Aetiology

Aetiology is unknown at present. However, several aetiological factors have been suggested.

  • Genetics: <5% of monozygotic and dizygotic twins are clinically concordant for systemic sclerosis. Most of the monozygotic twins are concordant for antinuclear antibodies. A genetic predisposition has been suggested following a monozygotic twin study and a study showing the increased prevalence of the disease among first-degree relatives of probands.[8][9][10] The association of human leukocyte antigen polymorphisms has also been described.[11] Genetic polymorphisms of several candidate genes have also been identified (IL1A, AIF-1, PTPN22, and MIF).

  • Immunology: about 90% of patients have a positive ANA by indirect immunofluorescence. Among this group, there are subsets of mutually exclusive auto-antibodies that are associated with distinct clinical phenotypes:

    • Anti-topoisomerase I (anti-Scl 70) antibody is seen in about 20% of cases and is associated with an increased risk of interstitial lung disease and with diffuse skin involvement

    • Anti-RNA polymerase III antibody (also about 20% of cases) is associated with renal crisis

    • Anti-centromere antibodies (20% to 25% of cases) are associated with limited skin involvement and a better overall prognosis

    • The remaining 40% have scleroderma but do not have an as-yet-identified scleroderma-specific auto-antibody.

  • Environmental: several factors have been postulated as having an association with scleroderma, including exposure to silica dust and multiple solvents, but no clear link has been identified.[12]

Pathophysiology

The precise pathophysiology is unknown, but many models have been postulated. The main components include:

  • Vasculopathy

  • Fibrosis

  • Immune system activation with autoimmunity.

The peripheral vasculopathy is treated by calcium-channel blockers and other vasodilators. Immunomodulators target the fibrosis and immune system activation. Cyclophosphamide has been demonstrated to decrease the progression of pulmonary fibrosis in early scleroderma.

Early in the course of the disease, immune system activation, endothelial-cell activation and damage, and fibroblast activation all occur. Selection and activation of a hyper-proliferative fibroblast sub-population is also implicated. These cells, which produce high levels of collagen, are over-represented in scleroderma.

Activated T-cells promote disease activity by producing pro-fibrotic cytokines. A diverse variety of cytokines is capable of inducing, in vitro, the scleroderma fibroblast phenotype of enhanced proliferation and synthetic function. Cytokines thought to be involved in the enhancement of matrix synthesis include:

  • Transforming growth factor-B

  • Leukotriene B4

  • Interleukins-1, -4, and -6

  • Type 1 interferons.

Down-regulation of cytokines involved in inhibition of growth or synthesis include:[13]

  • Interferon-gamma

  • Tumour necrosis factor-alpha

  • Fibroblast growth factor

  • Endothelial growth factor

  • Interleukin-8.

There is great interest in the development of anti-cytokine therapy for scleroderma, but there have been no successful trials to date.

Classification

The American College of Rheumatology and European League Against Rheumatism criteria for the classification of systemic sclerosis[1]

  1. These criteria are applicable to any patient considered for inclusion in a SSc study.

  2. These criteria are not applicable to patients having a systemic sclerosis-like disorder better explaining their manifestations, such as nephrogenic sclerosing fibrosis, scleredema diabeticorum, scleromyxoedema, erythromelalgia, porphyria, lichen sclerosis, graft versus host disease, and diabetic chierarthropathy. Patients with 'skin thickening sparing the fingers' are also not classified as having SSc.

  3. These criteria have been demonstrated to be more sensitive for the classification of SSc compared with the 1980 ACR classification criteria, particularly for early SSc patients.[2][3]

Criteria : add the maximum weight (score) in each of the following categories to calculate the total score. Patients having a total score of 9 or more are classified as having definite systemic sclerosis. Patients having a total score of 6-8 can be considered as having probable scleroderma, although this classification has not been evaluated.

  • Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (9)

  • Skin thickening of the fingers (only count the highest score)

    • puffy fingers (2)

    • whole finger, distal to MCP (4)

  • Finger tip lesions (only count the highest score)

    • digital tip ulcers (2)

    • pitting scars (3)

  • Telangiectasia (2)

  • Abnormal nail-fold capillaries (2)

  • Pulmonary arterial hypertension and/or interstitial lung disease (2)

  • Raynaud’s phenomenon (3)

  • Scleroderma-related antibodies (any of anticentromere, anti-topoisomerase I [anti-Scl 70], anti-RNA polymerase III) (3)

Definitions of the SSc classification criteria items[1]

  • Skin thickening: skin thickening or hardening not due to scarring after injury, trauma, etc.

  • Puffy fingers: swollen digits - a diffuse, usually non-pitting increase in soft tissue mass of the digits extending beyond the normal confines of the joint capsule. Normal digits are tapered distally with the tissues following the contours of the digital bone and joint structures. Swelling of the digits obliterates these contours. Not due to other reasons such as inflammatory dactylitis.

  • Finger tip ulcers or pitting scars: ulcers or scars distal to or at the PIP joint not thought to be due to trauma. Digital pitting scars are depressed areas at digital tips as a result of ischaemia, rather than trauma or exogenous causes.

  • Telangiectasia: telangiectasias in a scleroderma like pattern are round and well demarcated, and found on hands, lips, inside of the mouth, and/or large matt-like telangiectasias. Telangiectasias are visible macular, dilated, superficial blood vessels, which collapse upon pressure and fill slowly when pressure is released. They are distinguishable from rapidly filling spider angiomas with central arteriole and from dilated superficial vessels.

  • Abnormal nail-fold capillary pattern consistent with SSc: enlarged capillaries and/or capillary loss with or without peri-capillary hemorrhages at the nail-fold and may be seen on the cuticle.

  • Pulmonary arterial hypertension: pulmonary arterial hypertension diagnosed by right heart catheterisation, according to standard definitions.

  • Interstitial lung disease: pulmonary fibrosis on high-resolution CT or chest radiograph, most pronounced in the basilar portions of the lungs, or presence of 'velcro' crackles on auscultation not due to another cause, such as congestive heart failure.

  • Raynaud’s phenomenon: self-report or reported by a physician with at least a 2-phase colour change in finger(s) and often toe(s); consisting of pallor, cyanosis, and/or reactive hyperaemia in response to cold exposure or emotion; usually one phase is pallor.

  • Scleroderma-specific antibodies: anticentromere antibody or centromere pattern on antinuclear antibody (ANA) testing; anti-topoisomerase I antibody (anti-Scl70 antibody); or anti-RNA polymerase III antibody. Positive, according to local laboratory standards.

LeRoy classification of scleroderma according to extent of skin involvement[4]

  • Diffuse cutaneous systemic sclerosis: skin thickening on the proximal extremities or the trunk in addition to face and distal extremities.

  • Limited cutaneous systemic sclerosis: skin thickening confined to sites distal to the elbows and knees, but can also involve the face.

  • Sine scleroderma: characteristic internal organ involvement along with vascular and serological abnormalities, but without clinically detectable skin thickening; estimated to constitute <5% of all cases.

Use of this content is subject to our disclaimer