The Role of
Environmental Factors in Rheumatic Diseases
Daniel J. Wallace, MD
Michael H. Weisman, MD
Division of Rheumatology
Cedars-Sinai Medical Center/UCLA School of Medicine
Los Angeles, CA
Summary Points
It is difficult to know if there is any causal relationship between
environmental factors and rheumatic diseases because of the difficulty in obtaining
sufficient numbers of patients and adequate controls and defining the exposure.
There are some examples of environmental agents inducing rheumatic
diseases, including contaminated rapeseed oil causing a scleroderma-like disease and
contaminated L-tryptophan causing eosinophilic myalgia syndrome.
Ultraviolet light may trigger lupus, and smoking may aggravate or
worsen a number of rheumatic diseases.
Introduction
Rheumatic and
autoimmune disorders stem from a combination of factors. The current accepted hypothesis
is that in the presence of certain susceptibility genes, drugs, chemicals, and other
agents in the environment are thought to play inciting
Our understanding of the role of the environment has been less
successful (1). In place of scientific evidence, unsubstantiated theories of the role of
certain non-infectious environmental agents (eg, contaminated ground water causes lupus
and scleroderma) has led to costly litigation and an industry that has been called “junk
science” (2). The lack of substantiated work in this area has resulted in confusion
among organizations that advocate for
patients with rheumatic diseases. In an Arthritis & Rheumatism editorial, Rose
concluded that “establishing a cause-and-effect relationship between an agent and a
disease…requires a valid statistical association between the putative agent and the
disease, and a feasible biologic mechanism to account for the association” (3).
Environmentally
Related Rheumatic Syndromes
Several
syndromes appear to fulfill Rose’s criteria. In 1981, 20,000 individuals in Spain
developed multisystem complaints characterized by fever, malaise, headache, cough,
myalgias, interstitial lung disease, and rashes. Over time, some patients developed a
variety of symptoms and signs, which included intense myalgias, severe muscle weakness,
joint contractures, Raynaud’s phenomenon, scleroderma-like cutaneous lesions, and
pulmonary hypertension. Three-hundred fifty
deaths were observed and attributable to “toxic oil syndrome.” It was discovered
that rapeseed oil used in cooking had been denatured with aniline, initiating the process
(4).
In 1989, a
similar condition was reported in individuals who ingested L-tryptophan as a dietary
supplement intended to promote sleep and muscle relaxation. Peripheral eosinophilia was
prominent in these patients as well as dermal thickening. A defect in the purification
process from a single manufacturer was thought to be the culprit for “eosinophilic
myalgia syndrome” (5). Known previously as “Shulman’s disease,”
occasional reports were noted in patients postulated to shunt large amounts of
L-tryptophan to the toxic kyneurenine alternate pathway (6).
The environment
may play an important role in what are called “scleroderma-related diseases.”
For example, some industrial workers involved in the polymerization of polyvinyl chloride
have been reported to develop a clinical state consistent with scleroderma with the
addition of occasional liver tumors, acral osteolysis, and cryofibrinogenemia. These
associations have been limited to case reports and do not yet meet Rose’s criteria
(7).
Some proposed non-infectious environmentally
induced rheumatic syndromes have not met statistical scrutiny. These include mercury amalgem syndrome, multiple
chemical sensitivity, and siliconosis (patients with breast implants who do not fulfill
established criteria for lupus, rheumatoid arthritis, or scleroderma, etc.) (8).
Problems With Interpreting the Literature About Potentially
Environmental-Related Rheumatic Diseases
There are
problems with some of the literature suggesting an environmental link to rheumatic
diseases. Some of the papers are just not scientifically sound. The following are some of
the other problems that influence the interpretation.
Animals
are not humans. Articles have appeared in the lay press about disease in animal
models. For example, one type of mouse lupus tolerated caffeine poorly, and another made
autoantibodies when fed with certain nightshade vegetables such as broccoli. Lupus
patients – some limited by dietary
restrictions – flooded their organizations with inquiries, while other simply stopped
eating otherwise safe foods. No clinical studies have shown any danger of coffee or
vegetables in humans with lupus. Heavy metals such as mercury or cadmium produce
autoimmune-like glomerulopathies in animals, but despite Web sites claiming otherwise,
human reports in peer-reviewed literature do not exist (9).
An
abnormal serology does not imply the presence of disease. The prevalence of
antinuclear antibody was reported to be increased in Canadian farmers exposed to
herbicides, residents of Phoenix exposed to contaminated ground water, or in certain
occupations with organic solvent exposure. However, it has not
been shown that any of these individuals developed lupus (9,10).
Self-reported
disease does not mean the patient has the disease. A Lupus Foundation of America
marketing survey concluded that 1.2 to 2.4 million people in the United States have been
told by a physician they have systemic lupus (11). On the other hand, the National
Arthritis Data Workshop prevalence estimates are only 239,000 (12). Hochberg et al helped
resolve this discrepancy by showing that only one-third of self-reported cases of lupus
actually fulfilled the American College of Rheumatology criteria for the disease. Self-report
data included undifferentiated connective tissue disease and fibromyalgia with a
positive ANA, which is not lupus (13).
Some very large surveys have put forth conclusions about the influence of chemicals (eg,
silicones) on rheumatic diseases relying upon self-report questionnaires sent to
individuals in order to document the presence of lupus (14). None of the patients were
examined by a physician-author, and medical charts were not
reviewed. Although the conclusions of these studies may be valid, they can be listed only
as “possibilities” rather than “probabilities.”
Clusters
of disease require further study. A study by the Arizona Health Department
suggested that industrial contamination in Nogales, Arizona, was associated with an
increased prevalence of lupus among Mexican Americans (many of whom were Native Americans)
in that community (15). Though it received considerable media attention and frightened
many people, this claim was never substantiated nor published in the peer-reviewed
literature. It turned out that general practitioners had diagnosed the patients (no
rheumatologist was involved in their care),
and when compared with the prevalence of lupus among Native Americans (as opposed to
overall prevalence in the United States), there was not a significant finding (16).
Environmental
Factors That May Influence Rheumatic Diseases (9,17-22)
Climate. Cold
weather definitely makes Raynaud’s phenomenon worse (Table 1). Raynaud’s
phenomenon may be part of scleroderma and other connective tissue diseases. Giant cell
arteritis and polymyalgia rheumatica are more prevalent in cooler latitudes. It is not
know if this is due to the cold weather or the genetic makeup of people living in those
areas. Changes in barometric pressure produce more stiffness and aching in rheumatoid
arthritis.
Lifestyle. Chronic
cutaneous lupus is more active in smokers, and smoking may make antimalarial agents less
effective. Smoking also has been associated with development of nodules and more severe
disease in rheumatoid arthritis. Fish oil – if taken in large quantities – may
reduce the inflammation in rheumatoid arthritis (Table 1). Excessive alcohol intake and
thiazide diuretics can trigger attacks of gout. The following have only possible
associations and need further verification:
Behcet’s activity might
improve in smokers.
Caffeine intake may flare
rheumatoid arthritis.
Noncaffeinated coffee may increase
the risk of rheumatoid arthritis.
Ingestion of alfalfa sprouts may
aggravate lupus.
Disease Transmission in Exposed Groups. Disease transmission has never been documented in lupus lab workers who may have a higher rate of
antinuclear antibody positivity or in owners
of dogs or cats with lupus. Possible scleroderma clusters exist in industrialized regions
of the United Kingdom and United States.
Stress and trauma.
Probably all rheumatic diseases may flare in times of stress.
Occupational exposure/chemicals/ultraviolet light. Ultraviolet light exposure definitely helps psoriasis, but
flares lupus. Scleroderma may occur in uranium miners or sandblasters exposed to silica,
organic solvents, and certain aliphatic hydrocarbons. Raynaud’s may be associated
with jackhammer and pneumatic drill use. Lupus flares with hydrazine, tartrazine, eosin
lipstick, FD &C yellow #5 exposure.
Immunizations. Case
reports exist of disease flares or induction of disease following a variety of
vaccinations in nearly all autoimmune/rheumatic disorders. However, there is no
epidemiologic survey that has shown an association with immunizations causing or flaring a
rheumatic disease.
Adjuvant disease.
Silicone injections or instillations have not been shown to cause autoimmune disease.
Also, there are no studies showing aggravation of pre-existing autoimmune disease.
Conclusion
We conclude that other than
tobacco and sun avoidance in lupus; tobacco and cold avoidance in Raynaud’s; and
eating more fish oil and stopping smoking for rheumatoid arthritis, no definite
recommendations can be made on the basis of the studies summarized. The vast amount of
misinformation and advice from incompletely studied environmental issues may result in
lifestyle changes that are without merit in rheumatic disease patients.
Love identified factors that need
to be considered when studying the relationship of environmental factors to rheumatic
diseases, including the adequacy of surveillance systems, the heterogeneity of clinical
syndromes, difficulty in obtaining adequate controls, and the rarity of syndromes for any
particular exposure (23). The Arthritis Foundation, the American College of Rheumatology,
and other nonprofit patient advocacy groups should undertake initiatives in this area so
that knowledge will replace speculation for practitioners and patients.
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