Systemic scleroderma

Mehlhorn, J. et al., Analysis for the association between progressive systemic scleroderma, exposure to quartz dust, and silicosis in East German uranium mining, Zbl. Arbeitsmed., 49, 134, 1999. 

Hahne T, Baida BR. Fingerkuppennekrosen nach Dihydroergotaminmedikation bei hmitierter systemischer Sklerodermie. [Finger tip necroses after dihydroergotamine medication in limited systemic scleroderma.] Hautarzt 1998 49(9) 722-4. 

A few examples of animal models used in immunotoxicologic testing of drugs include Brown Norway rat and Lewis rat models, which are described in detail below. Other established mouse models of autoimmune diseases, e.g.,systemic lupus erythematosus, collagen-induced arthritis,pristane-induced arthritis and systemic scleroderma, may be considered for potential application in immunotoxicology evaluation. 

The definition of an overlap syndrome dictates that the criteria for diagnosis of both disorders (in the present context, of PM/DM and of some other connective tissue disorder), are fulfilled. It is not unexpected that those syndromes which overlap with PM/DM are also either known autoimmune conditions or ones in which an autoimmune basis is strongly suspected. The association of these disorders with PM/DM syndromes may not materially alter the basic histopathological featmes expected in PM/DM but some differences may be identifiable. The disorders most frequently associated with an overlap syndrome are rheumatoid arthritis, systemic lupus erythematosis, scleroderma, and mixed connective tissue disease. 

Deletions in the elastin gene (located at 7qll.23) have been found in approximately 90% of subjects with Williams syndrome, a developmental disorder affecting connective tissue and the central nervous system. The mutations, by affecting synthesis of elastin, probably play a causative role in the supravalvular aortic stenosis often found in this condition. A number of skin diseases (eg, scleroderma) are associated with accumulation of elastin. Fragmentation or, alternatively, a decrease of elastin is found in conditions such as pulmonary emphysema, cutis laxa, and aging of the skin. 

Systemic lupus erythematosus Scleroderma Sleep apnea Drugs ... 

Preexisting collagen-vascular diseases (e.g., scleroderma and systemic lupus erythematosus)... 

It has been shown that lung macrophages from patients with systemic sclerosis (SS) produced the elevated levels of nitric oxide, superoxide, and peroxynitrite and expressed the enhanced level of iNOS [281], NAC administration reduced peroxynitrite production and might be possibly recommended for the treatment SS patients. Solans et al. [282] found the significant enhancement of lipid peroxidation in erythrocytes from SS patients. Cracowski et al. [283] showed that in vivo lipid peroxidation was enhanced in scleroderma spectrum disorders including SS and undifferentiated connective tissue disease. 

A recent report by the National Institutes of Health estimated that at 14 to 22 million people in the United States are affected by an autoimmune disease.1 As a group, these diseases represent a leading cause of death among women under age 65, with systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes being the major sources of this impact on mortality.2 The autoimmune thyroid diseases, type 1 diabetes and rheumatoid arthritis are the most common of the autoimmune diseases (Table 25.1).3-5 Most autoimmune diseases disproportionately affect women. In the thyroid diseases, primary biliary cirrhosis, scleroderma, systemic lupus erythematosus, and Sjogren s syndrome, more than 85% of patients are female, but it is not known why the female predominance is so high in these specific diseases. 

For some autoimmune diseases, little is known about environmental factors involved in the initiation or progression of the disease. For other diseases, however, considerable research has been conducted on one or more types of exposures. Most epidemiologic studies of environmental influences have focused on multiple sclerosis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, and small vessel vasculitis, but experimental studies using murine models of these diseases is limited (Table 25.1). 

Occupational exposure to silica dust has been identified as a risk factor for several systemic autoimmune diseases. This literature dates back almost 100 years, to the description by Bramwell of diffuse scleroderma in stone masons.26 Rheumatoid arthritis and scleroderma in miners were described in the 1950s, and more formal cohort studies of miners and of granite workers were conducted in the 1980s. Other studies focusing on silicosis patients, and several case-control studies of these diseases and of Wegner... 

Toxicology. Occupational exposure to vinyl chloride is associated with an increased incidence of angiosarcoma of the liver and other malignant tumors, acroosteolysis, Raynaud syndrome, scleroderma, thromhocytopenia, circulatory dismrbances, and impaired liver function. Very high concentrations cause central nervous system (CNS) depression. 

Autoimmune disease There have been rare reports of various autoimmune diseases (eg, scleroderma, systemic lupus erythematosus, rheumatoid arthritis) in... 

Agranulocytosis and neutropenia maybe noted in those with collagen vascular disease, including scleroderma and systemic lupus erythematosus, and impaired renal function. 

The effectiveness of immunosuppressive drugs in autoimmune disorders varies widely. Nonetheless, with immunosuppressive therapy, remissions can be obtained in many instances of autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes, Hashimoto s thyroiditis, and temporal arteritis. Improvement is also often seen in patients with systemic lupus erythematosus, acute glomerulonephritis, acquired factor VIII inhibitors (antibodies), rheumatoid arthritis, inflammatory myopathy, scleroderma, and certain other autoimmune states. 

The administration of glucocorticoids should be undertaken with caution in progressive systemic sclerosis and the concomitant administration of anticoagulants to prevent scleroderma renal crisis is recommended when administering glucocorticoids in high doses, especially by pulse therapy (SEDA-21, 415 150). 

Yamanishi Y, Yamana S, Ishioka S, Yamakido M. Development of ischemic colitis and scleroderma renal crisis following methylprednisolone pulse therapy for progressive systemic sclerosis. Intern Med 1996 35(7) 583-6. 

Autoimmune responses seem to be the underlying basis for a number of diseases, including rheumatoid arthritis, diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, scleroderma, polymyositis/der-matomyositis, and several other disorders.25,27,44 As indicated previously, it is not exactly clear what factors cause autoimmune responses, as well as why certain individuals are more prone to autoimmune-related diseases. Nonetheless, drugs that suppress the immune system can limit damage to various other tissues, and these drugs may produce dramatic improvements in patients with diseases that are caused by an autoimmune response. 

Scleroderma is a progressive systemic sclerosis with a multisystem connective tissue disease. A number of industrial chemicals have been implicated as causative factors in human scleroderma. Industrial chemicals (e.g., toluene, benzene, xylene, aromatic mixers or white spirit, vinyl chloride, trichloroethylene, perchloroethylene, naphtha-n-hexane, epoxy resins,... 

Although there are reports of associations between exposure to organic solvents and various connective tissue diseases, such as systemic sclerosis, scleroderma, undifferentiated connective tissue disease, systemic lupus erythematosus, and rheumatoid arthritis, the evidence of a causal association is weak (44). 

Hietaharju A, Jantti V, Korpela M et al. (1993). Nervous system involvement in systemic lupus erythematus, Sjogren syndrome and scleroderma. Acta Neurology Scandinavica 88 299-308... 

The connective tissue disorders comprise a unique family of systemic diseases that have distinctive yet nonspecific systemic manifestations associated with organ involvement. Such diseases as rheumatoid arthritis (RA), rheumatic fever, systemic lupus erythematosus (SEE), scleroderma, and periarteritis nodosa all demonstrate the typical histologic and clinical findings characteristic of this category of diseases. 

The most common types of arthritis in the UK are osteoarthritis (UK prevalence 23%) and rheumatoid arthritis (1%). The less common t3 es of inflammatory arthritis include juvenile idiopathic arthritis spondylarthritis (ankylosing spondylitis, Reiter s syndrome, psoriatic arthritis, arthritis associated with inflammatory bowel disecise) and reactive arthritis associated with infection. Joint pains (arthralgia) are common in many other diseases, for example the connective tissue diseases (systemic lupus erythematosus, scleroderma), endocrine conditions (hypo-and h5 erthyroidism) and malignancies, but in these, joint inflammation and damage do not usually occur. 

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