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Arthritis & Vol. 71, No. 8, August 2019, pp 1217–1224 DOI 10.1002/art.40858 © 2019, American College of Rheumatology

Investigating , Allergic Disease, Passive Smoke Exposure, and Risk of Rheumatoid

Vanessa L. Kronzer,1 Cynthia S. Crowson,1 Jeffrey A. Sparks,2 Robert Vassallo,1 and John M. Davis III1

Objective. Rheumatoid arthritis (RA) is postulated to originate at mucosal surfaces, particularly the airway muco- sa. To investigate this hypothesis, we determined the association between RA and asthma, passive smoke exposure, and age at start of smoking. Methods. For this case–control study, we identified 1,023 cases of RA (175 incident) within a single- center biobank population, using a rules-based algorithm that combined self-report with 2 diagnostic codes. Exposures were self-reported on biobank questionnaires. Logistic regression models were used to calculate the association of exposures with RA, adjusting for potential confounders. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results. After adjustment for , urban environment, and passive smoke exposure, asthma was found to be associated with RA in the full cohort (OR 1.28 [95% CI 1.04–1.58; P = 0.02]) but not the incident RA cohort (OR 1.17 [95% CI 0.66–2.06; P = 0.60]). History of allergic disease was associated with RA in both the full cohort (OR 1.30 [95% CI 1.12–1.51; P < 0.001]) and the incident RA cohort (OR 1.61 [95% CI 1.11–2.33; P = 0.01]), especially food , which was significantly associated with RA in the full cohort (OR 1.38 [95% CI 1.08–1.75; P = 0.01]) and showed a trend toward significance in the incident RA cohort (OR 1.83 [95% CI 0.97–3.45;P = 0.06]). Passive smoke exposure at home or work was not associated with RA. Finally, age at start of smoking was not associated with increased odds of developing RA in either the full cohort (OR 1.03 [95% CI 1.00–1.06; P = 0.03]) or the incident RA cohort (OR 1.00 [95% CI 0.92–1.08; P = 0.98]). Conclusion. Asthma and allergies may be associated with increased risk of RA. Passive smoke exposure and early age at start of smoking do not appear to influence risk of RA.

INTRODUCTION and asthma (13,14). It is unclear whether asthma is associated with RA after adjustment for these important confounders. Rheumatoid arthritis (RA) is one of the most common autoim- Second, the association between personal smoking and RA mune diseases, affecting nearly 1 in 100 individuals (1). Seroposi- has been well-established (15,16), yet only 3 studies have investi- tive RA in particular is hypothesized to originate from gated the association between passive smoke exposure and RA in the respiratory tract, resulting in formation that (10,17,18). The results of these studies conflict, with 2 suggesting later leads to disease (2,3). However, several questions about this an association between passive smoking and RA and the other hypothesis of disease generation remain, which, if answered, may showing no association. None of these prior reports characterized help elucidate disease pathogenesis. workplace smoke exposure alone or contained information about First, several studies have shown an association between both the duration and intensity to allow a dose- response analysis. asthma and RA, which may be explained by a shared immuno- Earlier age of smoking may also be important, but has not yet logic mechanism (4–8). However, a major limitation of these pre- been studied in patients with RA (19). vious studies is the lack of adjustment for allergic disease. More- Our goal in this study was to clarify these gaps in knowl- over, none included adjustment for secondhand cigarette smoke edge related to the oral-respiratory factors that may mediate RA or urban pollution, which are known contributors to RA (9–12) pathogenesis. Specifically, we aimed to determine the association

Supported by a Rheumatology Research Foundation Resident Research No potential conflicts of interest relevant to this article were reported. Preceptorship. Address correspondence to Vanessa L. Kronzer, MD, MSCI, Mayo Clinic, 1Vanessa L. Kronzer, MD, MSCI, Cynthia S. Crowson, PhD, Robert Vassallo, 200 First Street SW, Rochester, MN 55905. E-mail: kronzer.vanessa@mayo. MD, John M. Davis III, MD, MS: Mayo Clinic, Rochester, Minnesota; 2Jeffrey A. edu. Sparks, MD, MMSc: Brigham and Women’s Hospital, Harvard Medical School, Submitted for publication September 11, 2018; accepted in revised form Boston, Massachusetts. February 7, 2019.

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of RA with asthma after controlling for allergic disease, urban who self- reported RA on the follow- up questionnaire but not the environment, passive smoke (exposure at home and work), and baseline questionnaire, for a total of 175 incident cases. age at start of smoking. We hypothesized that the association with To determine the accuracy of our RA definition in the full cohort, asthma would be attenuated after adjustment for allergy and envi- we performed manual chart verification using the 2010 ACR criteria ronmental pollutants, that passive smoke at higher doses would in a subset of 100 randomly selected RA cases (23). One of the be associated with RA, and that earlier age at start of smoking authors (VLK) performed the main chart review, and another author would be associated with an increased risk of RA. (JMD) adjudicated any cases with uncertainty. Of the 100 patients selected, 87 were found to have RA or seronegative consistent with RA, for a PPV of 87% (Supplementary Table PATIENTS AND METHODS 1, available on Arthritis & Rheumatology web site at http://onlineli- Study design. This case–control study was performed brary.wiley.com/doi/10.1002/art.40858/abstract). according to the Strengthening the Reporting of Observational We defined the index date as the date of RA diagnosis. The studies in Epidemiology (STROBE) guidelines for observational date of RA diagnosis came from the earliest diagnostic code for RA, studies (20). The study was approved by the Mayo Clinic and provided this date was in the age range of RA diagnosis reported by Olmsted County Institutional Review Boards (approval nos. the patient (≤19, 20–49, 50–64, 65–79, or 80+ years), or earlier. If the 17- 010806 and 060- OMC- 17), and was in compliance with the first diagnostic code occurred after the patient- reported date of RA Declaration of Helsinki. diagnosis, then we used the patient- reported date of RA diagnosis. Questionnaire data for this study came from the Mayo Clinic Controls for this study included biobank participants without Biobank repository (21). Active recruitment took place from April self- reported RA and no diagnostic codes for RA to ensure none 2009 to December 2015 in both Minnesota and Florida. Eligibility had RA (negative predictive value >99%). We used 3:1 match- criteria included age of 18 years or older, ability to communicate ing for the remaining biobank participants, with matching criteria in English, capacity to consent, and residence in the US. Approx- consisting of recruitment year (within 5 years), recruitment location imately 29% of those invited agreed to participate and completed (Minnesota or Florida), distance from recruitment location (within a baseline questionnaire, yielding the 55,898 current participants. 500 miles), age at baseline survey (within 5 years), and sex. The Of those, 77% completed the follow- up questionnaire sent ~4 index date for each control was defined as the date of RA diagno- years later. To ensure the validity and quality of data, all ques- sis for the corresponding case. tionnaires were visually examined for errors and omissions. Those with >10 errors were returned to participants for correction. A Measures. The prespecified primary exposures of interest computer program was also used to find logical errors and incor- included self-reported asthma, presence of passive smoke expo- rect skip patterns, flagging records for manual verification. Of the sure at home and work, and age at start of smoking regularly. 55,898 biobank participants, ~87% were recruited from primary For passive smoke exposure, we also studied the age the smoke care locations, including internal medicine, preventive medicine, exposure started, years of exposure before index date, packs per family medicine, and obstetrics/gynecology. Most of the remaining day, and pack- years before index date. Home and workplace participants were recruited from orthopedics. smoke exposure in packs per day was only available in the second version of the baseline questionnaire. Self- report is the most accu- Study population. In this study, we defined cases of RA rate way to study smoking history, and studies suggest that self- using a rules-based algorithm that combined self- reported RA on reported asthma has a high PPV as well (24,25). We performed either the baseline or follow-up questionnaire with at least 2 RA a manual verification of self- reported asthma on a random subset diagnostic codes (714.0 or 714.9) 30 days apart. We excluded of 50 study participants. We used previously published criteria 38 individuals who reported RA on the baseline questionnaire but to identify “definite” asthma as a physician diagnosis of asthma not on the follow- up questionnaire, as those individuals are likely during a clinical visit in the chart and/or the presence of each of to have misrepresented RA status. Using a separate cohort of 732 the following 3 conditions: 1) history of cough with wheezing or individuals screened for inclusion in the RA cohort of the Roches- dyspnea, 2) variability in symptoms, and 3) ≥2 features supportive ter Epidemiology Project (1), which used the 1987 American Col- of the diagnosis, including sleep disturbance, nonsmoker, nasal lege of Rheumatology classification criteria for RA (22), we found polyps, blood , elevated IgE level, history of wheezing the positive predictive value (PPV) of this definition to be 88%. This on exposure to antigen, pulmonary function test results indicative accuracy was superior to that obtained using diagnostic codes of asthma, and/or favorable clinical response to bronchodilator alone, which is a widely accepted method. (26). We defined “probable” asthma as having the first 2 condi- We also included 78 participants who did not self-report RA tions but not the third. Using these criteria, we found 82% of these but had 3 or more diagnostic codes for RA, with the first code 50 participants with self-reported asthma to have definite asthma occurring at least 90 days after the most recent survey (presumed and 8% to have probable asthma (Supplementary Table 2, http:// incident RA). The incident RA group also included 97 individuals onlinelibrary.wiley.com/doi/10.1002/art.40858/abstract). ORAL-RESPIRATORY EXPOSURES AND RA | 1219

Table 1. Characteristics of the RA cases and controls at index date of diagnosis* RA cases Incident RA subset Controls (n = 1,023) (n = 175) (n = 3,061) Age, mean ± SD years 50 ± 16 63 ± 14 50 ± 16 Female sex, no. (%) 741 (72) 119 (68) 2215 (72) , mean ± SD kg/m2† 30 ± 7 30 ± 6 29 ± 6 White, non- Hispanic race, no. (%) 1,000 (98) 172 (98) 2,982 (97) Education, no. (%) Less than high school 21 (2) 1 (0.6) 61 (2) High school degree 181 (18) 24 (14) 496 (16) Technical school 111 (11) 20 (11) 272 (9) Some college 281 (28) 46 (26) 722 (24) Bachelor’s degree 213 (21) 37 (21) 732 (24) Graduate degree 201 (20) 43 (25) 736 (24) Other 15 (2) 4 (2) 42 (1) Personal smoking Never, no (%) 532 (52) 91 (52) 1,796 (59) Past, no. (%) 431 (42) 77 (44) 1,105 (36) Current, no. (%)† 60 (6) 7 (4) 160 (5) Duration of smoking, years 22 (13–31) 26 (12–23) 18 (10–28) Packs per day 0.8 (0.5–1.5) 0.8 (0.5–0.8) 0.8 (0.5–0.8) Pack-years 15 (8–29) 19 (10–35) 13 (6–24) Age started smoking regularly, years 18 (16–19) 18 (16–20) 18 (16–20) Asthma, no. (%)† 169 (17) 21 (13) 383 (13) Urban environment, no. (%) 741 (73) 124 (72) 2260 (74) Any allergy, no. (%)† 643 (64) 112 (65) 1739 (58) Food 106 (11) 17 (10) 241 (8) Grass, pollen, or dust 323 (32) 56 (33) 932 (31) Pets 125 (12) 19 (11) 360 (12) Insects 76 (8) 11 (6) 228 (8) Other 380 (38) 67 (39) 957 (32) Home smoke exposure Yes, no. (%) 665 (65) 104 (60) 1890 (62) Age home smoke exposure started, years 0 (0–15) 0 (0–15) 0 (0–15) Duration, years 18 (12–21) 20 (16–29) 18 (10–20) Packs per day 0.8 (0.5–1.5) 0.8 (0.5–1.5) 0.8 (0.5–1.5) Pack-years 14 (8–27) 17 (9–29) 12 (8–26) Workplace smoke exposure Yes, no. (%) 394 (39) 62 (35) 1105 (36) Age workplace smoke exposure started, years 25 (17–25) 25 (17–25) 25 (17–25) Duration, years 10 (5–20) 10 (5–20) 10 (5–19) Packs per day 0.8 (0.5–1.5) 0.8 (0.5–1.5) 0.8 (0.5–1.5) Pack-years 8 (4–15) 10 (4–20) 8 (3–15) Dental visit in previous year, no. (%)† 863 (85) 154 (88) 2646 (87) * Except where indicated otherwise, values are the median (interquartile range). RA = rheumatoid arthritis. † Values at time of baseline questionnaire rather than index date.

History of allergy was another exposure of interest in this participants were prompted to mark all allergies that apply: “food study. The questionnaire included the query, “Do you have any allergies such as shellfish or nuts,” “grasses, pollen, or dust,” allergies?” to which participants responded yes or no. If yes, “pets,” “insect stings or bites,” and/or “other.” 1220 | KRONZER ET AL

Secondary exposures of interest included history of personal Table 2. Association between asthma and RA* smoking (yes/no), current smoking (yes/no), smoking duration OR (95% CI) before index date (years), packs per day, and pack-years before Incident RA index date. Data for all exposures and confounders of interest All RA cases subset came from the baseline and follow-up questionnaires. Age, sex, (n = 1,023) (n = 175) body mass index (BMI), and race were confirmed by the Mayo Unadjusted 1.38 (1.14–1.68) 1.28 (0.75–2.20) Clinic medical records, leading to complete data for these fields Standard 1.37 (1.12–1.67)‡ 1.31 (0.74–2.28) (27). Obesity was defined as BMI ≥30 kg/m2. adjustment† Full adjustment§ 1.28 (1.04–1.58)‡ 1.17 (0.66–2.06) Statistical analysis. Chi- square tests were used to com- * RA = rheumatoid arthritis; OR = odds ratio; 95% CI = 95% confi- pare proportions, and Wilcoxon’s sum tests were used to dence interval. compare continuous variables. To assess the relationship between † Adjusted for age, sex, body mass index, race, education, and per- sonal smoking (never/past/current). each exposure and case/control status, unconditional logistic ‡ P < 0.05. regression models were used. Sensitivity analyses were performed § Adjusted for allergic disease, urban environment, and home/ among the 175 cases of incident RA to allow for interpretation of workplace smoke exposure, in addition to the factors listed above. results with clear timing of exposures before disease and without any possibility of recall bias. An additional sensitivity analysis was statistically significant in the incident RA subset (OR 1.17 [95% performed in the subset of 189 participants with known serologic CI 0.66–2.06; P = 0.60]) (Table 2). status, of whom 111 were positive for (RF) and/ History of any allergy type was also found to be associated or to cyclic citrullinated peptide (CCP). with RA in the full study cohort (OR 1.30 [95% CI 1.12–1.51; Of the 4,084 study participants, 322 (7.8%) had missing data P < 0.001]). Further analyses examined the association of RA for at least 1 of the key questionnaire items, including history of among different allergy types. Food allergies in particular were asthma, allergy, and personal, home, or workplace smoking expo- most highly associated with RA (OR 1.38 [95% CI 1.08–1.75; sure. Because of the low frequency of missing data and even lower P = 0.01]) (Figure 1). The association with allergy was also sig- missingness among each of the individual models, the impact of nificant in the incident RA subset (OR 1.61 [95% CI 1.11–2.33; missing data on the main study results was deemed low. Partic- P = 0.01]). In particular, a history of showed a trend ipants with missing data were excluded from the model pertain- toward an increase in the odds of developing RA in the incident ing to that exposure. All analyses were prespecified in a protocol RA subset (OR 1.83 [95% CI 0.97–3.45; P = 0.06]). unless described as “post hoc.” We performed analyses using SAS There was no evidence of an association between home version 9.4 (SAS Institute), with a 2- sided alpha level of 0.05 as the or workplace smoke exposure and RA in either the full cohort threshold for significance and 95% confidence intervals (95% CIs). or the incident RA subset, except for years of home smoke exposure (Table 3). When home and workplace smoke expo- sure were combined in a post hoc analysis, participants with RESULTS the highest levels of cumulative passive smoke exposure had This study included 1,023 cases of RA from the 55,898 biobank participants. The mean ± SD age at index date of RA diagnosis for both cases and controls was 50 ± 16 years, while the mean ± SD age at the time of the baseline survey was 62 ± 13 years. In unadjusted analyses, the RA group included a higher proportion of individuals with a history of personal smoking and allergies, along with increased home smoke exposure pack-years compared to controls (Table 1). Characteristics of the incident RA subgroup were similar to those of the full RA cohort, except for slightly longer dura- tion of smoking before RA and lower frequency of workplace smoke exposure and asthma (Table 1). In the full study cohort in the unadjusted analysis, asthma was significantly associated with RA (odds ratio [OR] 1.38 [95% Figure 1. Adjusted association between allergy types and CI 1.14–1.68; P < 0.001]). This difference remained statisti- rheumatoid arthritis (RA). Each data point represents a separate cally significant even after controlling for home and workplace model adjusted for age, sex, body mass index, race, education, and smoke exposure, urban environment, and presence of allergies personal smoking (never/past/current). Referent is patients without (OR 1.28 [95% CI 1.04–1.58; P = 0.02]). However, it was not the particular allergy. 95% CI = 95% confidence interval. ORAL-RESPIRATORY EXPOSURES AND RA | 1221

increased odds of developing RA in the full cohort (OR 1.37 had a different effect among nonsmokers compared to smok- [95% CI 1.02–1.84]), but not in the incident RA subset (OR 1.34 ers (P for interaction = 0.29, 0.65, and 0.67, respectively). [95% CI 0.68–2.67]) (Table 3). To determine whether the effect Personal smoking, and its duration, intensity, and pack- of passive smoke exposure may be higher among nonsmokers, years, were all significant predictors of RA in the full cohort but we performed an additional analysis examining the interaction not in the incident RA subset (Table 4). Age at start of smoking between history of personal smoking (yes or no) and pack- was not associated with an increase in the odds of developing years of home, workplace, and combined home/workplace RA in either the full cohort (OR 1.03 [95% CI 1.00–1.06]) or the smoke exposure. There was no evidence that passive smoking incident RA cohort (OR 1.00 [95% CI 0.92–1.08]).

Table 3. Adjusted association between passive smoke exposure and RA* Multivariable OR (95% CI) All RA cases Incident RA subset Passive smoke type (n = 1,023) (n = 175) Home smoke exposure Yes 1.06 (0.91–1.23) 0.81 (0.56–1.18) Age home exposure started† 1.00 (0.99–1.01) 0.99 (0.96–1.01) Duration, years‡ 1.09 (0.99–1.21) 1.37 (1.08–1.72)§ Packs per day 1.12 (0.94–1.01) 1.20 (0.74–1.94) Pack-years‡ 1.03 (0.97–1.09) 1.14 (0.99–1.32) None (referent) 1.00 1.00 1–9 0.97 (0.78–1.21) 0.63 (0.35–1.17) 10–19 1.13 (0.88–1.45) 0.83 (0.43–1.62) 20–29 1.27 (0.94–1.71) 1.41 (0.68–2.92) 30–39 1.13 (0.71–1.78) 1.07 (0.35–3.34) 40+ 1.14 (0.80–1.63) 1.09 (0.47–2.51) Workplace smoke exposure Yes 1.01 (0.86–1.17) 1.04 (0.71–1.52) Age workplace exposure started† 1.01 (0.99–1.03) 1.03 (0.97–1.07) Duration, years‡ 1.01 (0.85–1.19) 1.05 (0.66–1.67) Packs per day 1.15 (0.97–1.36) 1.20 (0.74–1.93) Pack-years‡ 1.04 (1.00–1.09) 1.12 (0.83–1.49) None (referent) 1.00 1.00 1–9 1.01 (0.81–1.26) 0.94 (0.51–1.74) 10–19 0.88 (0.61–1.25) 0.92 (0.38–2.21) 20–29 0.84 (0.46–1.52) 1.12 (0.21–6.09) 30–39 1.80 (1.01–3.19)§ 2.36 (0.56–9.94) 40+ 1.17 (0.64–2.13) 3.55 (0.64–19.8) Combined home/workplace smoke exposure Pack-years‡ 1.04 (1.00–1.09) 1.15 (1.02–1.29) None (referent) 1.00 1.00 1–9 0.93 (0.74–1.17) 0.65 (0.35–1.21) 10–19 1.08 (0.84–1.39) 0.63 (0.31–1.26) 20–29 1.07 (0.79–1.45) 0.96 (0.46–2.01) 30–39 1.13 (0.76–1.67) 1.07 (0.31–3.76) 40+ 1.37 (1.02–1.84)§ 1.34 (0.68–2.67) * Each variable was assessed in a separate model with adjustment for age, sex, body mass index, race, education, and personal smoking (never/past/current). RA = rheumatoid arthritis; 95% CI = 95% confidence interval. † Adjusted for pack-years of passive smoke exposure, in addition to the factors listed above. ‡ Odds ratios (ORs) reported per 10 units. § P < 0.05. 1222 | KRONZER ET AL

Table 4. Adjusted association between personal smoking and RA* On the other , the presence of a positive association Multivariable OR (95% CI) between allergy and RA was initially unexpected, since current immunologic theory segregates RA into the Th1 pathway and All RA cases Incident RA subset (n = 1,023) (n = 175) allergy into the Th2 pathway (37). A review of older literature shows that the association between allergy and RA was such a strong Ever smoked vs. 1.26 (1.09–1.46)† 1.26 (0.88–1.81) never clinical observation that rheumatologists thought allergy might be Current smoker 1.07 (0.78–1.46) 0.68 (0.29–1.59) involved in the pathogenesis of RA (38,39). Subsequently, sev- vs. past/never eral small studies showed no association between and RA Duration, years‡ 1.18 (1.06–1.31)† 0.97 (0.77–1.22) (32–34,40,41). More recently, however, several larger cohort stud- Packs per day 1.20 (1.03–1.40)† 1.06 (0.71–1.58) ies have repeatedly demonstrated a positive association between Pack- years‡ 1.07 (1.01–1.13)† 0.96 (0.84–1.10) allergic disease and RA (5,29,42–44), and a study in The Nether- * Each variable was assessed in a separate model with adjustment lands showed that parental increased the odds of for age, sex, body mass index, race, education. RA = rheumatoid offspring allergic disease (45). Biologic support for this association arthritis; OR = odds ratio; 95% CI = 95% confidence interval. includes higher levels of IgE antibodies (46), interleukin- 4 produc- † < 0.05. P tion (47), and mast cells (48) in patients with RA. It is possible that ‡ Odds ratios (ORs) reported per 10 units. as with RA and asthma, a broader problem with immune dysreg- Finally, a sensitivity analysis was performed among the ulation underlies both types of diseases, and having one predis- subset of patients known to have elevated RF and/or CCP poses to the other. antibodies. Although the group positive for antibodies was Passive smoke exposure at home or the workplace, includ- small, associations were similar to the main results of the study ing the age the exposure began, duration, intensity, and pack- (see Supplementary Table 3, http://onlinelibrary.wiley.com/ years, was not associated with RA. A prior study also showed doi/10.1002/art.40858/abstract). However, there was a sugges- no evidence of association when combining home and work- tion of a stronger association with grass allergy and home smoke place exposure (17). However, because information about the exposure (yes or no). Characteristics of patients with missing intensity of smoke exposure was not collected in that study, the data are shown in Supplementary Table 4 (http://onlinelibrary. dose-response effect was not evaluated. When stratifying pas- wiley.com/doi/10.1002/art.40858/abstract). sive smoke exposure by pack-years, we did find evidence of an association between RA and the highest levels of workplace smoke exposure and combined home and workplace smoke DISCUSSION exposure. Thus, high levels of passive smoke exposure may This study addresses several gaps related to the oral- place individuals at higher risk for RA, even among smokers. respiratory hypothesis of RA pathogenesis. Namely, the results This finding may explain why an association of passive smok- support the concept of a marginal association between asthma ing with RA was suggested in 2 other studies, especially among and RA, identify a connection between allergy and RA, and pro- individuals with a longer duration of exposure extending back to vide evidence against the notion that passive smoke or earlier childhood (10,18). age of smoking predisposes individuals to RA. Personal smoking was also associated with RA compared First, in the full cohort, asthma was associated with RA even to nonsmoking in the full cohort. This is consistent with find- after adjustment for allergy and pollutants, which is an associa- ings in previous studies (10,16), which provides reassurance tion not previously shown. The association between asthma and about the validity of our study. However, personal smoking RA is potentially biologically plausible. Both are immunologic was not associated with RA in our incident RA cohort. There disorders profoundly influenced by environmental factors that are several potential explanations for this. One is that the inci- induce oxidative stress such as cigarette smoke, wood smoke, dent RA cohort reflects a different subtype of RA, compared to and environmental pollution (9–14). Moreover, there are many older cases with disease etiology rooted in factors other than potential mechanisms that may mediate both disorders, includ- smoking. Alternatively, it is possible that there were more sub- ing Th17 inflammation, infectious triggers, premature immune jects who were misclassified in the incident RA group than the senescence, or other inflammation mediators, such as tumor full RA cohort, biasing results in that group to the null hypoth- factor and leukotrienes (28). However, the strength of esis. Thus, it is important to consider both the full RA cohort association was attenuated after adjustment for newly consid- and the incident RA cohort when interpreting study findings. A ered confounders, and the relationship was not statistically sig- novel finding related to personal smoking history was that ear- nificant in the incident RA cohort. Thus, the overall findings from lier age of smoking was not associated with increased odds of this study reflect the uncertainty of existing literature, with some developing RA. Therefore, earlier age at start of smoking may studies supporting an association between asthma and RA not be more dangerous compared to start of smoking later in (4–8,29–31) and others refuting such an association (24,32–36). life, with respect to RA risk. ORAL-RESPIRATORY EXPOSURES AND RA | 1223

One strength of this study is its large sample size. Another is 2. Janssen KM, de Smit MJ, Brouwer E, de Kok FA, Kraan J, its detailed questionnaire data. These detailed survey questions Altenburg J, et al. Rheumatoid arthritis-associated in non- rheumatoid arthritis patients with mucosal inflammation: a provided impressive granularity for the exposures of interest such case- control study. Arthritis Res Ther 2015;17:174. as personal and passive smoking, and also potential confound- 3. Quirke AM, Perry E, Cartwright A, Kelly C, De Soyza A, Eggleton P, ers including allergies, urban environment, and educational back- et al. is a model for chronic bacterial infection ground. Future studies can leverage not only these questionnaire inducing autoimmunity in rheumatoid arthritis. Arthritis Rheumatol 2015;67:2335–42. data, but also the associated lifestyle, clinical, genetic, and sero- 4. Sheen YH, Rolfes MC, Wi CI, Crowson CS, Pendegraft RS, King KS, logic data contained within this rich and novel dataset (21). et al. Association of asthma with rheumatoid arthritis: a population- There are also several important limitations to consider. First, based case- control study. J Allergy Clin Immunol Pract 2018;6:219–26. using a convenience sample from clinics rather than a population- 5. Lai NS, Tsai TY, Koo M, Lu MC. Association of rheumatoid arthritis based study creates potential selection bias and limits general- with allergic diseases: a nationwide population- based cohort study. Allergy Asthma Proc 2015;36:99–103. izability, even when the population comes mainly from primary 6. Hemminki K, Li X, Sundquist J, Sundquist K. Subsequent care as in this study. Second, recall bias is possible when ask- autoimmune or related disease in asthma patients: clustering of ing patients about past exposures. However, participants were diseases or medical care? Ann Epidemiol 2010;20:217–22. asked about all comorbidities and exposures both related and 7. De Roos AJ, Cooper GS, Alavanja MC, Sandler DP. Personal and family medical history correlates of rheumatoid arthritis. Ann unrelated to RA, and the similarity of the results from the inci- Epidemiol 2008;18:433–9. dent RA group (which did not have RA at the time of the sur- 8. Hassan WU, Keaney NP, Holland CD, Kelly CA. Bronchial reactivity vey) provides some reassurance. Third, the definition of RA relied and airflow obstruction in rheumatoid arthritis. Ann Rheum Dis partially on self-report, creating potential misclassification bias. 1994;53:511–4. Nevertheless, such bias would have reduced any observed asso- 9. Hart JE, Laden F, Puett RC, Costenbader KH, Karlson EW. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ ciations, and the similarity with incident RA cases was reassuring. Health Perspect 2009;117:1065–9. Furthermore, the high PPV found with the 2 verification methods 10. Costenbader KH, Feskanich D, Mandl LA, Karlson EW. Smoking provides further reassurance about the rules- based definition of intensity, duration, and cessation, and the risk of rheumatoid arthritis RA used in this study. Finally, for many study participants, data on in women. Am J Med 2006;119:503. RA autoantibody status were not available, limiting the number of 11. Chang KH, Hsu CC, Muo CH, Hsu CY, Liu HC, Kao CH, et al. Air pollution exposure increases the risk of rheumatoid arthritis: a calculations that could be performed in the sensitivity analysis. longitudinal and nationwide study. Environ Int 2016;94:495–9. Notably, Hedstrom et al showed no difference in the association 12. De Roos AJ, Koehoorn M, Tamburic L, Davies HW, Brauer M. between passive smoke and RA by status (17). Proximity to traffic, ambient air pollution, and community noise in In conclusion, our results show that asthma and allergies relation to incident rheumatoid arthritis. Environ Health Perspect 2014;122:1075–80. may be associated with increased risk of developing RA, but 13. Burke H, Leonardi- J, Hashim A, Pine-Abata H, Chen Y, passive smoke exposure and age at start of smoking are not. Cook DG, et al. Prenatal and passive smoke exposure and incidence Future studies investigating the relationship between RA and of asthma and wheeze: and meta-analysis. early- life atopy are needed. Pediatrics 2012;129:735–44. 14. Guan WJ, Zheng XY, Chung KF, Zhong NS. Impact of air pollution on the burden of chronic respiratory diseases in China: time for urgent ACKNOWLEDGMENT action. Lancet 2016;388:1939–51. 15. Chang K, Yang SM, Kim SH, Han KH, Park SJ, Shin JI. Smoking and The authors would like to thank Mayo Clinic Center for Indi- rheumatoid arthritis. Int J Mol Sci 2014;15:22279–95. vidualized Medicine. 16. Di Giuseppe D, Discacciati A, Orsini N, Wolk A. Cigarette smoking and risk of rheumatoid arthritis: a dose-response meta-analysis. Arthritis Res Ther 2014;16:R61. AUTHOR CONTRIBUTIONS 17. Hedstrom AK, Klareskog L, Alfredsson L. Exposure to passive smoking and rheumatoid arthritis risk: results from the Swedish EIRA All authors were involved in drafting the article or revising it criti- study. Ann Rheum Dis 2018;77:970–2. cally for important intellectual content, and all authors approved the final version to be published. Dr. Kronzer had full access to all of the data in 18. Seror R, Henry J, Gusto G, Aubin H, Boutron-Ruault M, Mariette X. the study and takes responsibility for the integrity of the data and the Passive smoking in childhood increases risk of developing accuracy of the data analysis. rheumatoid arthritis. Rheumatology (Oxford) 2018. E-pub ahead of Study conception and design. 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