Systemic sclerosis

Dr Ankan Chakraborty
Chairperson: Dr Sujoy Sarkar
19th March 2024
Introduction
• Scleroderma or Systemic sclerosis
(SSc) manifested by
1. Autoimmunity
2. Inflammation
3. Functional and structural
alternation of small blood vessels
4. Interstitial and vascular fibrosis
affecting the skin and internal
organs
Etiology
• Genetic susceptibility
• Epigenetic factors
• Environmental factors
i. Infectious agents and viruses
ii. Chemicals, drugs and dietary
supplements
Etiology
• Genetic susceptibility: • Epigenetic factor:
1. Increased risk for first degree 1. DNA methylation
relatives 2. Histone modifications
2. HLA DRB1*11:04, DQA1*05:01, 3. Expression of noncoding (long and
DQB1*03:01 micro) RNAs
3. Non HLA MHC genes NOTCH4,
PSORSC1
4. Other genes: PTPN 22 (associated
with SLE, myasthenia gravis, vitiligo,
Addison’s disease), NLRP1, IRF5,
STAT4, BANK1 etc
Etiology
• Environmental factors :

1. Infectious agents and viruses: EBV, CMV, Parvovirus B19

2. Chemicals: Silica, Heavy metals (Mercury), Organic chemicals (Vinyl

chloride, Benzene, Toluene, Trichloroethylene

3. Drugs: Bleomycin, Pentazocine, Cocaine

4. Dietary supplements/Appetite Suppressants: L-tryptophan,

Mazindol, Fenfluramine, Diethylpropion
Pathogenesis:
Vascular events
Pathogenesis:
Autoimmunity
Pathogenesis:
Fibrosis
Pathology
• Non inflammatory proliferative/obliterative
vasculopathy
• Loss of capillaries (rarefication)
• Fibrosis mainly at skin, lungs, heart
• Vascular Pathology:
• Raynaud’s phenomenon,
mucocutaneous telangiectasia
PAH, Digital tip ulcer
• Intimal proliferation and medial
hypertrophy Systemic sclerosis vasculopathy
 Pathology: Skin

Perivascular infiltration is
present in the dermis with
inflammatory cells of
multiple lineages.
Microvascular endothelial cell
activation and increased
extra-cellular matrix
deposition are also seen (A)

Later, regression of the

inflammatory features occurs.
Secondary structures within
the skin such as hair follicles
and sebaceous and sweat
glands are reduced, and rete
A B pegsare flattened (B)
Pathology: Lungs
• Early Histological
features are Patchy
infiltration of the
alveolar walls with
lymphocytes, plasma
cells, macrophages and
eosinophils
• Interstitial lung fibrosis
and vascular damage are
late features
Pathology: Occlusion of intrarenal
arteries with neointima
Kidney formation, fibrinoid
necrosis of the vessel
• Small interlobular and wall, and reduplication
arcuate arteries show of the internal elastic
reduplication of elastic lamina
lamina, marked intimal
proliferation and fibrinoid
necrosis
• Luminal narrowing and total
obliteration of the lumen
• Microangiopathic hemolysis
Pathology: Other organs
• GIT:
• Fibrosis of lamina propria, submucosa, muscular layers
• Abnormal peristaltic movements
• Sever GERD, Barrett’s esophagus

• Others:
• Thyroid gland fibrosis with absence of inflammation
• Erectile dysfunction
• Fibrosis of lacrimal gland and salivary gland
Diagnostic Criteria
• 1980 ACR criteria :

• CREST Criteria : CREST Criteria

Must have three of the five features:
a. Calcinosis
b. Raynaud’s phenomenon
c. Esophageal dysmotility
d. Sclerodactyly
e. Telangiectasias
ACR/EULAR Classification Criteria for the
Classification of Systemic Sclerosis 2013
ACR/EULAR
Classification
Criteria for the
Classification
of Systemic
Sclerosis 2013
Classification and clinical Subsets

Type 1 Type 2 /
Early/ Sine SSc Diffuse SSc
Limited SSc Intermediate
Autoantibodies
Target Antigen SSc types Clinical features
Topoisomerase I dcSSc Digital ischemic ulcers, scleroderma, extensive
(Scl-70) skin involvement, early ILD, cardiac
Speckled pattern involvement, scleroderma renal Crisis
Centromere proteins lcSSc Digital ischemic ulcers, calcinosis cutis, isolated
Discrete speckled PAH
(centromere) pattern
RNA polymerase III dcSSc Rapidly progressive skin involvement, tendon
Speckled pattern friction rubs, joint contractures, GAVE, renal
crisis, contemporaneous cancers
U3-RNP (fibrillarin) dcSSc/ PAH, ILD, scleroderma renal crisis, GI tract
Nucleolar pattern lcSSc involvement, myositis
Topoisomerase I
(Scl 70)
Speckled pattern
Centromere
pattern
RNA
polymerase III
Speckled pattern
U3-RNP
(Fibrillarin)
Nucleolar
pattern
Other Autoantibodies
Clinical
features of
lcSSc and dcSSc
Frequency of
clinical organ
involvement
in lcSSc and
dcSSc
Raynaud’s Phenomenon (RP)

• Exaggerated vascular response of the digital arterial circulation

• Trigger: cold ambient temperature and emotional stress

• Recurrent events of sharply demarcated pallor and/or cyanosis of the

skin of the digits

• 3% to 5% incidence in general population, more in females

Type of Raynaud’s Phenomenon
Primary RP Secondary RP
Exaggerated physiological response to Secondary to serious underlying disease
cold and stress
Normal Nail fold capillaries Abnormal nail fold capillaries
Symmetric attack Asymmetric attack
Necrosis, ulcers absent Ischemic skin lesions, pulp pitting
present
Age < 30 years Age > 30 years
ESR, CRP Normal ESR, CRP Raised
ANA negative ANA other antibodies maybe present
 Stages of Raynaud’s Phenomenon
• Stages:
A. Blanching reflects
digital arterial
vasospasm
B. Cyanosis occurs
as a result of the
deoxygenation of
sluggish venous
blood flow
C. Skin blushing
(redness) due to
reactive
hyperemia after
regular blood flow
has been restored
Nail-fold capillaroscopy
• Visualisation of nailfold capillary blood vessels
• Primary RP: Normal, thin, palisading nail-fold capillary loops
• Secondary RP:
• Capillary loop dilatation, microhaemorrhage are features of early
disease
• Drop outs, avascular areas, signs of neo angiogenesis with bizarre
architectural distortion present at later stage
• RP with abnormal nail fold changes is ‘early’ phenotype.
• Features of scleroderma develops with in 2 -4 years
Nail-fold
capillaroscopy

G: Giant capillaries
L: Loss of capillaries
M: Microhemorrhages
N: Neoangiogenesis
 Skin involvement in SSc
• Bilateral symmetrical skin thickening and hardening
• Diffuse tanning might be an early feature
• Hypopigmentation sparing the perifollicular areas called
Salt-and-pepper appearance of the skin
• Clinical signs of inflammation present at earliest, called
edematous phase manifest as non pitting edema of
effected body parts.
• In lcSSc this is limited to digits
• In dcSSc it can mimic fluid overload causing local tissue
compression
• Scerodactyly
Skin involvement in SSc
• Mauskopf facial appearance with taut and shiny
skin, loss of wrinkles, expressionless facies, small
oral and orbital apertures
• Dilated skin capillaries in face, hand, lips and oral
mucosa i.e Telangiectasia
Pulmonary involvement in SSc
• 2 form of disease: 1) Interstitial lung disease 2) Pulmonary vascular
disease
• Interstitial lung disease:
• High risk at males, diffuse skin involvement, sever GERD, scl-70
• Anti centromere antibody is protective
• Incidence at Limited SSc 20 %, Diffuse SSc 60%
• Declining lung volumes and increase pulmonary fibrosis
• NSIP pattern
• PFT s/o restrictive pattern
• Decline of FVC >10 % from baseline indicative of bad prognosis
ILD : HRCT Thorax

Increased subpleural attenuation with

out GGO
↓
Increased GGO
↓
Pulmonary fibrosis
↓
Honey combing, cystic air space
Pulmonary involvement : PAH
• Defined as mean pulmonary artery pressure ≥ 20 mmHg with
pulmonary capillary wedge pressure ≤ 15 mmHg and pulmonary
vascular resistance > 3 Wood units
• Vascular remodelling of small pulmonary arteries
• Can be isolated or associated with ILD
• Risk factor:
i. Limited Systemic Sclerosis
ii. Old age
iii. Cutaneous telangiectasia
iv. Antibody to Centromere, U3 RNP, B23
Scleroderma renal crisis (SRC)
• Occurs in 5% to 10% of patients
with scleroderma
• Risk Factors:
• dsSSc
• high dose of corticosteroid
• low dose of cyclosporine
• positive anti-U3-RNP, Anti
polymerase III
• When to suspect?
• Malignant hypertension
• Thrombocytopenia
• Microangiopathic hemolytic
anemia
• AKI
• Tendon crepitation rub
• Headache, malaise, hypertensive
retinopathy, encephalopathy,
pulmonary edema
Scleroderma renal crisis (SRC)
• Obliterative vasculopathy with consequent intravascular hemolysis
• ARF + < 2 gm/day proteinuria + mild hematuria
• Worse prognosis:
• Microangiopathic hemolytic anemia with thrombocytopenia in
normotensive
• Oliguria
• Males
• Creatinine > 3 mg/dL
• D/D : TTP
Scleroderma renal crisis (SRC):
Treatment
Gastrointestinal involvement in SSc
Oropharynx Perioral tight skin Regular dental and
Decreased oral aperture periodontal care
Periodontitis, gum disease
Dry mouth Artificial saliva
Swallowing difficulties Targeted swallowing
Coughing, aspiration exercises and
rehabilitation

Decreased Periodontitis: Loosing of teeth,

oral aperture regression of gum
Gastrointestinal involvement in SSc
Esophagus Acid reflux (heartburn) Lifestyle modifications
Dysphagia Proton pump inhibitors
Prokinetics
Strictures Endoscopic treatments
Barrett’s esophagus and procedures
Stomach Gastroparesis, dyspepsia Prokinetic agents
GAVE Endoscopic laser
cryotherapy
Small and large intestine Hypomotility, constipation Laxative
SIBO Promotility agents
Pseudo-obstraction Antibiotics
Malabsorption Nutritional support
CREST syndrome
• Previously known as lcSSc
• Components:
1. Calcinosis
2. Raynaud phenomenon
3. Esophageal dysmotility
4. Sclerodactyly
5. Telangiectasia
Other system involvement
• Musculoskeletal complications:
• Carpal tunnel syndrome
• Tendon friction rub
• Erosive polyarteritis
• Endocrine complications:
• 10% - 15% of SSc patients have
thyroid disorders
• Hypothyroidism due to Graves’ or
Hashimoto’s disease
• Cardiac complications:
• Pericarditis, pericardial effusions,
constrictive pericarditis
• Cardiac tamponade
• Patchy myocardial fibrosis
• Myocarditis
• Others:
• Erectile Dysfunction
• Trigeminal neuropathy
Summary of
clinical features
Management

Kowal-Bielecka O, Fransen J, Avouac J, et al. Ann Rheum Dis 2017;76:1327–1339.

 Updated EULAR recommendations for treatment
of systemic sclerosis 2017
Organ Recommendation Strength
Involvem
ent
• Dihydropyridine-type calcium antagonists, usually oral A
nifedipine, should be considered as first-line therapy for
SSc-RP
• PDE-5 inhibitors should also be considered in treatment
SSc-RP of SSc-RP
• Intravenous iloprost should be considered for severe A
SSc-RP.
• intravenous iloprost should be used for treatment of SSc
RP attacks after oral therapy.
 Updated EULAR recommendations for treatment
of systemic sclerosis 2017
Organ Recommendation Strengt
Involveme h
nt
Intravenous iloprost should be considered in the A
treatment of digital ulcers in patients with SSc.
PDE-5 inhibitors should be considered
Digital digital ulcers in patients with SSc. in treatment of A
ulcers in
SSc Bosentan should be considered for reduction of the A
number of new digital ulcers in SSc, especially in patients
with multiple digital ulcers despite use of calcium channel
blockers, PDE-5 inhibitors or iloprost therapy.
 Updated EULAR recommendations for treatment
of systemic sclerosis 2017

Organ Recommendation Strengt

Involve- h
ment
ERA (ambrisentan, bosentan and macitentan), PDE-5 inhibitors A
(sildenafil, tadalafil) or riociguat should be considered to treat
SSc-related PAH.
SSc- Intravenous epoprostenol should be considered for the A
PAH treatment of patients with severe SSc-PAH (class III and IV).
Prostacyclin analogues (iloprost, treprostinil) should be B
considered for the treatment of patients with SSc-PAH.
 Updated EULAR recommendations for
treatment of systemic sclerosis 2017
Organ Recommendation Stre-
Involvement ngth
Methotrexate may be considered for treatment of skin manifestations A
of early diffuse SSc.
Cyclophosphamide should be considered for treatment of SSc-ILD, in A
Skin and particular for patients with SSc with progressive ILD.
lung
disease in HSCT should be considered for treatment of selected patients with A
SSc rapidly progressive SSc at risk of organ failure. In view of the high risk of
treatment-related side effects and of early treatment-related mortality,
careful selection of patients with SSc for this kind of treatment and the
experience of the medical team are of key importance.
 Updated EULAR recommendations for treatment
of systemic sclerosis 2017

Organ Recommendation Strength

Involve-
ment
Immediate use of ACE inhibitors in the treatment of SRC. C
Several retrospective studies suggest that glucocorticoids C
SRC are associated with a higher risk of SRC. Blood pressure
and renal function should be carefully monitored in
patients with SSc treated with glucocorticoids.
 Updated EULAR recommendations for treatment
of systemic sclerosis 2017

Organ Recommendation Strengt

Involveme h
nt
PPI should be used for the treatment of SSc-related GERD and B
SSc prevention of oesophageal ulcers and strictures
related Prokinetic drugs should be used for the management of SSc-related C
gastro- symptomatic motility disturbances (dysphagia, GERD, early satiety,
intestinal bloating, pseudo-obstruction, etc).
disease Intermittent or rotating antibiotics to treat symptomatic small D
intestine bacterial overgrowth in patients with SSc
 Systemic sclerosis and pregnancy
• Majority are stable during pregnancy but 20% report a deterioration
• High Risk:
• dcSSc within five years of disease onset
• Anti-topoisomerase or anti-RNA polymerase III antibodies
• Organ involvement prior to conception
• SRC is often difficult to distinguish from pre-eclampsia or HELLP syndrome
• ACE inhibitors should not be stopped as risk to the mother outweighs any potential
risk to the fetus
• SSc-PAH patients with pregnancy should undergone early termination
• Modify DMARDs, Use: azathioprine, tacrolimus, HCQS, rituximab and treat reflux
• Stop: MMF, MTX
• Corticosteroid can be used upto 15 mg/day with monitoring
Obstet Med. 2020 Sep;13(3):105-111.
SSc and Pregnancy
Take home points
• Scleroderma/systemic sclerosis (SSc) has a complex pathogenesis and clinical
manifestations that reflect the underlying early immune dysregulation and
microangiopathy, and subsequent systemic fibrosis
• Marked patient-to-patient variability exists
• Vascular lesions in small blood vessels occur early and progress to obliterative
vasculopathy that causes tissue hypoxia, oxidative stress, and vascular
complications
• Immune dysregulation manifested by autoantibodies
• Fibrosis is associated with sustained mesenchymal cell activation
• Organ specific management is recommended
Thank you