity of tongue with short frenulum

Rigidity & tenderness of oral mucosaRigidity & tenderness of oral mucosa

Malalignment of teethMalalignment of teeth

Oropharyngeal dysphagiaOropharyngeal dysphagia: 25%: 25%

Oropharyngeal incoordination: 25%Oropharyngeal incoordination: 25%

Sjogren’s syndromeSjogren’s syndrome

Impaired mastication & deglutitionImpaired mastication & deglutition

Salehi I.Salehi I.


Esophageal involvement (90%):Esophageal involvement (90%):

Lower two-thirds of Esophagus:Lower two-thirds of Esophagus:

• Reduced or No peristalsisReduced or No peristalsis

• Dilated lumenDilated lumen

• Decreased LES toneDecreased LES tone

GERD: pyrosis GERD: pyrosis

Dysmotility: dysphagiaDysmotility: dysphagia

Hiatal herniaHiatal hernia

Salehi I.Salehi I.


Esophageal involvement (90%):Esophageal involvement (90%):

In past: Manometry, Barium swallowIn past: Manometry, Barium swallow

Nowadays: Esophagoscopy if:Nowadays: Esophagoscopy if: Complications are suspectedComplications are suspected

Persistent symptoms after PPI therapyPersistent symptoms after PPI therapy

Esophagoscopy:Esophagoscopy: Reflux esophagitis, candidiasisReflux esophagitis, candidiasis

Barrett’s esophagus, LE strictureBarrett’s esophagus, LE stricture

Salehi I.Salehi I.


Gastric involvement:Gastric involvement:

Gastric emptying: delayedGastric emptying: delayed

Mucosal telangiectasia:Mucosal telangiectasia:

• Watermelon stomachWatermelon stomach

• Upper GI bleedingUpper GI bleeding

Gastric antral venous ectasia (Gastric antral venous ectasia (GAVEGAVE):):

• Unexplained IDAUnexplained IDA

Gastroparesis: rareGastroparesis: rare

Salehi I.Salehi I.


Watermelon stomachSalehi I.Salehi I.


Small bowel involvement:Small bowel involvement:

Reduced peristalsisReduced peristalsis

• Abdominal distensionAbdominal distension

• Bacterial overgrowthBacterial overgrowth

• Intermittent diarrhea-constipationIntermittent diarrhea-constipation

• MalabsorptionMalabsorption

• Pseudo-obstruction & PerforationPseudo-obstruction & Perforation

• Pneumatosis cystoides intestinalisPneumatosis cystoides intestinalis

• VolvulusVolvulus

• Pseudo-obstructionPseudo-obstruction

• Bacterial overgrowthBacterial overgrowth

• Pneumatosis intestinalisPneumatosis intestinalis

• Rectal prolaps, incontinenceRectal prolaps, incontinence

Salehi I.Salehi I.


Colonic disease:Colonic disease:

Anorectum: most commonAnorectum: most common

• Fecal incontinenceFecal incontinence

• Rectal prolapseRectal prolapse

Gastrocolic reflex: absentGastrocolic reflex: absent

Wide-mouthed diverticuliWide-mouthed diverticuli

ConstipationConstipation

Colonic perforationColonic perforation

Colonic infarctionColonic infarction

Salehi I.Salehi I.


Pulmonary involvement:Pulmonary involvement:

• In most patients with SSc: In most patients with SSc: 70%70%

• Leading cause of deathLeading cause of death

• Two main types:Two main types:

Interstitial Lung Disease (Interstitial Lung Disease (ILDILD))

Pulmonary Arterial Hypertension (Pulmonary Arterial Hypertension (PAHPAH))

Salehi I.Salehi I.


Pulmonary involvement:Pulmonary involvement: Less common types:Less common types:

• Aspiration pneumoniaAspiration pneumonia

• Pulmonary hemorrhagePulmonary hemorrhage

• Obliterative BronchiolitisObliterative Bronchiolitis

• Extraparenchymal restrictive lung diseaseExtraparenchymal restrictive lung disease

• Spontaneous pneumothoraxSpontaneous pneumothorax

• Drug induced lung diseaseDrug induced lung disease

• Lung cancer (Bronchoalveolar Carcinoma)Lung cancer (Bronchoalveolar Carcinoma)

Salehi I.Salehi I.


Pulmonary involvement:Pulmonary involvement: Common presentations:Common presentations:

• DOE: most commonDOE: most common

• Chronic dry cough: commonChronic dry cough: common

• Reduced exercise tolerance, fatigueReduced exercise tolerance, fatigue

• Chest pain: uncommonChest pain: uncommon

• Hemoptysis: RareHemoptysis: Rare

• Asymptomatic: 1/3Asymptomatic: 1/3

• Basal “Velcro” cracklesBasal “Velcro” crackles

Salehi I.Salehi I.


Interstitial lung disease:Interstitial lung disease:

• Up to 90% in autopsyUp to 90% in autopsy

• Up to 85% in HRCTUp to 85% in HRCT

• Up to 43% clinically: “Velcro” cracklesUp to 43% clinically: “Velcro” crackles

• CXR-PA: Lower lobes reticular patternCXR-PA: Lower lobes reticular pattern

Salehi I.Salehi I.



HRCT: one or combination of below patternsHRCT: one or combination of below patterns

• Reticular linear opacitiesReticular linear opacities

• Nodular opacitiesNodular opacities

• Honey comb cystic changesHoney comb cystic changes

• Ground glass opacificationGround glass opacification

Salehi I.Salehi I.



• FEV-1: UnaffectedFEV-1: Unaffected

• FVC: DecreasedFVC: Decreased

• FEV-1/FVC: Normal or increasedFEV-1/FVC: Normal or increased

• DLCO: DecreasedDLCO: Decreased

Salehi I.Salehi I.



Risk factors for ILD:Risk factors for ILD:


• African-American raceAfrican-American race

• Diffuse cutaneous SScDiffuse cutaneous SSc

• Severe GERDSevere GERD

• Presence of anti-topoisomerase-IPresence of anti-topoisomerase-I

• Low FVC or DLCO at initial presentationLow FVC or DLCO at initial presentation

Salehi I.Salehi I.



Rapid progressive ILDRapid progressive ILD

• Within the first 3 years of diseaseWithin the first 3 years of disease

• Significant DOESignificant DOE

• Extensive “Velcro” cracklesExtensive “Velcro” crackles

• Extensive pattern in HRCT Extensive pattern in HRCT

• The FVC can decline by 30%/yearThe FVC can decline by 30%/year

Salehi I.Salehi I.



Bronchoalveolar lavage (BAL):Bronchoalveolar lavage (BAL):

• PMN > 2% &/or Eosinophils > 3% is correlated with more PMN > 2% &/or Eosinophils > 3% is correlated with more

extensive ILD in HRCTextensive ILD in HRCT

Serum level of KL-6:Serum level of KL-6:

• Measurement of KL-6, a glycoprotein found in type II Measurement of KL-6, a glycoprotein found in type II

pneumocytes and alveolar macrophages is a biomarker pneumocytes and alveolar macrophages is a biomarker

for the detection and serial monitoring of ILD in SScfor the detection and serial monitoring of ILD in SSc

Salehi I.Salehi I.


Salehi I.Salehi I.


Pulmonary arterial hypertension (PAH):Pulmonary arterial hypertension (PAH):

Definition: Definition:

• Mean Pulmonary arterial pressure > 25 mmHgMean Pulmonary arterial pressure > 25 mmHg

• Pulmonary capillary wedge pressure < 15 mmHgPulmonary capillary wedge pressure < 15 mmHg

In 10-15% of patients with SScIn 10-15% of patients with SSc

Development of RHFDevelopment of RHF

DOE, Angina, Exertional near-syncopeDOE, Angina, Exertional near-syncope

With significant mortalityWith significant mortality

Salehi I.Salehi I.



Risk factors of PAH:Risk factors of PAH:

• Limited cuteneous SSc Limited cuteneous SSc

• Positive ACAPositive ACA

• Late age at disease onsetLate age at disease onset

• Severe Raynaud’s ph.Severe Raynaud’s ph.

• Anti U1-RNP, U3-RNP (Fibrillarin) and B23Anti U1-RNP, U3-RNP (Fibrillarin) and B23

Salehi I.Salehi I.



Doppler Echocardiography:Doppler Echocardiography:

• Used as screeningUsed as screening

• PA systolic pressure > 40 mmHg at rest PA systolic pressure > 40 mmHg at rest

suggest PAHsuggest PAH

Serum level of brain natriuretic peptide (BNP):Serum level of brain natriuretic peptide (BNP):

• Used as screening and monitoring of PAHUsed as screening and monitoring of PAH

Salehi I.Salehi I.


Renal involvement:Renal involvement:

• 50% clinical involvement50% clinical involvement

• 60-80% in autopsy60-80% in autopsy

• Sclerodermal Renal Crisis (SRC)Sclerodermal Renal Crisis (SRC)

– The most dreaded complication of SScThe most dreaded complication of SSc

– Almost always within first 4 years of Almost always within first 4 years of

disease disease

Salehi I.Salehi I.


Sclerodermal Renal Crisis: Sclerodermal Renal Crisis: • In 10-20% of dcSScIn 10-20% of dcSSc

• ARF with NL U/AARF with NL U/A

• New & a few Pr or RBC or granular casts in U/ANew & a few Pr or RBC or granular casts in U/A

• Abrupt onset of Marked HTN Abrupt onset of Marked HTN (10% NL HTN):(10% NL HTN):

– Headache, blurred vision, chest painHeadache, blurred vision, chest pain

• Pericarditis, CHFPericarditis, CHF

• Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia

• Activated RAA system + nephrosclerosisActivated RAA system + nephrosclerosis

Salehi I.Salehi I.


Risk factors of SRC:Risk factors of SRC:

• Diffuse, advanced skin involvementDiffuse, advanced skin involvement


• African American raceAfrican American race

• Glucocorticoid use (MDS-HDS)Glucocorticoid use (MDS-HDS)

• Anti RNA polymeras I & IIIAnti RNA polymeras I & III

• CyclosporineCyclosporine

Salehi I.Salehi I.


Screening for SRC:Screening for SRC:

• In high risk pt.: Daily home BP measurementIn high risk pt.: Daily home BP measurement

• In other pt.: Biweekly BP measurementIn other pt.: Biweekly BP measurement

• In all pt.: Plasma Cr & Urine Pr Checking every In all pt.: Plasma Cr & Urine Pr Checking every

3-6 months3-6 months

Salehi I.Salehi I.


Alarm signs of impending SRC:Alarm signs of impending SRC:

• Palpable tendon friction rubsPalpable tendon friction rubs

• Pericardial effusionPericardial effusion

– Pericardial friction rubPericardial friction rub

• New unexplained anemiaNew unexplained anemia

• New unexplained thrombocytopeniaNew unexplained thrombocytopenia

Salehi I.Salehi I.


Outcome of SRC:Outcome of SRC:

• Oliguria or Cr > 3 mg/dl at presentation predicts Oliguria or Cr > 3 mg/dl at presentation predicts

poor outcome, with permanent hemodialysis poor outcome, with permanent hemodialysis

and high mortalityand high mortality

• Using short-acting ACE inhibitors to achieve Using short-acting ACE inhibitors to achieve

adequate BP control before the onset of renal adequate BP control before the onset of renal

failure results in improved prognosisfailure results in improved prognosis

Salehi I.Salehi I.


Lung CancerLung Cancer

• The risk is increased similarly in both The risk is increased similarly in both

lcSSc & dcSSclcSSc & dcSSc

• The risk is 5 x nl populationThe risk is 5 x nl population

• 1/3 of cancer in SSc1/3 of cancer in SSc

Salehi I.Salehi I.


Other CancersOther Cancers

• TongueTongue

• BreastBreast

• Esophagus ( Barrett’s Esophagus ( Barrett’s Adenocarcinoma) Adenocarcinoma)

Salehi I.Salehi I.


Cardiac involvement:Cardiac involvement:

• In dcSSc more than lcSScIn dcSSc more than lcSSc

• Within 3 years of the onset of skin thickeningWithin 3 years of the onset of skin thickening

• Often clinically silentOften clinically silent

• All layers of heart may be involvedAll layers of heart may be involved

Salehi I.Salehi I.



• Secondary to systemic HTN or PAH: Secondary to systemic HTN or PAH:

– most commonmost common

– LVH, RVH, and CHFLVH, RVH, and CHF

• Pericarditis Pericarditis ++ effusion: effusion: PE alarm sign of SRCPE alarm sign of SRC

• Myocardial fibrosisMyocardial fibrosis, Myocarditis, Myocarditis

• Valvular regurgitationValvular regurgitation

Salehi I.Salehi I.



• Angina pectorisAngina pectoris

• Conduction disturbancesConduction disturbances

• Arrhythmias: Atrial & Ventricular tachycardiasArrhythmias: Atrial & Ventricular tachycardias

• Tissue Doppler Echo (TDE) & Cardiac MRITissue Doppler Echo (TDE) & Cardiac MRI

• Thallium perfusion studiesThallium perfusion studies

• Serum level of NT-Pro-BNP as a marker of primary Serum level of NT-Pro-BNP as a marker of primary

cardiac involvement cardiac involvement

Salehi I.Salehi I.


Musculoskeletal disease:Musculoskeletal disease:

In early stage of disease:In early stage of disease:

• CTS: common & may be presenting featureCTS: common & may be presenting feature

• Edema & swelling of handsEdema & swelling of hands

• Generalized arthralgia-myalgiaGeneralized arthralgia-myalgia

• Hand joints: most commonHand joints: most common

Salehi I.Salehi I.



• Stiff joints in dcSSc:Stiff joints in dcSSc:

Elbow, Shoulder, KneeElbow, Shoulder, Knee

• Large joint contracturesLarge joint contractures

• Tendon friction rubsTendon friction rubs

Fingers, wrist, elbow, knee and ankleFingers, wrist, elbow, knee and ankle

• True arthritis uncommonTrue arthritis uncommon

• Erosive polyarthritis of hands: may be Erosive polyarthritis of hands: may be

Salehi I.Salehi I.



Muscle weakness: commonMuscle weakness: common

• Disuse atrophyDisuse atrophy

• MalnutritionMalnutrition

• Overlap with polymyositisOverlap with polymyositis

• MyopathiesMyopathies

Salehi I.Salehi I.


Musculoskeletal disease:Musculoskeletal disease:•

• Erosive polyarthritis with positive RF: Erosive polyarthritis with positive RF:

overlap of RA & Scloverlap of RA & Scl

• HA arthropathyHA arthropathy

• OA of DIP & CMC1OA of DIP & CMC1

• Acro-osteolysis, resorption of mandibular Acro-osteolysis, resorption of mandibular

condyles, osteolysis of ribs and distal claviclescondyles, osteolysis of ribs and distal clavicles

Salehi I.Salehi I.


Neurologic involvement:Neurologic involvement:

NeuropathiesNeuropathies• Cranial, Peripheral, AutonomicCranial, Peripheral, Autonomic

• Entrapment, CutaneousEntrapment, Cutaneous

Trigeminal neuralgiaTrigeminal neuralgia

CNS: uncommon to rareCNS: uncommon to rare• Headache, Seizures,Headache, Seizures,

• Stroke, Vascular diseaseStroke, Vascular disease

• Radiculopathy, myelopathyRadiculopathy, myelopathy

Salehi I.Salehi I.


Genitourinary involvement:Genitourinary involvement:

In men:In men:• Erectile dysfunction: 80%Erectile dysfunction: 80%• Male impotenceMale impotence

In women:In women:• Sexual dysfunctionSexual dysfunction• Vaginal drynessVaginal dryness• Constriction of the vaginal introitusConstriction of the vaginal introitus• Dyspareunia: > 1/2Dyspareunia: > 1/2

Salehi I.Salehi I.


• Sjogren’s syndromeSjogren’s syndrome

• HypothyroidismHypothyroidism

• PBC: lcSScPBC: lcSSc

• Difficult pregnancy: dcSScDifficult pregnancy: dcSSc

Salehi I.Salehi I.


CREST CREST syndrome :syndrome :

CCalcinosisalcinosis

RRaynaud’s ph.aynaud’s ph.

EEsophageal dysmotilitysophageal dysmotility

SSclerodactylyclerodactyly

TTelangiectasiaelangiectasia

Salehi I.Salehi I.


Lab. Data:Lab. Data: CBC: AnemiaCBC: Anemia

ESRESR

Renal FT, Liver FTRenal FT, Liver FT

FANA: 95%, speckledFANA: 95%, speckled

• Scl-70Scl-70

• ACAACA

CXRCXR

Salehi I.Salehi I.


Lab. Data:Lab. Data:

• AOCD; mild, most commonAOCD; mild, most common

• IDA: GAVE, chronic esophagitisIDA: GAVE, chronic esophagitis

• Macrocytic anemia: Macrocytic anemia:

• B12, Folate deficiencyB12, Folate deficiency

• Drugs: MTXDrugs: MTX

• Microangiopathic hemolytic anemia:Microangiopathic hemolytic anemia:

• SRCSRC

Salehi I.Salehi I.



• Pancytopenia:Pancytopenia:

• DrugsDrugs

• SRCSRC

• MalignancyMalignancy

• Elevated ESR:Elevated ESR:

• MyositisMyositis

• MalignancyMalignancy

Salehi I.Salehi I.



AntitopoisomeraseAntitopoisomerase I (Scl-70)I (Scl-70)

• Highly specific for SScHighly specific for SSc

• High risk of ILDHigh risk of ILD

• Associated with Associated with dcSScdcSSc

Anti-centromere antibodies (ACA)Anti-centromere antibodies (ACA)

• Associated with Associated with lcSSclcSSc

Salehi I.Salehi I.



AntiPM-Scl: PM + SclAntiPM-Scl: PM + Scl

AntiU3-RNP (Fibrillarin): SSc + PAHAntiU3-RNP (Fibrillarin): SSc + PAH

Anti RNA polymerase I & III: only in SSc Anti RNA polymerase I & III: only in SSc

Anti RNA polymerase II: in SLE or SScAnti RNA polymerase II: in SLE or SSc

RF: 25%RF: 25%

Salehi I.Salehi I.


Attention please:• Scl-70Scl-70 & &

• ACAACA & &

• Anti-RNA polymerase III Anti-RNA polymerase III antibody testsantibody tests

are highly specific (> 99.5%) but only are highly specific (> 99.5%) but only moderately sensitive (20-50%)moderately sensitive (20-50%)

• Over 95% of SSc patients have at least Over 95% of SSc patients have at least one autoantibodies one autoantibodies

Salehi I.Salehi I.


Lab. Data:Lab. Data:• GI EndoscopyGI Endoscopy

• Doppler EchocardiographyDoppler Echocardiography

• HRCT of lungHRCT of lung

• Hand X-RayHand X-Ray

• Manometry, DlcoManometry, Dlco

• Spirometry, PletismographySpirometry, Pletismography

• Thyroid FT Thyroid FT

• Skin biopsy Skin biopsy

Salehi I.Salehi I.


Skin biopsy:Skin biopsy:

• Not necessary for diagnosis of SScNot necessary for diagnosis of SSc

• Only done in doubtful casesOnly done in doubtful cases

• For DD with Scleroderma-like disordersFor DD with Scleroderma-like disorders

• May be necessary for localized SclerodermaMay be necessary for localized Scleroderma

• Should include subcutaneous tissue, fascia, Should include subcutaneous tissue, fascia,

and muscleand muscle

Salehi I.Salehi I.


Scleroderma-like disorders:Scleroderma-like disorders:• Scleredema Scleredema • ScleromyxedemaScleromyxedema• Diabetes MellitusDiabetes Mellitus• HypothyroidismHypothyroidism• Nephrogenic systemic fibrosisNephrogenic systemic fibrosis• AmyloidosisAmyloidosis• Eosinophilic fasciitisEosinophilic fasciitis• Chronic GVHDChronic GVHD

Salehi I.Salehi I.


Limited Cutaneous SSc (lcSSc):Limited Cutaneous SSc (lcSSc):

• Raynaud’s ph. For yearsRaynaud’s ph. For years

• Acro-facial skin sclerosisAcro-facial skin sclerosis

• Dilated nailfold capillary loops( Dilated nailfold capillary loops( no drop-outno drop-out ) )

• Accompanied by CREST syndromeAccompanied by CREST syndrome

• Pulmonary Artery Hypertension( PAH )Pulmonary Artery Hypertension( PAH )

• ILD lately & SRC rarely occursILD lately & SRC rarely occurs

• ACAACA: 70 - 80% : 70 - 80%

Salehi I.Salehi I.


Diffuse Cutaneous SSc (dcSSc):Diffuse Cutaneous SSc (dcSSc):

• Raynaud’s ph. Followed, within one year, by Raynaud’s ph. Followed, within one year, by

puffy skin changespuffy skin changes

• TrunkalTrunkal & acro-facial & acro-facial skin sclerosisskin sclerosis

• Tendon friction rubsTendon friction rubs

• Nailfold capillary dilatation (with drop-out)Nailfold capillary dilatation (with drop-out)

• Early & significant incidence of SRC, ILD, GI & Early & significant incidence of SRC, ILD, GI &

cardiac diseasecardiac disease

• Anti-Scl-70Anti-Scl-70: 30%: 30%

Salehi I.Salehi I.


Pre-SclerodermaPre-Scleroderma

Subclinical SclerodermaSubclinical Scleroderma

Early Scleroderma Early Scleroderma

Salehi I.Salehi I.


Pre-Scleroderm Pre-Scleroderm

• Raynaud’s phenomenon plusRaynaud’s phenomenon plus

• Nailfold capillary changes &/orNailfold capillary changes &/or

• Autoantibodies:Autoantibodies:• Scl-70Scl-70

• ACAACA

• Anti-RNA polymeraseAnti-RNA polymerase

• No skin involvementNo skin involvement

Salehi I.Salehi I.


Diagnosis of SSc:Diagnosis of SSc:

• Clinical: UponClinical: Upon

History &History &

Physical examinationPhysical examination

• No skin biopsy: only for No skin biopsy: only for

Localized Scl.Localized Scl.

DD with Scl. Like disordersDD with Scl. Like disorders

Salehi I.Salehi I.


Diagnosis of SSc:Diagnosis of SSc: Combination of Combination of skin induration plus skin induration plus >> 1 of: 1 of:

• Heartburn &/or dysphagia of new onsetHeartburn &/or dysphagia of new onset

• Acute onset of HTN & renal failureAcute onset of HTN & renal failure

• DOE + ILD, or PAHDOE + ILD, or PAH

• Diarrhea with malabsorptionDiarrhea with malabsorption

• Facial, lip, or hand telangiectasiaFacial, lip, or hand telangiectasia

• Digital infarctions & or pitting ulcerDigital infarctions & or pitting ulcer

• Erectile dysfunctionErectile dysfunction

Salehi I.Salehi I.


Attention please:

The presence of :The presence of :

• Calcinosis cutisCalcinosis cutis

• HyperpigmentationHyperpigmentation &/or &/or Skin Skin

telangiectasia andtelangiectasia and

• FacialFacial and and FingersFingers features features

Can differentiate SSc from other DDCan differentiate SSc from other DD

Salehi I.Salehi I.


Prognosis & Mortality:Prognosis & Mortality:

Mortality rate:Mortality rate:• in dcSSc # 5-8 fold higher than nl populationin dcSSc # 5-8 fold higher than nl population• In lcSSc # 2 foldIn lcSSc # 2 fold

The most common cause of death in The most common cause of death in dcSSc:dcSSc:• Pulmonary fibrosis &/or PAHPulmonary fibrosis &/or PAH• SRCSRC• CardiacCardiac

Salehi I.Salehi I.


Management:Management:

• No cure, No remissionNo cure, No remission• Localized or Systemic Scl.Localized or Systemic Scl.• Which type of systemic Scl.Which type of systemic Scl.• Nonpharmacologic therapyNonpharmacologic therapy• PharmacologicPharmacologic• Symptomatic therapySymptomatic therapy• Systemic therapy:Systemic therapy:

• Vascular + Immunologic + FibroticVascular + Immunologic + Fibrotic• Minor vs majorMinor vs major

Salehi I.Salehi I.


Attention please:

• Elucidation of the precise interplay Elucidation of the precise interplay

between the Vascular, Immunologic between the Vascular, Immunologic

and Fibrotic components of SSc is and Fibrotic components of SSc is

likely to be an important first step likely to be an important first step

towards more effective therapytowards more effective therapy

Salehi I.Salehi I.


Disease modifying therapy:

• Immunosuppressive therapy:Immunosuppressive therapy:

– Glucocorticoids (LDS)Glucocorticoids (LDS)

– MTXMTX

– Mycophenolate mofetilMycophenolate mofetil

– CyclophosphamideCyclophosphamide

– Autologous stem cell transplantationAutologous stem cell transplantation

Salehi I.Salehi I.



• Anti-fibrotic therapy:Anti-fibrotic therapy:

– D-penicillamine:D-penicillamine:

• Standard-dose: 750 mg/dayStandard-dose: 750 mg/day

• Low-dose: 125 mg qodLow-dose: 125 mg qod

Salehi I.Salehi I.



Vascular therapy:Vascular therapy:• Calcium channel blockers: Calcium channel blockers: DiltiazemDiltiazem• Angiotensin II receptor blockers: Angiotensin II receptor blockers: LosartanLosartan• Alpha-1 blocker: prazocinAlpha-1 blocker: prazocin• 5-phosphodiesterase inhibitors: 5-phosphodiesterase inhibitors: SildenafilSildenafil• SSRI: SSRI: FluoxetineFluoxetine• Topical nitroglycerineTopical nitroglycerine• IV prostaglandine: IV prostaglandine: IloprostIloprost• Anti-platelet agent: low-dose Anti-platelet agent: low-dose AspirinAspirin• Endothein-1 receptor antagonist: Endothein-1 receptor antagonist: BosentanBosentan

Salehi I.Salehi I.


Pulmonary therapy:

Severe acute ILD:Severe acute ILD:

• Cyclophosphamide plusCyclophosphamide plus

• Medium dose GlucocorticoidsMedium dose Glucocorticoids

Symptomatic PAH:Symptomatic PAH:

• BosentanBosentan

• SildenafilSildenafil

Salehi I.Salehi I.


Gastrointestinal therapy: GERD: PPIGERD: PPI• Omeprazole, PantozolOmeprazole, Pantozol• Nexium (esomeprazole)Nexium (esomeprazole)

GI bleeding: Watermelon, GAVEGI bleeding: Watermelon, GAVE• Laser photocoagulationLaser photocoagulation

Bacterial overgrowth:Bacterial overgrowth:• MetronidazoleMetronidazole• Erythromycin & TetracyclineErythromycin & Tetracycline

Chronic hypomotility:Chronic hypomotility:• OctreotideOctreotide

Salehi I.Salehi I.


Scleroderma Renal Crisis therapy:

ACE inhibitors: 90% of casesACE inhibitors: 90% of cases

Hemodialysis: 2/3 of casesHemodialysis: 2/3 of cases

• In ½ of cases: recoveryIn ½ of cases: recovery

• In ½ of cases who are unable to D/C dialysis In ½ of cases who are unable to D/C dialysis

after 2 years: Renal transplantationafter 2 years: Renal transplantation

• Recurrency of SRC in transplanted kidney is rare Recurrency of SRC in transplanted kidney is rare

Salehi I.Salehi I.


Symptomatic therapy:

• PruritusPruritus

• Dry skinDry skin

• DyspareuniaDyspareunia

• Facial telangiectasisFacial telangiectasis

• DOEDOE

Salehi I.Salehi I.


Salehi I.Salehi I.


scleroderma. in the name of god the merciful the compassionate

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