Epidemiology of organic solvents and connective tissue disease

Case reports suggest that solvents are associated with various connective tissue diseases (systemic sclerosis, scleroderma, undifferentiated connective tissue disease, systemic lupus erythematosis, and rheumatoid arthritis), particularly systemic sclerosis. A small number of epidemiological studies have shown statistically significant but weak associations between solvent exposure, systemic sclerosis, and undifferentiated connective tissue disease. However, the interpretation of these positive findings is tempered by a lack of replication, an inability to specify which solvents convey risk, and an absence of increasing risk with increasing exposure. Existing studies, on aggregate, do not show conclusively that solvents (either as a group of chemicals or individual chemicals) are causally associated with any connective tissue disease. Further investigations should be carried out to replicate the positive existing findings and to specify the solvents and circumstances of exposure that carry risk.     

Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant.

The lupus anticoagulant was found in the plasma of 31 of 60 patients with systemic lupus erythematosus and other connective tissue disorders (mixed connective tissue disease, systemic vasculitis, polyarteritis nodosa, primary sicca syndrome, discoid lupus, Behcet''s syndrome, and systemic sclerosis). Strong associations were found with biological false positive seroreaction for syphilis and thrombocytopenia. The most striking association, however, was with the high prevalence of thrombosis. This tendency to thrombosis was independent of disease activity of systemic lupus erythematosus. The lupus anticoagulant appears to be a useful marker for a subset of patients with systemic lupus erythematosus at risk for the development of thromboembolic complications.     

Risk of connective tissue disease and related disorders among women with breast implants: a nation-wide retrospective cohort study in Sweden.

OBJECTIVE: To examine the relation between connective tissue disease and related conditions and breast implants. DESIGN: Retrospective cohort study of all women in the Swedish national inpatient registry who underwent breast augmentation surgery with artificial implants during 1964-93, compared with women who underwent breast reduction surgery during the same period. SETTING: Sweden. SUBJECTS: 7442 women with implants for cosmetic reasons or for reconstruction after breast cancer surgery and 3353 women with breast reduction surgery. MAIN OUTCOME MEASURES: Subsequent hospitalisation for definite connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, and Sjögren''s syndrome) or related disorders. RESULTS: 29 women with implants were hospitalised for definite connective tissue disease compared with 25.5 expected based on general population rates (standardised hospitalisation ratio 1.1 (95% confidence interval 0.8 to 1.6)). There were no diagnoses of systemic sclerosis, and no significant excess in risk for polymyalgia rheumatica, fibromyalgia, and several related disorders. Among women who underwent breast reduction surgery, 14 were hospitalised for definite connective tissue disease compared with 10.5 expected (standardised hospitalisation ratio 1.3 (0.7 to 2.2)). Compared with the breast reduction group, women with breast implants showed a slight reduction for all definite connective tissue disease (relative risk 0.8 (95% confidence interval 0.5 to 1.4)). CONCLUSIONS: This large nationwide cohort study shows no evidence of association between breast implants and connective tissue disease.     

Association between the CTGF -945C/G polymorphism and systemic sclerosis: A meta-analysis

BACKGROUND: The -945C/G polymorphism of the connective tissue growth factor (CTGF) has been associated with systemic sclerosis, however, results were conflicted. The aim of this study was to validate the evidence for the CTGF -945C/G polymorphism and systemic sclerosis risk. METHODS: Electronic search of PubMed was conducted to select studies. Case-control studies containing available genotype frequencies of -945C/G were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association. RESULTS: Six published case-control studies including 3335 cases and 3589 controls were identified. The overall results suggested that the variant genotypes were not associated with the systemic sclerosis risk (OR=0.947, 95% CI: 0.792-1.132, p=0.55). The stratified analysis in Caucasian (OR=1.002, 95% CI: 0.837-1.2, p=0.788) did not suggest an association either. However, analysis in Asian (OR=0.632, 95% CI: 0.459-0.869, p=0.005) showed that CC/CG genotype greatly decreased the susceptibility of systemic sclerosis in a dominant model. Asymmetric funnel plot, the Egger's test (p=0.292), and the Begg's test (p=0.593) were all suggestive of the lack of publication bias. CONCLUSION: This meta-analysis supports that CC/CG genotype greatly decreased the susceptibility of systemic sclerosis in Asian. Due to the limited samples in subpopulations, further prospective studies with larger number of participants worldwide are needed to examine the association between the CTGF -945C/G polymorphism and systemic sclerosis.     

Clinical relevance of autoantibodies in systemic rheumatic diseases

Autoantibodies directed to intracellular antigens are serological hallmarks of systemic rheumatic diseases. Identification of circulating autoantibodies is helpful in establishing the correct diagnosis, indicating the prognosis and providing a guide to treatment and follow-up. Some autoantibodies are included in diagnostic and classification criteria for diseases such as anti-Sm antigen and anti-double-stranded DNA antibodies in systemic lupus erythematosus, anti-U1 nuclear ribonucleoprotein antibodies in mixed connective tissue disease, and anti-SS-A/Ro and anti-SS-B/La antibodies in Sjögren's syndrome. Over the past 30 years, the identification of new autoantibody systems was advanced by the initiation or adaptation of novel techniques such as double immunodiffusion to detect antibodies to saline-soluble nuclear antigens, extraction-reconstitution and ELISA techniques to detect histone and chromatin antibodies, immunoblotting and immunoprecipitation to detect a wide range of antibodies directed against naturally occurring and recombinant proteins. These techniques have been made possible by advances in cellular and molecular biology and in turn, the sera from index patients have been important reagents to identify novel intracellular macromolecules. This paper will focus on the clinical relevance of several autoantibody systems described by Tan and his colleagues over the past 30 years.Abbreviations ANA antinuclear antibody - CENPs centromere proteins - CTD connective tissue disease - DIA drug-induced autoimmunity - DIL drug-induced lupus - HIV human immunodeficiency virus - IIF indirect immunofluorescence - JCA juvenile chronic arthritis - MCTD mixed connective tissue disease - MSA mitotic spindle apparatus - NOR nucleolar organizer - NuMA nuclear mitosis antigen - PBC primary biliary cirrhosis - PCNA proliferating cell nuclear antigen - PM polymyositis - RA rheumatoid arthritis - RNP ribonucleoprotein - SLE systemic lupus erythematosus - SS Sjögren's syndrome - SSc systemic sclerosis - UCTD undifferentiated connective tissue disease     

Immunopathologic effects of silicone breast implants.

Silicone-gel breast implants have been associated with a myriad of autoimmune and connective tissue disorders by anecdotal reports and small observational series. To date, no prospective epidemiologic studies have been done to substantiate these observations, but an increasing body of literature is being developed and older studies are being recognized that point to immunotoxic or inflammatory effects of these breast implant components. The development of disease due to implants would depend on the interaction of genetic host factors so that only a few patients would potentially be at risk. Based on the example of other chemically mediated disorders, such as scleroderma in association with silica exposure, latency periods of more than 30 years before disease develops may be possible. Herein we review studies on silicone and immunity.     

The clinical relevance of autoantibodies in scleroderma

Scleroderma (systemic sclerosis) is associated with several autoantibodies, each of which is useful in the diagnosis of affected patients and in determining their prognosis. Anti-centromere antibodies (ACA) and anti-Scl-70 antibodies are very useful in distinguishing patients with systemic sclerosis (SSc) from healthy controls, from patients with other connective tissue disease, and from unaffected family members. Whereas ACA often predict a limited skin involvement and the absence of pulmonary involvement, the presence of anti-Scl-70 antibodies increases the risk for diffuse skin involvement and scleroderma lung disease. Anti-fibrillarin autoantibodies (which share significant serologic overlap with anti-U3-ribonucleoprotein antibodies) and anti-RNA-polymerase autoantibodies occur less frequently and are also predictive of diffuse skin involvement and systemic disease. Anti-Th/To and PM-Scl, in contrast, are associated with limited skin disease, but anti-Th/To might be a marker for the development of pulmonary hypertension. Other autoantibodies against extractable nuclear antigens have less specificity for SSc, including anti-Ro, which is a risk factor for sicca symptoms in patients with SSc, and anti-U1-ribonucleoprotein, which in high titer is seen in patients with SSc/systemic lupus erythematosus/polymyositis overlap syndromes. Limited reports of other autoantibodies (anti-Ku, antiphospholipid) have not established them as being clinically useful in following patients with SSc.     

Effects of maternal occupational exposure to organic solvents on offspring visual functioning: a prospective controlled study

BACKGROUND: Previous studies in adults and animals with high level exposure to organic solvents suggested impairments in visual functioning. The objective of this pilot study was to examine the effects of maternal occupational exposure to organic solvents during pregnancy on offspring color vision and visual acuity, the development of which may be especially vulnerable to organic solvent exposure. METHODS: We conducted a prospective cohort study of 32 offspring of women who were exposed occupationally to organic solvents during pregnancy compared with 27 nonexposed children. Monocular and binocular color vision and visual acuity were assessed using the Minimalist Test and the Cardiff Cards, respectively. Children with known hereditary color vision loss were excluded. RESULTS: Solvent-exposed children had significantly higher error scores on red-green and blue-yellow color discrimination, as well as poorer visual acuity compared with the control group. Exposure index (an estimated measure of exposure intensity) was not significantly related to color discrimination or visual acuity score. Despite excluding all children with a known family history of color vision loss, clinical red-green color vision loss was found among 3 of the 32 exposed children compared with none of the matched controls. CONCLUSIONS: These preliminary findings suggest that occupational exposure to organic solvents during pregnancy is associated with an increased risk of color vision and visual acuity impairment in offspring. The importance of routine visual function screening in risk assessment after prenatal exposure to chemicals warrants further attention.     

Myeloid calcium binding proteins: expression in the differentiated HL-60 cells and detection in sera of patients with connective tissue diseases

A differentiation antigen induced in 1,25-dihydroxyvitamin D3 (VD3)-treated HL-60 cells was identified as being comprised of the myeloid calcium binding proteins CaBP-p8 and -p14 by determining its amino acid and DNA sequence. Northern blot analysis using a DNA fragment of the gene encoding p14 as a probe indicated that the gene was not expressed in undifferentiated HL-60 cells but transcribed starting on day 1 after VD3 treatment. The level of p 14 mRNA reached a peak on day 2, then declined, and little mRNA remained on day 10, indicating that the p14 gene is activated once and then inactivated during HL-60 differentiation due to VD3. In contrast, thymidylate synthase (TSase) mRNA was present in undifferentiated HL-60 cells but disappeared quickly after VD3 treatment. Both p8 and p14 of CaBP were found at elevated levels in sera of some patients with connective tissue diseases [highly elevated in rheumatoid arthritis (RA), Sjogren's syndrome (SjS), systemic lupus erythematosus (SLE), and progressive systemic sclerosis (PSS), and moderately in polymyositis or dermatomyositis (PM/DM) and mixed connective tissue disease (MCTD)]. These results were in sharp contrast with the finding that p14 is always at a highly elevated level but little p8 is present in the sera of cystic fibrosis (CF) patients [Bruggen et al. (1988) Nature 331, 570).     

Genetic epidemiology: systemic sclerosis

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised phenotypically by fibrosis and ischaemic atrophy. Its aetiology is most likely multifactorial. A genetic predisposition to the condition is suggested by reports of familial SSc (a positive family history is the strongest risk factor yet identified), by animal models, and by disease-association studies, in which researchers have examined a wide variety of genes including those involved in fibrosis, in vascular function and structure, and in autoimmunity - the relative rarity of SSc has precluded linkage studies, except in the Choctaw Indians. Recent advances in genetic methodologies should further our understanding of this complex disease process.     

Vitamin D or hormone D deficiency in autoimmune rheumatic diseases,including undifferentiated connective tissue disease

Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of autoimmune diseases. The presence of vitamin D receptors in the cells of the immune system and the fact that several of these cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties, and now potent immuno-mudulatory activities on dendritic cells, Th1 and Th17 cells, as well as B cells have been confirmed. Patients with undifferentiated connective tissue disease also show vitamin D deficiency and, interestingly, patients who progress into connective tissue diseases have lower vitamin D levels than those who remain in the undifferentiated connective tissue disease stage.     

Studies on precipitating and hemagglutinating antibodies in systemic lupus erythematosus

We studied the precipitating and hemagglutinating autoantibodies in the sera of patients with various connective tissue diseases in general and lupus in particular. Saline soluble extract of goat thymus had adequate antigenic materials as compared to other organs. Twenty per cent of patients with systemic lupus erythematosus were positive for precipitating autoantibodies by immunodiffusion and 44% by counterimmunoelectrophoresis. Normal human subjects, nonrheumatic disease patients and patients with rheumatoid arthritis and progressive systemic sclerosis were all negative. Forty seven per cent of positive systemic lupus erythematosus sera showed two precipitin systems. Enzyme sensitivities were used as the basis of identification of most of the antigenic specificities. Passive hemagglutination was carried out to identify antibodies to non-histone nuclear protein and nuclear ribonucleo-protein antigens. Thirty eight % of systemic lupus erythematosus patients were positive by this technique. Passive hemagglutination although a highly sensitive technique could not detect antibodies against antigenic systems other than non-histone nuclear protein and nuclear ribonucleoprotein.     

Blisters on your fingers

Mesenchymal progenitor cells play a key role in fibrogenesis. An exciting paper was recently published showed that blister fluid from the skin patients with the autoimmune connective tissue disease scleroderma (systemic sclerosis, SSc) preferentially activated mesenchymal progenitor cells (Taki et al. in Arthritis Rheumatol 72(8):1361–1374, 2020). These data provide new and invaluable insights into the complex interactions in the connective tissue microenvironment that ultimately result in persistent, pathological fibrosis.     

Helicobacter pylori infection in connective tissue disorders is associated with high levels of antibodies to mycobacterial hsp65 but not to human hsp60

Background. To investigate whether the Helicobacter pylori status influences levels of antibodies against mycobacterial heat shock protein (hsp) 65 and human hsp60 in systemic autoimmune diseases and to study the concentration of anti‐H. pylori antibodies in autoimmune patients and healthy controls. Materials and Methods. Antibodies against human heat‐shock protein hsp60, mycobacterial heat‐shock protein hsp65 were analyzed by ELISA. Anti‐Helicobacter antibodies were determined by enzyme immunoassay. Results. There was a markedly higher prevalence of H. pylori infection in undifferentiated connective tissue disease (82%) (n = 33) and systemic sclerosis (78%) (n = 55) but not in systemic lupus erythematosus (n = 49), polymyositis/dermatomyositis (n = 14), rheumatoid arthritis (n = 21) or primary Raynaud's syndrome (n = 26) compared with controls (59%) (n = 349). In autoimmune diseases H. pylori infection was associated with elevated levels of antihsp65 (p = .008) but not of antihsp60. Anti‐hsp65 levels were significantly higher in H. pylori‐infected (n = 129) than in uninfected patients (n = 69) (p = .0007). Conclusions. These findings indicate that in autoimmune diseases the infection with the H. pylori bacterium is associated with increased concentration of antimycobacterial hsp65.     

Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions

Fibrosis, characterized by excessive extracellular matrix accumulation, is a common feature of many connective tissue diseases, notably scleroderma (systemic sclerosis). Experimental studies suggest that a complex network of intercellular interactions involving endothelial cells, epithelial cells, fibroblasts and immune cells, using an array of molecular mediators, drives the pathogenic events that lead to fibrosis. Transforming growth factor-beta and endothelin-1, which are part of a cytokine hierarchy with connective tissue growth factor, are key mediators of fibrogenesis and are primarily responsible for the differentiation of fibroblasts toward a myofibroblast phenotype. The tight skin mouse (Tsk-1) model of cutaneous fibrosis suggests that numerous other genes may also be important.     

Protection against fine particle-induced pulmonary and systemic inflammation by omega-3 polyunsaturated fatty acids

BackgroundExposure to fine particulate matter, such as through air pollution, has been linked to the increased incidence of chronic diseases. However, few measures have been taken to reduce the health risks associated with fine particle exposure. The identification of safe and effective methods to protect against fine particle exposure-related damage is urgently needed.MethodsWe used synthetic, non-toxic, fluorescent fine particles to investigate the physical distribution of inhaled fine particles and their effects on pulmonary and systemic inflammation in mice. Tissue levels of omega-3 fatty acids were elevated via dietary supplementation or the fat-1 transgenic mouse model. Markers of pulmonary and systemic inflammation were assessed.ResultsWe discovered that fine particulate matter not only accumulates in the lungs but can also penetrate the pulmonary barrier and travel into other organs, including the brain, liver, spleen, kidney, and testis. These particles induced both pulmonary and systemic inflammation and increased oxidative stress. We also show that elevating tissue levels of omega-3 fatty acids was effective in reducing fine particle-induced inflammation, whether as a preventive method (prior to exposure) or as an intervention (after exposure).ConclusionsThese results advance our understanding of how fine particles contribute to disease development and suggest that increasing tissue omega-3 levels may be a promising nutritional means for reducing the risk of diseases induced by particle exposure.General significanceOur findings demonstrate that elevating tissue omega-3 levels can prevent and treat fine particle-induced health problems and thereby present an immediate, practical solution for reducing the disease burden of air pollution.     

Vasculitis: mechanisms involved and clinical manifestations

Systemic vasculitis, an inflammatory necrotizing disease of the blood vessel walls, can occur secondary to autoimmune diseases, including connective tissue diseases. Various pathogenic mechanisms have been implicated in the induction of vasculitis, including cell-mediated inflammation, immune complex-mediated inflammation and autoantibody-mediated inflammation. This inflammatory activity is believed to contribute to accelerated atherosclerosis, and also leads to increased risk for cardiovascular events in patients with rheumatoid arthritis and systemic lupus erythematosus. Endothelial cell activation is a common pathogenic pathway in the systemic vasculitis associated with rheumatoid arthritis and systemic lupus erythematosus, with elevated levels of endothelin-1 potentially inducing vascular dysregulation.     

A review of psychological outcomes and suicide in aesthetic breast augmentation

Aesthetic surgery is an essential component of plastic surgery and has become increasingly popular in American society. In 2002, 1.8 million surgical cosmetic procedures were performed in the United States, representing a 294 percent increase from 1992. The 1992 U.S. Food and Drug Administration moratorium on silicone breast implants arose in response to numerous reports of connective tissue disease associated with silicone gel breast augmentation and has led to a decade-long battle over the safety of silicone breast implants that continues today. Numerous scientific and epidemiologic studies of the past decade have established that there is no association between silicone breast prostheses and systemic disease. Recently, a new front has opened in the conflict regarding the safety of breast augmentation: the psychological impact of breast augmentation. Quality studies assessing the psychological characteristics of breast augmentation patients and the psychological impact of breast augmentation surgery are few and most studies are flawed in their methods. Recent reports have provided corroborating evidence to support the psychological benefits of cosmetic surgery and breast augmentation. New reports citing an increased risk for suicide among women with breast implants have brought renewed concerns but are unable to demonstrate a cause-and-effect relationship between breast implants and suicide. The present challenge is to determine whether the increased risk reported in epidemiologic studies is falsely associated with breast implants or whether it represents underlying risk factors or psychopathology in women undergoing breast augmentation that puts them at increased risk for suicide. The purpose of this article is to review the literature regarding the psychological impact of breast augmentation and assesses current scientific findings, with emphasis on the validity of suicide risk in breast augmentation patients.     

Noise-Induced Hearing Loss in Korean Workers: Co-Exposure to Organic Solvents and Heavy Metals in Nationwide Industries

Background

Noise exposure is a well-known contributor to work-related hearing loss. Recent biological evidence suggests that exposure to ototoxic chemicals such as organic solvents and heavy metals may be additional contributors to hearing loss. However, in industrial settings, it is difficult to determine the risks of hearing loss due to these chemicals in workplaces accompanied by excessive noise exposure. A few studies suggest that the effect of noise may be enhanced by ototoxic chemicals. Therefore, this study investigated whether co-exposure to organic solvents and/or heavy metals in the workplace modifies the risk of noise exposure on hearing loss in a background of excessive noise.

Methods

We examined 30,072 workers nationwide in a wide range of industries from the Korea National Occupational Health Surveillance 2009. Data on industry-based exposure (e.g., occupational noise, heavy metals, and organic solvents) and subject-specific health outcomes (e.g., audiometric examination) were collected. Noise was measured as the daily 8-h time-weighted average level. Air conduction hearing thresholds were measured from 0.5 to 6 kHz, and pure-tone averages (PTA) (i.e., means of 2, 3, and 4 kHz) were computed.

Results

In the multivariate linear model, PTA increment with occupational noise were 1.64-fold and 2.15-fold higher in individuals exposed to heavy metals and organic solvents than in unexposed individuals, respectively.

Conclusion

This study provides nationwide evidence that co-exposure to heavy metals and/or organic solvents may exacerbate the effect of noise exposure on hearing loss in workplaces. These findings suggest that workers in industries dealing with heavy metals or organic solvents are susceptible to such risks.     

Systemic sclerosis: new insights in autoimmunity.

The strong female predilection of systemic sclerosis, especially in women after their childbearing years, and the clinical and histopathological similarities with chronic graft-versus-host disease make systemic sclerosis an interesting subject of debate. Recent studies concerning the pathogenesis of this disease demonstrated the persistence of fetal cells in the maternal circulation in a majority of female patients. How or whether microchimerism is involved in the pathogenesis of systemic sclerosis remains to be elucidated. The present paper reviews the recent findings on the subject.