Systemic sclerosis is an autoimmune disease characterized by fibrosis of the skin, internal organs, and blood vessels. It can cause Raynaud's phenomenon, digital ischemia, thickening and tightening of the skin, and organ involvement like lung, heart, gut, and kidney disease. The cause is unknown but likely involves genetic susceptibility and environmental triggers. It results from tissue fibrosis, blood vessel damage, and autoimmune inflammation. Treatment focuses on slowing organ damage and related complications through medications, lifestyle changes, and organ-specific interventions. Prognosis depends on organ involvement, with lung fibrosis and pulmonary hypertension being leading causes of death.

1. Systemic Sclerosis

2. Systemic sclerosis is an autoimmune disorder of connective tissue,
which results in fibrosis affecting the skin, internal organs and
vasculature.
It is characterized typically by Raynaud’s phenomenon, digital
ischaemia, sclerodactyly and cardiac, lung, gut and renal disease.

3. Systemic Sclerosis
Diffuse cutaneous SScl (30%) Limited cutaneous SScl (70%)

4. Epidemiology
Systemic sclerosis is a relatively rare disease. Overall prevalence is
10-20 per 100,000 with a 4:1 female to male ratio. The peak
incidence is between 30 to 50 years of age. It is rare in children.

5. Etiology
The cause of SScl is not completely understood. There is evidence for a genetic component
and association with alleles at the HLA locus have been found.
In some cases it seems likely that environmental agents, usually toxins such as silica dust,
vinyl chloride, epoxy resins and trichloroethylene may trigger the disease.
Genetic factors alone cannot fully explain disease expression. Thus, one hypothesis is that
infection, particularly with a virus, in particular Cytomegalovirus, may trigger a cascade of
events in a genetically susceptible host leading to systemic sclerosis (SSc) and associated
autoimmunity.
Several drugs have been associated with the development of systemic sclerosis (SSc)-like
syndromes such as Bleomycin, pentazocaine, cocaine, docetaxel, paclitaxel etc.

6. Figure: Summary of etiological factors and pathogenesis of systemic sclerosis

7. Pathophysiology
1. Tissue fibrosis: T lymphocytes, especially those of the Th17 subtypes, infiltrates the skin
causing abnormal Fibroblast activation → Increased Collagen deposition (primarily
type 1) as well as fibronectin and glycosaminoglycans. This is more apparent in the Skin
& Lungs resulting in symmetrical thickening, tightening and induration of the skin
(scleroderma).
2. Vasculopathy : Arterial and arteriolar narrowing occurs due to intimal proliferation and
vessel wall inflammation. Endothelial injury causes release of vasoconstrictors and
platelet activation, resulting in further ischaemia, which exacerbates the fibrotic
process.
3. Autoimmunity and Inflammation: Development of autoantibodies that cause
inflammatory manifestations such as arthritis and myositis.

9. Skin
Initially, there is non-pitting oedema of fingers and flexor tendon sheaths. Subsequently, the skin becomes
shiny and taut, and distal skin creases disappear. There can be capillary loss. The face and neck are often
involved, with thinning of the lips and radial furrowing.
Raynaud’s Phenomenon
This occurs in more than 95% of the cases. Involvement of small blood vessels in the extremities may cause
critical tissue ischaemia, leading to localized distal skin infarction and necrosis.
Musculoskeletal features
Arthralgia and flexor tenosynovitis are common. Restricted hand function is due to skin rather than joint
disease and erosive arthropathy is uncommon. Muscle weakness and wasting can result from myositis.
Gastrointestinal involvement
Smooth muscle atrophy and fibrosis in the lower 2/3rd of the esophagus lead to reflux with erosive
oesophagitis. Dysphagia and odynophagia may also occur. Stomach involvement causes early satiety and
occasionally outlet obstruction.
Small intestinal involvement may lead to malabsorption due to bacterial overgrowth and intermittent bloating,
pain or constipation. Dilatation of bowel due to autonomic neuropathy may cause pseudo-obstruction with
nausea, vomiting, abdominal discomfort and distension, often worse after food. Symptoms can mimic acute
abdomen.

10. Systemic sclerosis. Hands showing tight, shiny skin,
sclerodactyly, flexion contractures of the fingers and
thickening of the left
middle finger extensor tendon sheath.
Oral manifestations of systemic sclerosis
(A) Perioral skin tightening with decreased oral aperture, furrowing around the lips, and dry
mucous membranes.
(B) Periodontal disease with regression of gum and loosening of teeth.
(C, D) Telangiectasias on lips and tongue.

11. Scleroderma and Raynaud phenomenon can be associated with ischemic and traumatic
digital ulcerations and digital ischemia.
(A) Traumatic ulcers over the proximal interphalangeal joints.
(B, C) Ischemic digital tip ulcerations secondary to small arterial disease.
(D) Digital gangrene secondary to vascular disease.

12. Pulmonary involvement
Interstitial lung disease is the number one cause of mortality in patients with SScl. It is very common and
around 70% of patients tends to develop ILD at some time of the disease course. ILD is common in patients
with DcSScl who have topoisomerase 1 antibodies (Scl70). Patient may present with tachypnea, tachycardia,
cyanosis, clubbing and clinically there may be reduced chest expansion and fine early inspiratory crackles.
Pulmonary hypertension may also occur in patients with SScl, though it is six times more prevalent in lcSScl
than in dcSScl.
Renal involvement
One of the main cause of death is hypertensive renal crisis, characterized by rapidly developing accelerated
phase hypertension and renal failure. More common in dcSScl & in patients with topoisomerasae 1 and RNP
antibodies.

13. Investigations
As SScl can affect multiple organs, routine hematology, renal, liver and bone function test
and urinalysis are essential.
Autoantibodies:
• ANA is positive about 70% of the cases.
• Scl-70 (topoisomerase 1) is positive in 30% of patients with dcSScl.
• Anticentromere antibodies is positive in 60% of patients with lcSScl syndrome.
Chest x-ray, Echocardiography, lung function test, HRCT are recommended to assess for
interstitial lung disease and pulmonary hypertension. If PAH is suspected, right heart
catheter measurements should be arranged at a specialist cardiac centre.
A barium swallow can assess oesophageal involvement. A hydrogen breath test can
indicate bacterial overgrowth.

14. Treatment
No treatments are available that halt or reverse the fibrotic changes that underlie the
disease. The focus is to slow the effects of the disease on target organs.
• Raynaud’s Phenomenon and digital ulcers: Avoidance of cold exposure, use of thermal
insulating gloves/socks and maintenance of high core temperature may help. For
persistent symptoms; CCB, losartan, fluoxetine and sildenafil have efficacy. For critical
ischaemia, courses of IV Prostacyclin are used. Endothelin receptor 1 antagonist
Bosentan is used for treating ischaemic digital ulcers. Topical Fucidin-hydrocortisone
maybe used for maintaining digital tip tissue health.
• Gastrointestinal complications: Oesophageal reflux should be treated with PPI and anti-
reflux agents. For bacterial overgrowth, rotating courses of antibiotics may be required
(e.g. rifaximin, tetracyclince and metronidazole) while domperidone, metoclopramide
maybe used for symptoms of dysmotility/ pseudo-obstruction.

15. • Hypertension: Aggressive treatment with ACE inhibitors is needed, even if renal
impairment is present.
• Joint involvement: This maybe treated with analgesics and/or NSAIDs. If synovitis
present, both RA and OA have been ruled out, low dose MTX can be of value.
• Progressive pulmonary hypertension: Early treatment with Bosentan is required. In
severe cases, heart-lung transplant maybe considered.
• ILD: Glucocorticoids and (pulse IV) cyclophosphamide are the mainstays of treatment in
patients who have progressive ILD.

16. Prognosis
There is a substantial increase in the risk of death in patients with SScl.
Most deaths among patients with SScl are related to pulmonary
fibrosis, pulmonary arterial hypertension, or cardiac causes. Other
significant causes of death include renal disease, malignancy,
gastrointestinal, and infectious causes.