Systemic sclerosis Hadi poormoghim professor of Rheumatology.

Systemic sclerosis

Hadi poormoghimprofessor of

Rheumatology

Scleroderma Sclero= Thick Derma= Skin

inflammation . fibrosis vasculopathy in the blood vessels, skin, synovium , skeletal muscle, and certain internal organs, notably the GI, lung, heart, and kidney

Systemic Sclerosis

Raynaud’s phenomenon Tightening and thickening of skin Involvement of internal organs, including GI tract, lung,

heart. kidney, accounts for increased morbidity and mortality

Risk of internal organ involvement strongly linked to extent and

progression of skin thickening

Scleroderma

Epidemiology True incidence of scleroderma is unknown Most reported studies are hospital based Incidence 0.6-19 / 1000,000 general population / per year 420-1330 in Iran

Prevalence Varying prevalence and severity among different racial and

ethnics groups 125-250 / 1000,000 in 1977-80 8750-17500 in Iran

Female to male ratio 3:1

Familial aggregation and concordance of disease in twin pairs rarely occur

Anti-topoisomerase & anti-centromere have HLA association

Pathogenesis of scleroderma

Genetic susceptibility

Collagen synthesis

Fibroblast proliferation

vascular injury

Enviromental factorsViral: retrovirussuperAgChemical agents: vinyl chlorideBenzeneTolueneToxic oilDrugs:BleomycinL-tryptophan

immune mediator release

Cellular immune activation

Systemic sclerosis is a notable complex interaction of

Immunologic abnormalities: T cell activation and autoantibody production

Vascular injury, obliteration (role of enothelial cell, macrophage, platelets, mast cells)

Fibroblast overactivity, fibrosis

Clinical feature in Systemic Sclerosis (SSc)

1. Peripheral vascular 2. Skin3. gastrointestinal4. Muscloskeletal5. Pulmonary6. Cardiac7. Kidney

Vascular involvement Reynaud's phenomenon

Hand blanching Hand cyanosis

Reversible skin color change

White to blue to red, due to vasospasm

Induce by cold or emotion

Vascular involvement Capilloroscopy

capilloroscopyDilated, tortous capillary loop and avascular area

Dilation and drop out of capillaries

Vascular involvement Telangectasia

Telangectasia

Vascular involvement calcinosis

Subcutaneous calcinosis:Composed calcium hydroxy apatite deposits at site of trauma

More common in limited scleroderma (CREST subset)

Associated with anti-centeromere Ab

Ulceration and infection may occur

Vascular involvement dig tip ulcer/ Acro-osteolysis/ dig gangren

Digital pitting scars and ulcers associated withComplicated Raynaud,s phenomen in SS

3. Atrophic phase

2. Indurative phase

1. Puffy phase

Skin involvement

Skin involvement

mouskopf

Telangectasia in CREST syndrome

Histology of skin in diffuse cutaneous SSc

A, There is perivascular infiltration in the dermis with inflammatory cells of multiple lineages. Microvascular endothelial cell activation and increased extracellular matrix deposition also are seen

B, Later, there is regression of the inflammatory features. Secondary structures within the skin, such as hair follicles and sweat glands, are reduced, and rete pegs are flattened. (Hematoxylin and eosin stain, original magnification ×40.)

Skin involvement

Salt and pepper skin 2nd to perifollicular sparing of pigmented loss

Radial furrowing, oral aperture is reduced,Neck sign

Truncal scleroderma

Skin involvement Rodnan scoring

Muscloskeletal involvement

Arthralgia/ myalgia

Arthritis of fingers, wrist, knees or ankles (destructive arthritis)

Tendon friction rub, tendon sheath fibrosis

Muscle weakness: 1. result of extension of fibrosis to

muscles 2. overlap syndrome 3. dysuse atrophy - Muscle atrophy

TYPES OF PULMONARY INVOLVEMENT IN SSc

SSc LUNGINVOLVEMENT

ILD PAHPLEURAL DISEASE

ASPIRATIONPNEUMONIA

BRONCHOECTASISSPONTANOUS

PNEUMOTHORAX

DRUG ASSOCIATEDpneumonitis

CANCER

Reason of attention to Pulmonary disease in SSc:

Pulmonary involvement in > 80% (SSc) 2nd in frequency after esophageal symptoms The availability of treatmentAssociated with worse prognosis in SSc / the most common cause of death

Pulmonary involvement

disease symptoms sign

Pulmonary fibrosis DyspneaDry cough

Reduce Chest expansionrales, clubbing

Pulmonary hypertension

Dyspnea-ankle edema

Loud P2-RV heave

Pleural involvement Pleuritic chest paindyspnea

Pleural rub/ effusion (rare)

bronchiectasis Cough/ purulent sputum/ dyspnea

Basal crepitation

Spontanous pneumothorax

Chest pain, hemoptesis

Resonance percusionReduce breath sound

Lung cancer(scar type) Alveolar cell

Cough/ hemoptesis

? Sign of collapse

Respiratory failure Dyspnea, reduce lung expansion

hypoventilation

Pulmonary involvement

PARACLINICAL WORK UP

CXRHRCTPFTDLCO

Account for the greatest , morbidity and mortality

Gastrointestinal involvement

GI difficulty in 80-90%

ANATOMICAL SITES:OropharynxEsophagus Small bowel Large bowel

Abnormal bowel motility result from:Micro vascular disease make ischemia in neural tissueSmooth muscle atrophySub mucosal fibrosis

Malabsorption: Sub mucosal fibrosis, motility disorder lead to bacterial overgrowth


Oropharynx

Small oral aperture dry mucosa periodontal disease

Gastrointestinal (GI) manifestation of SSc

The most visceral complication of SSc Affects 75-90% of SSc patients

Difficulty swallowing & reflux

Large bowel functionabnormalities:

Diarrhea, constipation

Malabsorption &Weight loss

Early satisfaction & bloating

Bowel pseudo-obstructions

Fecal incontinence,Intussusception

rectocele

bleeding

Pathology of GI involvement in SSc

Neural damage ( early event)

Smooth muscle atrophy

and fibrosis (late event)

Impaired GI motility

Oesophageal and intestinal dysmotilityOesophageal reflux disease

Small bowel bacterial overgrowth, malabsorption, psudo-obstraction

Slow colon transitAnorectal dysfunction-fecal incontinence

Vascular malformation


Esophagus & stomachEsophageal dysfunction in 80-90% of casesStrongly associated with Reynaud's phenomena

Symptoms:

Dysphagia/ dyspepsia RegurgitationDelay empty of stomach

Complications of esophageal disease:HoarsenessAspirationUnexplained coughAtypical chest painLocalized candida infection


Small bowel

Sign, symptoms:AsymptomaticAbdominal painDiarrhea/Constipation, obstipationWeight lossAcute abdomen

Pathology:

Dysmotility /MalabsorptionPneumonitis intestinalis


Colon involvement

DysmotilityConstipation/ diarrhea

Muscular layer atrophyWide mouth dierticuleRectal prolapseStool incontinency

Wide-mouthed diverticula

renal involvement

Proteiurea Microscopic hematurea Nonmalignant hypertension Normal function kidney with typical

renovasculopathy SRC- Scleroderma renal crisis

Cortical hemmorhage seen in acute hypertension

Renal crisis

Accelerated hypertension->170/130 mm Normotensive renal crisis in 11%

Microangiopathic hemolytic anemia, thrombocytopeniaCHF, asymptomatic pericardial effusion,dyspnea,

Headache, fundoscopic changes, seizure, Abnormal urinanalysis

Left:normal, right: irregular narrowing OF interlobular vessels in SRC case

Fragmented RBC ,thrombocytopenia

Intimal fibrosis,luminal stenosis media is perseved The glomeruli and tubules are shrunken

Renal crisis

Predictive of SRC Not predective of SRC

Early disease New elevation of BP

Diffuse subset Abnormal U/A

Rapid progression of skin thightening New moderate increase in Cr

New anemia Elevated plasma renin activity

New cardiac events:Pericardial effusionCHF

Pathologic abnormality in renal blood vessel

Possible high dose steroid-normotensive

Anti-scl70

RNA polymeras -----------------

Hand blanching

renal involvement pathology

Cortical hemmorhage seen in acute hypertension

Intimal fibrosis,luminal stenosis media is persevedThe glomeruli and tubules are shrunken Fibrinoid necrosis

Left:normal, right: irregular narrowing OF interlobular vessels in SRC case

cardiac involvement

Usually subtle in expression, not seen until the late

Symptoms:Dyspnea on exertionPalpitationChest discomfort

Clinical manifestationPericarditis/ temponade CHFPulmonary hypertensionArrythmia+Myocarditis*

Pericardial effusion

Pericardial effusion after treatment

Other common clinical problems

Depression Sexual dysfunction, impotence Problem with conception, decrease fertility, spontanous abortion Sicca complex Trigeminal neuropathy Enterapment neuropathy Hypothyroidism (fibrosis, Autoimmue thyroiditis) Primary biliary cirrhosis with CREST

Other common clinical problems

Sicca complex

SSc is associated with multiple organ involvement

Pulmonary diseasePulmonary fibrosisPAH

Renal diseaseSRC

GI diseaseReflux and dyspepsiaConstipation/ diarrheaMalabsorptionColonic perforation

Cardiac diseaseMyocardial fibrosisCardiomyopathypericarditis

VascularRaynaud’s phenomenonDig ulcer

Muscloskeletal diseaseArthralgiaArthritisFlexion contracturesmyositisSkin

Skin sclerosis

Classification of Scleroderma

Systemic sclerosis Diffuse Limited Sine scleroderma Overlap Undiffrentiated Localized scleroderma morphea Linear (including “en coup de sabre”)

Scleroderma-like syndrome Toxic oil syndrome Eosinophilia-myalgia syndrome Eosinophilic fascitis

Systemic Sclerosis ( ACR preliminary criteria for

classification of SSc)

Major criteriaProximal scleroderma (proximal to metacarpophalangeal joints)

Minor criteria1. Sclerodactyly2. Digital pitting scar or loss of substance from finger pad3. Bibasilar pulmonary fibrosis

Major criteria or 2 minor criteria for diagnosis

Systemic Sclerosis (criteria for classification of early &

limited SSc)

early SSc Limited cutaneous SSc

Raynaud’s phenomen (objective documentation)

plus

Nailfold capillaroscopy abnormality orSSc specific autoantibodies

Previous criteria

plus

Distal sclerodermatous skin changes (distal to the elbows and or knees

VEDOSSVery Early Diagnosis Of SSc

Raynaud’s phenomenon

Puffy fingers

Positive antinuclear antibodies

VEDOSS red flags

VEDOSSVery Early Diagnosis Of SSc

1. Capillaroscopy 2. Serology (TOPO I, ACA)

Precence of red flags rises Suspicious of very early SSc

If either one is positive, diagnosis of very early SSc & furthur investigations

1.Oesophageal manometry2. Chest HRCT3. Pulmonary function test

1st level:suspicious

VEOSS

VEOSS

Item Sub-item(s) Weight/score

Skin thickening of the fingers of both hands extending proximal to the MCP joints (sufficient criteria)

9

Skin thickening of the fingers (only count the higher score)

Puffy fingers

Sclerodactyly of the fingers ( distal to the MCP and proximal to IP joints)

2

4

Fingertip lesion ( only count the higher score)

Digital tip ulcersFingertip pitting scares

23

Telangectasia 2

Abnormal capillorscopy 2

PAH and/or ILD (maximum score 2) PAHILD

22

Raynaud ‘s phenomenon 3

SSc-related autoantibodies (ACA, anti-TOPO, anti-RNA polymerase)(maximum score 3)

ACA, anti-TOPO,anti-RNA polymerase

3

Patients with a total sore >=9 classified as having definite SSc

Natural history of disease There are some differences between

limited and diffuse subtype

Diffuse scleroderma is typified by rapid progression of skin involvement

In diffuse subtype, new internal organ involvement occurs early, not remit with time

Limited disease slowly increase in severity of skin disease

In limited subtype organ involvement is typically delayed until second decade of disease

Clinical course is divergent in early years

In later disease, improving diffuse and worse limited disease are nearly in distinguished

Natural history of disease Stage of disease

Stage of disease

Primary concern Action to consider

Diffuse,early < 3 years

Joint, lung,heart, kidney

Examine every 3 monthsFrequent monitor BP, CrBaseline PFT,treatment of esophagitisDisease modifying drugMouth, hand, joint exercise

Diffuse, late+3 years

Lung, heart, joints Examine every 12 monthsJoint reconstructive surgery

Limited, early< 10 years

Peripheral vascular

Examine every 12 monthsVasodilators, endothelial protective agents

Limited, late +10 years

Esophageal strictureMalabsorptionPulm.hypertensionVasculitisLung cancer

Examine every 24-36 monthsEsophageal dilationRotating antibioticsHyperalimentationPFT, DLCOHyperalimentationSjogren’s evaluationChest radiography

SSc diffuse cutaneous vs limited cutaneous

Diffuse limited

Extent of extermity skin thickening Above elbow Below elbow

Pace of extermity skin thickening Rapid Slow

Timing of relationship between skin thickening and Raynaud’s

Simultaneous / skin first Prolonged raynoud,s before skin

Capillary microscopy Loops, dropout loops

Joint, tendons Contractures, friction rub Infrequent involvement

Calcinosis Uncommon Prominent

Visceral involvement Renal, myocardial Pulmonary hypertension

Serum auto antibodies Anti-scl70, anti-RNA polymerase

Anti-centeromere, anti-Th/To

Systemic Sclerosis (SSc) specific serum Autoantibodies

Pattern of AutoAb recognized:

speckleNucleoliAnti-centeromere

Targets of treatment

Fibrosis as a target of treatment imatinib

vasculopathy as a target of treatment

inflammation and autoimmunity as a target of TreatmentMTX / AZA

Cyclophosphamide / prednisolone

Linear scleroderma

Localized Scleroderma

Morphea

Coup de sabre

Scleroderma-like syndrome

Eosinophilic fascitisEosinophilic-myalgic syndrome (l-tryptophan)scleromyxedemaGeneralized subcutaneous morpheaAmyloidosisCarcinoid syndromePentazocine-induced scleroderma

Scleroderma-like syndrome sclerosis sparing the fingers

Eosinophilic fascitisSome patients develoed :thrombocytopenia, rarely aplastic anemia, may occur as a paraneoplastic syndrome associated with myeloid or lymphoid malignancy

‘cobblestone’ skin

Eosinophilic myalgia syndrome

Associated with tryptophan ingestion Cutaneous sclerosis of extremities sparing the hands and feet

The patients usually lack:Raynaud, nailfold abnormalities and body telangiectases

peau d’orange is common myalgias , polyarthritis are common

Biopsy: The fascial inflammation exclude scleroderma

Scleroderma-like syndrome sclerosis sparing the fingers


Scleromyxedema (papular mucinosis, lichen myxedematosus)

Thickening of the face skin -Clubbing nail- cobblestonning of forearm skinCollagen fibers are spread apartly by dense gray-pink mucopolysaccaride (hylaronic acid) in dermal region.Hypothyroidism and gamapathy frequently with the disease

Scleromyxedema is a rare disorder associated with monoclonal gammopathy , hypothyroidism dermal deposits of hyaluronic acid

induration of the hands, face, arms and, lesser degree, the trunk , lower extremities associated with:multiple fine waxy papulesmyopathy , polyarthritis

Reynaud's phenomenon, are rare

scleredema : in Obese, non-insulin-dependent diabetes mellitus patients a benign skin tightening

develops rapidly over the neck and upper back

Sclerodactyly : in long standing diabetes mellitus

Scleroderma-like syndrome sclerosis

monoclonal gammopathies / POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin

changes) is associated with: hyperpigmentation and thickened, tight, but not bound down, skin

Scleroderma-like syndrome sclerosis


A paraneoplastic condition Palmar fasciitis, and polyarthritis

syndrome may be confused with scleroderma Bound down palmar or plantar fascia

Carcinoid tumor: Scleroderma-like lesions of the lower

extremities


Primary amyloid rarely associated with scleroderma-like

lesions, but waxy cutaneous papules and purpura are

more characteristic

Scleroderma-like syndrome Affecting the fingers

Diabetic digital sclerosisVinyl chloride diseaseVibration syndromeBleomycine-induced sclerodermaRSDSAmyloidosisAcrodermatosis chronica atrophican

reflex sympathetic dystrophy vasomotor instability in the early phase of illness , unilateral expression helpful in distinguishing the late phase of from

scleroderma

Scleroderma-like syndrome Affecting the fingers

Werner’s syndrome, progeria, and phenylketonuria : Disorders of childhood associated with scleroderma-like skin


features Primary Reynaud's

Systemic sclerosis

Sex F:M 20:1 4:1

Age at onset Puberty 25 yrs or older

frequency <5 /day > 5-10 attack/day

precipitant Cold, emotion cold

Ischemic injury Absent present

ANA Absent 90-95%

ACA Absent 50-60%

Ant-scl 70 Absent 20-30%

Abnormal capillaroscopy

Absent >95%

In vivo platlet activation

Absent >75%

Primary vs secondary raynaud’s

Differential diagnosis of Reynaud's phenomenon

Structural vasculopathy

Large & medium arteriesTOS / Takayasu’s arteritis / Crutch pressure

Small artery and arteriolarSLE / DM / Overlap / Vibration disease / Thromboangitis obliteransBleomycine, vinblastine , PVC

Normal vessel- abnormal blood elementsCryoglobulinemia / paraproteinemia/ PCV

Normal blood vessels- abnormal vasomotionPrimary raynoud’s / Drug induced (beta blockers, ergots, metylsergide) / pheochromocytoma / Migrine, prinzmetal / carcinoid syndromes

Diffrential diagnosis of visceral features

Primary PHT

Primary biliary cirrhosis

Idiopathic intestinal hypomotility

Collagenous colitis

Idiopathic pulmonary fibrosis

Pathophysiology , treatment

Slide10.13Slide 11.3

Pathology

Small vessel vasculopathy (endothelial cell damage)

T and B cell , macrophage , mast cell activation Fibroblast proliferation, platelet activation

Vasculopathy and fibrosis arise in the setting of autoimmunity

Pathophysiology , treatmentInteraction between: Endothelial cells, leukocytes, fibroblasts in scleroderma

Possible sites for theraputic intervention:1. Prevent endothelial cell cytotoxicity by mononuclear cells: MTX, AZA, prednisolon2. Alter communication between mononuclear cell subsets: cyclosporine on TH3. Prevent mononuclear cell stimulation of fibroblasts: interferon alfa, gamma4. Prevent mast cell degranulation: ketotefen5. Block fibroblast production of procollagen: colchecin6. Increase solubilization of performed collagen; D-pencillamine, bosentan

1

2

56

4

3

Management of lung involvement

Management of lung involvement

Slide 11.8

Prognosis and survival

Poor prognosis Arrythmia dcSSc DLCO< 40% Pulmonary hypertension SRC Male sex Older age Anti-scl70,

antiRNApolymerase

Pregnancy in scleroderma Advised against pregnancy in the first 4-6 years of disease, especially with aggressive skin

involvement

Consider scleroderma pregnancy as a high-risk pregnancy

Assess extent and severity of system involvement at pregnancy onset

Discontinue D-pencillamine

Follow every month for the first 4-6 months for pregnancy, and more frequent thereafter: blood pressure creatinine, urine analysis PFT at onset and monthly or prn

ACE inhibitors for renal crisis and dialysis if necessary

Corticosteroids may be used for aggressive fibrosing alveolitis, pericarditis, and inflammatory myopathy, without fear of harming the fetus

PHYSIOTHERAPY

Trigeminal neuropathy

is the most common cranial nerve manifestation

In one series of 442 patients with SSc, trigeminal neuropathy occurred in 4 %

most frequently in those with clinical features of the MCTD

It may be the initial SSc manifestation

Trigeminal neuropathy

Pathophysiology

The pathophysiology of trigeminal neuropathy in SSc patients is unknown

Electrophysiologic studies suggest that site of disease is gasserian ganglion

Trigeminal neuropathy Clinical manifestations and findings , Symptoms

slowly progressive unilateral /bilateral facial numbness

pain (50% of patients)

Paresthesia (60%)

Quality of pain: burning

Numbness is most common in the mandibular or maxillary divisions of the nerve, with symptoms in the cheek or around the mouth

the maximal deficit is usually reached after 6 to 24 months

Trigeminal motor function (muscles of mastication) usually is not affected

Sensory loss is present upon physical examination The corneal reflex is sometimes depressed or absent

Trigeminal neuropathy Differential diagnosis

It includes neuropathy associated with

Diabetes mellitus

Sinus disease

Multiple sclerosis

Trauma

Vertebrobasilar ischemia

Tumors: brain stem, CP angle, skull base, nasopharynx

Trigeminal neuropathy Treatment

Glucocorticoids is probably not beneficial

Chronic pain may require the use of analgesics, antidepressants

and/or

Anticonvulsant medications

Anticonvulsant medications as utilized in a manner similar to that for patients with chronic neuropathic

pain due to other etiologies

Systemic sclerosis Hadi poormoghim professor of Rheumatology.

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Transcript of Systemic sclerosis Hadi poormoghim professor of Rheumatology.