Asthma and the Risk of Rheumatoid Arthritis: An Insight into the Heterogeneity and Phenotypes of Asthma

1. Positive association between asthma and the risk of RA

There are eight studies available in the literature which showed a positive association between asthma and the risk of RA (Table 2): three cohort studies474849, three case-control studies505152, and two cross-sectional studies5354.

The largest cohort study was conducted by Lai et al.47 using a nationwide health claims database in Taiwan in which asthma and RA were defined by International Classification of Diseases (ICD) codes. Their results showed that asthma (adjusted hazard ratio [aHR], 1.67; 95% CI, 1.32-2.62) and allergic rhinitis (aHR, 1.62; 95% CI, 1.33–1.98) were significantly associated with an increased risk of RA. This association remained significant even after excluding those subjects who had concurrent diagnoses of asthma and allergic rhinitis. Of note, allergic rhinitis was independently associated with an increased risk of RA as well47, which infers that chronic respiratory disorders, namely, asthma and allergic rhinitis, exhibit biological coherence with regard to the subsequent development of RA. Another population-based cohort study conducted in Finland by Kero et al.48 corroborated the study findings by Lai et al.47; the effect size was in the range of relative risk of 2.66 (1.23–5.78) and overall results suggested that patients with asthma have an increased risk of RA, compared to those without asthma. Apart from the cohort study design, the main strength of these cohort studies is a large sample size representing the general population of each country, namely Taiwan47, Finland48, and Sweden49. At the same time, the major limitations of these cohort studies are the use of ICD-9 codes for asthma, resulting in a potential misclassification bias474849; inclusion of subjects less than 7 years of age48, which is much younger than the average age at which RA usually develops; and the fact that they did not fully adjust for possible confounders or risk factors for RA, such as socioeconomic status, smoking status, and/or body mass index (i.e., potential susceptibility bias)474849.

Because the incidence of RA is low, it is challenging to conduct a cohort study with adequate statistical power with suitable ascertainment of exposure (i.e., asthma status) and outcome (i.e., RA). Thus, case-control study design has been commonly implemented by previous studies. There are few population-based case-control studies51. De Roos et al.51 conducted a nested case-control study among women included in the Agricultural Health Study in Iowa and North Carolina and defined asthma by questionnaire and RA by self-report plus confirmation by their physician. The overall effect size was odds ratio of 3.7 (95% CI, 1.3–10.5) for the association between asthma and the risk of RA51. The results were replicated by others5052. Another case-control study investigated the prevalence of airway obstruction and bronchial reactivity to inhaled methacholine in 100 RA patients and 50 controls and found that a significantly higher number of patients with RA had a history of wheeze when compared with the controls (18% vs. 4%, p<0.05), that lung function measures, such as forced expiratory volume in 1 second (FEV₁), forced vital capacity (FVC), FEV₁/FVC, forced expiratory flow at 25% and 75% of the pulmonary volume (FEF_25-75%), forced expiratory flow at 25% (FEF_25%), forced expiratory flow at 50% (FEF_50%), and forced expiratory flow at 75% (FEF_75%), were all significantly lower in the RA group, and that a significantly higher number of patients with RA showed bronchial reactivity to inhaled methacholine (55% vs. 16%, p<0.05), thus demonstrating objective evidence that RA patients may have decreased lung function52. The major limitations of these case-control studies were inclusion of women only51, a questionnairebased diagnosis of asthma5051 and/or RA51, and a relatively small number of incident cases51.

Of the two cross-sectional studies, the largest cross-sectional study was conducted by Dougados et al.54 based on 3,920 patients with RA recruited in 17 countries where they defined RA by the 1987 American College of Rheumatology (ACR) classification criteria for RA55; there was no mention on how they diagnosed asthma. Of 3,920 patients with RA analyzed, the second most frequently associated disease (past or current) was asthma (6.6%) following depression (15%). Of note, their study is the first population-based, cross-sectional observational study to assess comorbidities among a large size of subjects with RA in 17 countries on five continents. One additional cross-sectional study has shown similar results of a higher prevalence of allergic respiratory diseases in patients with RA (16.6%) compared with that in the general population53. The major limitations of these cross-sectional studies are that they did not include control subjects5354, did not state how they defined asthma54, and used an interview-based asthma diagnosis53.

These eight epidemiological studies consistently support the positive association of asthma or lung functions and other atopic conditions such as allergic rhinitis with the risk of RA. Despite the differences in study settings, populations, designs, and ascertainment approaches for exposure and outcomes, the effect size was relatively consistent. The most striking aspect of these studies was that despite the broad range of different definitions of exposure status (e.g., asthma status or other atopic conditions by ICD codes or self-report, FEV₁ and FEV₁/FVC, and methacholine challenge test), they have shown “consistent findings” with regard to the positive association between asthma and the risk of RA and biological coherence. Also, considering the fact that treatments for severe asthma often include systemic corticosteroids and high-dose inhaled corticosteroids, corticosteroid administration did not obscure or mitigate the association between asthma and the risk of RA. Thus, although a population-based cohort study is needed using a well-defined population and suitable ascertainment of asthma and RA status, the existing evidence from these previous studies is quite compelling and strongly supports the association between asthma or other atopic conditions and the risk of RA.

2. Inverse (negative) association between asthma and the risk of RA

There are four studies available in the literature which showed inverse associations between asthma and the risk of RA (Table 3): one cohort study56, two case-control studies5758, and one cross-sectional study59.

Tirosh et al.56 conducted a cohort study using data from the Israeli Defense Force database in which they defined asthma by physician-diagnosis; however, they did not specify which criteria were used for RA56. They concluded that women with asthma had a significantly lower prevalence of type 1 DM, vasculitis, immune thrombocytopenic purpura, inflammatory bowel disease, and RA and that men with asthma had a lower prevalence of type 1 DM, vasculitis, and RA compared with those without asthma. The incidence of RA was higher in nonasthmatic versus asthmatic subjects with an unadjusted overall risk ratio of 2.21 (95% CI, 1.34–3.64; p=0.001). The main strength of this cohort study was that they included a large sample size of 37,641 asthma patients and 448,734 nonasthma subjects; however, their study is limited in that the age of the study population was too young (18–21 years) to develop RA, RA criteria were not clearly defined, temporality between asthma status and RA was not fully established, and the risk ratio was not adjusted for potential confounders and covariates. Thus, the nature of the association was unclear.

There are no population-based case-control studies showing inverse associations between asthma and the risk of RA. Case-control studies with the findings of inverse associations between asthma and risk of RA are all hospital-based studies 5758 and included unsuitable controls as their controls were the patient's sister- or brother-in-law, neighbor, or friend57 or were recruited from a different department of the same hospital58. For example, Hilliquin et al.57 conducted a case-control study based on RA patients admitted to their hospital and defined atopic symptoms (i.e., asthma, hay fever, and atopic eczema) by using a standardized questionnaire and RA by using the 1987 ACR classification criteria55. Of 173 cases and 173 controls, the cumulative incidence of atopy was significantly lower in RA patients than in matched control subjects (7.5% vs. 18.8%; aOR, 0.39; 95% CI, 0.19–0.81; p<0.01). In this study, controls had a higher socioeconomic status than cases, which might result in a differential susceptibility bias (higher identification or detection of atopic conditions in controls). Their major limitations are potential unsuitability of cases and controls (and potential Berkson bias toward controls)5758, unreliable point prevalence of atopic conditions57, the use of questionnaire for atopic diseases or asthma diagnosis5758, and relatively small sample sizes5758. Thus, these case-control studies have significant limitations in addressing the relationship between asthma and the risk of RA.

The cross-sectional study conducted by Rudwaleit et al.59 was based on RA patients who were followed-up at hospital outpatient clinics. They defined atopy including asthma, hay fever, and atopic dermatitis by questionnaire and RA by the 1987 ACR classification criteria55. The prevalence of any current (past 12 months) atopic disorder was 13.1% (64/487) in patients with RA and 20.7% (111/536) in controls (p=0.001). RA patients were less likely to have hay fever (42/487 [8.6%] vs. 82/536 [15.3%], p=0.001) and the proportion of patients with asthma (21/487 [4.3%] vs. 35/536 [6.5%], p>0.05) and atopic dermatitis (14/487 [2.9%] vs. 26/536 [4.9%], p>0.05) was decreased in the RA group versus controls; the results were not significant but consistent. Of note, among atopic patients with RA, the RA severity score was significantly lower in those who developed an atopic disorder before the onset of RA than in those who developed the first signs and/or symptoms of an atopic disorder at the time of or after the onset of RA (p=0.027). The major limitations are that they included control subjects from hospital staff, potentially resulting in a detection bias (higher likelihood of detecting atopic conditions). In addition, atopy was limited to the past 12 months only, thus eliminating patients who may have had asthma prior to the previous year. Asthma itself was not associated with the risk of RA in this study, while the overall atopy prevalence was.

These four epidemiological studies are in favor of the inverse association between asthma and the risk of RA. However, these studies are limited in that they used questionnaires to diagnose atopic diseases including asthma575859, unsuitable study populations (i.e., young adults56, and hospital-based cases and controls5758), unclear sampling frame58, or inadequate adjustments58. The overall evidence for the inverse association between asthma and the risk of RA was weak and inconsistent.

3. No association between asthma and the risk of RA

There are five studies available in the literature which showed no association between asthma and the risk of RA (Table 4): one population-based retrospective cohort study33, three case-control studies606162, and one cross-sectional study63.

The population-based retrospective matched cohort study of 2,392 patients with asthma and 4,784 controls was conducted in Minnesota, USA by Yun et al.33 where they used predetermined criteria for asthma64 and RA55. They determined the association between asthma and proinflammatory diseases, such as irritable bowel disease, RA, DM, and CHD and found that asthma was associated with increased risks of DM (HR, 2.11; 95% CI, 1.43–3.13; p<0.001) and CHD (HR, 1.47; 95% CI, 1.05–2.06; p=0.02) but not with increased risks of irritable bowel disease or RA. Besides the cohort study design, the main strength of this study was that they assessed the association of asthma with other chronic inflammatory diseases along with RA and defined asthma status based on predetermined criteria for asthma instead of ICD codes or self-report; however, their study was significantly underpowered given the low incidence of RA and had inherent limitations as a retrospective study. In addition, approximately 45% of the study participants were less than 18 years old at the end of the follow-up, which might have reduced the statistical power in detecting any association between asthma and risk of RA because individuals usually develop RA in late adulthood.

Three case-control studies showing no association of asthma with risk of RA are all hospital-based studies606162. The largest case-control study was performed by Olsson et al.61 where they recruited RA patients from two hospitals in Sweden, and controls from the general population. Allergic diseases including asthma were established through a postal questionnaire, and RA by the 1987 ACR classification criteria55. They showed that RA was inversely, but nonsignificantly, associated with certain manifestations of rhinitis, but there was no association between RA and asthma and eczema, respectively. The major limitations are inadequate statistical power and imprecise definitions of exposure variables as they used a postal questionnaire to diagnose allergic diseases. In addition, the sample frame was often unclear.

The cross-sectional study was conducted by O'Driscoll et al.63 where they conducted two sets of studies; the first set based on 266 atopic patients attending an allergy clinic, and the second set based on 40 RA patients recruited at a rheumatology clinic and 40 controls at a general hospital. They concluded that two patients of 266 atopic patients had RA (0.8%), a prevalence similar to that observed in the general population and that patients with RA had a prevalence of atopy and atopic diseases similar to that seen in the controls. Their major limitations are inadequate statistical power, unsuitable study populations (sampling from specialty clinic at a hospital), and imprecise definitions of exposure variables.

These five epidemiological studies are limited in that they are underpowered6063, used imprecise definitions of exposure variables60616263, or recruited unsuitable study populations (e.g., inclusion of osteoarthritis patients as controls60 or inclusion of young adult populations who are generally not susceptible to RA33). None of these studies reported statistical power to detect the effect size of interest. Therefore, overall, the evidence for supporting the null hypothesis in these five studies was weak.

In summary, while the existing literature concerning the association between asthma and the risk of RA is inconsistent, overall, in terms of consistency, biological coherence, and study quality, evidence supporting the positive association between asthma and the risk of RA is much stronger than that supporting otherwise. For example, while multiple cohort studies showed consistent and coherent findings backing the positive association of asthma with the risk of RA474849, only one cohort study looking at young military soldiers showed an inverse relationship56. Nonetheless, as previous epidemiological studies failed to recognize asthma as a disease with a potential systemic inflammatory feature, they did not perform analysis in a way that can provide an insight into heterogeneity and phenotypes of asthma in relation to the risk of RA and the potential coexistence of T_H2 and T_H1 conditions. For example, characterizing asthma in relation to the risk of RA has not been carefully analyzed (e.g., asthmatics with and without other atopic conditions, early- [or long-standing] vs. late-onset asthma, atopic vs. nonatopic asthma, eosinophilic vs. neutrophilic asthma, young vs. elderly asthma, and asthmatics with and without susceptibility to infections). The primary rationale for the lack of this further characterization of patients with asthma or the failure to address heterogeneity and phenotypes of asthma in the literature was that the conceptual framework for the hypothesis testing was mainly based on the counter-regulatory T_H1 versus T_H2 theory precluding other biological plausibility or mechanistic pathways underlying the relationship between asthma and the risk of RA, which is described in the next section.

1. Genetics

Asthma and RA are both diseases developed as the result of a complex interplay among aberrant regulatory T cell function or other mechanisms by which breakdown of immune tolerance ensues. In this regard, previous studies have suggested that immune tolerance is influenced by costimulatory molecules. A recent study looking at 200 cases of asthma, 184 cases of RA, and 182 healthy controls, reported that subjects with the T/T genotype of -3479T>G CD86 and the A/A genotype of -3458A>G CD40L were more likely to develop asthma and RA than those with the T/T genotype of -3479T>G CD86 and A/-genotype of -3458A>G CD40L, suggesting that a genetic interaction between CD86 and CD40L favored the development of both asthma and RA65. HLA-DRB1 and HLA-DQB1 genes were independently associated with asthma and its related traits in several candidate gene association studies66, and HLA-DRB1 is the major determinant of the association with RA susceptibility67. Furthermore, a recent study found that patients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage, higher all-cause mortality, and better response to tumor necrosis factor inhibitor therapy68. Taken together, genetic factors associated with both asthma and RA may account—at least partially—for predisposition to both diseases. It is important to recognize the functional aspect of each involved gene for both asthma and RA and its functional studies of each gene might reveal the causal pathways of how genes and their biological functions determine the nature of the association between asthma and the risk of RA.

2. Environmental factors

It is possible that certain environmental factors predispose individuals to developing asthma and RA. For example, studies have suggested that smokers are at increased risk of developing asthma69 and RA70 independently. Furthermore, recent studies have reported insights into the molecular and cellular mechanisms which establish the pathogenesis of smoking-related RA7172. Possible mechanisms are as follows: smoking commences chronic inflammatory process in the lungs, which induces the release of the enzymes, namely peptidylarginine deiminases 2 and 4 from smoke-activated, resident, and infiltrating pulmonary phagocytes. Peptidylarginine deiminases mediate conversion of diverse endogenous proteins to presumed citrullinated autoantigens. In genetically susceptible subjects who have the shared epitope (SE)-containing HLA-DRB1 alleles71, this SE might provoke the generation of anti–cyclic citrullinated peptide (CCP) and pathogenic autoantibodies (anti-CCP antibodies), which play a critical role in initiating inflammatory responses in RA72. Accordingly, genetic studies have reported that the HLA-DRB1 SE alleles are particularly associated with anti-CCP–positive RA73 and also influence the magnitude of the anti-CCP antibody production74. Therefore, gene-environmental interaction could be a potentially important pathway accounting for the association between asthma and RA.

3. Natural killer group 2D

Natural killer group 2D (NKG2D), a transmembrane protein expressed on natural killer (NK) cells, CD8⁺ αβ T cells, γδ T cells, CD4⁺CD28⁻ T cells, and some CD4⁺ T cells7576, may be important in the pathogeneses of both diseases. It is an activating receptor known to mediate the “stress surveillance” function of the cells, and recognizes ligands from the H60, MULT-1, and the Rae-1 families in mice, and MHC class I chain-related molecules (MICA or MICB) and UL16-binding proteins in humans, which are upregulated in response to DNA damage and on transformed cells7778. Recent work by Farhadi et al.79 determined the role of NKG2D and NK-cell effector functions mediated by granzyme B using house dust mite (HDM)–induced allergic inflammation murine models and found that allergic inflammation was significantly decreased after HDM exposures in NKG2D-deficient mice, and was restored in the mice by adoptive transfer of wild-type NK cells but not granzyme B deficient-NK cells. Therefore, they postulated that NK cell intrinsic expression of NKG2D is needed for allergic pulmonary inflammation following HDM allergen and that NK cells activate allergic pulmonary inflammation by the production of granzyme B. In clinical studies, it has been reported that high NK activity is observed in the peripheral blood sample of subjects with asthma808182. Moreover, in severe asthma, NK cells display up-regulated expression of NKG2D, and expression levels of this surface molecule correspond well with the percentage of eosinophils in peripheral blood83.

With regard to RA, patients often exhibit increased frequencies of highly differentiated effector CD4⁺CD28⁻ T cells in peripheral blood as compared with healthy controls848586. These CD4⁺CD28⁻ T cells have proinflammatory and cytotoxic properties and may contribute to the development of typical RA signs and symptoms8788. A recent study looking at 44 patients with RA reported that CD4⁺CD28⁻ T cells found in the synovial fluid of RA patients demonstrated additional effector functions such as interleukin 17 (IL-17) coproduction as compared to the same subset in the peripheral blood samples, indicating an important role for these cells in the continuation of inflammation in disease target organs in the subset of patients having a CD28 (null) population89. Furthermore, a significant proportion of CD4⁺CD28⁻ T cells from RA patients were reported to express NKG2D, which triggered autoreactive responses against synoviocytes expressing abnormally high NKG2D ligands MICA or MICB8890. Collectively, we postulate that in a subset of asthmatics, enhanced NKG2D activity in immune cells may contribute towards generation of autoimmunity that facilitates development of RA.

4. T_H17 cells

T_H17 cells are a subgroup of T cells that produce various cytokines such as IL-17A, IL-17F, IL-22, and TNF-α. T_H17 cells are differentiated from naive T cells in the presence of IL-6 (increased expression associated with aging) and transforming growth factor β, which up-regulates the transcription factors retinoid acid–related orphan nuclear hormone receptor γt and signal transducer and activator of transcription 391. T_H17 cells are regulated by IL-23, which is a cytokine to facilitate development of inflammation in many models of immune pathology. Previous mouse models of allergic asthma have demonstrated that IL-17A and IL-17F play a critical role in the development of airway inflammation, notably neutrophilic inflammation9293; increase T_H2-associated eosinophilia94; and increase airway hyperresponsiveness and airway Mucin 5AC (MUC5AC) expression9596. Studies have suggested that IL-17A and IL-17F are expressed in the airways of patients with asthma 9798. In addition to contributing to antigen induction process of airway inflammation, the IL-23–T_H17 axis is considered to be important in the host response reaction to respiratory tract bacterial and potentially viral infections99. Thus, it is plausible that T_H17 cells are engaged in the asthma exacerbation and in the pathogenesis of late-onset asthma following repeated respiratory tract infections.

The up-regulation of IL-17 is also known to play a role in the pathogenesis of RA. For instance, previous studies have reported that the IL-17 expression is found to be increased in RA patients compared with healthy subjects and that T_H17 cells isolated from RA patients can induce chronic destructive disorder and inflammation via a proinflammatory feedback loop mechanism in which T_H17 cells induce IL-6, IL-8, and inflammatory enzymes (i.e., matrix metalloproteinase-1 and -3) from the RA patients' synovial fibroblasts (RASFs) via IL-17A secretion and RASFs enhance IL-17A expression by T_H17 cells100101. Therefore, upregulated T_H17 cells in asthma patients may induce chronic destructive disorder and inflammation of joints in the same patients later in life. In this respect, the current epidemiological studies are limited in testing the hypothesis whether asthma severity affects susceptibility to and severity of RA. This aspect needs to be addressed in future clinical studies.

5. Leukotrienes

Leukotrienes, a family of lipid mediators, are synthesized in the leukocytes from arachidonic acid via the actions of 5-lipoxygenase and are divided into two groups: leukotriene B4 (LTB4) and cysteinyl leukotrienes102103. LTB4 and cysteinyl leukotrienes exert their biological effects by binding to cognate receptors, which belong to the G protein-coupled receptor superfamily104. LTB4 is thought to be a proinflammatory mediator engaged in the recruitment, activation, and survival of leukocytes, including neutrophils, macrophages, monocytes, eosinophils, and dendritic cells, whereas cysteinyl leukotrienes are robust bronchoconstrictors that have effects on airway remodeling105106107108109. Studies carried out in subjects with asthma have reported an important role for LTB4; for example, increased LTB4 levels are observed in sputum, bronchoalveolar lavage fluid, urine, exhaled breath condensate, and arterial blood samples from subjects with asthma 110111112113114115. Increased LTB4 synthesis by the up-regulation of 5-lipoxygenase and LTA4 hydrolase has been demonstrated in both adults116 and pediatric subjects117 with asthma. As an important determinant of LTB4 level, platelet-activating factor (PAF) has been considered a crucial inflammatory mediator responsible for airway hyperresponsiveness and airway inflammation through eosinophilic recruitment into lung in asthma118119. PAF induces formation of leukotriene B4 from monocytes and leukotriene C4 from eosinophils120. PAF acetylhydrolase activity, which catalyzes PAF (removal of 2-actyl group) causing PAF degradation, is lower or deficient in patients with asthma 121122123. Therefore, PAF in patients with asthma is sustained and further stimulate LTB4, which in turn results in causing inflammation in synovia as discussed below.

LTB4 levels have been reported to be significantly higher in the synovial fluid of RA subjects as compared with the levels in the synovial fluid of osteoarthritis subjects and that LTB4 levels significantly correlate with cell numbers in the synovial fluid from RA patients124. This study finding suggests that the increased level of this mediator in synovial fluid may contribute to perpetuation of inflammation and tissue destruction in RA124. This is not surprising given the nature of LTB4 as a powerful chemoattractant for neutrophils. For example, several studies suggest that LTB4 in the synovial fluid increases the influx of neutrophils into the joints, thus leading to the articular degradation by producing inflammatory cytokines and matrix metalloproteinases 125126127. Apart from LTB4, LTC4, and LTD4 also contribute to inflammation in synovium as TNF-α secretion by human mast cells-1 was significantly increased when they were incubated with LTC4 and LTD4 and suppressed by CYsLT1R antagonist, montelukast128. The activated 5-lipoxygenase pathway in subjects with asthma may continue to induce chemotaxis, aggregation, and degranulation of neutrophils into the joints, ultimately causing the articular degradation by generating proinflammatory cytokines and matrix metalloproteinase. While the current CysLT1R antagonist (e.g., montelukast) blocks the effect of leukotriene C4 and D4 on CysLT1R during airway inflammation and improves asthma symptoms, as CYsLT1R is also expressed in synovial mast cells129, CYsLT1R antagonist, montelukast, has shown to improve inflammation of RA in a mouse model129. Thus, patients with asthma who have RA might be potential candidates for treatment with CYsLT1R antagonist to alleviate their symptoms.

6. TNF-α

TNF-α is a pleiotropic cytokine that binds to the type 1 TNF receptor and is an important cytokine in the innate immune response. Upon activation, it promotes canonical stimulation of nuclear factor-κB (NF-κB). Previous studies have reported high expression of both TNF-α and NF-κB in adult patients with severe asthma130131132 and children with moderate-to-severe asthma133. Furthermore, small, non–placebo-controlled studies of adults with corticosteroid-refractory asthma and increased TNF-α levels have shown clinical progress with TNF-α antagonist therapy130132.

TNF-α is abundantly present in RA patients' serum and arthritic synovium134 and plays a key role in the pathogenesis of RA. Recent evidence has shown that TNF-α induced regulatory T (T_reg) cell dysfunction through the Ser418 dephosphorylation and TNF-α–induced T_reg dysfunction corresponded well with increased numbers of IL-17⁺ and interferon-γ⁺CD4⁺T cells within the inflamed synovium of RA patients, suggesting that TNF-α controls the balance between T_reg cells and pathogenic T_H17 and T_H1 cells in the synovium of subjects with RA through FOXP3 dephosphorylation135. The activated TNF-α pathway in patients with severe or corticosteroid-refractory asthma may continue to impair T_reg function, which then results in an imbalance between T_reg cells and pathogenic T_H17 and T_H1 cells in the synovial cells, ultimately leading to the development of RA.

1. Research

Literature investigating asthma and an increased susceptibility to RA or other ARC is limited. The primary reason for this limitation is due to the limited conceptual understanding for the relationship between asthma and the risk of RA, which primarily focuses on the counter-regulatory T_H1/T_H2 theory. This theory may not be suitable for generalizing the counter-regulatory relationship between T_H1 versus T_H2 cells at an immunological level or for understanding the relationship between T_H1-versus T_H2-predominant clinical conditions at an epidemiological level as the development of human disease is much more complex than the pathways demonstrated at a cellular level. In addition, this simple conceptual framework precludes other potential biological mechanisms underlying the relationship between asthma and the risk of RA as described above, which, in turn, deters us from examining the positive relationship between asthma and the risk of RA.

Nonetheless, the main conceptual limitation of the current literature is a failure to recognize asthma “as a chronic inflammatory disease with systemic inflammatory features that go beyond the airway.” Emerging evidence suggests that asthma poses a significant impact on immune dysfunction and dysregulation at a systemic level in both adults and children in a way that poses them at risk for significantly higher morbidity and mortality from ARC23242526272829323334353637383940414247484950515253545657585960616263136137. In this regard, the current literature suggests that asthma poses a significantly increased risk of RA in subjects with asthma. However, the underlying mechanisms remain unknown. In this review, we explored the potential mechanistic pathways underlying the positive association between asthma and the risk of RA. This mechanistic understanding is crucially important because the systemic impact of asthma on a broad range of common and serious communicable and noncommunicable diseases is largely unrecognized by clinicians and researchers. In addition, the knowledge on which subgroups of asthmatics are at higher risks is currently markedly limited despite the serious morbidity and mortality from ARC such as myocardial infarction, DM, and RA. The discovery of clinical and biological markers to identify subgroups of asthmatics at risk of serious ARC directly depends on the knowledge of the mechanistic underpinnings of the relationship between asthma and chronic proinflammatory diseases such as RA.

While there is important progress in characterizing patients with asthma in relation to endotypes and genotypes revealing potential pathways overlapping with ARC46, there is still a long way to go in this research area as none of the previous cluster analyses or phenotypic characterization studies included ARC as a phenotype of asthma138139140141142143144145146147148149150151152153154. We believe that studying the mechanistic pathways underlying the association between asthma and the risk of RA or other ARC may advance our understanding of the nature of asthma and ARC, and it will ultimately benefit scientists and clinicians in understanding the nature of chronic proinflammatory diseases by providing insight into the diseases. Apart from the mechanistic studies discovering biomarkers to identify a subgroup of asthmatics at a high risk of developing ARC, clinical studies are needed to determine whether asthma control status, severity status, and medications affect the outcomes of ARC in terms of susceptibility and severity of ARC. In conjunction with these studies, clinical studies are warranted to determine clinical characteristics of a subgroup of asthmatics at a high risk of ARC, which will guide scientists to elucidate the mechanistic pathways and to discover suitable biomarkers to identify such asthmatics.

2. Patient management

Apart from the Centers for Disease Control and Prevention guidelines recommending a single dose of 23-valent pneumococcal polysaccharide vaccine to patients with asthma aged 19–64 years155, the current asthma guidelines do not address the significance and management of ARC. Thus, no specific recommendations for management of RA among patients with asthma are available. At present, the systemic effect of asthma on susceptibility to and severity of a broad range of common and serious communicable and noncommunicable diseases such as RA is largely unrecognized by clinicians and researchers. For example, in recent years, while the respiratory morbidity due to poorly controlled asthma continues, the mortality directly related to the respiratory morbidity from poorly controlled asthma is relatively low because of the recent evidence-based guidelines and advanced asthma treatment. However, we speculate that ARC (e.g., invasive pneumococcal diseases or myocardial infarction) might pose a significant threat to the life of patients with asthma and unfortunately, these consequences of asthma are out of the clinical radar screen. The potential impact of poorly controlled asthma on the risk and severity of ARC has been rarely studied and recognized as clinicians primarily focus on respiratory morbidity. A few aspects can be considered for clinicians who manage patients with asthma.

First, it is important for clinicians to be cognizant of the increased risks of RA and other ARC among patients with asthma as this awareness by clinicians may enable early identification and intervention, thereby avoiding delay of therapeutic and preventive interventions. They need to have a low threshold for screening or evaluating ARC for asthmatics who present with ARC-related signs and symptoms. For example, patients with asthma who complain of mild joint stiffness and soreness need to be properly evaluated for RA and other inflammatory diseases as corticosteroids (e.g., high dose inhaled corticosteroid or systemic corticosteroid) administered to asthma patients might potentially mitigate their symptoms. Similarly, patients with asthma who have persistent chest pain should not be routinely considered as asthma-related symptoms because it could be an early manifestation of CHD. Second, clinicians should consider vaccinating patients with asthma with pneumococcal vaccines and other vaccines such as the zoster vaccine in order to reduce the risk of vaccine-preventable diseases. This is supported by recent studies by our group demonstrating a significantly increased risk of zoster among adults24 and children2526 with asthma. Independent studies in England28, Spain29, and Taiwan156 corroborated this finding. As zoster vaccine was approved for adults >50 years of age by the U.S. Food and Drug Administration, consideration for adults with asthma as a target group for the zoster vaccine should be granted. For children, as our study showed that the varicella vaccine reduces the risk of zoster26, children with asthma should be vaccinated with two doses of the varicella vaccine. Patients who develop vaccine-preventable diseases should be carefully evaluated for their immune status, revaccinated with proper vaccines and checked to see if they have appropriate vaccine responses, and monitored carefully for ARC in the future. Third, specific treatment approaches for RA among patients with asthma can be considered. For example, in managing RA in patients with asthma, clinicians might consider administering CYsLT1R antagonist (e.g., montelukast) as another therapeutic option when treatment is being stepped up for asthma control and there is the need to follow these patients carefully129. Clinical trials are needed to address this issue. Finally, until we have a better understanding of ARC, regardless of asthma status, patients with asthma who develop ARC must undergo proper evaluations for its etiology. When we define the immunogenetic nature and underpinnings of ARC, routine and costly immunological investigations for patients with “certain (not all) ARC,” may not be indicated. For example, patients with asthma who have a history of frequent, but not serious respiratory infections (e.g., otitis media or S. pyogenes infection) may not need routine expensive immunological investigations. However, based on the current understanding and progress of research in this area, there is a lot of work to be done to reach this point.

3. Public health

Asthma is a common chronic condition, affecting 5.7% of the Korean population4 and nearly 10% of the US population 56, with trends indicating the incidence will only continue to increase7. Asthma is not only common, but also costly; it is estimated that the total incremental cost of asthma on society in 2007 was $56 billion157. Management of asthma can cost $3,500 per patient per year which is a severe economic burden, especially for low-income patients157. RA also has a significant societal burden, affecting 0.27% (95% CI, 0.26–0.28) in the general population of Korea158 and nearly 1% of the U.S. population159. Joint inflammation associated with RA can be very painful and can lead to work disability in conjunction with progressive physical disability. The cost of management is high, indicating further societal and economic burden160. Addressing the underlying risks associated with asthma may allow for better management of asthma and the ability to better predict and subsequently treat the onset of RA, ultimately reducing the economic and societal burden of these chronic conditions. Additionally, a better understanding of the relationship between asthma and RA may reveal new immunological mechanisms regarding the two disorders, leading to better treatment and management and reduction of societal burdens.

Specifically, at present, the effects of asthma epidemiology on RA epidemiology at a population level are unknown. A better understanding of the potential effects of asthma on the risk and epidemiology of chronic inflammatory diseases such as RA may not only provide an important basis for public health surveillance of these effects, but also lead to novel ways to identify a subgroup of patients with asthma who are at a risk of developing RA at a population level. Therefore, given the large proportion of individuals affected by asthma, surveillance of asthma epidemiology in relation to the epidemiology of ARC including RA has important public health implications. In this regard, our group showed that asthma affects vaccine-preventable diseases such as pneumococcal diseases, pertussis, and varicella. It is unknown the extent to which asthma affects the risk of vaccine-preventable diseases at a population level. Serious emerging and re-emerging outbreaks threatening public health have occurred throughout the world. A crucial question, which has not been addressed to date, is: whether asthma status and epidemiology in a given population affect the degree, timing, and duration of vaccine-preventable reemerging outbreaks through primary and secondary vaccine failure and whether it is true for the emerging outbreaks. These questions call for further research into this area and deserve further public attention and support.