Environment, Lifestyles, and Climate Change: The Many Nongenetic Contributors to The Long and Winding Road to Autoimmune Diseases

Abstract

A critical unanswered question is what is causing the increase in the prevalence of autoimmunity and autoimmune diseases around the world. Given the rapidity of change, this is likely the result of major recent alterations in our exposures to environmental risk factors for these diseases. More evidence is becoming available that the evolution of autoimmune disease, years or even decades in the making, results from multiple exposures that alter susceptible genomes and immune systems over time. Exposures during sensitive phases in key developmental or hormonal periods may set the stage for the effects of later exposures. It is likely that synergistic and additive impacts of exposure mixtures result in chronic low‐level inflammation. This inflammation may eventually pass thresholds that lead to immune system activation and autoimmunity, and with further molecular and pathologic changes, the complete clinical syndrome emerges. Much work remains to be done to define the mechanisms and risk and protective factors for autoimmune conditions. However, evidence points to a variety of pollutants, xenobiotics, infections, occupational exposures, medications, smoking, psychosocial stressors, changes in diet, obesity, exercise, and sleep patterns, as well as climate change impacts of increased heat, storms, floods, wildfires, droughts, UV radiation, malnutrition, and changing infections, as possible contributors. Substantial investments in defining the role of causal factors, in whom and when their effects are most important, the necessary and sufficient gene‐environment interactions, improved diagnostics and therapies, and preventive strategies are needed now to limit the many negative personal, societal, and financial impacts that will otherwise occur.

Introduction

Over recent decades, the frequency and possibly the types and severity of autoimmunity and autoimmune diseases developing in various global locations appear to be changing. ¹ , ² , ³ , ⁴ , ⁵ Although the capacity to accurately assess the incidence, prevalence, and presentation of these syndromes is limited given the lack of dedicated registries and repositories around the world, analyses of health care and insurance systems and other available databases suggest that many autoimmune diseases have increased in incidence and prevalence. ⁴ These increases vary based on the specific disease and location, but some estimates are that globally, they range from 3.7% to 7.1% per year. ¹ Furthermore, the ways in which some autoimmune diseases are presenting and evolving may have also changed as we have deciphered different phenotypes and endotypes of disease. ⁶ Crucially, these changes are occurring too quickly to be due to the evolution of genetic risk factors, which, in fact, play only moderate roles in pathogenesis. Therefore, they likely result from changes in our environmental exposures and daily life habits, as well as the impact of climate change, acting on specific genetic, immune, developmental, and hormonal backgrounds to produce their effects. ⁴ , ⁷

There are examples in which an exposure, such as a medication, has a relatively rapid apparent effect on the development of an autoimmune disease (challenge), which resolves when the exposure is removed (dechallenge) and recurs with re‐exposure (rechallenge). ⁸ , ⁹ But this is an exception, and in most cases, no precise antecedent exposures can be identified as definite triggers for an autoimmune syndrome. This may be because the processes by which these diseases are initiated and evolve take place over years or possibly decades, are poorly understood, and are diverse and dependent on many interacting cofactors yet to be fully elucidated.

Furthermore, it is likely that many more insults or activations of the immune system are needed during the process of disease development than we currently understand. Also, perhaps a particular sequence of events is essential. For example, one exposure may be needed early to result in epigenetic or immune changes that then allow for later exposures to have their effects, or there may be synergistic impacts from multiple exposures. ¹⁰ This relates to the concept that chronic ongoing systemic inflammation at a low level may be at the core of multiple diseases, including cancer and autoimmune disorders, and the contributors to and sustainers of this continuing inflammatory state are many. ¹¹ How environmental insults and chronic inflammation may result in autoimmune diseases remain unclear. However, the impacts could involve genetic and epigenetic changes, cytotoxic effects, oxidative stress, mitochondrial dysfunction, endocrine disruption, altered intercellular communication, and effects on the microbiome. ¹² In a sense, this could be considered a process that may be called “disease by a thousand cuts.” This review summarizes the environmental, lifestyle, and changing climatic factors that could be playing a role, the direct and indirect evidence for their influences on autoimmune diseases, and how to minimize their impact to address the apparent autoimmune epidemic.

The environment and autoimmune diseases

The current paradigm driving much research in the field is that gene–environment risk factor interactions, in the relative absence of protective factors, are the basis for the immunologic changes that result over time in clinically apparent autoimmune diseases. ¹³ , ¹⁴ Molecular and technological advances have allowed great progress in defining shared and unique genetic risk factors for autoimmune phenotypes. ¹⁵ Yet identifying the even greater contribution of environmental risk factors has been more difficult. The concept of the exposome, the totality of all exposures since conception, has emphasized the complexity of our environmental interactions and their many and changing forms. ¹⁶ But we only have limited, relatively simplistic ways of measuring these at any given time point, let alone their cumulative levels and effects over time, and we have very few insights into how they impact the immune and other systems in the short and long term. More validated environmental exposure measurement tools need to be developed because those we have are expensive and include many possible inaccuracies. Moreover, exposure questionnaires are often limited by recall bias and confounding. A further complication is that we experience exposure to constantly changing mixtures that might have different effects in different combinations and concentrations via synergistic or antagonistic interactions. ¹⁷

A growing list of chemicals, air and water pollutants, medications, occupational exposures, infections, hormones, and radiation have been implicated in triggering autoimmune diseases. ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² The evidence supporting these as risk factors comes from multiple scientific approaches with different confidence levels, including laboratory and animal studies, epidemiologic investigations of different disease cohorts, and research correlating exposures with disease activity. Nonetheless, many exposures have been shown to have effects in comparable directions and magnitude using different methods in different settings, thus strengthening the level of scientific support for their importance. ⁹ Solid evidence for environmental risk factors comes from studies of air pollution, occupational exposure to silica and solvents, dietary gluten, medications, hormones, ionizing and UV radiation, and infections for selected disorders. ⁸ , ¹⁸ , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ The mechanisms through which these alter immune function and eventually result in autoimmunity need to be delineated through further investigation.

Lifestyle factors and autoimmune disease

Several lifestyle factors can also impact the immune system and appear to be involved as risk or protective factors for the onset of multiple immune‐mediated diseases, in addition to being important factors for developing comorbidities, flares of established disease, and death (Table 1). Most of these lifestyle factors contribute to metabolic changes that result in chronic inflammation, lipid peroxidation, and increased oxidative stress. ²⁸ Although the strength of evidence varies, lifestyle factors with the strongest supporting data are tobacco smoking, alcohol intake, unhealthy diets and their impacts on the microbiome, obesity, decreased physical activity, decreased sleep, and increased psychosocial stress. ²⁹ , ³⁰

Table 1.

Lifestyle factors and likely impacts on autoimmune diseases^*

Lifestyle factors	Likely impacts on autoimmune diseases	References, author (year)
Tobacco smoking	Increased rates of multiple diseases, including RA, SLE, and psoriasis; decreased rates of ulcerative colitis and unclear effects on others	Harel‐Meir et al 31 (2007), Perricone et al 32 (2016)
Moderate alcohol intake	Possible decreased rates of SLE and RA; unclear effects on other diseases and of higher alcohol intake	Caslin et al 33 (2021)
Unhealthy diets high in sugar, fat, salt, red meat, and ultraprocessed foods	Increased rates of RA, SLE, scleroderma, ANCA‐associated vasculitis, and others, as well as associated cardiopulmonary complications	Christ et al 34 (2019)
Obesity	Increased rates of type 1 diabetes, multiple sclerosis, RA, SLE, and possibly others	Frazzei et al 35 (2022), Matarese 36 (2023)
Decreased physical activity	Increased rates of proinflammatory markers and multiple diseases, along with poorer outcomes	Sharif et al 37 (2018)
Decreased sleep duration and quality	Increased rates of RA, SLE, ankylosing spondylitis, systemic sclerosis, and possibly others	Hsiao et al 38 (2015)
Increased stress	Increased rates of autoimmune thyroid disease, Sjögren disease, SLE, Crohn disease, ulcerative colitis, giant cell arteritis, and likely others; increased disease flares likely	Song et al 39 (2018)

^*ANCA, antineutrophil cytoplasmic antibody; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Tobacco smoking and indirect exposures to tobacco smoke are the best studied of these and are linked to many autoimmune diseases. ³¹ , ³² The varied and complex components of tobacco smoke make defining the specific causative agents difficult. Surprisingly, some components appear to be inhibitory for the immune and other systems in certain individuals given the protective effect of smoking on the development of ulcerative colitis and unclear impacts on other autoimmune syndromes. Smoking may also influence the clinical presentations, responses to therapy, and outcomes of certain autoimmune diseases, especially rheumatoid arthritis (RA). ³² Gene–environment interactions are involved in these processes, with HLA antigens playing especially important roles in determining the strength and direction of these associations. ⁴⁰ , ⁴¹

Although alcohol intake generally has adverse health effects at many doses, ⁴² the impacts on autoimmune diseases are less clear. Based on current evidence, at higher doses, alcohol appears to alter the gut barrier and can lead to changes in the microbiome, bacterial wall products, and liposaccharides. ³³ These changes can stimulate toll‐like receptors on immune cells and increase monocytes, T cells, cytokines, and immunoglobulin levels, contributing to end‐organ damage. However, at low to moderate doses, alcohol appears to be able to improve risk and progression in some autoimmune diseases, particularly systemic lupus erythematosus (SLE) and RA. This may be due to increases in protective gut microbes and alterations in acetate, polyunsaturated fatty acids, high‐density lipoprotein, and nitric oxide. ³³

Diets high in salt, sugar, fats, red meat, and ultraprocessed foods are known to produce inflammation, whereas more natural diets high in fruits, vegetables, olive oil, fiber, and fish (foods most related to the Mediterranean diet) tend to be anti‐inflammatory. ³⁴ The impact of many foods on the body and the intestinal and other microbiomes is still being defined. Nonetheless, the key to these effects may be the alterations in immune activity and misbalancing or dysbiosis of the gut microbial community that is associated with disease. ⁴³ , ⁴⁴ Related to these issues is obesity and its role as a risk factor for autoimmune disorders. ³⁶ For example, high body mass index at birth is strongly associated with type 1 diabetes, and studies in young individuals with obesity found a 1.6‐ to 1.9‐fold increase in the risk of developing multiple sclerosis during adolescence. Obesity is also a risk factor for RA and SLE, although the associations are less robust than seen in other diseases. ³⁵ The adipokines produced in fat cells have varied effects, but many are proinflammatory and are thought to contribute to these associations. ⁴⁵

Physical activity and exercise are essential in maintaining general health and preventing many diseases. Muscle movement significantly impacts the immune and other systems, tends to be protective for developing autoimmune diseases, and can decrease flare rates and improve function for those with existing autoimmune disorders. ³⁷ Physical activity is generally anti‐inflammatory in that it decreases many markers of inflammation and increases T regulatory cells, alters Th1/Th2 ratios, decreases antigen presentation to T cells and Ig secretion, and promotes the release of multiple myokines, including interleukin‐6 (IL‐6) from muscle cells that induce IL‐10 secretion and IL‐1β inhibition. ³⁷ , ⁴⁶ , ⁴⁷ , ⁴⁸ Consistent with these findings, incidences of RA, multiple sclerosis, inflammatory bowel disease, and psoriasis are higher in those persons less engaged in physical activity, and outcomes are generally improved in patients with autoimmune diseases when they are more physically active. ³⁷

The shortening duration, variable timing, and deteriorating quality of sleep are unaddressed problems in most societies. All of these have been shown to have adverse effects on many body functions, including the immune system. ⁴⁹ It has been reported that nonapneic sleep disorders are associated with an increased risk of many autoimmune illnesses, including RA, ankylosing spondylitis, SLE, and systemic sclerosis. ³⁸ Mechanisms remain poorly understood but likely include alterations in circulating numbers and activity of leukocytes and other specific cell subsets, elevation of systemic and tissue proinflammatory markers, cytokines, chemokines, acute phase proteins, and altered antigen presentation and immune cell responses. ⁴⁹

Emotional and psychological stress, brought on by reactions to perceived adverse life events, can trigger a variety of stress‐related hormones and other chemical changes in the body. Additionally, stress can alter lifestyles, including inducing sleep disruption, food or substance abuse, and increased smoking, all of which themselves may promote further inflammation and increase the risk of the development of or flares of autoimmune diseases. ⁵⁰ Physical trauma can also cause posttraumatic stress disorder, inflammation, secondary emotional stress, and lifestyle changes, which can activate different parts of the immune system and can be associated with the onset of new autoimmune diseases or increases in disease activity in established autoimmune diseases. ⁵¹ Recent studies have shown that prior exposure to a stress‐related disorder was significantly associated with an increased risk of many subsequent autoimmune diseases. ³⁹ The exact mechanisms and step‐by‐step processes are not fully understood, and more research is clearly needed in this area.

The impacts of climate change on autoimmune diseases

Climate change, driven mainly by greenhouse gas emissions from burning fossil fuels, is causing increasingly severe weather. ⁵² This includes ambient air and water temperature increases and more frequent extreme weather events. The number and severity of weather emergencies, including more intense and costly hurricanes and related storms, floods, drought, sand and dust storms, wildfires, heat waves, and heat domes, are rapidly rising. These and other effects of climate change are having a variety of direct and indirect impacts on autoimmune diseases, as summarized in Table 2. Even though studies on the roles of the outcomes from climate change on autoimmune diseases are limited, climate change influences are already occurring and are projected to be greater over time. ⁷ , ⁵³

Table 2.

Climate change effects and likely impacts on autoimmune diseases^*

Climate change effect	Likely impacts on autoimmune diseases	References, author (year)
Extreme weather disasters resulting in poor access to health care, medications, adequate food, water, and housing	Possible induction and flares of many diseases	Rocque et al 54 (2021)
Increased air pollution from storms, droughts, and wildfires	Increased rates of RA, SLE, scleroderma, ANCA‐associated vasculitis, and others, as well as associated cardiopulmonary complications	Zhao et al 55 (2022), Dellaripa et al 7 (2024)
Increased vector‐borne and other infectious diseases	Increased frequencies of and broader distribution of Lyme disease and West Nile and chikungunya virus cases and autoimmune complications	Thomson and Stanberry 56 (2022), Semenza et al 57 (2022)
Increased pesticide and other chemical exposures	Increased rates of RA, SLE, and possibly others	Duchenne‐Moutien and Neetoo 58 (2021), Parks et al 59 (2011), Woo et al 60 (2022)
Increased UV radiation exposure	Increased rates and flares of SLE, dermatomyositis, Sjögren disease, and possibly others	Dellaripa et al 7 (2024), Parks et al 61 (2020), Estadt et al 62 (2022), Barnes et al 63 (2022)
Increased malnutrition and food insecurity	Increased severity of RA, SLE, scleroderma, inflammatory bowel disease, and possibly others, with effects on mortality	Tian et al 64 (2023), Codullo et al 65 (2015), Correa‐Rodríguez et al 66 (2019), Massironi et al 67 (2023)
Increased psychosocial stress from major weather events	Increases in autoimmune thyroid disease, Sjögren disease, SLE, Crohn disease, ulcerative colitis, giant cell arteritis, and possibly others; possible disease flares	Neria et al 68 (2008), Song et al 39 (2018)

^*ANCA, antineutrophil cytoplasmic antibody; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Climate change results in weather that is less predictable, and past temperatures, rainfalls, and storm patterns are no longer valid predictors of future events, resulting in what some experts have called “climate instability” or “climate chaos.” Severe weather events often result in decreased air and water quality, population and health care provider evacuations, infrastructure damage, and transportation and supply chain disruptions. All of these limit access to health care, medications, adequate food, water, and housing, as well as add psychosocial stress to residents of vulnerable communities. Together, these can impact both the onset and flare of many disorders, including autoimmune diseases. ⁵⁴ However, these changes affect different populations in different ways, and younger and older age, pre‐existing medical conditions, occupation, geographic location, and socioeconomic status are some factors that influence vulnerabilities and outcomes related to climate change impacts. ⁶⁹ , ⁷⁰ Heat exposure itself impacts the immune system and is associated across autoimmune conditions with an increased risk of recurrent hospitalizations. ⁷¹ Of interest, mice with experimental autoimmune uveitis exposed to high temperatures have more severe pathology and alterations of Th1 and Th17 cells and neutrophil extracellular traps. ⁷²

Perhaps the most substantial evidence for the impacts of climate change on autoimmune diseases relates to the effects of increased air pollution. ⁷ Alterations in temperature and precipitation have amplified ground‐level ozone and particulate matter. This, plus increased wildfires, has resulted in greater air pollution, which is directly connected to the risk for the development of autoimmunity and autoimmune diseases. ⁷ , ⁵⁵ , ⁷³ , ⁷⁴ , ⁷⁵ Studies have found associations between exposure to inhalable particulate matter of 10 μm in size and the higher prevalence of RA and between increased inhalable particulate matter of 2.5 μm in size exposure and the higher prevalences of anticitrullinated protein autoantibodies, RA, and other connective tissue diseases. This tropospheric ground‐level air pollution activates systemic inflammation via the fine and ultrafine particles that can be inhaled and transferred to the blood, thus potentially triggering chronic immune and inflammatory responses. ⁷ , ²⁵

Air pollution has also decreased the protective upper atmospheric (stratospheric) ozone layer, increasing ground‐level UVB radiation, a known risk factor for the onset and flares of some autoimmune diseases. ⁶¹ , ⁶² Although UVB radiation exposure tends to suppress immune responses in most healthy people, it is associated with the induction and flares of disease in numerous autoimmune disorders, including SLE, dermatomyositis, and Sjögren disease. The ozone depletion, along with the behavioral response to increased heat resulting in more time outside with less clothing, will increase net population UVB radiation exposure and intensify the impact of photosensitizing medications, likely resulting in increases in the prevalence of SLE, dermatomyositis, and Sjögren disease and flares of existing disease. ⁷⁶

Vector‐borne and other infectious diseases are changing in type, geographic distribution, prevalence, and seasonal extent because of climate change. ⁵⁶ Higher temperatures, changes in rainfall, and alterations in ecosystem dynamics from climate change increase the range and extend the transmission seasons of vector‐borne and other infectious diseases. Epidemiologic data show the emergence and re‐emergence of infectious diseases after the majority of extreme weather events. ⁷⁷ An example is the general increase in the number of cases and geographic range expansion of Lyme disease and Zika and chikungunya viral diseases in North America due to a warming atmosphere and the effect of such warming on deer, mice, and tick populations. ⁵⁶ , ⁷⁸ Transmissions of influenza infections are also enhanced with higher temperatures. Given the association of Lyme disease, influenza, and Zika and chikungunya viral diseases with the induction and flare of multiple immune‐mediated diseases, it is reasonable to expect increases in infection‐induced autoimmune diseases over time. ⁵⁷ , ⁷⁹ , ⁸⁰ , ⁸¹ Novel vector‐borne, zoonotic, and other pathogens associated with climate extremes and habitat degradation, wildlife and human dislocations and movements, melting permafrost, and rising sea levels are additional issues of concern for their likely adverse impacts on the prevalence and severity of many disorders. ⁸² , ⁸³

Rising temperatures and increasing atmospheric carbon dioxide (CO₂) levels create longer crop growing seasons and, in addition to altering the occurrence and virulence of foodborne pathogens, are likely to increase agricultural pest ranges and distributions. ⁵⁸ Studies show that increased temperatures, CO₂ levels, and pest pressures lead to dilution and increased volatilization of pesticides and fungicides in plants. This lowers their concentration and thereby reduces their effectiveness against pests and pathogens. This can lead to greater field application of pesticides, food contamination, and exposure within the food chain, along with more toxic heavy metal accumulations. ⁵⁸ Pesticide and heavy metal exposures are associated with acute toxicities and multiple chronic diseases, including RA and SLE. ⁵⁹ , ⁶⁰

Climate change has impacted the nutritious value and availability of many foods and is likely to increase stresses on the world's food supplies as the climate disasters multiply. The resulting malnutrition will probably impact the frequency and nature of many diseases, including autoimmune disorders. Beyond causing vitamin and other micronutrient deficiencies, malnutrition leads to changes in immune function and gut microbiome alterations via a dysbiotic state, which can initiate and exacerbate inflammatory responses. ⁶⁷ It is known that inadequate food intake can increase RA and SLE disease severity, with implications for death. ⁶⁴ , ⁶⁶ Malnourished patients with systemic sclerosis also have altered disease manifestations and increased mortality. ⁶⁵ Inflammatory bowel disease can be both influenced by and result in malnutrition as well. ⁶⁷

Natural disasters can have many effects on mental health, including increased aggression, posttraumatic stress disorder, suicides, and anxiety. ⁶⁸ Studies attempting to understand the mechanisms involved are limited, but extreme weather events have been associated with altered immune functions ranging from imbalanced T and B cell immune responses to greater expression of inflammatory immune cell–specific marker genes to generation of age‐related molecular immune phenotypes. ⁸⁴ , ⁸⁵ Because stressful life events are associated with development of multiple autoimmune and rheumatic diseases, including thyroid disease, Sjögren disease, SLE, Crohn disease, ulcerative colitis, and giant cell arteritis, it would be expected that climate change–related natural disasters would increase stress and hence the rates of these and possibly other disorders. ³⁹

Implications and future needs

Current findings suggest that many more factors play roles in the development of autoimmune diseases than have been previously considered. In addition to those already highlighted here, others have been less well documented but have been suggested as additional risk factors through laboratory and animal studies, case series, and epidemiologic investigations. These include vaccines, heavy metals and other xenobiotics, vitamin D deficiency, pollens, medical implants, solar cycles, birth dates, socioeconomic status, pandemics, and proximity to roadways, concentrated animal feeding operations, and hazardous waste sites. ⁵ , ⁶⁰ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ , ⁹⁰ , ⁹¹ , ⁹² , ⁹³ Rather than searching for a “single smoking gun” in terms of an environmental trigger for autoimmune disease in an individual patient, it seems most likely that these are cases of “disease by a thousand cuts,” and in fact, there will have been numerous contributing exposures over long periods of time leading to an autoimmune syndrome (Figure 1). If most people require exposures to multiple environmental risk factors that may interact over time and in particular sequences or in combinations operating on susceptible genomes and immune systems to develop autoimmune disease, this further complicates any single study's ability to identify such risk factors and may help explain why so few disease triggers have thus far been identified.

Figure 1.

The multiple contributors to the long and winding road to autoimmune diseases. Numerous interacting environmental and lifestyle risk factors, as well as the impacts of climate change, in the relative absence of protective factors may work together over years or even decades to result in autoimmune diseases. Many more insults or activations of the immune system are likely needed for disease development during this process than we currently appreciate. The continuous impacts of exposures on our genes, hormones, immune systems, and metabolism—perhaps in a particular sequence of synergistic events and at particularly vulnerable periods during life as indicated in the yellow boxes—may result in chronic inflammation, autoimmunity, early signs and symptoms, and eventually fully developed clinical syndromes in a process that may be called “disease by a thousand cuts.”

Nonetheless, based on the growing body of literature, we can already consider key suggestions for decreasing the risks of autoimmune disease, beginning with educating health care providers and the public on potential areas for intervention. Knowledge about protective and disease‐triggering factors should be included in practical health care guidance to allow for the possibility of prevention. ⁹⁴ , ⁹⁵ Everyone, especially those at high risk for developing autoimmune diseases based on family history, known genetic risks, and socioeconomic status and those who already have autoimmunity or another autoimmune disease, should be educated on how to minimize toxic exposures and lifestyle activities that endanger their health and should seek professional advice on diet, exercise, weight loss, sleep, stress avoidance or reduction, and relaxation approaches. ²⁸ Health care systems should be made more resilient to weather‐related disasters and the public should be educated and prepared for the many effects of climate change. ⁵² , ⁷⁶ , ⁹⁴

A number of rheumatologists and others who share a common concern about the effects of climate change on patients with rheumatic diseases have recently organized as a group known as Rheumatology Engaged in Action for Climate Health (REACTRheum). Their goal is to provide the community, both professionals and patients, with information about the potential impacts of climate change on the field based on data‐driven studies and to suggest practical, cost‐effective, and sustainable solutions to the problems raised by climate change, as detailed on their website (https://reactrheum.org/).

But beyond these practical and preventive approaches, the dramatic and costly increases in autoimmunity and autoimmune diseases around the world necessitate a change in the scope and scale of global stakeholder coordination and activity. Action is urgently needed to systematically improve our ability to understand, diagnose, and treat autoimmune disorders. ⁴ We need to pool all available expertise and resources to develop an agenda that coordinates global research and other activities to enhance current efforts, increase efficiencies, and minimize duplication of efforts. Integrated activities should address the many unmet needs in these areas, including improving the coordination of funding organizations, pharmaceutical companies, government agencies, researchers, health care providers, and patient groups to identify the most promising research opportunities and priorities and to integrate basic research, animal model studies, and clinical research agendas.

Establishing and expanding comprehensive standardized registries and repositories is also vital to define the incidence, prevalence, and geographic “hot and cold spots” for autoimmune syndromes and to monitor how they change over time as a guide to whether improvements are being made. Although this review has highlighted some of the known and suspected risk and protective environmental, lifestyle, and climate factors involved in development of autoimmune conditions, we are only at the beginning of achieving a fundamental appreciation of both shared and unique pathogeneses and the full array of risk and protective factors for various phenotypes. We need to greatly expand consideration of the number, range, and latency of exposures and begin to assess and understand the little‐studied impacts of climate change. Novel approaches, which include multiomics, state‐of‐the‐art clinical and laboratory technologies, and machine learning methods, evaluating large, diverse, and deeply phenotyped prospective cohorts will be needed to begin to decipher the many gene–environment interactions and disease mechanisms that evolve over a lifetime on the path to autoimmune conditions.

Identifying the optimal combinations of clinical features, nongenetic and genetic risk factors, and laboratory biomarkers to develop earlier and more accurate diagnostic approaches would allow for therapies to be initiated before irreversible disease damage occurs and could improve outcomes. Finally, enhancing the efficiency and effectiveness of clinical trials using novel trial designs and enhanced technologies could greatly expand available therapeutic options.

Conclusions

Further research elucidating the many contributors to autoimmune disease relating to the environment, lifestyles, and climate change may alter the roadmap for understanding disease development and eventually allow for conquering the autoimmune syndromes. Perhaps it may entail taking roads less traveled by today's researchers. Although there are many challenges ahead to meet these goals, by working together persistently and resolutely, we can address these barriers and decrease the future frequency, morbidity, mortality, and costs of autoimmune diseases.

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Miller confirms that all authors have provided the final approval of the version to be published, and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Helsinki Declaration requirements.

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