Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 May 1.
Published in final edited form as: Curr Opin Rheumatol. 2020 May;32(3):279–288. doi: 10.1097/BOR.0000000000000705

Inhalants other than personal cigarette smoking and risk for developing rheumatoid arthritis

Lauren C Prisco 1,*, Lily W Martin 1,*, Jeffrey A Sparks 1,2
PMCID: PMC7233294  NIHMSID: NIHMS1585958  PMID: 32141952

Abstract

Purpose of review:

This review summarizes the current evidence on inhalants other than personal cigarette smoking and risk for developing rheumatoid arthritis (RA).

Recent findings:

Personal cigarette smoking has been implicated as an environment risk factor for seropositive RA, perhaps by inducing autoimmunity at pulmonary mucosa. Since many patients with RA are non-smokers, other inhalants are being investigated as potential RA risk factors. Recent case-control and cohort studies have investigated passive cigarette smoking, air pollution, inhalant-related occupations, silica, pesticides, household environment, and allergic inhalants as inhalant exposures for RA risk. Inhalant-related occupations and silica inhalants have the most consistent evidence for associations with increased RA risk. However, most studies relied on retrospective designs and had limited ability to adjust for personal cigarette smoking or investigate associations among non-smokers.

Summary:

Several inhalants other than personal cigarette smoking may be associated with increased risk for developing RA. These results support the hypothesis that inhalants, pulmonary mucosal inflammation, and RA pathogenesis may be linked. Future studies are needed to firmly establish the independence of these findings from personal cigarette smoking and to determine the specific inhalants and biologic mechanisms related to RA pathogenesis.

Keywords: rheumatoid arthritis, inhalants, passive smoking, silica, pollution

Introduction

Rheumatoid arthritis (RA) is a common systemic autoimmune disorder characterized by a painful and disabling polyarthritis[1]. Personal cigarette smoking has the strongest evidence as an environmental RA risk factor[2-4]. Personal cigarette smoking is specifically associated with seropositive (rheumatoid factor [RF] or anti-citrullinated protein antibody [ACPA] positivity) RA, responsible for up to 35% of the risk for seropositive RA[5, 6]. Smoking cessation has also been associated with reduced risk for developing seropositive RA[7]. The mucosal paradigm for seropositive RA pathogenesis hypothesizes that RA may develop at inflamed pulmonary mucosa in individuals with genetic predisposition where autoantibodies may be produced years prior to clinical RA onset[8-14].

Other environmental exposures are also likely to be related to RA since many non-smokers develop RA. While smoking rates have steadily declined over the last few decades in the United States, the incidence of RA has remained stable arguing that other environmental risk factors are important in RA pathogenesis[15]. Similar to personal cigarette smoking, other inhalants are hypothesized to induce local pulmonary mucosal and systemic inflammation[16]. In addition, specific inhalants may induce protein citrullination that could result in loss of immune tolerate to generate ACPA locally in pulmonary tissue prior to systemic production and articular inflammation. Thus, inhalants other than personal cigarette smoking may be important in RA pathogenesis. However, studies investigating inhalants for RA risk need to carefully account for cigarette smoking in analyses. For example, some inhalant-related occupations may be highly correlated with personal cigarette smoking making it difficult to identify independent associations. Smoking status (never/past/current) may be insufficient to capture granularity on intensity and duration of smoking. Investigating associations among never smokers may overcome some of these challenges.

The purpose of this narrative review is to provide an overview of recent studies that are investigating inhalants other than personal cigarette smoking for RA risk. We described the following inhalants that have the most literature for an association with RA: passive cigarette smoking, air pollution, inhalant-related occupations, silica, pesticides, household environment, and allergic inhalants. We did not include personal cigarette smoking since this has been detailed in previous reviews[4, 17-20].

Passive Cigarette Smoking

Several studies have investigated passive cigarette smoking and RA risk, reporting conflicting results (Table 1)[21-25]. The nuances of passive smoking, including age at exposure, intensity, duration, intensity, and location (home/work) of exposure, are challenging to measure and self-report may be prone to error or recall bias. Careful measurement and study design for analysis of personal cigarette smoking is important since passive and personal smoking are highly correlated and personal smoking likely imparts higher doses of harmful inhalants than passive smoking. Stratifying by personal smoking status or restricting the analysis to never smokers provides the highest evidence for the effect of passive smoking on RA risk since the never smoker subgroup is unlikely to be confounded by personal smoking. If smokers are analyzed, adjustment for personal smoking is essential, with continuous pack-years preferred over never/past/current (or never/ever) status, since smokers may have very different duration/intensity of smoking and could introduce confounding. Failure to account for personal smoking when investigating the association between passive smoking and RA risk may weaken the validity of the results. Even investigating childhood smoking is likely mediated/confounded by later personal smoking (highly correlated with parental smoking), so these studies should ideally still account for personal smoking. Table 1 provides details about the methods of accounting for personal smoking in each study.

Table 1.

Selected studies associating passive cigarette smoking with risk of rheumatoid arthritis.

Reference Study
design		 Population
Sample (n)
RA outcomes (n)		 Passive smoking
exposure methods		 RA outcome methods Personal cigarette
smoking and other adjustment variables		 Effect size
(95%
confidence interval) for passive
smoking
and RA risk		 Comments
Jaakkola JJ, Int J Epidemiol (2005) [24] Prospective cohort Finland, national registries, singleton births, <7 years of age n=58,841 n=44 incident RA Finnish Medical Birth Registry, categorical (no smoking, <10 cigarettes/day, >10 cigarettes/day) Hospitalization and/or billing code No personal smoking adjustment (but population was <7 years old) Sex, maternal parity, maternal age, marital status, maternal occupation, birth weight, gestational age RA and other polyarthritis in first 7 years of life: OR 2.10 (1.30-3.40)

  • Effect of maternal smoking on RA risk limited to girls

  • Higher exposure to smoke increased the risk of RA and other polyarthritis in girls

  • All cases were juvenile-onset; may not be generalizable to adult RA
Costenbader KH, Am J Med (2006) [25] Prospective cohort United Status, Nurses’ Health Study, female nurses n=103,818 n=453 incident RA Self-report, categorical (per 10 years lived with smoker) 1987 ACR criteria Stratified by ever/never smokers and ever smoker analysis adjusted for personal smoking (continuous, pack-years) BMI, alcohol use, paternal occupation, age at menarche, parity, duration of breastfeeding, postmenopausal hormone use All RA among ever smokers, >30 years lived with smoker (reference: 0 years): RR 1.59 (0.92-2.74) All RA among never smokers, >30 years lived with smoker (reference: 0 years): RR 1.46 (0.92-2.32)

  • Living with smoker for >30 years associated with increased RA risk, although not statistically significant

  • No dose effect

  • Measured smoke exposure at home and work
Hedström AK, Ann Rheum Dis (2018) [21] Case-control Sweden, never-smokers aged 18-70 years (EIRA) n=2,353 n=589 incident RA Self-report, categorical (per 10 years passive smoke exposure) 1987 ACR criteria All never smokers Age, sex, residential area, ancestry ACPA-positive RA: OR 1.0 (0.8-1.2) ACPA-negative RA: OR 0.9 (0.7-1.2)

  • No trend between duration of passive smoking and RA risk

  • No significant age- or sex-related differences
Seror R, Rheumatology (2019) [23] Prospective cohort France, females (E3N Cohort) n=71,248 n=371 incident RA Self-reported (≤a few hours a week vs >a few hours a day of childhood smoke exposure, <1 hour/day vs ≥1 hour/day of adult smoke exposure) Self-report and billing code No personal smoking adjustment (stratified analysis as never/ever smoking) Age Childhood passive smoking and all RA: HR 1.43 (0.97-2.11) Adult passive smoking and all RA: HR 0.96 (0.69-1.34)

  • RA onset earlier in smokers also exposed to smoke in childhood

  • No association between adult passive smoking and RA
Kronzer VL, Arthritis Rheumatol (2019) [22] Case-control Minnesota and Florida, Mayo Clinic Biobank participants n=4,084 n=1,023 prevalent/incident RA Self-report, categorical (/10 years smoke exposure, exposure in home vs workplace) Self-report, billing code, and/or 2010 ACR criteria Personal smoking status (never/past/current) Age, sex, BMI, race, education, year, residential area Home exposure and all RA: OR 1.06 (0.91-1.23) Workplace exposure and all RA: OR 1.01 (0.86-1.17) Combined home and workplace and all RA per 10 pack-years: OR 1.04 (1.00-1.09)

  • Also investigated age at first exposure, duration, and packs/day

  • Potential dose effect observed

  • No difference in effect of passive smoking on non-smokers vs smokers

  • Also investigated asthma and allergies for RA risk
Open in a new tab

Statistically significant results are bolded.

ACPA, anti-citrullinated protein antibody; ACR, American College of Rheumatology; BMI, body mass index; E3N, Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale; EIRA, Epidemiological Investigations of Rheumatoid Arthritis; HR, hazard ratio; OR, odds ratio; RA, rheumatoid arthritis.

Fetal exposure to cigarette smoking has been shown to increase RA risk[24]. Evidence from two studies suggested that smoke exposure during childhood may be associated with an increased RA risk[23, 24]. Neither study adjusted for personal smoking as the populations of interest were children, but those who were exposed to high levels of passive smoking may have been more likely to become smokers themselves[23, 24]. One of the studies stratified by adult personal smoking status (never/ever)[23].RA onset was earlier in smokers exposed to passive smoke during childhood than those without childhood exposure, although not statistically significant[23]. Passive smoke exposure during adulthood has not consistently been linked with increased RA risk[21-23, 25]. Three studies found no association between various measures of passive smoking and RA risk, after considering personal smoking [21, 22, 25]. Two of these studies were performed among only never smokers[21, 25] while the other adjusted for adult personal smoking status (never/ever/current)[22]. The absence of a relationship between passive smoking and RA risk may be explained by a minimum threshold below which there is no effect of passive smoke exposure on RA risk[21], although most studies use a binary passive smoke exposure of exposed/not exposed. One study using a higher passive smoking pack-year cut-point suggested a possible dose effect on RA risk[22]. Further research is needed to investigate passive smoking and RA risk independent of personal cigarette smoking.

Air Pollution

Ambient pollutants are composed of a mixture of gases (carbon monoxide [CO], nitrogen dioxide [NO2], ozone [O3], and sulfur dioxide [SO2]) and fine particulate matter [PM2.5: ≤2.5 μm in diameter; PM10 ≤10 μm in diameter]). Several studies reported an association between high levels of air pollution and increased RA risk, although there is less evidence linking specific air pollutants and RA[26-32]. The mechanisms linking air pollution and RA may be explained by the association between air pollutants, including wood-smoke, O3, and PM and the production of RA-specific autoantibodies[31-36]. Industrial emissions have been linked to elevated ACPA[35]. Conversely, there was no association between PM and RA-related autoantibodies[37]. These conflicting results may be explained by differences in methods of measuring air pollution exposures.

Industrial air emissions have also been linked to increased RA risk[26]. A study investigating the 1952 London Great Smog in London found an association between this early-life exposure to air pollution and subsequent RA risk[26]. Intense dust cloud exposure from the 9/11/01 World Trade Center terrorist attack in the US was associated with an almost two-fold increased risk of systemic autoimmune diseases, most commonly RA[32]. However, a prospective cohort study found no association between the risk of RA and adult exposure to gaseous pollutants (NO2 and SO2) or PM[38]. Two other studies corroborated these null findings[30, 39]. The importance of time windows of exposure to air pollution and source of pollutants in relation to RA risk should be a focus for future research.

Several other studies have used proximity to traffic as a marker of air pollution[30, 31, 39]. Traffic proximity was associated with an increased risk of RA[30, 39] and serum CRP level[31]. Socioeconomic status (SES) was found to be an important confounder, with a negative correlation between RA risk and SES[29, 33]. Many studies investigating the association between air pollution and RA risk considered markers of SES as confounding factors, including area-level income, education, and ZIP code, but there is likely still unmeasured confounding[26-34, 40].

Inhalant-related Occupations

Several studies have investigated inhalant-related occupations as RA risk factors. Among these studies, some investigated RA risk for occupations as a group compared to a control group not in that occupation[39, 41-44], while others investigated different exposures within a given type of occupation for RA risk[40, 45-48].These occupations fall primarily under the category of manual labor work that are more common for men (Table 2)[45, 49]. Individuals in manual labor occupations that involve high levels of repetitive physical strain may induce joint damage that results in higher levels of osteoarthritis and health care utilization, both of which may impact the likelihood of receiving a clinical diagnosis of RA[45, 46]. These occupations often involve many potential inhalant exposures, making it difficult to identify which factor may be responsible for associations[50]. Farming has been associated with increased RA risk[41, 42, 46, 49-51]. Pesticide use is the most commonly studied exposure among farmers, with recent studies now addressing other tasks and exposures in the farming industry[43]. Table 2 shows the associations found among regular application of chemical fertilizer, non-gasoline solvents, and other cleaning solvents[43]. Fertilizer use was found to be associated with increased RA risk[44, 50], and a statistically significant association for substantial organic solvent use[42]. In contrast, exposure to farm animals was found to be inversely associated with RA risk, though not statistically significant[50], while another study found farm animal dust to be significantly associated with increased RA risk[40, 47]. Grain and crops also showed an association with increased RA risk, though not statistically significant[44, 50]. Age and timing of these inhalant exposures along with accounting for the use of protective gear is warranted for future studies[43]. Solvents are less studied for RA risk, yet are present in other occupations such as engineering, painting, and simple tasks like cleaning hands[43].

Table 2.

Selected studies associating inhalant-related occupations with risk of rheumatoid arthritis.

Reference Study design Selected occupations
investigated		 Effect size (95% confidence
interval) for occupation and
all RA risk		 Postulated
occupational
inhalants		 Comments
Lundberg I, Scand J Rheumatol (1994) [46] Retrospective cohort

  • Farmers

  • Spray painters and lacquer workers

  • Concrete and construction workers

  • Male: RR 1.3 (1.0-1.6)

  • Male: RR 2.4 (1.1-5.4)

  • Male: RR 1.4 (1.1-2.0)

 Organic solvents and other various noxious airborne particles

  • Analyzed workers exposed to same occupation for 10+ years

  • Also investigated other manual labor jobs

  • Did not adjust for smoking
Olsson A, Scand J Work Environ Health (2000) [48] Case-control

  • Farmers

  • Asphalters

  • Textile workers

  • Male: OR 1.8 (1.0-3.5)

  • Male: OR 14.0 (1.2-16.2)

  • Male: OR 2.0 (0.3-16.2)

 Various noxious airborne particles

  • Required 20 years from time of work exposure to date of RA diagnosis

  • Adjusted for age and smoking status

  • Also investigated other manual labor occupations
De Roos AJ, Ann Epidemiol (2005) [39] Nested case-control

  • Farmers

  • Welders

  • OR 1.8 (0.6-5.0)

  • OR 1.8 (0.6-5.6)

 Pesticides
Welding fumes

  • Adjusted for age and state but not for smoking

  • Investigated types of pesticides used and frequency
Noonan C, Environ Health Perspect (2006) [51] Nested case-control

  • Military

  • Shipyard worker/ship construction

  • Construction

  • OR 2.11 (1.04-4.30)

  • OR 1.80 (0.72-4.46)

  • OR 1.32 (0.66-2.65)

 Asbestos

  • Evaluated number of exposure pathways

  • Adjusted for smoking history

  • Measures based on self-report
Li X, J Rheumatol (2008) [40] Retrospective cohort

  • Farmers

  • Textile workers

  • Miners and quarry workers

  • Male: SIR 1.2 (1.1-1.2); Female: SIR 1.0 (0.9-1.2)

  • Male: SIR 0.8 (0.6-1.1); Female SIR 0.8 (0.7-1.1)

  • Male: SIR 1.4 (1.0-1.9)

 Various noxious airborne particles

  • Analyses were stratified by predominant male and female occupations

  • Adjusted for age, years, region, and education
Jones K, J Occup Environ Med (2012) [53] Prospective cohort

  • Military

  • OR 1.17 (0.83-1.64)

  • OR 1.07 (0.77-1.50)

 Smoke from open-air burn pits

  • Adjusted for smoking status, sex, age, and race

  • Investigated several other working-class occupations
Cappelletti R, J Occup Med Toxicol (2016) [54] Retrospective cohort

  • Scrap Recyclers

  • RR 6.7 (2.00-19.02)

 Particulate matter

  • Did not adjust for smoking
Ilar A, Arthritis Care Res (2018) [52] Case-control

  • Bricklayers/concrete workers

  • Material handling operators

  • Electrical and electronic workers

  • OR 2.9 (1.4-5.7)

  • OR 2.4 (1.3-4.4)

  • OR 2.1 (1.1-3.8)

 Various noxious airborne particles

  • Adjusted for smoking pack-years, alcohol, BMI, and education

  • Also investigated other occupations
Parks CG, Occup Environ Med (2019) [47] Prospective cohort

  • Farming (high chemical fertilizer use)

  • Farming (high non-gasoline solvent use)

  • Farming (high other cleaning solvent use)

  • HR 1.5 (1.11-2.02)

  • HR 1.4 (1.09-1.80)

  • HR 1.40 (1.09-1.80)

 Chemical fertilizer
Non-gasoline solvents
Other cleaning solvents

  • Adjusted for smoking pack-years, state, education, and pesticides

  • Also investigated several other tasks and exposures related to farming
Schmajuk G, Arthritis Care Res (2019) [55] Case-control

  • Coal miners

  • OR 3.6 (2.1-6.2)

 Coal

  • Analyzed men from Appalachia (coal mining region)

  • Adjusted for smoking status, ergonomic factors, and race/ethnicity
Open in a new tab

Statistically significant results are bolded.

ACR, American College of Rheumatology; HR, hazard ratio; OR, odds ratio; RA, rheumatoid arthritis; RR, relative risk; SIR, standardized incidence ratio.

Another commonly studied inhalant-related occupation for RA risk includes construction workers[49]. Asbestos is a common exposure for construction workers, and some studies suggest an association with RA risk[42, 44, 48, 50]. However, two studies showed no significant association [9,10]. Tasks within construction work such as bricklaying, or material handling operators are significantly associated with increased risk of RA due to exposure to various noxious airborne particles[52]. Among military workers smoke from burn pits has been associated with RA[53]. One found no association of metal working with RA risk[49], while others suggested increased RA risk but were not statistically significant[42-44]. A significant association was found for scrap recyclers and RA risk[54]. Other dusts such as mineral dust and noxious particles from the coal mining industry/quarry workers have shown to be associated with RA risk[49, 55].

Since women are more likely than men to develop RA, female-predominant occupations have also been studied for RA risk. Within the textile industry, women exposed to textile dust were suggested to be at higher risk for developing RA[56], and other studies have reported higher rates of RA in the textile industry overall[44, 50].

Silica

Several studies support the association between silica exposure and increased RA risk (Table 3)[40, 57-63]. Three large studies found an association between silica exposure and both seropositive and seronegative RA[40, 57, 64]. The link between silica and seropositive RA was corroborated by two other studies, although they did not find a significant association with seronegative RA[59, 60]. Conversely, one study showed a protective effect of silica exposure on risk of RA [65]. However, the study population was small and limited to pottery, sandstone, and refractory materials workers and may have been prone to depletion of susceptibility bias since many of these workers had kept their occupations for decades when assessed for RA risk[65].

Table 3.

Selected studies associating silica inhalants with risk of rheumatoid arthritis.

Reference Study
design		 Population
Sample (n)
RA outcomes (n)		 Silica exposure methods RA outcome methods Cigarette
smoking and
other
adjustment
variables		 Effect size
(95%
confidence
interval) for
silica and RA
risk		 Comments
Klockars M, Br Med J (1987) [62] Retrospective cohort Central and south western Finland, male granite workers aged 15 to 72 years n=1,026 silica-exposed n=35 RA Dust concentration measured in workplace 1987 ACR criteria No smoking adjustment Age, residential area Incidence of disability pensions for RA: RR 5.08 (3.31-7.79)

  • Prevalence of RA and prevalence of patients receiving free medications for RA were significantly higher among granite workers than the general population
Turner S, Occup Environ Med (2000) [65] Case-control United Kingdom, pottery, sandstone, and refractory material (aluminosilicate or silica) workers n=290 n=58 RA Duration of physician-performed occupational history Physician-diagnosed RA Smoking status (ever or never) Age, sex, date, occupation, parity, pneumoconiosis Per 10 years silica exposure and all RA: OR 0.31 (0.16-0.61)

  • Only study suggesting a protective effect of silica for RA risk

  • Also investigated other cumulative silica exposures
Stolt P, Ann Rheum Dis (2005) [61] Case-control Sweden, men aged 18 to 70 years (EIRA Study) n=552 n=276 incident RA Self-reported exposure to stone dust, rock drilling, or stone crushing 1987 ACR criteria Smoking status (ever or never) Age, residential area All RA: OR 2.2 (1.2-3.9) RF-positive RA: OR 1.9 (0.9-4.0) RF-negative RA: OR 2.1 (0.8-5.1)

  • Older men were at particularly increased risk of all RA
Stolt, Ann Rheum Dis (2010) [60] Case-control Sweden, men aged 18-70 years (EIRA Study) n=1,236 n=577 incident RA Self-reported exposure to stone dust, rock drilling, or stone crushing 1987 ACR criteria No smoking adjustment Age, residential area All RA: OR 1.39 (0.98-1.96) ACPA-positive RA: OR 1.67 (1.13-2.48) ACPA-negative RA: OR 0.98 (0.57-1.66)

  • Rock drilling exposure showed particularly high risk of ACPA-positive RA

  • Analyses were also stratified by smoking and shared epitope status

  • Detected statistically significant silica-smoking interaction for ACPA-positive RA
Yahya A, Mod Rheumatol (2014) [59] Case-control Malaysia, males aged 18-70 years (MyEIRA Study) n=362 n=129 incident RA Self-reported exposure to stone dust, rock drilling, or stone crushing 1987 ACR criteria No smoking adjustment Age, sex, residential area All RA: OR 2.0 (0.9-4.6) ACPA-positive RA: OR 2.4 (1.0-5.6) ACPA-negative RA: OR 0.9 (0.2-4.5)

  • Also stratified by smoking status and investigated silica-smoking interaction

  • All subjects exposed to silica were also smokers
Blanc PD, Am J Med (2015) [57] Retrospective cohort Sweden, male construction workers aged 30 to 84 years n=240,983 n=713 incident RA Job-exposure matrices Billing code Smoking status (ever or never) Age All RA: RR 1.33 (1.11-1.60) Seropositive RA: RR 1.28 (1.02-1.61) Seronegative RA: RR 1.46 (1.03-2.07)

  • Also investigated other organic dusts and risk of autoimmune diseases
Vihlborg P, BMJ Open (2017) [58] Retrospective cohort Sweden, male iron foundry workers and general Swedish population n=2,187 n=18 seropositive RA Silica dust measurements for job categories (mg/m3) Billing code No smoking adjustment Age, sex, year Seropositive RA: SIR 1.70 (1.01-2.69)

  • Also investigated sarcoidosis
Ilar A, RMD Open (2019) [50] Case-control Sweden, EIRA Study and national registers n=126,534 n=11,285 RA Job-exposure matrices 2+ visits for RA and DMARD receipt Smoking pack-years (continuous) Age, sex, county, year, alcohol use All RA: OR 1.3 (1.2-1.5) Seropositive RA: OR 1.4 (1.2-1.5) Seronegative RA: OR 1.2 (1.0-1.4)

  • OR for seropositive RA higher with number of years exposed to silica

  • Results attenuated among women
Open in a new tab

Statistically significant results are bolded.

ACPA, anti-citrullinated protein antibody; ACR, American College of Rheumatology; DMARD, disease modifying anti-rheumatic drug; EIRA, Epidemiological Investigations of Rheumatoid Arthritis; OR, odds ratio; RA, rheumatoid arthritis; RF, rheumatoid factor; RR, relative risk; SIR, standardized incidence ratio.

Many studies have observed a dose-response effect between silica exposure and increased RA risk[40, 58, 60, 61, 63]. The risk of developing seropositive RA was particularly high among highly-exposed individuals, such as those working in rock drilling[60, 61] or stone crushing[58, 61, 63]. Furthermore, the duration of silica exposure was associated with increased seropositive RA risk[40]. This dose-response relationship may explain why the risk of RA was attenuated among women, as women had lower duration and intensity of silica exposure than men[40]. Conversely, older men had a particularly increased risk of RA, as they had a higher duration of silica exposure[61].

Several studies have investigated silica-smoking interactions, suggesting higher risk among individuals exposed to both silica and personal cigarette smoking than either exposure alone or neither inhalant exposure[57, 59, 60, 63, 64]. Three studies observed a significant silica-smoking interaction for seropositive RA[59, 60, 64].

Several studies have investigated the association between silica exposure and the production of RA-specific autoantibodies, such as RF[66, 67]. One study observed a positive relationship between duration of silica exposure and elevation of RF[67]. However, RF was only present in RA patients with silicosis[67]. Another study found no association between silica exposure and RF[66].

Pesticides

Studies observed a modest, non-significant association of pesticide use and RA[42, 51]. Another study found no relation of pesticides with RA in both males and females[50]. Childhood residential exposure to pesticides was associated with RA[68]. The association among different age groups supports the need for further research is needed across the lifespan regarding pesticide exposure and risk for RA[69].

Female spouses of pesticide applicators exposed to specific agricultural pesticides were found to have a greater risk for RA[68], and maneb/mancozeb pesticide was newly associated with increased overall risk for RA[68]. The most commonly used pesticide, glyphosate was only found to be moderately associated with RA[68]. In contrast, another study of female spouses did not find an association between specific classes of pesticides and RA[39]. Among postmenopausal women, a dose response trend for personal application was found[70]. Measured serum levels of dioxin and non-diozin like polychlorinated biphenyls were found to be associated with RA among women[41].

A study of male pesticide sprayers and RA risk measured four levels of exposure among several different pesticide classes[71]. They found fonofos, carbaryl, and chlorimuron ethyl to be associated with RA; trends were identified with the use of atrazine and toxaphene[71]. A study of male pesticide sprayers found statistically significant associations with RA perhaps related to pesticide, insecticide, fungicide, organophosphate, guanidine, and quinoe exposures[72].Several limitations are observed when studying this exposure such as exposure misclassification, timing and frequency of pesticides[68], as well as other unidentified specific exposures[69]. Furthermore, quantification of pesticide exposure varied across studies. Some studies classified occupations as exposed or non-exposed[43, 46], while more rigorous exposure assessments also accounted for method of application, duration, quantity, and frequency of pesticide exposure[69-73].

Household Environment

Moisture damage to buildings and homes may cause mold and other microbial growth with negative health outcomes[73, 74]. Some studies investigated the link between indoor mold and microbial inhalants and RA risk[73, 74]. Two prospective cohort studies followed for clusters of systemic inflammatory rheumatic diseases in moisture-damaged offices[73, 74]. The populations of both studies were mostly women and there were only a few RA outcomes[73, 74]. Another cluster of patients that developed systemic inflammatory rheumatic diseases was studied among a group of 11 workers in a moisture-damaged office, some of which developed seropositive RA[74]. The cases of rheumatic diseases tended to accumulate among subjects working closest to the wall with the worst microbial damage[74]. More rigorously designed studies are needed to determine whether household environment inhalants may be related to RA.

Allergic Inhalants

Allergies and autoimmune disorders like RA may result from hypersensitivity to antigens[75]. Since HLA loci are the strongest genetic risk factors for both allergies and RA, some individuals may have common genetics that predispose to both conditions. Some studies found that the presence of allergies and occurrence of autoimmune disorders act as antagonists due to being mediated by either Th1 and Th2 immune responses. However, the literature has conflicting results related to allergies and RA risk. For example, individuals with hay fever may have lower RA risk[76, 77]. In contrast, allergies were found to be associated with increased risk of RA[22]. Individuals with atopic dermatitis had increased RA risk[78], while a Taiwanese study found significant associations between allergic conditions such as atopic dermatitis or allergic rhinitis and increased RA risk[79]. A Danish prospective cohort study found no statistically significant associations between atopic dermatitis and RA[75]. Another study also found no evidence of an inverse relationship is present between atopic dermatitis and autoimmune disorders[80].

Other Inhalants

While relatively prevalent in the general population, to our knowledge other forms of inhaling tobacco or nicotine using devices like vapes, hookah, and cigars have not been studied in relation to RA risk. Vaping (or e-cigarette use) is a relatively new inhalant method that has also not been studied for RA risk. Prescription and recreational drug inhalants have also not been also studied in relation to RA risk. Investigating the relationship between these inhalant behaviors and risk for developing RA or RA-related autoantibodies would be a promising future research direction.

Conclusion

The identification of cigarette smoking as a strong environmental risk factor for RA has helped to elucidate a paradigm for RA pathogenesis related to inhalants and pulmonary mucosal inflammation. This has also led to investigations around other inhalants since many non-smokers develop RA. Many inhalants have been investigated for RA risk. Inhalant-related occupations and silica inhalants have the most consistent literature suggesting associations with increased RA risk. However, the data supporting these associations rely on mostly retrospective designs with limited ability to account for personal smoking. For example, many miners are also cigarette smokers so it is difficult to establish an independent relationship with RA. Adjusting for smoking status may not sufficiently capture the nuances of smoking intensity and duration. Many of the inhalant-related occupations are predominantly male so may not be generalizable to the female majority of RA patients. The literature is relatively conflicted for other inhalants such as passive cigarette smoking, air pollution, pesticides, household environment, and allergic inhalants for RA risk. Many of these inhalant exposures are relatively difficult to measure and rely either on self-report or geographic location which may introduce error or be difficult to replicate in other studies. Lack of data on personal cigarette smoking in some of these studies may be limiting since smoking likely provides a higher dose of noxious inhalants than the exposures being investigated. The timing of exposure throughout the life course is also challenging to analyze since many of the studies only had a relatively small time window of measurement of these chronic exposures. While inhalants are hypothesized to be specific to seropositive RA, many studies were unable to phenotype RA by serologic status. Despite these limitations, there have substantial advances in identifying potential inhalants related to RA risk over the past few years. Overall, these results provide further support the hypothesis that inhalants, pulmonary mucosal inflammation, and RA pathogenesis may be linked. Future prospective studies are needed to firmly establish the independence of these findings from personal cigarette smoking and to determine the specific inhalants and biologic mechanisms related to seropositive RA pathogenesis.

Acknowledgments

FINANCIAL SUPPORT AND SPONSORSHIP: Dr. Sparks is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253, and P30 AR072577), the Rheumatology Research Foundation K Supplement Award, and the Brigham Research Institute. Dr. Sparks has received research support from Amgen and Bristol-Myers Squibb and performed consultancy for Bristol-Myers Squibb, Optum, Janssen, and Gilead unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health.

Footnotes

CONFLICTS OF INTEREST: All authors declare no conflicts of interest.

REFERENCES

  • 1.Sparks JA, Rheumatoid Arthritis. Ann Intern Med, 2019. 170(1): p. ITC1–ITC16. [DOI] [PubMed] [Google Scholar]
  • 2.Sugiyama D, et al. , Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis, 2010. 69(1): p. 70–81. [DOI] [PubMed] [Google Scholar]
  • 3.Di Giuseppe D, et al. , Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis. Arthritis Res Ther, 2014. 16(2): p. R61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Sparks JA and Karlson EW, The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis. Curr Rheumatol Rep, 2016. 18(3): p. 15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Kallberg H, et al. , Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis, 2011. 70(3): p. 508–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Sparks JA, et al. , Contributions of familial rheumatoid arthritis or lupus and environmental factors to risk of rheumatoid arthritis in women: a prospective cohort study. Arthritis Care Res (Hoboken), 2014. 66(10): p. 1438–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Liu X, et al. , Impact and Timing of Smoking Cessation on Reducing Risk of Rheumatoid Arthritis Among Women in the Nurses' Health Studies. Arthritis Care Res (Hoboken), 2019. 71(7): p. 914–924.** Prospective cohort study showing that smoking cessation may reduce the risk of developing seropositive RA
  • 8.Kim K, et al. , Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis. Arthritis Rheumatol, 2015. 67(10): p. 2611–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Jiang X, et al. , An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis. Rheumatology (Oxford), 2016. 55(1): p. 149–55. [DOI] [PubMed] [Google Scholar]
  • 10.Holers VM, et al. , Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol, 2018. 14(9): p. 542–557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Zaccardelli A, et al. , Asthma and elevation of anti-citrullinated protein antibodies prior to the onset of rheumatoid arthritis. Arthritis Res Ther, 2019. 21(1): p. 246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Lucchino B, et al. , Mucosa-Environment Interactions in the Pathogenesis of Rheumatoid Arthritis. Cells, 2019. 8(7). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Joshua V, Chatzidionisyou K, and Catrina AI, Role of the lung in individuals at risk of rheumatoid arthritis. Best Pract Res Clin Rheumatol, 2017. 31(1): p. 31–41. [DOI] [PubMed] [Google Scholar]
  • 14.Chatzidionisyou A and Catrina AI, The lung in rheumatoid arthritis, cause or consequence? Curr Opin Rheumatol, 2016. 28(1): p. 76–82. [DOI] [PubMed] [Google Scholar]
  • 15.Crowson CS, et al. , The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum, 2011. 63(3): p. 633–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Catrina AI, et al. , Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol, 2014. 10(11): p. 645–53. [DOI] [PubMed] [Google Scholar]
  • 17.Friedlander HM, et al. , Obstructive lung diseases and risk of rheumatoid arthritis. Expert Rev Clin Immunol, 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Wang D, et al. , Mechanisms of lung disease development in rheumatoid arthritis. Nat Rev Rheumatol, 2019. 15(10): p. 581–596. [DOI] [PubMed] [Google Scholar]
  • 19.Perry E, et al. , The lung in ACPA-positive rheumatoid arthritis: an initiating site of injury? Rheumatology (Oxford), 2014. 53(11): p. 1940–50. [DOI] [PubMed] [Google Scholar]
  • 20.Baka Z, Buzas E, and Nagy G, Rheumatoid arthritis and smoking: putting the pieces together. Arthritis Res Ther, 2009. 11(4): p. 238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Hedstrom AK, Klareskog L, and Alfredsson L, Exposure to passive smoking and rheumatoid arthritis risk: results from the Swedish EIRA study. Ann Rheum Dis, 2018. 77(7): p. 970–972.* Population-based case-control study showing no association of passive smoking with RA risk.
  • 22.Kronzer VL, et al. , Investigating Asthma, Allergic Disease, Passive Smoke Exposure, and Risk of Rheumatoid Arthritis. Arthritis Rheumatol, 2019. 71(8): p. 1217–1224.* Large case-control suggesting asthma, combined work/home passive smoking, and allergies may be related to RA risk.
  • 23.Seror R, et al. , Passive smoking in childhood increases the risk of developing rheumatoid arthritis. Rheumatology (Oxford), 2019. 58(7): p. 1154–1162.* Large prospective cohort study suggesting passive smoking may be related to RA risk.
  • 24.Jaakkola JJ and Gissler M, Maternal smoking in pregnancy as a determinant of rheumatoid arthritis and other inflammatory polyarthropathies during the first 7 years of life. Int J Epidemiol, 2005. 34(3): p. 664–71. [DOI] [PubMed] [Google Scholar]
  • 25.Costenbader KH, et al. , Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am J Med, 2006. 119(6): p. 503 e1–9. [DOI] [PubMed] [Google Scholar]
  • 26.Shepherd A and Mullins JT, Arthritis diagnosis and early-life exposure to air pollution. Environ Pollut, 2019. 253: p. 1030–1037. [DOI] [PubMed] [Google Scholar]
  • 27.Shin J, et al. , Association between Exposure to Ambient Air Pollution and Rheumatoid Arthritis in Adults. Int J Environ Res Public Health, 2019. 16(7). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Chang KH, et al. , Air pollution exposure increases the risk of rheumatoid arthritis: A longitudinal and nationwide study. Environ Int, 2016. 94: p. 495–499. [DOI] [PubMed] [Google Scholar]
  • 29.Hart JE, et al. , Ambient air pollution exposures and risk of rheumatoid arthritis: results from the Swedish EIRA case-control study. Ann Rheum Dis, 2013. 72(6): p. 888–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Hart JE, et al. , Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ Health Perspect, 2009. 117(7): p. 1065–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Lanki T, et al. , Air Pollution from Road Traffic and Systemic Inflammation in Adults: A Cross-Sectional Analysis in the European ESCAPE Project. Environ Health Perspect, 2015. 123(8): p. 785–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Miller-Archie SA, et al. , Systemic autoimmune disease among adults exposed to the September 11, 2001, terrorist attack. Arthritis Rheumatol, 2019. [DOI] [PMC free article] [PubMed]
  • 33.Sigari N, et al. , Anti-cyclic citrullinated peptide (CCP) antibody in patients with wood-smoke-induced chronic obstructive pulmonary disease (COPD) without rheumatoid arthritis. Rheumatol Int, 2015. 35(1): p. 85–91. [DOI] [PubMed] [Google Scholar]
  • 34.Zhao T, et al. , Short-term exposure to ambient ozone and inflammatory biomarkers in cross-sectional studies of children and adolescents: Results of the GINIplus and LISA birth cohorts. Environ Pollut, 2019. 255(Pt 2): p. 113264. [DOI] [PubMed] [Google Scholar]
  • 35.Bernatsky S, et al. , Industrial air emissions, and proximity to major industrial emitters, are associated with anti-citrullinated protein antibodies. Environ Res, 2017. 157: p. 60–63. [DOI] [PubMed] [Google Scholar]
  • 36.Liu Q, et al. , Ambient particulate air pollution and circulating C-reactive protein level: A systematic review and meta-analysis. Int J Hyg Environ Health, 2019. 222(5): p. 756–764. [DOI] [PubMed] [Google Scholar]
  • 37.Gan RW, et al. , Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA. Ann Rheum Dis, 2013. 72(12): p. 2002–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Hart JE, et al. , Ambient air pollution exposures and risk of rheumatoid arthritis. Arthritis Care Res (Hoboken), 2013. 65(7): p. 1190–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.De Roos AJ, et al. , Rheumatoid arthritis among women in the Agricultural Health Study: risk associated with farming activities and exposures. Ann Epidemiol, 2005. 15(10): p. 762–70. [DOI] [PubMed] [Google Scholar]
  • 40.Ilar A, et al. , Occupational exposure to asbestos and silica and risk of developing rheumatoid arthritis: findings from a Swedish population-based case-control study. RMD Open, 2019. 5(2): p. e000978.* Swedish case-control study implicating asbestos and silica for RA risk
  • 41.Lee DH, Steffes M, and Jacobs DR, Positive associations of serum concentration of polychlorinated biphenyls or organochlorine pesticides with self-reported arthritis, especially rheumatoid type, in women. Environ Health Perspect, 2007. 115(6): p. 883–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Lundberg I, et al. , Occupation, occupational exposure to chemicals and rheumatological disease. A register based cohort study. Scand J Rheumatol, 1994. 23(6): p. 305–10. [DOI] [PubMed] [Google Scholar]
  • 43.Parks CG, et al. , Farming tasks and the development of rheumatoid arthritis in the agricultural health study. Occup Environ Med, 2019. 76(4): p. 243–249.** Large prospective cohort study implicating many inhalant-related farming tasks with RA risk
  • 44.Olsson AR, Skogh T, and Wingren G, Occupational determinants for rheumatoid arthritis. Scand J Work Environ Health, 2000. 26(3): p. 243–9. [DOI] [PubMed] [Google Scholar]
  • 45.Murphy D and Hutchinson D, Is Male Rheumatoid Arthritis an Occupational Disease? A Review. Open Rheumatol J, 2017. 11: p. 88–105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Gold LS, et al. , Systemic autoimmune disease mortality and occupational exposures. Arthritis Rheum, 2007. 56(10): p. 3189–201. [DOI] [PubMed] [Google Scholar]
  • 47.Ilar A, et al. , Occupational exposure to organic dusts and risk of developing rheumatoid arthritis: findings from a Swedish population-based case-control study. RMD Open, 2019. 5(2): p. e001049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Noonan CW, et al. , Nested case-control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspect, 2006. 114(8): p. 1243–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Li X, Sundquist J, and Sundquist K, Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden. J Rheumatol, 2008. 35(6): p. 986–91. [PubMed] [Google Scholar]
  • 50.Olsson AR, et al. , Occupations and exposures in the work environment as determinants for rheumatoid arthritis. Occup Environ Med, 2004. 61(3): p. 233–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Khuder SA, Peshimam AZ, and Agraharam S, Environmental risk factors for rheumatoid arthritis. Rev Environ Health, 2002. 17(4): p. 307–15. [DOI] [PubMed] [Google Scholar]
  • 52.Ilar A, et al. , Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population-Based Case-Control Study. Arthritis Care Res (Hoboken), 2018. 70(4): p. 499–509. [DOI] [PubMed] [Google Scholar]
  • 53.Jones KA, et al. , Newly reported lupus and rheumatoid arthritis in relation to deployment within proximity to a documented open-air burn pit in Iraq. J Occup Environ Med, 2012. 54(6): p. 698–707. [DOI] [PubMed] [Google Scholar]
  • 54.Cappelletti R, et al. , Health status of male steel workers at an electric arc furnace (EAF) in Trentino, Italy. J Occup Med Toxicol, 2016. 11: p. 7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Schmajuk G, et al. , Prevalence of Arthritis and Rheumatoid Arthritis in Coal Mining Counties of the United States. Arthritis Care Res (Hoboken), 2019. 71(9): p. 1209–1215.** Large study showing that coal miners are at very elevated risk for developing RA
  • 56.Too CL, et al. , Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case-control study. Ann Rheum Dis, 2016. 75(6): p. 997–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Blanc PD, Jarvholm B, and Toren K, Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers. Am J Med, 2015. 128(10): p. 1094–101. [DOI] [PubMed] [Google Scholar]
  • 58.Vihlborg P, et al. , Risk of sarcoidosis and seropositive rheumatoid arthritis from occupational silica exposure in Swedish iron foundries: a retrospective cohort study. BMJ Open, 2017. 7(7): p. e016839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Yahya A, et al. , Silica exposure is associated with an increased risk of developing ACPA-positive rheumatoid arthritis in an Asian population: evidence from the Malaysian MyEIRA case-control study. Mod Rheumatol, 2014. 24(2): p. 271–4. [DOI] [PubMed] [Google Scholar]
  • 60.Stolt P, et al. , Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis, 2010. 69(6): p. 1072–6. [DOI] [PubMed] [Google Scholar]
  • 61.Stolt P, et al. , Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann Rheum Dis, 2005. 64(4): p. 582–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Klockars M, et al. , Silica exposure and rheumatoid arthritis: a follow up study of granite workers 1940-81. Br Med J (Clin Res Ed), 1987. 294(6578): p. 997–1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Calvert GM, et al. , Occupational silica exposure and risk of various diseases: an analysis using death certificates from 27 states of the United States. Occup Environ Med, 2003. 60(2): p. 122–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Zeng P, et al. , Amount of smoking, duration of smoking cessation and their interaction with silica exposure in the risk of rheumatoid arthritis among males: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study. Ann Rheum Dis, 2018. 77(8): p. 1238–1241.** Most comprehensive study implicating smoking, silica, and smoking-silica interaction with RA risk.
  • 65.Turner S and Cherry N, Rheumatoid arthritis in workers exposed to silica in the pottery industry. Occup Environ Med, 2000. 57(7): p. 443–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Aminian O, et al. , Antinuclear antibody and rheumatoid factor in silica-exposed workers. Arh Hig Rada Toksikol, 2009. 60(2): p. 185–90. [DOI] [PubMed] [Google Scholar]
  • 67.Zaghi G, et al. , Autoantibodies in silicosis patients and in silica-exposed individuals. Rheumatol Int, 2010. 30(8): p. 1071–5. [DOI] [PubMed] [Google Scholar]
  • 68.Parks CG, et al. , Rheumatoid Arthritis in Agricultural Health Study Spouses: Associations with Pesticides and Other Farm Exposures. Environ Health Perspect, 2016. 124(11): p. 1728–1734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Parks CG, D'Aloisio AA, and Sandler DP, Childhood Residential and Agricultural Pesticide Exposures in Relation to Adult-Onset Rheumatoid Arthritis in Women. Am J Epidemiol, 2018. 187(2): p. 214–223.* First study to investigate childhood exposure to pesticides with RA risk in adulthood.
  • 70.Parks CG, et al. , Insecticide use and risk of rheumatoid arthritis and systemic lupus erythematosus in the Women's Health Initiative Observational Study. Arthritis Care Res (Hoboken), 2011. 63(2): p. 184–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Meyer A, et al. , Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study. Environ Health Perspect, 2017. 125(7): p. 077010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Koureas M, et al. , Increased Frequency of Rheumatoid Arthritis and Allergic Rhinitis among Pesticide Sprayers and Associations with Pesticide Use. Int J Environ Res Public Health, 2017. 14(8). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Luosujarvi RA, et al. , Joint symptoms and diseases associated with moisture damage in a health center. Clin Rheumatol, 2003. 22(6): p. 381–5. [DOI] [PubMed] [Google Scholar]
  • 74.Myllykangas-Luosujarvi R, et al. , A cluster of inflammatory rheumatic diseases in a moisture-damaged office. Clin Exp Rheumatol, 2002. 20(6): p. 833–6. [PubMed] [Google Scholar]
  • 75.Skaaby T, et al. , Specific IgE positivity against inhalant allergens and development of autoimmune disease. Autoimmunity, 2015. 48(5): p. 282–8. [DOI] [PubMed] [Google Scholar]
  • 76.Verhoef CM, et al. , Mutual antagonism of rheumatoid arthritis and hay fever; a role for type 1/type 2 T cell balance. Ann Rheum Dis, 1998. 57(5): p. 275–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Hartung AD, et al. , Th2-mediated atopic disease protection in Th1-mediated rheumatoid arthritis. Clin Exp Rheumatol, 2003. 21(4): p. 481–4. [PubMed] [Google Scholar]
  • 78.Schmitt J, et al. , Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. J Allergy Clin Immunol, 2016. 137(1): p. 130–136. [DOI] [PubMed] [Google Scholar]
  • 79.Lai N-S, et al. , Association of rheumatoid arthritis with allergic diseases: A nationwide population-based cohort study. Allergy and asthma proceedings, 2015. 36(5): p. 99–103. [DOI] [PubMed] [Google Scholar]
  • 80.Sheikh A, Smeeth L, and Hubbard R, There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: Lack of support for the hygiene hypothesis. J Allergy Clin Immunol, 2003. 111(1): p. 131–5. [DOI] [PubMed] [Google Scholar]

RESOURCES