SCLERODERMA DR MAGDI AWAD SASI 2016 LMB

SCLERODERMA 2016 DR MAGDI AWAD SASI LIBYAN MEDICAL BOARD 7TH OCTOPER HOSPITAL

SCLERODERMA

DEFINITION:

It is a chronic autoimmune disease condition of unknown aetiology characterised by

increased fibroblast activity and fibrosis in a number of different organ systems in the

form of hardened, sclerotic skin and other connective tissues.

Scleroderma = hard skin = skin fibrosis

2

Types of Scleroderma

Scleroderma

Localized

Scleroderma

Systemic

Scleroderma(Systemic Sclerosis)

MorpheaLinear

Scleroderma

Limited

Scleroderma

Diffuse

Scleroderma

Sine

Scleroderma

PATHOPHYSIOLOGY:

TISSUE FIBROSIS OBLITERATION OF PRODUCTION OF AUTO- CELLULAR ARTERIOLES/SMALL ARTERIES ANTIBODIES IFILTRATION


PREVALENCE:

Incidence in US of 9-19 cases per million per year

Prevalence in US of ~286 cases per million

250 patients / million / in USA

New cases 20 /million /year

SEX: Female to male ---- 4 to 5 times in female

AGE: Average at time of diagnosis 50 years

The prevalence and manifestation of scleroderma vary among racial and ethinic groups!

ex; scleroderma is 100 times more common among the choctan native Americans in

Oklahoma ; the disease is characterized by diffuse skin disease and pulmonary fibrosis.

Milder limited disease is more common among white women and African American are

more likely to have sever disease.

The disease expression is influenced by:

1. Ethinic and racial groups

2. Family clustering

3. Specific autoantibodies with specific HLA

4. Environmental factors

CLINICAL FEATURES:

The most frequent symptoms (( in descending order )) are:

A. Raynauds phenomena

B. Gastro-esophageal reflux

C. Swollen fingers

D. Musculoskeletal pain /Arthralgias

You have to be aware of scleroderma ;WHY?

Because early intervention can reduce morbidity and prevent life threatening complications.

The diagnostic criteria for scleroderma :

1. Thickened skin changes proximal to MCP joints. OR

2. Two of the following:

i. Sclerodactaly

ii. Digital pitting ---loss of tissue on finger pads

iii. Bibasilar pulmonary fibrosis


The diagnosis of limited scleroderma can be made if the patient has 3/5 of CREST: 1. Calcinosis 2. Raynaud phenomena 3. Esophageal dysmotility 4. Sclerodactly 5. telangiectasia

Early presentation of scleroderma:-

A. musculoskeletal discomfort

B. fatigue

C. weight loss

D. heart burn due to GERD

when the symptoms are accompanied by raynauds or new onset of cold

sensitivity ,scleroderma is more likely.

Classical presentation:

There are three patterns of disease:

A.LIMITED CUTANEOUS SYSTEMIC SCLEROSIS : -----

Long H/O Raynauds phenomena ---Raynaud's may be first sign

Scleroderma affects face and distal limbs predominately

Swelling or skin thickening of the fingers.

Gastroesophageal reflux and dysphagia.

Systemic --- weight loss ,dyspnea ,arthralgia

Associated with anti-centromere antibodies

CREST syndrome is an older term for the limited

cutaneous form. CREST syndrome is a subtype of

limited cutaneous systemic sclerosis: Calcinosis,

Raynaud's phenomenon, Esophageal dysmotility,

Sclerodactyly, Telangiectasia

Complications of CREST syndrome: Malabsorption

can develop in these patients secondary to bacterial

overgrowth of the sclerosed small intestine

(dysmotility secondary to infiltration of the intestinal

wall with fibrous tissue).

Also, unfortunately pulmonary hypertension is one

of the more common late complications seen in such

patients.

EX: Female pt. with SOB, lung fibrosis, GERD, Raynaud’s, +ve ANA >> Systemic sclerosis as CREST develop pulmonary HTN NOT ILF.


B.DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS ------

New onset of Raynauds phenomena

Rapid change of skin texture and edema ,pain ,pruritis

Significant systemic symptoms with arthralgia ,weight loss ,tendon friction rubs

Internal organ involvement –lung ((dyspnea)) ,Kidney

((HTN)) , GIT ((malabsorption)).

Scleroderma affects trunk and proximal limbs

predominately ((ALL THE BODY)).

Associated with scl-70 antibodies

Poor prognosis

Whilst diffuse systemic sclerosis is associated with more

severe and rapid internal organ involvement ,it is also

seen in the limited form.

C. Morphea (Localized Scleroderma) (without internal organ involvement)

Tightening and fibrosis of skin.

May manifest as plaques (morphoea) or linear.

This is a well-defined oval to round plaque. (Like a painless lesion to his left

subcostal region, dry, indurated and slightly coarse to palpation).

The pathogenesis is poorly defined.

An autoimmune component is suggested by enhanced T helper 2 (Th2) dependent

interleukin 4 (IL-4) activity, which in turn up regulates transforming growth factor

beta (TGF -beta). TGF-beta stimulates fibroblast production of collagen and other

extracellular matrix proteins.

SYMPTOMS AND SIGNS:

A. SKIN:

The skin is one of the most universally and prominently involved organs in both

diffuse and limited cutaneous disease. Initially may manifest as diffuse swelling,

especially in the hands and fingers. This is followed by progressive skin tightening

from excess collagen deposition. A notable difference in diffuse vs limited disease

(and one that largely defines the different subsets) is that the skin changes in

limited disease are confined to areas below the elbows and knees. Skin

involvement in diffuse disease is more widespread, involving the entire arm

and/or leg as well as skin on the trunk. Be aware that the skin on the face is

typically involved in both disease subsets.

Other skin findings may include hard calcium deposits under the skin, known as

calcinosis cutis (seen more often in limited cutaneous systemic sclerosis). Small,

spider-like, visible, dilated blood vessels called telangiectasias can be seen (often

on the face and chest). Skin ulcers and pigment changes are not uncommon.


a. Thickening of the skin:

- Most easily recognizable manifestation

- Not prominent in all patients

- Scleroderma classified according to the amount and location of

involvement.

Patient with limited disease:---

Skin changes on the face and distal to knees and elbows ex; CREST

1. Typically only involves the skin of fingers distal to the MCPJ –Sclerodactly.

2. Marked Telengectasias ((dilatated capillaries ))that occur on the skin of face ,the

palmer surface of the hands and the mucous membranes.

3. Subcutaneous calcinosis ---fingers ,extensor surface of forearm.

Patient with diffuse disease----

Patient with proximal extremity or truncal skin involvement

The amount of skin thickening can be quantified by skin score .

The skin is pinched between the examiners thumbs in 17

specified areas of the patients body .

0 (( Normal )) --- ------------ 3 (( Very thick))

Higher skin scores correlates with greater degree of internal

organ involvement.

The early stage----- inflammatory face:

Skin edematous and inflamed

Skin erythema

Pigmentary changes ---hyperpigmented areas with

depigemntation—salt&pepper appearance.

Pruritis and discomfort

Lasts weeks –months

Fibroblasts ---over produce

extracellular matrix that

leads to increased collagen

deposition in the skin

leading to collagen cross

linking –skin tighting

The later stages----

Skin become thickening , dry ,scaly because of the loss of its natural oily due to sebaceous

gland damage.

Dry skin are intensly pruritic causing excoriation.


B. Vascular disease:

A diffuse vasculopathy of peripheral arteries is manifested by :

1. Intimal proliferation

2. Activation of arterial smooth muscles.

3. Narrowing of the vessel lumen.

Critical ischemia occurs in the tissues when vasoconstriction occlude these vessels.

Evidence suggested that this vascular disease is fundamental to organ damage.

Heart----------CMP

Lung -----------PHTN

Kidney --------- scleroderma renal crisis ((SRC))

Table 1: ACR/EULAR Revised Systemic Sclerosis Classification Criteria

Item Sub-item(s) Score

Skin thickening of the fingers of both hands extending proximally to the metacarpophalangeal joints (presence of this criterion is sufficient criterion for SSc classification)

None 9

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

Puffy fingers 2

Sclerodactyly (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints)

4

Fingertip lesions (count the higher score only)

Digital tip ulcers 2

Fingertip pitting scars

3

Telangiectasia None 2

Abnormal nailfold capillaries None 2

Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2)

Pulmonary arterial hypertension

2

Interstitial lung disease 2

Raynaud phenomenon None 3

Systemic sclerosis–related autoantibodies (maximum score is 3)

Anticentromere 3

Anti–topoisomerase I 3

Anti–RNA polymerase III 3

The total score is determined by adding the maximum score in each category. Patients

with a total score equal to or greater than 9 are classified as having definite systemic

sclerosis (modified from van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification

criteria for systemic sclerosis: an American College of Rheumatology/European League

against Rheumatism collaborative initiative.


C/F---

A) Raynauds phenomenon:

Is the first manifestation of the disease in almost every patient.

RP is an episodic self limited and reversible vasomotor disturbance manifested as a

color changes bilaterally in the fingers ,toes sometimes ears ,nose and lips.

The color changes are pallor ,cyanosis and then erythema((white ,blue ,then red)).

There is triad of colours: initial whitening of the fingers resulting from vasospasm,

followed by blue discolouration and then reddening and pain.

Raynaud's phenomena may be:

Primary (Raynaud's disease) or Secondary (Raynaud's phenomenon)

Raynaud's disease typically presents in young women (e.g. 30 years old) with

symmetrical attacks.

There is no need for the three color for diagnosis.

Episodic pallor or cyanosis that reverses to erythema or normal skin color may be

all that is seen.

Patient may describe symptoms of numbness ;tingling or pain on recovery.

Stress and cold temperature induce an exaggerated vasoconstriction of the small

arteries ,arterioles and AV shunts of the skin of the digits.

This is manifested clinically as PALLOR & CYANOSIS of the digits followed by

reactive hyperemia after rewarming.

The attacks are often painful and lead to digital ulceration ,gangrene or

amputation.

In patient with Raynauds phenomena ,to suggest early SS: a) Positive ANA ,Antitopoisomerase ( SCL 70) ,Anticentromer AB b) Nail fold capillary abnormality c) GERD d) Puffy swollen fingers or legs e) Tendon friction rubs

Raynauds phenomena occur in limited and diffuse scleroderma.

If RP precedes skin changes by a year === LIMITED

If RP occur simultaneously with skin changes ==DIFFUSE

For treatment; i. Calcium channel blocker---Nifedipine ,Diltiazem ii. Antiadrenergic agents ----Prazosin ,Methyldopa iii. ACE-I ,AGB II iv. Aspirin ,Niacin

NOTE:

Patient > 30 years in whom RP develops should be screened with an ANA test and

nail fold examination if they have sever painful episodes and signs of digital

ischemia.

Patient with scleroderma almost always have positive ANA.


A negative ANA makes diagnosis of scleroderma unlikely.

HOW TO DIFFERENTIATE BETWEEN PRIMARY AND SECONDARY RAYNAUDS PHENOMENA?

For primary ,

- Symmetrical episodes ,intermittent attacks.

- Affecting both hands, but not necessarily all fingers

- No evidence of peripheral vascular disease

- No evidence of tissue gangrene/digital

pitting/ulceration/severe ischaemia

- No suspicion of underlying disease

- Normal nail-fold capillary microscopy

- Negative ANA with normal ESR

For secondary,

- Male sex

- Onset > 40 years

- Unilateral symptoms

- Asymmetry of digits affected

- Painful attacks

- Digital ulcers

- Tissue ischemia-- gangrene or severe ischaemia of one

or more digits.

- Very rarely: chilblains (pernio) are itchy, painful purple

swellings which occur on the fingers and toes after

exposure to the cold.

- Symptoms and signs of CTD

- Rashes Features which may suggest RA or SLE, e.g. arthritis or recurrent

miscarriages ,calcinosis

- Presence of autoantibodies--- Positive ANA

The most useful initial assessment to determine whether the Raynaud’s is related to vasculitis or not >>>(( must include nail fold capillary loop examination, ideally by capillaroscopy or, if not available, by ophthalmoscopy using magnification ))>>> In CTD such as systemic sclerosis: dilated, distorted, missed nail fold capillary loops.

Secondary causes:

1) Connective tissue diseases (CTD): scleroderma (most common), RA, SLE, PAN,

Sjogren’s syndrome.

2) Type I cryoglobulinaemia, cold agglutinins.

3) Leukaemia , Polycythaemia , Thrombangitis obliterans (Buerger’s disease)

4) Use of vibrating tools , Drugs: oral contraceptive pill, ergot (NB: Ergotamine is

associated with Raynaud's phenomenon), βB, Vinblastine, Bleomycin.

5) Cervical rib.


Differential diagnosis of Raynaud's phenomenon includes:

A. Chilblains (perniosis): erythematous itchy swellings on fingers and toes in response

to cold.

B. Acrocyanosis: continuous blueness of the extremities aggravated by cold.

C. Erythromelalgia: painful erythema caused by paroxysmal dilatation of blood

vessels.

D. Vascular embolism.

E. Livedo reticularis.

F. Mottled, cyanotic discolouration of skin.

B) Lung involvement:

2 forms pulmonary HTN and inflammatory alveolitis –ILF

ILF PULMONARY HTN

Limited SS Bibasilar and non progressive ((20%))

(( 8----28%)) Poor prognosis

Diffuse SS More common and progressive ((30-60%))

Very rare

Over lap Common and can progress (( 85%)) 21----30%

1. INTERSTITIAL LUNG DISEASE:

Many patient are asymptomatic

Clinical symptoms can be insidious and include exertional dyspnea ,easy

fatigability and exertional dry cough.

Later ,it may progress to dyspnea at rest.

Clinical signs are typically early inspiratory fine crackles.

PFT or HR CT scanning can detect very mild and early disease.

Routine PFT is mandatory because early intervention may prevent progression.

80% of patients have restrictive ventilator defects on PFT

Only 10—20% suffer from progressive ILD.

Treatment:

Patient with disease restricted to bases ----no treatment

Patient with progressive disease ---treatment with progression to middle

&upper lobes.

Patient who respond to immunosuppressive have active alveolitis

a. Bronchoalveolar lavage ---- Neutrophils / Eosinophils > 5%

b. HR CT scan ---nonspecific interstitial pneumonitis ---ground glass

c. Lung biopsy

These patients may respond to prednisolone and cyclophosphamide.

Patients with progressive lung disease without alveolitis /UIP-usual interstitial

pneumonitis on HRCT scan /Lung biopsy do not respond to treatment.


WHY? Because fibrosis due to fibroblastic foci.

Treatment ---- antifibrotic therapy , alpha interferon

2. Pulmonary HTN:

Risk Factors for PAH in Scleroderma— 1) Long disease duration (usually >8 yr) 2) Limited scleroderma > diffuse scleroderma

3) Abnormal pulmonary function tests a. low DLCO <55% predicted and FVC %/DLCO % >1.6

4) Autoantibody profile

a. anticentromere antibody

b. antinucleolar pattern on ANA (anti-U3 antibody, which is not clinically available)

Due to pulmonary vascular disease.

Patient usually have an insidious onset of exertional dyspnea which can

become at rest with fatigue and loss of effort.

Physical exam ; loud P2 ,S3 RV ,TR ,PULMONARY REGURGITATION

Raised JVP ,pedal edema

Isolated pulmonary HTN occurs more commonly in limited SCL which have long

duration of disease.

Pulmonary HTN complicates the course in 10% CREST.

Treatment :

Initially ;patients are placed on nasal O2.

Ca channel blocker can be tried.

Full anticoagulation is often administered.

For sever pulmonary HTN , A. Continous I.V. epoprostenol ((PGI2)) B. Oral non specific endothelin antagonist ((bosentan))125mgBID

It is Contraindicated in: 1. Pregnancy 2. Cyclosporine 3. Glyburide 4. Hepatotoxic

C. Lung transplantation D. Silendafil

C) GIT:

Both upper and lower GIT are involved.

Highly variable in its clinical expression.

It can be asymptomatic ((mild constipation)) or profound

dysfunction((malnutrition)). The gastrointestinal tract is involved in almost all

cases of systemic sclerosis. Fibrotic and vascular changes all along the GI tract

interfere with normal motility, resulting in a host of problems including

gastroesophageal reflux disease (GERD), intestinal dilatation with abdominal pain,

bacterial overgrowth with diarrhea, and malabsorption. An increasingly recognized

problem in both diffuse and limited cutaneous forms of disease is gastric antral

vascular ectasia (GAVE). Analagous to dilated blood vessels seen on the skin, blood


vessels in the stomach can dilate and then rupture, with the

potential for massive blood loss. This photo shows the appearance

of the dilated blood vessels on endoscopy.

1. GERD:

The majority are symptomatic with dysphagia.

The patient is complaining of sensation of the food getting stuck in the mid

esophagus ,atypical chest pain ,or cough.

The patient often complain that they must drink liquids to swallow solid food

,meat or bread.

Reflux and dysphagia occur because of dysmotility of esophagus and stomach

((gastroparesis)).

This type of organ dysfunction results from atrophy of the esophageal smooth

muscle.

Complication: 1. Esophagitis 2. Esophageal ulceration with bleeding 3. Esophageal stricture 4. Barret esophagus 5. Candidiasis

GIT dysfunction is due to:

1. There is neural dysfunction thought to be due to arteriolar changes of vasa

nervourum leading to dysmotility.

2. Smooth muscle atrophy


Esophagealdysmotility is assesd by:

Manometry

Cine –esophagography

Endoscopy

Barium swallow

WHAT IS WATER-MELON STOMACH?

Gastric antral venous ectasia

It causes upper GIT bleeding in SS.

Treatment:

patient should not eat for 2—3 hours before bed time

The head of the bed should be elevated 4 inche.

Decrease the acidity of stomach by antacids.

Proton pump inhibitors can be used ---Esmoprazole ,Lansoprazole

Motility agents ((metoclopramide))before meals are helpful early in

the diagnosis.

Bowel involvement

Diminished peristalsis with stasis and dilatation

Bacterial over growth –H breathtest ,High folate

Malabsorption

Low albumin Low fat content Low B6/B12/folate/ vitD Low D xylose absorption test Low carotene

Patient may complain of abdominal distention ,obstructive symptoms ,diarrhea

,vitamin deficiencies.

Patient with large bowel involvement ---wide mouth diverticular on barium

enema.

Barium enema is contraindicated in patient with scleroderma.

Treatment:

Stimulation of gut motility ---metoclopramide ,erythromycin ,motilin agonist ,daily

injection octreotide 50microgm /6hr S/C ,fibers.

Diarrhea --bacterial overgrowth --metoclopramide ,tetracycline ,ciprofloxacin-10/d

Avoid loperamide ,paregoric

Smooth muscle atrophy of the bowel wall

Affect small and large intestine

Abnormal motility of the gut


Symptoms ----

Combination of constipation and diarrhea

Recurrent bouts of pseudo-obstruction

Bowel distention with leakage of air into the intestine—

pneumatosis coli intestinalis

Bowel rupture

Lower bowel dys-motility can lead to bacterial overgrowth,

diarrhea ,mal-absorption.

D) CVS:

Symptomatic cardiac disease is relatively rare. The lining

around the heart may become inflamed, a condition called pericarditis. Fluid can

build up around the heart (pericardial effusion) – the presence of this fluid may

herald scleroderma renal crisis. The heart muscle itself may be affected causing a

cardiomyopathy and the conduction system that carries electrical signals through

the heart may become damaged.

Usually subclinical

Cardiopulmonary morbidity

Ischemia ----reperfusion secondary to small arterial disease of myocardium

leads to necrosis and tissue fibrosis.

This leads to:

1. Cardiomyopathy 2. Arrhythmia 3. Heart failure 4. Pericarditis 5. Pericardial effusion

Pericardial effusion—

Detected by ECHO

Large PE associated with poor prognosis

It is usually clinically silent.

E) RENAL:

occurs almost exclusively in patients with diffuse cutaneous systemic sclerosis. It is characterized by HTN, anemia secondary to destruction of RBC (hemolytic anemia), and evidence of kidney damage (PROTEINURIA and HIGH creatinine). Patients at greatest risk for SRC include :

1. Rapid progression of skin involvement 2. Positive for anti-RNA polymerase III antibodies 3. Who have taken moderate or high doses of steroids in the preceding

weeks or months. This complication is usually seen within the first 4 years of disease onset. It is almost universally fatal if not treated early and aggressively. The treatment is ACEI

Clinically important kidney disease occur in minority of patients.

SCR develops in 10% of patients.

SCR occurs early in the course of diffuse scleroderma 2—3 years of onset

,more often in the fall and winter months.


SYMPTOMS:--

Symptoms are HEADACHE ,VISUAL CHANGES AND SEIZURES.

The clinical presentation is typically with the symptoms of malignant

hypertension: Headaches, Hypertensive retinopathy associated with visual

disturbances, Seizures, Heart failure and pulmonary oedema.

Renal failure may present as acute renal crisis , after prolonged HTN ,less

commonly as normotensive renal failure.

SCR is the abrupt onset of HTN ,appearance of flame shaped haemorrhage

,cotton wall exudates , grade III/IV retinopathy –papillodema and rapid

deterioration of renal function over a month.

The hypertension is almost always severe with a diastolic BP over 100

mmHg in 90% of patients.

There is hypertensive retinopathy in about 85% of patients with exudates

and haemorrhages and if severe, papilledema.

If malignant HTN left untreated ,it can lead to renal failure

Some are asymptomatic and normotensive with aprupt rise of creatinine.

There may also be microangiopathic haemolytic anaemia (↓ Hb with

blood film shows schistocytes and helmet cells), thrombocytopenia and

raised renin levels. Renal function is impaired and usually deteriorates.

TREATMENT:

Scleroderma renal crisis is a medical emergency. Aggressive treatment is

required to prevent the occurrence of irreversible vascular injury.

ACE-I is the treatment of choice

First line treatment is a gradual reduction in blood pressure (10-15 mmHg

per day) with an oral ACEIs until the diastolic pressure reaches 85-90

mmHg. Upto to 400mg doses can be given to control BP.

ACEI will improve hypertension and slow further renal impairment.

This approach leads to a response in 90% of patients by reversing the

angiotensin II mediated vasoconstriction.

An abrupt fall in BP should be avoided as it can further diminish renal

perfusion and increase the risk of ATN. Therefore, parenteral

antihypertensive agents (for example, IV nitroprusside or IV labetalol)

should be avoided.

CCBs, usually nifedipine, may be added where there is inadequate

reduction of BP with ACEI alone.

Additional oral hypotensive agents (for example, labetalol) can be used if

required, and if pulmonary oedema is present a nitrate infusion may be

indicated.

High dose of steroids increased the risk of renal failure in SS.

There is anecdotal evidence that IV prostacyclin helps the microvascular

lesion without precipitating hypotension, and this is used in some UK

centres.

LABRATORY ----- Renal crisis is linked with a positive ANA speckled pattern,

anti-RNA polymerase I and II antibodies and absence of anti-centromere

antibodies.


Increased RFT & RENIN ,microangiopathic hemolysis ,low platelets .

Renal biopsy is not necessary in patients presenting with classical features

of renal crisis

Renal biopsy specimen –intestinal hyperplasia ,vasospasm of cortical

arteries.

F) MUSCULOSKELETAL INVOLVEMENT:

Signs and symptoms related to involvement of the musculoskeletal system are

found in systemic sclerosis. Many patients have joint and/or muscle pain. In

diffuse cutaneous systemic sclerosis, tendon inflammation can result in an audible

sound upon movement of involved structures (most commonly the fingers and

wrists) known as a tendon friction rub. This finding is a

marker of aggressive disease and puts patients at higher risk

of serious organ involvement. Resorption of the most distal

aspects of bones is a result of severe ischemia-osteolysis.

Mild arthralgia

Non erosive arthritis with synovitis

Morning stiffness

Deep tissue fibrosis ((tendon sheaths inflamed))

Areas around the tendons

Active and passive range of joints motions are limited &painful

Tendon friction rub over the wrists ,ankles and knees.

DSS patients develop tendon friction rubs.

Hand deformities and ankylosis are seen

Bone ---resorption of bone---acrosclerosis and osteolysis

Resoprption of ribs ,mandible ,radius ,ulna.

G) MUSCLE:

1. Mild proximal weakness---fiber 2 myopathy

2. Mild elevation of muscle enzymes with waxing & waning of symptoms

3. Inflammatory type of myopathy with CPK increased(( overlap))—polymyositis.

INVESTIGATION:

Let’s look at a typical case of someone presenting with fairly early systemic sclerosis. The

patient would statistically more likely be a female between the ages of 30-50 years old.

She might complain of diffuse joint pain, fatigue and swollen hands and fingers. She might

admit to new acid reflux and also to frequent episodes of her fingers turning colors when

exposed to cold and pain in the fingers when they warm up. This is the Raynaud’s

phenomenon already mentioned.

Physical Exam:

o Diffusely swollen hands/fingers

o Early skin tightening in most distal


o aspects of extremities and around face

o Changes in nail fold capillaries

An important part of the physical exam is nail-fold microscopy (or nail-fold

capillaroscopy). This is accomplished by looking closely with an ophthalmoscope at

the capillaries near the cuticles. The picture on DOWN demonstrates possible

findings.

Panel a: normal nailfold capillaries

Panel b: mild abnormalities (dilation of capillary loops)

Panel c: dilation of capillaries and “dropout”

Panel d: grossly abnormal

Nailfold capillaroscopy is very important because many people, especially young

women, experience Raynaud’s, but most of them never go on to develop systemic

sclerosis or any other disease related to the Raynaud’s. This is called primary

Raynaud’s (as opposed to secondary Raynaud’s when it is related to an underlying

condition). Patients with primary Raynaud’s will have normal nailfold capillaries. If

the nailfold capillaries are abnormal, the risk of going on to develop systemic

sclerosis or another connective tissue disease is much greater.


LABORATORY:

1. ANA:

Are the most frequently detected

Not specific for SCL.

Seen in up to 10% normal people.

>95% of SCL patients

Anticentromere –

o 20—40% of patients with SCL.

o Associated specifically with CREST ,sever

digital ischemia and ulceration ,digital loss

o Can be found in patient with PBC and sjogrens syndrome.

Antitopoisomerase I (( antiSCL 70 ))

20---40% of patient with SCL

Typically have diffuse skin changes ,ILD ,and worse prognosis

Africans Americans

Highly specific for SCL.

Anti –RNP I II III (( RNA polymerase ))

Associated with diffuse skin changes ,cardiac ,renal involvement and increased mortality.

Anti U3 RNP ---antifibrillarian ----8% lung disease ,diffuse

Anti U1 RNP ---------------------------5% MCTD

Anti TH/TO ---------------------------- 1—5% limited cutaneous ,lung

2. Baseline kidney and liver function, CBC, ESR and CRP

3. LUNG INVOLVEMENT:

Recommendations for Screening and Detection of

SSc-Associated PAH---

A. Initial SSc Screening Evaluation:

FT with DLCO (high)

Transthoracic echocardiogram (TTE) (high)

NT- Pro BNP (mod)

DETECT algorithm if DLCO% < 60% and >3 yrs

disease duration (mod)

B. Frequency of Noninvasive Tests

TTE annually as screening (low); if new signs or

symptoms develop (high)

PFT with DLCO annually as screening (low qual); if

new signs or symptoms develop (low)

NT-Pro BNP if new signs of symptoms develop (low)

ECHO OR RIGHT HEART CATHETERIZATION---

Recommendations for Screening and Detection of SSC-Associated PAH

General Evidence-based Guidelines:

1) All patients with SSc should be screened for PAH .

2) All SSc and scleroderma-spectrum patients with a positive non-invasive screen

should be referred for RHC .

3) RHC is mandatory for diagnosis of PAH.


TREATMENT:

There is no cure for systemic sclerosis. However, there are treatments that ameliorate

symptoms and prolong organ and patient survival. These treatments are instituted on a

case-by-case basis, depending on the specific disease manifestations in an individual

patient. Care of patients with systemic sclerosis requires an understanding of the potential

complications of the disease and close monitoring, so treatment can be started early.

BASICS IN TREATMENT---

No effective therapy for underlying disease process

Treatment is targeted to specific organs involved

Early recognition of internal organ involvement and aggressive treatment improve

quality of life and increases survival time.

Successful management of patients with SSc requires an understanding of the potential

complications of the disease, close monitoring, and early institution of targeted therapies .

Treatment of Raynaud’s Phenomenon:

A cornerstone of management of Raynaud’s is patient education to achieve behavioral

modification. All patients with Raynaud’s should be instructed to maintain a warm core body

temperature and to avoid extreme temperature changes. They also should be counseled to avoid

certain factors that can aggravate Raynaud’s, particularly smoking. Use of certain drugs like

decongestants and repeated trauma should also be avoided.

If pharmacologic intervention is necessary, the first line class of drugs is calcium channel blockers.

This class of drugs is by far the most commonly used in the treatment of Raynaud’s, although their

effectiveness is variable. If calcium channel blockers are ineffective or not tolerated, there are

other classes of drugs frequently used, also with varying effectiveness.

Behavioral Maintain warm core body temperature

Avoidance of smoking, sympathomimetic drugs (decongestants), and repeated trauma/vibration of the hands and fingers

Pharmacologic

First line: Long-acting calcium channel blockers (amlodipine, nifedipine) Selective serotonin reuptake inhibitors (fluoxetine) Phosphodiesterase-5 inhibitors (sildenafil) Angiotensin II receptor blockers (losartan) Topical nitrates

α 1-adrenergic receptor antagonists (prazosin)

• Raynaud’s

• Pulmonary arterial hypertension

• Scleroderma renal crisis Vascular

• Interstitial lung disease

• Cutaneous/Musculoskeletal Immune suppressors/anti-

inflammatories

• Gastroesophageal reflux

• GI dysmotility Symptomatic


Treatment of Severe Raynaud’s and Digital Ulcers:

Severe, digit-threatening Raynaud’s requires the use of potent vasodilating drugs. Most of these

medications require intravenous or injection administration and carry significant side effects.

They are also quite costly.

Potent vasodilators

Intravenous prostaglandin (iloprost, epoprostenol)

Endothelin antagonist (bosentan)

Treatment of Pulmonary Arterial Hypertension:

cGMPcAMP

Vasoconstriction and

proliferation

Endothelin receptor A

Exogenous

nitric oxideEndothelin-receptor

antagonists

Endothelinreceptor B

Phosphodiesterase

type 5 inhibitor

Vasodilation

and antiproliferation

Phosphodiesterase

type 5 Vasodilation

and antiproliferation

Prostacyclin

derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial

cells

Proendothelin

Endothelial

cells

Arachidonic

acid

Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells

ProstacyclinsEpoprostenol, Treprostinil

Iloprost (inhaled)

PDE-5 InhibitorsSildenafil, Tadalafil

SGC StimulatorRiociguat

Endothelin Receptor AntagonistsBosentan, Ambrisentan ,

Macitentan

Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

Many of the same vasodilating drugs that are used in severe Raynaud’s are also used to treat pulmonary

arterial hypertension. Typically the prostaglandin analogues are used as first line treatment in PAH and

carry the burden of requiring continuous IV or subcutaneous infusion. An inhaled prostacyclin (iloprost) is

available – this requires administration up to 9 times daily.

Potent vasodilators

Parenteral prostaglandins (epoprostenol)

Inhaled prostacyclin (iloprost)

Endothelin receptor antagonist (bosentan)

Phosphodiesterase inhibitors (sildenafil)

Treatment of Scleroderma Renal Crisis

It is important for you to be familiar with the management of scleroderma renal crisis.

Remember, early recognition is critical. Patients at high risk for SRC require home blood

pressure monitoring. Evaluation of kidney function and red blood count should be done at

any sign concerning for development of SRC. If SRC does develop, an ACE-inhibitor should

be started immediately and titrated up to the maximum dose as tolerated. The ACE-

inhibitor should be continued even if the patient goes on to require dialysis. ACE-inhibitors

have revolutioned care of SRC – what used to be a fatal complication now carries 1- and 5-

year survival rates of >70% and 60%, respectively.


Close Monitoring! Home blood pressure readings daily

If BP rises, evaluate for evidence of kidney damage/dysfunction (blood in urine and rise in creatinine) and new anemia Treatment ACE-INHIBITORS (Treat aggressively to maximum dose as tolerated)

Dialysis if necessary (with continued Ace-inhibitor) Use of Ace-inhibitors has changed what used to be an almost universally fatal complication of SSc to one with 1-year survival >70%, 5-year survival 60% (and long-term renal survival is 50-80%)

Treatment of Inflammatory Manifestations----

Interstitial lung disease is largely mediated by an intense inflammatory reaction and is

treated with strong immunosuppressive drugs. Typically the initial treatment of ILD is

cyclophosphamide in combination with glucocorticoids. If the lungs improve, then less

potent agents can be substituted (such as azathioprine and mycophenolate mofetil). The

treatment of ILD is suboptimal – some patients do not respond and treatments are

potentially very toxic. Therefore, researchers are actively looking at more effective and less

toxic approaches. Some of the investigational therapies include stem cell transplant and

antibody-based therapies such as imatinib and rituximab.

Interstitial Lung Disease Cyclophosphamide (+/- low-dose glucocorticoids) Azathioprine

Mycophenolate mofetil Investigational approaches: hematopoetic stem cell transplant, imatinib,

rituximab, tadalafil Cutaneous/Musculoskeletal

Physical therapy

Methotrexate

Azathioprine

Low-dose glucocorticoids – with caution because of risk of SRC

Monitoring for Complications---

Treatment of patients with systemic sclerosis requires “anticipatory management” (ie close

monitoring for early detection of disease complications). It is reasonable to perform

transthoracic echocardiograms and pulmonary function tests up to once every year in

these patients to screen for pulmonary arterial hypertension, even if they don’t complain

of cardiopulmonary symptoms (as their functional status may be quite compromised).

Likewise, pulmonary function tests in combination with chest CT scan should be done at

regular intervals to assess for the presence of interstitial lung disease. In patients at risk of

scleroderma renal crisis, home blood pressure monitoring is indicated as is regular testing

of urine and blood.

Consider annual transthoracic echocardiography and pulmonary function tests to screen for pulmonary arterial hypertension (more frequent screening if symptoms develop)

Pulmonary function tests and high resolution chest CT to assess for interstitial lung disease

In patients at high risk for scleroderma renal crisis - home blood pressure readings daily and regular testing of kidney function and urine


PROGNOSIS:

The prognosis for patients diagnosed with systemic sclerosis is better now than it was 25

years ago, but the potential for significant morbidity and early mortality is still substantial.

Several factors are associated with a poor prognosis

Highlights ((summary of the talk)):

Systemic sclerosis is a multisystem autoimmune disease characterized by inflammation, disordered

connective tissue metabolism and functional and structural abnormalities in blood vessels, all

contributing to progressive fibrosis of the skin and visceral organs. The primary target organs are

skin, lungs, kidney, and gastrointestinal tract. The symptoms are quite varied but the most

characteristic clinical features are Raynaud’s, skin tightening/fibrosis, interstitial lung disease,

pulmonary arterial hypertension, scleroderma renal crisis, and GI tract dysmotility.

Systemic sclerosis is a multisystem autoimmune disease characterized by inflammation,

disordered connective tissue metabolism and functional and structural abnormalities in

blood vessels, all contributing to progressive fibrosis of the skin and visceral organs

Primary target organs: skin, lungs, kidney, GI tract

Cardinal clinical features: Raynaud’s, skin tightening, interstitial lung disease, pulmonary

arterial hypertension, scleroderma renal crisis, GI tract dysmotility

Important aspects of management include:

Close monitoring for complications (including home BP and close monitoring for

lung involvement)

Calcium channel blockers for Raynaud’s

•dcSSc 40-60% at 10 years

•lcSSc >70% at 10 years

Overall survival:

•Rapidly progressive skin involvement

•Older age at disease onset

•African- or Native-American race

•Severe lung involvement

•Large pericardial effusion

•Proteinuria, hematuria, renal failure

•Anemia

•Elevated ESR

•Abnormal ECG

•Anti-Scl 70 (anti-topoisomerase) antibodies – increased risk of severe pulmonary fibrosis

•Anti-RNA-polymerase antibodies – increased risk of scleroderma renal crisis

Poor prognosis associated with:


Ace-inhibitors for scleroderma renal crisis

Vasodilators for pulmonary arterial hypertension

Immunosuppression for interstitial lung disease

Documents

SCLERODERMA DR MAGDI AWAD SASI 2016 LMB