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SSc 101. Julia Rhiannon June 2013 j ulia.rhiannon@va.gov. outline. Intro and pathogenesis Classification dcSSc ~ diffuse cutaneous systemic sclerosis organ involvement with 2 cases Rodnan skin scoring lcSSc ~ limited cutaneous systemic sclerosis & case

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slide1

SSc 101

  • Julia Rhiannon
  • June 2013
  • julia.rhiannon@va.gov
outline
outline
  • Intro and pathogenesis
  • Classification
  • dcSSc ~ diffuse cutaneous systemic sclerosis
    • organ involvement with 2 cases
    • Rodnan skin scoring
  • lcSSc ~ limited cutaneous systemic sclerosis & case
  • Antibodies as clues to phenotype
  • Environmental/genetic contribution and epi
  • Therapy
ssc clinical manifestations result from
SSc clinical manifestations result from...
  • Autoimmunity
  • Small vessel obliterativevasculopathy
    • Raynaud’s, renal crisis, PAH
  • Pathological accumulation of collagen in skin and other organs
    • Sceroderma, lung parenchymaldz, GI dysmotility
localized scleroderma
Localized Scleroderma

Morphea

Linear Scleroderma

Coup de Sabre

case 1 puffy hands
Case 1: Puffy Hands
  • HPI - 45 y/o woman with 5 wks of puffy hands
    • recently finger turns white while grocery shopping or reaching into refrigerator. Hands feel itchy.
  • Exam - Diffusely swollen hands and wrists. Several fingers cyanotic. Pulses intact.
case puffy hands
Case: Puffy Hands

The next step would be:

1. Check for nailfold changes

2. Doppler study

3. Order ANA panel

4. Order ANCA

5. Skin biopsy

6. Pred 60mg IM x1

7. Tell her to take her

husband’s viagra

skin raynaud s
Skin: Raynaud’s
  • Classic three color change:-pallor (vasoconstriction)-cyanosis-rubor (least frequent)
  • Triggered by cold and emotion
raynaud s
Raynaud’s
  • Raynaud’s affects 3-5% of general population
    • Most are primary, usually with onset in 20s-30s
  • Raynaud’s assoc with SSc will likely have :
    • Increased severity in freq/duration/morbidity
    • Nailfold cap abn (47% PPV)
    • Positive serologies (ANA 30%PPV)
    • With stiffness and/or pitting +/- ulcers
    • Age >35
nailfold capillaroscopy
NailfoldCapillaroscopy

Normal

Dilatation

Dilatation

Dropout

Bizarre

Loops

images in raynaud s
Images in Raynaud’s

Cyanosis

Digital pitting

treatment of raynaud s
Treatment of Raynaud’s
  • Central warmth, good gloves, avoid cold exposure, handwarmers
  • Stress reduction
  • Dihydropyridine calcium channel blockers
    • nifedipine 30mg ER titrate up as tolerated
  • Phosphodiesterase5 inhibition (sildenafil/revatio/viagra)
  • Topical nitroglycerin for 20 minutes (or more) tid proximal to affected digit
  • Po and IV prostanoids (alprostadil)
  • Endothelin receptor antagonist (Bosentan)
  • Statins
  • Antiplatelet (ASA) and antioxidant (NAC)
severe digital ischemia
Severe Digital Ischemia
  • Treatment of impending digital gangrene requires hospitalization
  • Warm room, pain meds, anxiolytics, high dose Ca channel blockers or trial of IV alprostadil(5 nanograms/kg/min for 6 hours followed by 10 nanograms/kg/min for 66 hours via PICC line),
  • Antibiotics if infection present
  • May try sympathetic block at the wrist; consider digital sympathectomy if successful
early skin changes in diffuse ssc
Early Skin Changes in Diffuse SSc
  • Initially skin may be edematous
  • Hands only early
  • May have CTS
  • Edema resolves; skin then indurated
  • Extremities, face, trunk may be involved
  • Advancing skin involvement often pruritic
late skin changes
Late Skin Changes
  • As disease progresses, skin becomes atrophic
  • Ulcers may develop at pressure points or with trauma
  • Disappearance of finger tips due to resorption or gangrene
  • Secondary joint contractures
other skin changes
Other skin changes
  • Other
    • Thickened and tethered
    • Telangiectasia
    • Calcinosis
    • Narrowed oral aperture
case 2
44 y/o male with known dcSSc admitted to MICU for

BP 210/150

creatinine 1.5 mg/dl.

UA with +2 protein

Smear with schistocytes

Next step is to give:

plasma exchange

IV Solu-Medrol & Cytoxan

IV nitroprusside

ACEi (enalaprilat or poenalapril)

Renal bx STAT

Case 2
scleroderma renal crisis
Scleroderma Renal Crisis
  • Defined as accelerated arterial hypertension and/or rapidly progressive oliguric renal failure.
  • Occurs in 10% of patients with scleroderma
  • Occurs in 20-25% of pts with the RNA Pol III Ab
  • Etiology - mimics malignant htn, 2/2 microvascdz, vasospasm, and tissue ischemia… with elevated renin, and arteriolar fibrotic change
  • Knowledge from clinical studies:
    • Must keep exquisite control of BP
    • When in renal crisis use ACEs before ARBs or any other
    • Corticosteroids thought to predispose patients to renal crisis
renal involvement in diffuse scleroderma
Renal Involvement in diffuse scleroderma
  • Renal Crisis
    • rapidly progressive azotemia
    • malignant hypertension
    • microangiopathichemolytic anemia
    • thrombocytopenia
    • proteinuria, hematuria

Scleroderma renal crisis/malignant Htn

arteriolar fibrinoid necrosis

syndromes in systemic sclerosis
Vascular

Raynaud’s Phenomenon

Renal Crisis

Pulmonary Hypertension

Myocardial Change

+/- sudden death

Visceral Raynaud’s

Fibrotic

Skin Involvement

Interstitial Lung Disease

Intimal Hyperplasia

Immunologic

Alveolitis

Myositis

Tendonitis

Synovitis

Syndromes in Systemic Sclerosis
other organ involvement
Other Organ Involvement
  • Muscle
    • Inflammatory (overlap with polymyositis)
    • Type 2 fiber atrophy
  • Joint
    • Arthralgias (rarely arthritis)
    • Acrosclerosis
      • calcinosis and acrolysis
    • Tendon fibrosis
  • Nerve
    • Compressive neuropathy
    • Autonomic dysfunction
gastrointestinal involvement
Gastrointestinal Involvement
  • Esophageal dysmotility (90%)
  • Gastroparesis
  • Small bowel dysmotility
  • Large bowel
    • Diarrhea (bacterial overgrowth malabsorption)
    • Large mouth diverticuli
  • GAVE/Watermelon Stomach
lung involvement
Lung Involvement
  • Pulmonary hypertension
  • Interstitial lung disease
  • Diaphragmatic dysfunction
active ild in ssc likely to be nsip
Active ILD in SSc likely to be NSIP
  • Depressed FVC or declining FVC by >10% in 4-6mo
  • Bilateral
  • Basal predominant
  • Confluent
  • Ground glass
  • Reticular lines
  • Traction bronchiectasis
  • Will progress to PF without treatment
cardiac involvement
Cardiac Involvement
  • Myocardial fibrosis
    • most common manifestation
  • Coronary Artery Disease
  • Conduction System Disease and Arrhythmias
  • Pericardial Disease
diffuse disease assessment over time
Diffuse disease, assessment over time
  • Skin involvement reflects relative risk of new internal organ involvement
    • Pace
    • Progression
    • Extent
  • Must be able to track extent and severity of skin changes
  • Classification and prognosis depends on these determinations in addition to antibodies
  • Rodnan skin score is qualitative
    • 0 normal; 1 mild; 2 moderate; 3 severe thickening
    • summation of 17 body areas
clinical assessment of skin thickening modified rodnan skin score mrss

0

Uninvolved

1

Mild thickening

2

Moderate thickening

Face

3

Severe thickening

Upper arm

Upper arm

Anteriorchest

Abdomen

Forearm

Forearm

Hand

Hand

Fingers

Fingers

Thigh

Thigh

Leg

Leg

Foot

Foot

Clinical Assessment of Skin Thickening-Modified Rodnan Skin Score (MRSS)
clinical meaningfulness of change in mrss
Clinical Meaningfulness of Change in MRSS
  • Increase predicts worsening of SSc
  • Stability predicts reduced new internal involvement
  • Improvement predicts improved 5 and 10 year survival
  • High scores (>20) predict renal crisis (OR 6.64)
  • High scores (>20) predict mortality (OR 3.39)
  • Improved score correlates with HAQ-DI, hemoglobin
slide31
lcSSc (limited cutaneous systemic sclerosis)Calcinosis, Raynaud’s, Esophagealdysmotility,Sclerodactly, Telangiectasia
  • Raynaud’s often present for years prior to skin edema/thickening
  • Skin involvement limited
  • (fingers distal to MCPs)
  • PAH > ILD
  • Digital infarcts seen
  • CREST associated with PBC, occasionally also with Sjogren’s

Calcinosis

case 3
Case 3

HPI - A 52 y/o women with 10 yrs of Raynaud’shere w/ recently increasing problems with hands as well as dysphagia. She has also noted small red dots on her face and hands appearing over the last 6 months.

Exam - In the office she has active Raynaud’sand has multiple small red lesions on face, hands, and tongue.

case 31
Case 3

What pattern would you expect

to see on ANA testing?

1. Homogeneous

2. Nucleolar

3. Peripheral

4. Centromere

5. Speckled

classification of systemic sclerosis and organ involvement
Classification of Systemic Sclerosis and Organ Involvement
  • All systemic sclerosis
    • Raynaud’s
    • Esophageal dysmotility
    • Telangiectasias
  • dcSSc
    • Interstitial Lung disease
    • Renal Crisis
    • Cardiac Involvement
    • GI involvement
  • lcSSc
    • Pulmonary hypertension
    • Calcinosis
    • Overlap syndromes-Sjogren’s, RA, SLE, MCTD, PBC
ana pattern matters
ANA pattern matters

centromere

speckled

PAH risk

nucleolar

homogenous (diffuse)

ILD risk

antibodies as clues to phenotype organ involvement prognosis
Antibodies as clues to phenotype, organ involvement, prognosis
  • dcSSc
    • ANA positive 40-90% with nucleolar pattern on ANA
    • Scl-70 (anti-topoisomerase 1) with low sensitivity / high specificity for diffuse disease
    • RNA Polymerase III - most severe skin involv., highest freq of renal crisis, best overall prognosis
    • U3 RNP - diffuse but with PAH +/- ILD, skeletal and cardiac muscle inv
  • lcSSc
    • centromereANA very specific for CREST/limited disease in up to 90% of pts; PAH
    • U1 RNP – MCTD with SSc phenotype, risk of PAH
    • Th/To - PAH +/- ILD; more pulm fibrosis and renal crisis than anti-centromere+ pts

Arthritis Rheum. 2009 Apr;60(4):1112-28.

predominant features associated with scleroderma specific autoantibodies
Predominant Features Associated with Scleroderma-Specific Autoantibodies

Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35:35-42, 2005.

env occup genetics
Polyvinylchloride - 1930s

Toxic oil syndrome- Spain - rapeseed oil contaminated with aniline dye SScl like disease

contaminated L-tryprophan - 1989 – “eosinophiliamyalgiasyndrome”

Silica dust - case reports in miners

Organic solvents- textile industry / paint thinners and removers

Epoxy resins

Pesticides

Hand/arm vibration

Arch Occup Environ Health 2004; 77:10-16

1.6% of Ssc pts have a 1st degree relative with SSc (RR=13)

5.9% concordance in identical twins (300 times higher than chance)

Strong associations with HLA-A1, -B8, -DR3 haplotype and with DR3/DR52

Strong associations with C4AQ0 and DQA2

Well-defined cluster of Choctaw Indians with diffuse phenotype

Env/Occup Genetics
epidemiology
Epidemiology
  • Prevalence: 276-300 cases per million
  • Incidence: 20 cases per million/year
  • F:M = 4.6:1
  • Shows relative phenotypic severity in African Americans and Native Americans.
  • Onset peaks between 45-60 yrs of age.
  • Prognosis worsens with increasing age of onset.
treatment overview
Treatment overview
  • Htn
    • ACEi, CCB
  • Raynaud’s
    • CCB
    • PDE5 inhibition
    • nitrates
  • GI
    • Cholinergic agonists
    • PPI, H2B
    • antibiotics for bowel overgrowth
    • Reglan/domperidone
    • Argon coag for GAVE
  • Doxepinfor itching
  • Treat depression, anxiety, sleeplessness
  • PAH
    • Bosentan
    • Epoprostenol
    • PDE5 inhibition
  • DMARDS
    • methotrexate
    • MMF (CellCept/Myfortic)
    • Cyclophosphamide
    • Steroids, LD(<15mg)
    • N-acetylcysteine
    • Rituximab
    • Stem cell transplant
    • Tyr-kinase inhibition
    • Anti-CTGF
slide42

“No drug has been shown to be completely worthless until tried in Scleroderma” –Eric Bywaters

scleroderma 3k 5k walk
Scleroderma 3K/5K walk
  • June is SSc awareness month
  • Walk is this coming Sat, June 15th, 2013
  • www.scleroderma.org/steppingoutcherrycreek
references
References
                  • Shah, A and F. Wigley, Mayo Clin Proc. 2013 Apr; 88(4):377-393.
                  • Klippel, John, et.al., Primer on the Rheumatic Diseases, 13th ed. Springer, 2008.
  • Hochberg, Marc, et.al., Rheumatology, 4th ed., Mosby Elsevier, 2007.
  • Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35:35-42, 2005.
  • Arch Occup Environ Health 2004; 77:10-16
  • Gu, S., et.al., Seminars in Arthritis, 2008
                  • Arthritis Rheum. 2009 Apr;60(4):1112-28.
organ involvement and survival
Organ Involvement and Survival
  • Organ Involvement
    • L: Lung; H: Heart, K: Kidney

Medicine 81:139,2002

(1012 Italian patients)

therapy of localized scleroderma
Therapy of localized scleroderma
  • UVA
  • Topical steroids
  • Calcipotriol (Vit D analog)
  • Methotrexate
  • Experimental:
    • Anti-TGFbMAb
    • Halofuginone (interferes w/ TGFb induced collagen synth)
    • Topical TGFb1 binding peptides
    • thalidomide