SSc 101
Julia Rhiannon
June 2013
julia.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
• Antibodies as clues to phenotype
• Environmental/genetic contribution and epi
• Therapy
SSc clinical manifestations result from...
• Autoimmunity
• Small vessel obliterative vasculopathy
– Raynaud’s, renal crisis, PAH
• Pathological accumulation of collagen in skin
and other organs
– Sceroderma, lung parenchymal dz, GI dysmotility
Chicken vs Egg – Pathogenesis and
autoantibodies
Gu, S., et.al., Seminars in Arthritis, 2008
Localized
Scleroderma
Morphea
Linear Scleroderma
Coup
de
Sabre
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
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
• Classic three color change:
-pallor (vasoconstriction)
-cyanosis
-rubor (least frequent)
• Triggered by cold and emotion
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
Normal
Dilatation
Dropout
Dilatation
Bizarre
Loops
Images in Raynaud’s
Cyanosis
Digital pitting
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
• Phosphodiesterase 5 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
• 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
• 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
Early Skin Changes in
Diffuse SSc
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
– Thickened and
tethered
– Telangiectasia
– Calcinosis
– Narrowed oral
aperture
Case 2
• 44 y/o male with known Next step is to give:
dcSSc admitted to
1. plasma exchange
MICU for
– BP 210/150
– creatinine 1.5 mg/dl.
2. IV Solu-Medrol & Cytoxan
– UA with +2 protein
3. IV nitroprusside
– Smear with
schistocytes
4. ACEi (enalaprilat or po
enalapril)
5. Renal bx STAT
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 microvasc
dz, 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 Crisis
– rapidly progressive
azotemia
– malignant
hypertension
– microangiopathic
hemolytic 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
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
• Esophageal
dysmotility (90%)
• Gastroparesis
• Small bowel
dysmotility
• Large bowel
– Diarrhea (bacterial
overgrowth
malabsorption)
– Large mouth diverticuli
• GAVE/Watermelon
Stomach
Lung Involvement
• Pulmonary
hypertension
• Interstitial lung
disease
• Diaphragmatic
dysfunction
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
• Myocardial fibrosis
– most common
manifestation
• Coronary Artery
Disease
• Conduction System
Disease and
Arrhythmias
• Pericardial Disease
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
3
Severe thickening
Upper arm
Face
Upper arm
Anterior
chest
Abdomen
Forearm
Hand
Fingers
Thigh
Forearm
Hand
Fingers
Thigh
Leg
Leg
Foot
Foot
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
lcSSc (limited cutaneous systemic sclerosis)
Calcinosis, Raynaud’s, Esophageal dysmotility,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
HPI - A 52 y/o women with 10 yrs
of Raynaud’s here 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’s and has
multiple small red lesions on
face, hands, and tongue.
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
• 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
centromere
speckled
PAH risk
nucleolar
homogenous (diffuse)
ILD risk
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
– centromere ANA 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
Predominant Features Associated with Scleroderma-Specific
Autoantibodies
ACA
Th/To
U1RNP
PmScl
U3-RNP
Topo1
Pol 3
SSc
Subset
L
L
L
L
D
D
D
Lung
PH
ILD & PH
PH
ILD &
PH
ILD
Renal
-
-
-
+
+
-
Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35:35-42, 2005.
+
Survival according to antibody
Env/Occup
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Polyvinylchloride - 1930s
Toxic oil syndrome- Spain rapeseed oil contaminated
with aniline dye  SScl like
disease
contaminated L-tryprophan 1989 – “eosinophilia myalgia
syndrome”
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
Genetics
•
•
•
•
•
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
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
• Htn
– ACEi, CCB
• Raynaud’s
– CCB
– PDE5 inhibition
– nitrates
• GI
– Cholinergic agonists
– PPI, H2B
– antibiotics for bowel
overgrowth
– Reglan/domperidone
– Argon coag for GAVE
• Doxepin for 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
“No drug has been shown to be
completely worthless until tried in
Scleroderma” –Eric Bywaters
Scleroderma 3K/5K walk
• June is SSc awareness month
• Walk is this coming Sat, June 15th, 2013
• www.scleroderma.org/steppingoutcherrycreek
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
– L: Lung; H: Heart, K:
Kidney
Medicine 81:139,2002
(1012 Italian patients)
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