Prevention of Rheumatic Diseases




Rheumatic diseases affect a significant portion of the population and lead to increased health care costs, disability, and premature mortality; effective preventive measures for these diseases could lead to substantial improvements in public health. Natural history studies show that for most rheumatic diseases there is a period of preclinical disease development during which abnormal biomarkers or other processes can be detected. These changes are useful to understand mechanisms of disease pathogenesis; in addition, they may be applied to estimate a personal risk of future disease while individuals are still relatively asymptomatic and ultimately be used to identify individuals who may be targeted for preventive interventions.


Key points








  • A growing understanding of a preclinical period of many rheumatic diseases suggests that they could be approached in a preventive fashion.



  • Prevention of rheumatic diseases may be through primary prevention of initial autoimmunity or tissue injury, or through secondary prevention to halt progression of autoimmunity and/or tissue injury while subjects are still in an asymptomatic or minimally symptomatic phase.



  • Prevention may be approached through combinations of risk-factor modification, induction of tolerance, or pharmacologic interventions.



  • Additional research is needed to identify effective biological targets and methods for prevention of rheumatic diseases, as well as to learn how to apply effective screening and prevention strategies that are able to improve public health in a cost-effective fashion.






Introduction


Across the multiple fields of medicine there is increasing interest in preventive approaches to disease. To help guide preventive approaches to disease, in the 1960s, the World Health Organization (WHO) put forward recommendations for disease screening and prevention, as listed in Box 1 . Overall, these recommendations suggest that diseases targeted for screening and prevention should have an important impact on health, an identifiable asymptomatic (or minimally symptomatic) period during which individuals at high risk for future disease can accurately be identified, and that there be available an effective means for preventing the further evolution of disease. Screening and prevention approaches that follow these guidelines are in action for many diseases. For example, across the globe there is considerable effort put into to screening and preventing adverse outcomes from cardiovascular disease and many types of cancer, as well as programs to prevent many infectious diseases.



Box 1





  • The disease should represent an important health problem



  • A treatment should be available for the disease



  • Facilities for diagnosis and treatment of the disorder should be available



  • A latent (preclinical) stage of the disease should be detectable



  • A test or examination for the condition should exist



  • The screening test should be acceptable to the general population



  • The natural history of the disease should be adequately understood



  • An agreed policy on whom to treat is required



  • The total cost of identifying a case among the population should be economically balanced in relation to medical expenditure as a whole



  • Case finding should be a continuous process, necessitating regular repeat testing, and not just a once-and-for-all project



WHO recommendations regarding screening and prevention for a disease

Adapted from Wilson JMG, Jungner G. Principles and practice of screening for disease. WHO Public Health Papers 1968;34:1–163.


Although most rheumatologists agree that rheumatic diseases are important health problems and meet several of the other WHO criteria for screening, many key questions regarding prevention of rheumatic diseases are still unanswered. However, given the growing understanding of the causes of rheumatic disease, and, as discussed herein, a growing awareness that many rheumatic diseases have a period of largely asymptomatic disease development during which there are abnormalities of biomarkers that can be used to predict future risk for disease, there is hope that rheumatic diseases may join the list of preventable diseases.


This article discusses some general principles of disease prevention applicable to rheumatic disease, and outlines a potential research strategy for the development of effective preventive strategies that will be able to reduce the adverse impact of these diseases.




Introduction


Across the multiple fields of medicine there is increasing interest in preventive approaches to disease. To help guide preventive approaches to disease, in the 1960s, the World Health Organization (WHO) put forward recommendations for disease screening and prevention, as listed in Box 1 . Overall, these recommendations suggest that diseases targeted for screening and prevention should have an important impact on health, an identifiable asymptomatic (or minimally symptomatic) period during which individuals at high risk for future disease can accurately be identified, and that there be available an effective means for preventing the further evolution of disease. Screening and prevention approaches that follow these guidelines are in action for many diseases. For example, across the globe there is considerable effort put into to screening and preventing adverse outcomes from cardiovascular disease and many types of cancer, as well as programs to prevent many infectious diseases.



Box 1





  • The disease should represent an important health problem



  • A treatment should be available for the disease



  • Facilities for diagnosis and treatment of the disorder should be available



  • A latent (preclinical) stage of the disease should be detectable



  • A test or examination for the condition should exist



  • The screening test should be acceptable to the general population



  • The natural history of the disease should be adequately understood



  • An agreed policy on whom to treat is required



  • The total cost of identifying a case among the population should be economically balanced in relation to medical expenditure as a whole



  • Case finding should be a continuous process, necessitating regular repeat testing, and not just a once-and-for-all project



WHO recommendations regarding screening and prevention for a disease

Adapted from Wilson JMG, Jungner G. Principles and practice of screening for disease. WHO Public Health Papers 1968;34:1–163.


Although most rheumatologists agree that rheumatic diseases are important health problems and meet several of the other WHO criteria for screening, many key questions regarding prevention of rheumatic diseases are still unanswered. However, given the growing understanding of the causes of rheumatic disease, and, as discussed herein, a growing awareness that many rheumatic diseases have a period of largely asymptomatic disease development during which there are abnormalities of biomarkers that can be used to predict future risk for disease, there is hope that rheumatic diseases may join the list of preventable diseases.


This article discusses some general principles of disease prevention applicable to rheumatic disease, and outlines a potential research strategy for the development of effective preventive strategies that will be able to reduce the adverse impact of these diseases.




General strategies for disease prevention


Prevention strategies are typically categorized into primary, secondary, or tertiary interventions ( Fig. 1 ). The aim of primary prevention is to avoid the development of disease by eliminating specific risk factors or increasing an individual’s resistance to the condition. An example of this type of approach is vaccines against infections. The aim of secondary prevention is to reduce the progression from a latent or asymptomatic phase of disease to symptomatic disease. Thus a secondary preventive intervention attempts to interrupt the mechanisms of disease development before they evolve into an apparent illness. Examples of this type of approach include early identification of cancers through programs such as mammograms and colonoscopies.




Fig. 1


Natural history of rheumatic disease and possibilities for prevention. The natural history of rheumatic disease begins on the left with no disease, although genetic and environmental factors may be present. Over time, there is early evidence of disease that is not clinically apparent. Examples of this are autoantibodies, increased uric acid, or early cartilage injury. Later, clinically apparent disease develops that may be classifiable as a specific rheumatic disease. Once disease is clinically manifest, longer-term outcomes include issues such as response to therapy and disability. Throughout disease evolution, there are ongoing influences from genetic and environmental factors. Progression of rheumatic disease may be prevented at several points: before development of asymptomatic disease (primary prevention), during asymptomatic disease (secondary prevention), and after clinically apparent disease has developed (tertiary prevention).


The aim of tertiary prevention is to delay or to limit the impact of an established disease. Most rheumatic diseases are currently treated at this stage, and rheumatologists typically perform tertiary prevention by attempting to prevent progression of disease to disability or premature death after patient presents with clinically apparent disease (eg, swollen joints in rheumatoid arthritis [RA], or skin rash in systemic lupus erythematosus [SLE]). However, rheumatologists are less used to performing primary or secondary preventive interventions for rheumatic diseases. As knowledge of the risk factors for rheumatic diseases grows (eg, smoking for RA), primary prevention may become more of a priority for rheumatic diseases.




Potential primary preventive strategies


Environmental risk factors are of great interest for preventive strategies for rheumatic diseases, because they are potentially modifiable. In particular, lifestyle modifications are a common request from at-risk populations; specifically, when individuals at high risk for RA were interviewed about potential preventive interventions, most of them primarily mentioned lifestyle adjustments as approaches with which they would be comfortable.


Multiple environmental and lifestyle factors have been identified for rheumatic diseases. In RA, tobacco smoking is the best-established risk factor and is responsible for 1 in every 4 to 6 cases of RA (population attributable risk). The effect of tobacco is dose dependent and larger in shared-epitope–positive individuals. Other inhaled pollutants have also been implicated in the development of RA, such as silica dusts, factory dusts, or exposure to traffic pollution. Reproductive and hormonal factors also play a role in the development of RA and several other autoimmune diseases. Sex hormones have immunomodulatory effects, but the complex interactions among hormones are not fully understood. Oral contraceptive and hormone replacement therapy have been associated with a lower RA risk, but not all studies have confirmed these findings. Several studies have found an increased risk of RA with obesity and with lower social class. Dietary factors have generally given inconclusive results, but recently high intake of soda and salt have been associated with an increased risk of RA. In contrast, a moderate alcohol consumption has consistently been associated with a decreased risk of RA. In a similar way, tobacco smoking, occupational exposure to silica dust, and exposure to sunlight have also been associated with an increased risk of SLE, whereas moderate alcohol intake seems to decrease the risk. In some cases, specific disease triggers such as toxic oil, certain medications, or possibly exposure to certain mycotoxins may provide information on the pathophysiology of specific rheumatic diseases such as eosinophilic disease, drug-induced autoimmune syndromes, and potentially certain forms of osteoarthritis (OA) such as Kashin-Beck disease. Emerging data also suggest that microorganisms, such as Epstein-Barr Virus in SLE or bacterial organisms in RA, may be implicated in the development of certain rheumatic diseases. If the infectious cause for rheumatic diseases is confirmed, it could allow the development of preventive strategies involving vaccines against the causative organisms.


Risk factors for other rheumatic diseases are also known. For example, diet-related metabolic effects such as central obesity and diabetes as well as alcohol intake have been shown to be related to increased risk for gout. In addition, prior injury, obesity, and abnormal joint mechanics are risk factors for OA. Many more environmental risk factors for rheumatic diseases exist, although more research is warranted to elucidate the complex interactions between genetics and the environment, both to understand the cause of these diseases and to initiate preventive interventions.


Although there are many environmental factors that have been associated with the development of rheumatic diseases, few of the identified environmental triggers for rheumatic diseases have enough supportive evidence and strong enough effect sizes overall to warrant altering a specific environmental risk factor on a population level. Even tobacco smoke, which as discussed earlier is one of the best-established environmental risk factor for RA, still only explains ∼30% of seropositive disease. However, the effect of environmental risk factors may be much stronger in individuals with a certain genetic makeup.


An interesting approach to identify individuals for whom environmental factor(s) or and/or lifestyle modifications may be most effective is to combine several environmental risk factors to identify individuals at very high risk for rheumatic disease. For example, a British study has proposed a risk score for inflammatory polyarthritis based solely on easily ascertained lifestyle factors. This lifestyle risk score combines pack-years of smoking (every 10 pack-years), alcohol consumption (units/d), occupational class (professional, manual, neither), obesity (body mass index >30), presence of diabetes, parity (≥2), and duration of breastfeeding in women (years). Based on a summation of these lifestyle factors, this risk score can identify individuals who have up to a 6 times higher risk of developing polyarthritis. In addition, using the United States–based Nurses Health Study, Karlson and colleagues used a combination of family history, genetic factors, and environmental factors to predict future risk for RA, with area under the curve of greater than 0.8 for their best predictive models for RA. Although targeting single environmental factors in the general population may not be a feasible strategy for uncommon diseases, approaches combining genetic and environmental risk factors may be useful to detect specific individuals in whom a preventive intervention designed to modify lifestyle factors is most indicated.




Identification of preclinical phases of rheumatic disease


Because of the difficulty in identifying specific environmental risk factors for most rheumatic diseases as well as the weak effect sizes of known environmental risk factors when applied on a population basis, a more feasible approach to rheumatic disease prevention may be to focus on interventions in individuals who are at a very early phase of rheumatic disease development before the development of significant tissue injury. This concept has gained traction over the past few years in large part because of a growing understanding of the natural history of rheumatic diseases. Many autoimmune rheumatic diseases are currently thought to result from multistep processes, whereby an environmental trigger (or triggers) induces an immune reaction in genetically susceptible individuals ( Fig. 1 ). The genetic susceptibility may be assessed through a careful family history of disease or may be measured with specific genetic markers. Furthermore, in many rheumatic diseases, including SLE, RA, and antineutrophil cytoplasmic antibody–positive vasculitis, disease-specific autoantibodies may precede by several years the clinically apparent manifestations of disease, often termed preclinical disease. Other rheumatic diseases, such as gout and OA, also have preclinical phases with abnormal biomarkers (eg, uric acids ) or early structural changes (eg, hip dysplasia ), in the absence of significant clinical symptoms. Thus, a high-risk population could be identified either by identifying genetically susceptible individuals (ie, genetic screening using genetic risk scores, or using a family history of autoimmune disorders as a proxy), by detecting the presence of specific biomarkers (eg, autoantibodies), or by recognizing a set of highly relevant environmental exposures.




Potential secondary prevention strategies


Although many rheumatic diseases may be identified in their preclinical phases, it is not clear how to safely and effectively prevent either the initiation of early autoimmunity or the progression of early autoimmunity or other rheumatic disease mechanisms (eg, high uric acid in gout, or early cartilage damage in OA) while the disease is in an asymptomatic state. As discussed above, there are multiple environmental risk factors associated with rheumatic diseases, and as such is possible that environmental risk-factor modification could be effective to halt initiation of autoimmunity, or even progression of early autoimmunity to clinically apparent disease. However, there is still a lack of knowledge of which factors act to initiate and propagate autoimmunity once it develops. Furthermore, modulating an environmental risk factor or factors may be effective to prevent the development and/or progression of rheumatic disease but it may be difficult to measure its effect because the time between an intervention and the potential clinical benefit may be long. For example, using data from the Nurses’ Health Study, Karlson and colleagues found that risk of RA remained increased until 20+ years after smoking cessation ; such an effect would be difficult to measure in a clinical trial to show benefit in an evidence-based fashion. Tolerance-inducing regimens could also be an attractive approach for altering progression of autoimmunity; however, this approach is difficult to use unless specific antigen targets and immune regulatory pathways are well understood.


Given the difficulties of modulating environmental risk factors to prevent rheumatic disease, perhaps pharmacologic intervention using agents known to be effective for the treatment of established rheumatic diseases would be the best approach to prevent the progression of autoimmunity. In support of this approach, in animal models of autoimmune diseases, early therapeutic interventions are capable of averting the development of the clinical disease. However, to date, only indirect evidence supporting this hypothesis is available in humans: in the early stages of RA, a therapeutic window of opportunity seems to exist in which early antirheumatic therapy seems to modify and improve the disease permanently in some patients. Furthermore, in the Dutch probable rheumatoid arthritis: methotrexate versus placebo (PROMPT) study, a limited course of methotrexate in patients with early undifferentiated arthritis initially delayed or prevented the onset of classifiable RA in a proportion of patients, especially those with seropositivity for antibodies to citrullinated proteins, although the effects of this intervention seemed to wane after 5 years of follow-up. The exact mechanism for improved long-term outcomes is unclear, although several observations suggest that in the early stages of the disease process the immune system might still be amendable to immunologic reprogramming. It has also been suggested that early intervention prevents the recruitment and/or evolution of effector cells such as synovial fibroblasts to a more pathogenic phenotype.


Based on these findings, drugs already known to be effective in clinically apparent rheumatic diseases could be applied in the preclinical phase to halt progression to a more damaging phase of disease. For example, in individuals who are at risk for RA or SLE, drugs such as hydroxychloroquine or methotrexate could be applied in the preclinical phase of disease development. Furthermore, interventions at this early phase of disease may be more effective at altering autoimmunity because of less development of more persistent immune and inflammatory responses.


There is already limited evidence that such approaches may be effective in some rheumatic and other autoimmune diseases. In uncontrolled trials, use of hydroxychloroquine seems to reduce rates of progression from palindromic rheumatism (which may be a form of preclinical RA) to persistent inflammatory arthritis ; in addition, in uncontrolled studies of SLE, early use of hydroxychloroquine seemed to delay the fulfillment of classification criteria for SLE and reduce the expansion of autoantibodies. Furthermore, a small trial tested a limited preventive intervention in postpartum women with presumed preclinical Graves disease based on high titers of thyroid antibodies, and suggested that a short-term course of prednisolone may prevent the development of postpartum hypothyroidism. In addition, a clinical trial in The Netherlands is examining the efficacy and safety of rituximab to prevent the progression from systemic autoimmunity associated with RA (autoantibody-positive individuals) to clinically classifiable RA. The results of this study could be highly informative about potential preventive approaches to RA, which could be applied to other rheumatic diseases as well.

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Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Prevention of Rheumatic Diseases
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