Systemic SclerosisSystemic Sclerosis

CLINICAL FEATURESCLINICAL FEATURES

RaynaudRaynaud’’s Phenomenon.s Phenomenon.Skin Features.Skin Features.Pulmonary Features.Pulmonary Features.MuscuoMuscuo--skeletal Features.skeletal Features.GIT Features.GIT Features.Renal Features.Renal Features.Cardiac Features.Cardiac Features.

RAYNAUDRAYNAUD’’S PHENOMENON S PHENOMENON

It is the first symptom of SSC along with puffy It is the first symptom of SSC along with puffy fingers.fingers.

It is the episodic vasoconstriction of small arteries It is the episodic vasoconstriction of small arteries and arterioles of fingers and toes.and arterioles of fingers and toes.

StimulusStimulus : Cold exposure, vibration, emotional stress.: Cold exposure, vibration, emotional stress.

Pallor Cyanosis RuborPallor Cyanosis Rubor

RAYNAUDRAYNAUD’’S PHENOMENON S PHENOMENON

It precedes months / years in a case of It precedes months / years in a case of LSScLSSc..

While in diffuse form skin changes appear While in diffuse form skin changes appear within one year of the onset of raynaudwithin one year of the onset of raynaud’’s s phenomenon.phenomenon.

RaynaudRaynaud’’s Phenomenons Phenomenon

SKIN CHANGES SKIN CHANGES

Begin distally in the extremities with proximal Begin distally in the extremities with proximal advancement.advancement.

Three phases :Three phases :OedematousOedematous phasephase

Swelling of fingers & handsSwelling of fingers & handsPitting/nonPitting/non--pittingpitting

IndurativeIndurative phasephasefirm and thickened skin, tightly bound to the firm and thickened skin, tightly bound to the underlying tissue.underlying tissue.

Atrophic phaseAtrophic phaseSoftened and burned out skin.Softened and burned out skin.

Flexion contractures limiting full extension.Flexion contractures limiting full extension.((SclerodactylySclerodactyly))

Ulcers over Ulcers over volarvolar pads of fingers, bony pads of fingers, bony prominences (elbows, prominences (elbows, malleolimalleoli, IP joints)., IP joints).These ulcers may become secondarily infected.These ulcers may become secondarily infected.

Loss of soft tissue over Loss of soft tissue over volarvolar pads of fingers, with pads of fingers, with resorptionresorption of terminal phalanges.of terminal phalanges.

SALT & PEPPER APPEARANCE :SALT & PEPPER APPEARANCE :HypopigmentedHypopigmented areas with sparing of pigment areas with sparing of pigment around hair follicles.around hair follicles.

Dry & Coarse Skin.Dry & Coarse Skin.

Loss of hair, oil and Loss of hair, oil and sweat glands.sweat glands.

CutaneousCutaneous calcificationcalcificationin digital pads, extensor in digital pads, extensor surfaces of forearm.surfaces of forearm.

FACIAL FEATURESFACIAL FEATURES

-- Loss of wrinkles Loss of wrinkles -- LossLoss of Facial expressionof Facial expression-- TelangectesiasTelangectesias

-- Thinning of lipsThinning of lips-- MicroostomiaMicroostomia-- Wrinkles around the mouth perpendicular to lipsWrinkles around the mouth perpendicular to lips

FACIAL FEATURESFACIAL FEATURES

Pinched nosePinched nose

PULMONARY FEATURES PULMONARY FEATURES

Present in more that 2/3rd of patients .Present in more that 2/3rd of patients .Leading cause of death.Leading cause of death.

ExertionalExertional dyspnoeadyspnoea (MC symptom)(MC symptom)Dry CoughDry CoughB/L bibasilar B/L bibasilar ralesrales..Limited sclerosis lead to severe form of PAH Limited sclerosis lead to severe form of PAH after 10after 10--15 yrs of disease in <10% patients.15 yrs of disease in <10% patients.Mean duration of survival after Mean duration of survival after PAH is ~ 2 yrsPAH is ~ 2 yrs..Diffuse systemic sclerosis has risk of developing Diffuse systemic sclerosis has risk of developing pulmonary fibrosis.pulmonary fibrosis.

Risk factors for severe fibrosis :Risk factors for severe fibrosis :

Early disease, Early disease, DSScDSSc, Anti, Anti--SclScl 7070Limited SSC with anti Limited SSC with anti SclScl 70 70 FVC < 75%, Early in disease (18 FVC < 75%, Early in disease (18 mthsmths))Decrease of FVC by 10% per yearDecrease of FVC by 10% per year

Aspiration pneumonia due to lower Aspiration pneumonia due to lower esophageal tone.esophageal tone.

--There has been a decrease in the number of deaths due to SRC There has been a decrease in the number of deaths due to SRC with the use of ACEI.with the use of ACEI.

--But the most common cause of mortality is Pulmonary Fibrosis But the most common cause of mortality is Pulmonary Fibrosis and PAHand PAH

RENAL FEATURESRENAL FEATURESHigh risk of renal crisis seen in patients with rapidly High risk of renal crisis seen in patients with rapidly progressive skin thickening in first 2progressive skin thickening in first 2--3 yrs of disease.3 yrs of disease.Mechanism of renal crisisMechanism of renal crisis : activation of : activation of reninreninangiotensinangiotensin system.system.Renal Crisis :Renal Crisis :

MalignanatMalignanat HT.HT.Hypertensive encephalopathyHypertensive encephalopathySevere HeadacheSevere HeadacheRetinopathyRetinopathySeizuresSeizuresHematuria/proteinuria/oliguriaHematuria/proteinuria/oliguriaLVFLVF

MusculoMusculo--skeletal Features :skeletal Features :Pain, swelling, and stiffness of joints.Pain, swelling, and stiffness of joints.Symmetric Symmetric polyarthritispolyarthritis..Carpel Tunnel Syndrome.Carpel Tunnel Syndrome.Muscle Weakness.Muscle Weakness.

GIT Features :GIT Features :EpigastricEpigastric fullness.fullness.GERDGERDBarretBarret’’ss MetaplasiaMetaplasiaDysphagiaDysphagia (To solid foods)(To solid foods)

HypomotiltyHypomotilty of intestines.of intestines.

Bacterial overgrowth.Bacterial overgrowth.

MalabsorptionMalabsorption syndrome.syndrome.

Chronic constipation.Chronic constipation.

Anal incontinence.Anal incontinence.

““WaterWater--melon stomachmelon stomach”” : Vascular : Vascular ectasiaectasia of of stomach that appear on stomach that appear on endoscopyendoscopy as broad as broad stripes, may cause GI bleeding.stripes, may cause GI bleeding.

CARDIAC FEATURES CARDIAC FEATURES

PericarditisPericarditis..

Pericardial effusion.Pericardial effusion.

Heart failure.Heart failure.

Heart block/Heart block/ArrythmiasArrythmias..

CorCor pulmonalepulmonale due to PAH.due to PAH.

LVF due to systemic hypertension.LVF due to systemic hypertension.

CardiomyopathyCardiomyopathy (<10%).(<10%).

OTHER FEATURESOTHER FEATURES

BiliaryBiliary cirrhosis cirrhosis

Hypothyroidism Hypothyroidism

Dry Eyes/ Dry mouthDry Eyes/ Dry mouth

HOW TO DIAGNOSE SYSTEMIC SCLEROSIS ?

- History and examination

- Routine investigations--Hypoproliferative anemia

-Vitamin B12 and FA deficiency anemia

-Microangiopathic anemia

-Hypergammaglobinemia

-KFT , LFT , TFT

-Urine

CXR-PA

- Normal in 5 – 10 %

- Linear densities, mottling

- Sub-pleural cysts (honeycombing ) in lower 2/3 of lung

- Progressive volume loss

HRCTHRCT

- Architectural distortion with reticular opacities- Honeycombing and traction bronchiectasis- Interlobular septal thickening- Ground glass pattern (suggesting of alveolitis)- Esophageal dilatation (>80 % )

BONE RADIOGRAPHYBONE RADIOGRAPHY

- Generalized osteopenia

( M.C. of hands )

-Inter-articular calcification

- Thoracic inlet X-ray to exclude cervical rib

BARIUM STUDIESBARIUM STUDIES

-Dilatation of esophagus ,SI and LI

Manometry

-Decreased amplitude of peristaltic waves of lower 2/3 of esophagus.

PFTPFT

- Decreased VC

- Decreased DLCO

- Decreased PaO2 with normal or Decreased PaCO2

- Decreased Lung compliance

PFT is a useful guide to differentiate between PFT is a useful guide to differentiate between patients of interstitial fibrosis from PAHpatients of interstitial fibrosis from PAH

Interstital fibrosis VC and DLCO decreased at same time

FVC % / DLCO % < 1.4

Primary vasculopathy DLCO decrease out of proportion of FVC

FVC % / DLCO % > 1.8

Both FVC % / DLCO % is between 1.4 – 1.8

Suggestive of alveolits :-

Alveolar macrophages (>85%)

Neutrpphils ( 3-4% )

Eosinophils ( >2% )

Suggestive of fibrosis :-

IL-8, PDGF, TGF-B,

Endothelin 1

BALBAL

Other investigations :-

- ECG.

- 24 hour holter monitoring.

- Echocardiography.

- Right heart catheterization.

AUTOANTIBODIES FOUND IN SSC

1.Anti-topoisomerase/ anti-Scl 70 – against DNA Topoisomerase

2.Anticentromere - against protein Ag of kinetochore region ofchromosome

3. Antinucleolar ( anti RNA Polymerase I, II, III )

4. Anti Th RNP

5. Anti U1 RNP

6. Anti U3 RNP

7. Anti PM-Scl

AUTOANTIBODIES FOUND IN SSC

Anti Scl 70 DSSc 40%

Anticentromere LSSc 60-80 %

Anti RNA Polymerase I, II, III DSSc 5–40 %

Anti- Th RNP LSSc 14 %

Anti-U1 RNP LSSc 5–10 %

MCTD 95–100 %

Anti- U3 RNP DSSc + 5 %

(anti-fibrillarin) LSSc

Anti- PM / Scl Overlap 25%

(SSc,polymyositis)

Anticentromere Ab - Isolated PAH ( LSSc )

Anti Scl 70 Ab - Secondary PAH ( DSSc )

Antinucleolar Ab - Both LSSc and DSSc

SCLERODERMA SKIN SCORING METHODS

1. RODNAN skin score in scleroderma

2. Modified RODNAN skin score in scleroderma using 17sites

3. Modified RODNAN skin score in scleroderma using 5 sites

4. Hidebinding/Tethering skin score of FURST et al. for scleroderma

5. KAHALEH Skin score in scleroderma

MODIFIED RODNAN SKIN SCORE

• The body is divided into 17 sites.

• The skin involvement is graded as:-

0 – Normal skin

1 - Mild Thickening

2 – Moderate Thickening

3 – Severe Thickening

• This method does not take into account of digital ulcers, flexion contractures, hyper and hypo- pigmentation of skin.

Subsets of Systemic SclerosisDiffuse Limiteda

Skin involvement Distal and proximal extremities, face, trunk

Distal to elbows, face

Raynaud's phenomenon Onset within 1 year or at time of skin changes

May precede skin disease by years

Organ involvement Pulmonary (interstitial fibrosis); renal (renovascular hypertensive crisis); gastrointestinal; cardiac

Gastrointestinal; pulmonary arterial hypertension after 10-15 years of disease in <10% of patients; biliary cirrhosis

Nail fold capillaries Dilatation and dropout Dilatation without significant dropout

Antinuclear antibodies Antitopoisomerase 1 Anticentromere

a Also referred to as CREST (calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, telangiectasia).

HOW TO TREAT ?

The goals of treatment in SSc are:-

- Prevent internal organ damage

- Arrest/slow the deterioration of function of involved organs

- Improve the function of the involved organs

HOW TO TREAT ?Underlying processes in SSc are:-

- Vascular damage

- Immune cell activation

- Fibrogenesis

- A combination therapy treating all these processes is more likely to control disease than single agent therapy

- Therapy should be started in first 12-18 mths in order to prevent the disease progression.

- Therapy must match disease stage and subset

Early stage – Immunosupressives + Vasodilators

Late stage - Antifibrotics + Vasodilators

Treatment Strategies

Drugs toPrevent

Vascular Damage

Drugs that Supress

Autoimmunity &Infection

Drugs thatSupressfibrosis

ACEIEpoprostenolBosentan

CyclophosphamideMethotrexateAzathioprine5-FUChlorambucilStem Cell Transplant

D-PenicillamineIFN-γIFN-αRelaxinPlasma Exchange

D D -- PENICILLAMINE PENICILLAMINE

It is the most commonly used drug.It is the most commonly used drug.MOAMOA : Interferes with inter and intra molecular cross : Interferes with inter and intra molecular cross linkages of collagen with an linkages of collagen with an immunomodulatorimmunomodulator effect.effect.

BenefitsBenefits : Reduction in skin thickening and prevention of : Reduction in skin thickening and prevention of new organ involvement.new organ involvement.5 years survival rate of 80%.5 years survival rate of 80%.

DoseDose : start with a low dose , 250 mg/ day and then : start with a low dose , 250 mg/ day and then increased at one monthly intervals to 1.5 gm/day.increased at one monthly intervals to 1.5 gm/day.

DD-- PENICILLAMINEPENICILLAMINE

However a randomized double blind study* compared low dose (62.5 mg/d) with high dose (750 mg/d) in patients of DSSc.

No significant difference was observed between the groups as to degree of skin thickening, renal crisis, organ involvement and mortality .

*Clements PJ et al. Arth Rheumat 1999; 42: 1194-1203

IFNIFN--γγ ::Improvement in skin sclerosisImprovement in skin sclerosisBut worsening of raynaudBut worsening of raynaud’’s phenomenon and s phenomenon and renal crisis.renal crisis.

Recombinant human Recombinant human relaxinrelaxin ::Associated with decrease in skin thickening but Associated with decrease in skin thickening but subsequent follow up did not show any subsequent follow up did not show any significant benefit.significant benefit.

CYCLOPHOSPHAMIDE CYCLOPHOSPHAMIDE

It is used for systemic sclerosis associated It is used for systemic sclerosis associated alveolitisalveolitis (Early (Early ILD).ILD).There is an improvement in lung volumes and There is an improvement in lung volumes and DLcoDLco..

MOA MOA : Suppresses the production of : Suppresses the production of immunocompetentimmunocompetentleucocytes and depress inflammatory response.leucocytes and depress inflammatory response.

DoseDose : It is started at a dose of 2: It is started at a dose of 2--3 mg/kg/day.3 mg/kg/day.

Regular monitoring hematological profile and urine for Regular monitoring hematological profile and urine for RBCsRBCs and and protiensprotiens should be done.should be done.

GLUCOCORTICOIDS GLUCOCORTICOIDS

Indicated in SSc induced inflammatory myositis, Indicated in SSc induced inflammatory myositis, pericarditis, oedematous phase of skin involvement pericarditis, oedematous phase of skin involvement and early alveolitis of lung.and early alveolitis of lung.

It is not effective in controlling the progression of It is not effective in controlling the progression of disease.disease.

Dose Dose : Low dose (10: Low dose (10--20mg/day)20mg/day)

High dose (>30 mg/d) is associated with scleroderma High dose (>30 mg/d) is associated with scleroderma renal crisis. Therefore used cautiouslyrenal crisis. Therefore used cautiously..

PULSE PULSE glucocorticoidsglucocorticoids

Dose of 100mg Dose of 100mg dexamethasonedexamethasone in 5% dextrose given in 5% dextrose given I.V. for three days per pulse.I.V. for three days per pulse.

Improvement in skin thickness , raynaudImprovement in skin thickness , raynaud’’s s phenomenon and PFT.phenomenon and PFT.

Free of common side effects of long term steroids.Free of common side effects of long term steroids.

Role of PULSE steroids remain questionable in view Role of PULSE steroids remain questionable in view of reports regarding renal crisis with long term high of reports regarding renal crisis with long term high dose steroids.dose steroids.

CYCLOPHOSPHAMIDE + PREDNISOLONE CYCLOPHOSPHAMIDE + PREDNISOLONE

It is a promising approach for Pulmonary involvement It is a promising approach for Pulmonary involvement (Early (Early alveolitisalveolitis) in ) in SScSSc.*.*

Improvement in FVC, Improvement in FVC, DLCO, Skin Score has been observed.

Dose : Cyclophosphamide : 1-2mg/kg/day.Prednisolone : 10-20 mg/day.

*Calgumeri M et al. Clin Rheumatol 2003; 22: 289-294

MANAGEMENT OF RAYNAUDMANAGEMENT OF RAYNAUD’’S PHENOMENONS PHENOMENON

Aim Aim : To control vasospasm : To control vasospasm Simple measuresSimple measures

Hand warmingHand warmingProtective clothingProtective clothingAvoiding drugs like ergotamineAvoiding drugs like ergotamine

Oral vasodilators:Oral vasodilators:CCB CCB –– NifedipineNifedipine, , DiltiazemDiltiazem, , AmlodepineAmlodepine..55--HT Antagonist HT Antagonist –– KetanserinKetanserin..ACE Inhibitors ACE Inhibitors -- CaptoprilCaptopril, , EnalaprilEnalapril..ARBsARBs -- LosartanLosartan..ERAsERAs -- BosentanBosentan

Topical vasodilators :Topical vasodilators :NTG paste patchesNTG paste patches

ParentralParentral vasodilators :vasodilators :I.V. I.V. AlprostadilAlprostadil..I.V. I.V. IloprostIloprost..I.V I.V IpoprestenolIpoprestenol..

Surgical procedures :Surgical procedures :Lumbar Lumbar symphathectomysymphathectomyDigital Digital symphathectomysymphathectomyDebridementDebridement amputationamputation

The ACEI and ARB are better that CCB in inducing The ACEI and ARB are better that CCB in inducing vasodilatation and for recovery of scleroderma renal vasodilatation and for recovery of scleroderma renal crisis.crisis.

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin IACE InhibitorsACE Inhibitors

Angiotensin IIAngiotensin II

ProPro--FibroticFibrotic AgentsAgents

ORGAN BASED THERAPIESORGAN BASED THERAPIES

Renal CrisisRenal Crisis : : Early use of ACEI /ARB is recommended to Early use of ACEI /ARB is recommended to decrease blood pressure .decrease blood pressure .

ILDILD ::No consensus for the exact treatment of lung No consensus for the exact treatment of lung fibrosis but some benefits from fibrosis but some benefits from cyclophosphamide & steroids have been cyclophosphamide & steroids have been observed.observed.

PAHPAH ::Secondary PAH (Secondary to fibrosis).Secondary PAH (Secondary to fibrosis).Isolated PAH (Limited Scleroderma).Isolated PAH (Limited Scleroderma).

Treatment of PAHTreatment of PAHOxygen +Anticoagulation + Vasodilators.Oxygen +Anticoagulation + Vasodilators.Vasodilators :Vasodilators :

I.V. I.V. EpoprostenolEpoprostenolOral Oral BosentanBosentan..Inhaled Inhaled IloprostIloprost..CCBsCCBs..

Skin SclerosisSkin Sclerosis ::

UV A1 phototherapyUV A1 phototherapy : It induces : It induces collagenasecollagenaseactivity that is found to be decreased in activity that is found to be decreased in scleroderma fibroblast.scleroderma fibroblast.

PUVA PUVA : Oral : Oral psoralenspsoralens with UV A has been tried with UV A has been tried with limited success.with limited success.

SUPPORTIVE TREATMENTSUPPORTIVE TREATMENT

GIT reflux :GIT reflux :Small frequent meals, avoiding tea coffee Small frequent meals, avoiding tea coffee

alcohol.alcohol.ProkineticProkinetic agents like agents like DomperidoneDomperidone..PPIsPPIs

MalabsorptionMalabsorption Syndrome :Syndrome :Intermittent use of antibiotics like Intermittent use of antibiotics like metronidazole,tetracyclinesmetronidazole,tetracyclines

Intestinal obstruction :Intestinal obstruction :Stool softeners and laxatives.Stool softeners and laxatives.

ArthralgiasArthralgias and arthritis :and arthritis :NSAIDsNSAIDs, Physical therapy, Low dose CS., Physical therapy, Low dose CS.

Deformities :Deformities :Physical therapy.Physical therapy.

CalcinosisCalcinosis ::Saline compression to decrease pain and swelling.Saline compression to decrease pain and swelling.Excision calcified mass.Excision calcified mass.

Dry mouth :Dry mouth :Frequent sips of water, Frequent sips of water, pilocarpinepilocarpine hydrochloride hydrochloride to increase secretions.to increase secretions.

Skin Care :Skin Care :

Bathe oils, hydrophilic ointments to decrease Bathe oils, hydrophilic ointments to decrease dryness.dryness.Occlusive dressing for fingertip ulcers.Occlusive dressing for fingertip ulcers.Local NTG paste applied adjacent to the ulcer.Local NTG paste applied adjacent to the ulcer.Topical antibiotics for infected ulcers.Topical antibiotics for infected ulcers.

EXPERIMENTAL DRUGSEXPERIMENTAL DRUGS

Recombinant Human Recombinant Human RelaxinRelaxin ::Decreases synthesis of type I collagen by Decreases synthesis of type I collagen by scleroderma fibroblast.scleroderma fibroblast.

AntithymocyteAntithymocyte Globulin :Globulin :Immunosuppressive agent.Immunosuppressive agent.

High dose immunotherapy combined with High dose immunotherapy combined with immunoablationimmunoablation with with autologousautologous peripheral peripheral stem cell release.stem cell release. Good option for patients Good option for patients with high mortality but few therapeutic with high mortality but few therapeutic options. options.

MONITORING DISEASE ACTIVITYMONITORING DISEASE ACTIVITY

Skin thickness score.Skin thickness score.Maximal oral opening.Maximal oral opening.

Distance between the lips.Distance between the lips.

Flexion indexFlexion indexDistance between third distal fingertip and distal Distance between third distal fingertip and distal palmarpalmar crease.crease.

Frequency & episodes of Frequency & episodes of RaynaudRaynaud’’s s phenomenonphenomenonDeterioration or improvement of internal Deterioration or improvement of internal organ involvement on follow up.organ involvement on follow up.

MONITORING OF PATIENTS WITH MONITORING OF PATIENTS WITH ALVEOLITIS ALVEOLITIS

< 3 yrs of disease + SCL < 3 yrs of disease + SCL 70 + FVC < 75%70 + FVC < 75%

Other patients.Other patients.

PFT every 3PFT every 3--6 6 mthsmthsfor 3 yrs then yearly.for 3 yrs then yearly.

PFT yearly.PFT yearly.

COMPLICATIONSCOMPLICATIONS

Scleroderma renal crisisScleroderma renal crisisPAHPAHInterstitalInterstital fibrosisfibrosisRespiratory failureRespiratory failureCorpulmonaleCorpulmonaleCarcinomas Carcinomas –– Lung Ca is most commonLung Ca is most common

Others are skin , oral cavity, esophageal, breast, Others are skin , oral cavity, esophageal, breast, lymphomaslymphomas, ,

PROGNOSIS

Good prognosis – LSSc + Anti Scl70

Poor prognosis -- DSSc

Old age

Males

Rapidly progressing skin lesions

- Survival rate of DSSc at 5 and 10 years is 70 and 55% respectively

- Survival rate of LSSc at 5 and 10 tears is 90 and 75% respectively

Prognosis in patients with pulmonary fibrosisPrognosis in patients with pulmonary fibrosis

Prognosis in patients with PAHPrognosis in patients with PAH

All the All the best..best..