Scleroderma
Scleroderma, also known as systemic sclerosis, is a chronic, multisystem autoimmune connective tissue disease characterized by excessive fibrosis, vascular abnormalities, and immune system dysregulation. The pathogenesis involves an interplay of genetic predisposition, environmental triggers, and immune-mediated injury leading to fibroblast activation and overproduction of collagen and other extracellular matrix components. This results in progressive thickening and hardening of the skin and, in many cases, internal organs such as the lungs, heart, gastrointestinal tract, and kidneys. The disease process is marked by microvascular damage, chronic inflammation, and widespread tissue fibrosis, which collectively contribute to significant morbidity and increased mortality. Health impacts include skin changes, digital ulcers, Raynaud phenomenon, joint contractures, pulmonary arterial hypertension, interstitial lung disease, gastrointestinal dysmotility, and renal crisis, all of which can severely impair quality of life and functional status.
Limited cutaneous systemic sclerosis is characterized by fibrosis and thickening of the skin restricted to the distal extremities (below the elbows and knees) and face. Patients often present with longstanding Raynaud phenomenon before other symptoms develop. The limited form is associated with a relatively slower disease progression and a higher prevalence of anticentromere antibodies. Visceral involvement may occur, particularly pulmonary arterial hypertension and gastrointestinal complications, but is typically less severe and develops later than in the diffuse form.
Diffuse cutaneous systemic sclerosis involves more widespread skin thickening, including the trunk and proximal limbs, and is associated with a higher risk of early and severe internal organ involvement. This subtype progresses more rapidly and is often accompanied by interstitial lung disease, scleroderma renal crisis, and cardiac manifestations. Anti-topoisomerase I (Scl-70) antibodies are more commonly detected in this group. The diffuse form is generally associated with a worse prognosis due to aggressive visceral fibrosis.
Sine scleroderma is a rare variant characterized by the absence of clinically apparent skin thickening despite evidence of internal organ involvement and serological markers typical of systemic sclerosis. Patients may develop vascular and fibrotic complications affecting the lungs, gastrointestinal tract, or kidneys, and diagnosis relies heavily on laboratory and imaging findings rather than cutaneous symptoms.
Localized scleroderma is a distinct entity from systemic sclerosis and primarily affects the skin and subcutaneous tissues without systemic organ involvement. Morphea presents as circumscribed, indurated plaques, while linear scleroderma manifests as linear bands of skin thickening, often affecting underlying muscle or bone. Although less likely to cause life-threatening complications, localized forms can result in significant cosmetic and functional impairment, particularly in children.
Scleroderma is a rare disease with an estimated annual incidence of 10–20 cases per million and a prevalence ranging from 50 to 300 cases per million, varying by region and population. The condition predominantly affects women, with a female-to-male ratio of approximately 4:1, and most commonly manifests between the ages of 30 and 50 years. Although it can occur in all ethnic groups, certain populations demonstrate higher frequencies or distinct clinical features. Limited cutaneous systemic sclerosis is more prevalent than the diffuse form. Mortality is increased compared to the general population, with pulmonary, cardiac, and renal complications being the leading causes of death. Survival rates have improved over recent decades, but the overall prognosis remains guarded, particularly for those with early visceral involvement.
The diagnosis of scleroderma is based on a combination of clinical evaluation, serological testing, and imaging studies. The 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria are widely utilized and incorporate features such as skin thickening of the fingers (proximal to the metacarpophalangeal joints), fingertip lesions (ulcers or pitting scars), telangiectasia, abnormal nailfold capillaries, Raynaud phenomenon, specific autoantibodies (anticentromere, anti-topoisomerase I, anti-RNA polymerase III), and evidence of interstitial lung disease or pulmonary arterial hypertension. Laboratory evaluation includes antinuclear antibody (ANA) testing and more specific autoantibody panels. Nailfold capillaroscopy is useful for assessing microvascular changes. High-resolution computed tomography (HRCT) of the chest, echocardiography, pulmonary function tests, and gastrointestinal studies are employed to evaluate organ involvement. Biopsy of affected tissue may be performed in atypical cases. Early and accurate diagnosis is essential for risk stratification, monitoring, and management.
Intedanib, also known as nintedanib, is utilized in the treatment of scleroderma-associated interstitial lung disease, acting as a tyrosine kinase inhibitor to slow the decline in pulmonary function. Bosentan is an endothelin receptor antagonist indicated for the management of pulmonary arterial hypertension related to scleroderma, helping to improve exercise capacity and delay clinical worsening. Rituximab, a monoclonal antibody targeting CD20-positive B cells, is employed as an immunomodulatory agent in scleroderma to reduce immune-mediated tissue damage and fibrosis. Mycophenolate mofetil is an immunosuppressive medication used to treat scleroderma, particularly for skin and lung involvement, by inhibiting lymphocyte proliferation and modulating the autoimmune response. Aminobenzoate potassium, a salt of para-aminobenzoic acid, is administered as an antifibrotic agent in scleroderma to help reduce the progression of tissue fibrosis and improve skin flexibility.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | intedanib; nintedanib (USAN) | 656247-17-5 | C31 H33 N5 O4 | 539.625 |
 | bosentan (Rec INN; USAN; JAN) | 147536-97-8 | C27 H29 N5 O6 S | 551.614 |
| rituximab (Prop INN; USAN) | 174722-31-7 | |||
 | mycophenolate mofetil (USAN; BAN) | 128794-94-5 | C23 H31 N O7 | 433.495 |
 | aminobenzoate potassium; para-aminobenzoic acid potassium salt (USAN) | 138-84-1 | C7 H6 N O2 . K | 175.226 |
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