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Sjogren's Syndrome, Systemic Sclerosis & Mixed Connective Tissue Disease

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Pathophysiology

Summary

Sjogren syndrome is an autoimmune disorder that disproportionately affects women (9:1). The most distinguishing clinical symptoms are keratoconjunctivitis sicca, xerostomia. The onset of the disorder is usually precipitated by factors like infections or genetic mutations that lead to damage in exocrine glands, resulting in exposure to self-antigens that activate self-reactive lymphocytes, initiating the autoimmune process.

The pathogenesis involves a combined immune response from both T-cells and B cells against these self-antigens, leading to significant inflammation in the affected tissues. Key serological markers include anti-SSA (Ro) & anti-SSB (La) antibodies, though these antibodies are not directly responsible for tissue damage.

Histologically, Sjogren syndrome is characterized by a significant infiltration of CD4+ helper T cells & plasma cells into the salivary & lacrimal glands. This pronounced infiltration destroys normal glandular tissue, which can result in the formation of germinal centers in salivary glands—a hallmark of Sjogren syndrome. Salivary gland damage manifests as xerostomia while destruction of the lacrimal gland causes keratoconjunctivitis sicca. Xerostomia, in turn, can cause complications like ulceration, fissuring, and dental caries. Additionally, destruction of Bartholin's glands may lead to vaginal dryness, painful intercourse, and increased risk of infections.

Clinically, Sjogren syndrome often shows symptoms that overlap with other autoimmune diseases, most notably rheumatoid arthritis. A significant long-term risk associated with Sjogren syndrome is the elevated predisposition to non-Hodgkin B-cell lymphoma, due to the chronic state of lymphocytic infiltration and inflammation.

Systemic sclerosis is an autoimmune disorder that primarily affects adult women, and has two primary forms: diffuse systemic sclerosis and limited systemic sclerosis, also known as CREST syndrome. The pathogenesis is thought to stem from endothelial damage—possibly attributable to viral infections or toxins—that prompts the release of self-antigens and the formation of self-reactive lymphocytes (molecular mimicry). Subsequent endothelial damage promotes inflammation and an influx of CD4+ helper T cells, as well as the release of cytokines like IL-13 & TGF-β that stimulate fibroblasts to produce collagen. This results in fibrosis and destruction of native tissue, such as intimal fibrosis, which can lead to distal ischemic injury.

A hallmark of systemic sclerosis is skin fibrosis, resulting in stiff, thickened skin. In advanced cases, this fibrosis extends to the hands and fingers, leading to sclerodactyly. Skin biopsy often reveals perivascular CD4+ lymphocyte infiltration and widespread collagen deposition in the dermis, contributing to the skin's thickened appearance. Nodular subcutaneous calcification, or calcinosis cutis may also be present, especially in cases of limited sclerosis. Diffuse systemic sclerosis is associated with serum anti-DNA topoisomerase I (Scl-70) autoantibodies.

Limited systemic sclerosis, also known as CREST syndrome is characterized in the CREST acronym: Calcinosis cutis, Raynaud phenomenon, Esophageal hypomotility, Sclerodactyly, & Telangiectasias. Serological markers indicative of CREST syndrome are anti-centromere antibodies.

Mixed connective tissue disease (MCTD) also predominantly affects adult women and shares features of various autoimmune disorders including SLE, systemic sclerosis, rheumatoid arthritis, and more. The primary serologic marker for MCTD is anti-U1 ribonucleoprotein antibodies.

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FAQs

What are the hallmark symptoms of Sjogren's syndrome?

Sjogren's syndrome predominantly targets the lacrimal and salivary exocrine glands, leading to keratoconjunctivitis sicca, or severely dry eyes, and xerostomia, or severe dry mouth. Damage to these glands can result in corneal drying, erosion, and severe oral mucosa drying, which may further lead to dental caries and ulceration. The syndrome may also affect Bartholin's glands, causing vaginal dryness, dyspareunia, or painful intercourse, and an increased risk of urinary tract infections.

What distinguishes diffuse systemic sclerosis from limited systemic sclerosis?

Systemic sclerosis is an autoimmune disorder characterized by excessive collagen production, resulting in fibrosis and destruction of native tissue. It primarily affects adult women and may be initiated by endothelial damage from factors like viral infections or toxins. Diffuse systemic sclerosis is marked by extensive skin fibrosis, leading to skin thickening and loss of elasticity. Limited systemic sclerosis, also known as CREST syndrome, manifests with specific symptoms: Calcinosis cutis, Raynaud's phenomenon, Esophageal hypomotility, Sclerodactyly, and Telangiectasias.

Which serologic markers are indicative of Sjogren's syndrome and systemic sclerosis?

In Sjogren's syndrome, the key serologic markers are anti-SSA (Ro) and anti-SSB (La) antibodies. For systemic sclerosis, anti-DNA topoisomerase I (Scl-70) autoantibodies are associated with the diffuse systemic sclerosis, while anti-centromere antibodies are most specific to the limited systemic sclerosis, or CREST syndrome.

What systemic effects are associated with systemic sclerosis?

Systemic sclerosis has a broad impact on multiple body systems. Esophageal hypomotility and consequent dysphagia is often present as well as effects on the respiratory system like interstitial lung disease or pulmonary hypertension, both resulting from vessel narrowing and fibrosis. The kidneys are also impacted, with hypertension arising from decreased renal perfusion and activation of the renin-angiotensin-aldosterone system (RAAS).

What is mixed connective tissue disease and how is it related to other autoimmune disorders?

Mixed connective tissue disease is an autoimmune condition that shares features with multiple autoimmune disorders, including systemic lupus erythematosus (SLE), systemic sclerosis, and rheumatoid arthritis. The serologic marker for this disease is the presence of anti-U1 ribonucleoprotein antibodies. Like many other autoimmune conditions, mixed connective tissue disease predominantly affects adult women.