Rheumatoid arthritis (RA) most commonly affects the joints, but can also affect other organs, including the lungs. The Arthritis Foundation reports that >20% of patients with RA will eventually develop an RA-related lung disease, significantly increasing their risk of morbidity and mortality.1,2 Among such diseases, interstitial lung disease, which leads to progressive scarring of lung tissue secondary to chronic inflammation, is the most common.2 Other commonly observed RA-related lung conditions include pleural effusions and airway diseases such as bronchiolitis obliterans.2
Less recognized or understood is the association between asthma and RA, which have been thought to have an inverse (negative) relationship based on the commonly accepted T-helper 1 (Th1) and T-helper 2 (Th2) balance hypothesis. However, a recent literature review by Rolfes and colleagues in Tuberculosis & Respiratory Diseases indicates a strong association between these two diseases, which could have important implications for patient care, potentially enabling earlier disease recognition and opening the door to improved treatments.3
Challenging the Th1/Th2 Balance Hypothesis
RA and asthma are immune-mediated diseases. RA is associated with excessive Th1-type cytokine expression, whereas asthma is associated with a strong Th2-type cytokine expression. In the 1980s, a theory of immune regulation was developed based on a mouse model suggesting homeostasis between Th1 and Th2 activity, with Th1- and Th2-helper cells directing different immune response pathways and expressing different cytokine patterns.4
The hypothesis suggests that Th1 cells drive cellular immunity, fighting intracellular pathogens and cancerous cells and stimulating delayed-type hypersensitivity skin reactions, while Th2 cells drive humoral immunity, up-regulating antibody production to fight extracellular organisms, with overactivation of either pattern causing disease and each pathway downregulating the other pathway.4
Because of this cross-regulatory property, it was thought that Th1- and Th2-regulated diseases have an inverse relationship, but this finding has been challenged. An increasing number of studies have shown that many diseases previously classified as Th1- or Th2-dominant do not meet the set criteria, and Th1- and Th2-mediated diseases have been reported to coexist in many patients.3,4
Animal and human studies have assessed the role of Th1 cytokines in driving RA.4 In a human study including 14 patients with RA, assessment of cytokine messenger ribonucleic acid (mRNA) isolated from the blood showed mixed results, with 5 patients having elevated Th1 and 3 having elevated Th2.4,5 When 10 synovial tissue samples were assessed, 8 had elevated Th1 and 2 had elevated Th2.4,5 These results show variability in Th1 expression in RA, suggesting that not all patients may have disease driven by overexpression of Th1 cytokines. In addition, many factors have been reported to mediate Th1 and Th2 cytokine expression, including orthomolecular substances such as melatonin, dehydroepiandrosterone, progesterone, selenium, zinc, probiotics, and phytochemicals, indicating the biological mechanisms at play are complex and do not neatly fit the Th1/Th2 balance hypothesis.4
Although there is a paucity of literature directly assessing the relationship between asthma and the risk of RA, Rolfes and colleagues found 8 studies that showed a positive association between these conditions, 4 that showed an inverse relationship, and 5 that showed no association.3 Among the studies showing a positive relationship were 3 cohort studies, 3 case-control studies, and 2 cross-sectional studies.6-13
The largest of these studies included a cohort of >170,000 patients age ≥20 years included in the Taiwan National Health Insurance Research Database and examined the association between RA and allergic diseases, including allergic rhinitis, atopic dermatitis, and asthma.6 The study’s investigators found 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) to be significantly associated with incident RA, even after excluding patients with concurrent diagnoses of these conditions. Risk of RA was found to be highest in middle-aged and elderly women with >1 allergic disease.6
Of the cross-sectional studies, the largest included 3920 people from 17 countries and examined the prevalence of comorbidities in RA.13 It found asthma to be the second most frequently associated disease with RA, occurring in 6.6% of cases, despite significant variability between countries.12 Only depression was more common, with 15% of patients with RA affected.13
The studies showing an inverse or no relationship included smaller cohorts and tended to have more significant limitations.3 “For example, while multiple cohort studies showed consistent and coherent findings backing the positive association of asthma with the risk of RA, only 1 cohort study looking at young military soldiers showed an inverse relationship. 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 Th2 and Th1 conditions,” Rolfes and colleagues wrote.3 Based on their overall findings, the investigators concluded that the “evidence supporting the positive association between asthma and the risk of RA is much stronger than that supporting otherwise,” and they suggested several potential mechanisms to link these conditions.
Mechanisms for a Shared Connection
Several mechanisms potentially connecting RA and asthma have been suggested, including genetic and environmental factors.3 When considering genetics, several genotypes and genetic interactions have been shown to increase the risk of developing RA and/or asthma, including the T/T genotype of -3479T>G CD86 and the A/A genotype of -3458A>G CD40L.3 Additionally, amino acid polymorphisms in the HLA-DRB1 gene have been associated with both conditions.3
“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 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,” Rolfes and colleagues wrote.3
Some evidence has also suggested that environmental factors might increase the risk of both conditions, particularly in the setting of certain gene-environmental interactions.3 The most well studied environmental factor thus far has been smoking, which has been reported to increase the risk of asthma and RA independently.3 In addition, mechanisms leading to a cascade of biological responses has been suggested for smoking-related RA, which could also help explain the association between asthma and RA.
Rolfes and colleagues provided insights into one such possible mechanism.3 “Smoking commences [a] 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 RA,” they wrote.3
While higher-quality, more focused studies are needed to definitively define the association between asthma and RA, current evidence suggest these conditions can and do coexist and their coexistence should not be overlooked. Future research focusing on the pathways driving these diseases is warranted and could help improve the identification of high-risk patients, enabling improved prevention efforts, and, potentially, spur the development of more personalized treatment approaches that can more successfully target the heterogenous pathways that lead to these diseases.
- Arthritis Foundation. Rheumatoid arthritis and lung problems. http://blog.arthritis.org/rheumatoid-arthritis/rheumatoid-arthritis-lung-disease. Accessed May 4, 2017.
- Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev. 2015;24:1-16.
- Rolfes MC, Juhn YJ, Wi CI, Sheen YH. Asthma and the Risk of Rheumatoid Arthritis: An Insight into the Heterogeneity and Phenotypes of Asthma. Tuberc Respir Dis (Seoul). 2017; 80(2):113-135.
- Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003;8(3):223-246.
- Schulze-Koops H, Kalden JR. The balance of Th1/Th2 cytokines in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2001;15(5):677-691.
- Lai NS, Tsai TY, Koo M, Lu MC. Association of rheumatoid arthritis with allergic diseases: a nationwide population-based cohort study. Allergy Asthma Proc. 2015;36:99-103.
- Kero J, Gissler M, Hemminki E, Isolauri E. Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol. 2001;108:781-783.
- Hemminki K, Li X, Sundquist J, Sundquist K. Subsequent autoimmune or related disease in asthma patients: clustering of diseases or medical care? Ann Epidemiol. 2010;20:217-222.
- Karatay S, Yildirim K, Ugur M, et al. Prevalence of atopic disorders in rheumatic diseases. Mod Rheumatol. 2013;23:351-356.
- de Roos AJ, Cooper GS, Alavanja MC, Sandler DP. Personal and family medical history correlates of rheumatoid arthritis. Ann Epidemiol. 2008;18:433-439.
- Hassan WU, Keaney NP, Holland CD, Kelly CA. Bronchial reactivity and airflow obstruction in rheumatoid arthritis. Ann Rheum Dis. 1994;53:511-114.
- Provenzano G, Donato G, Brai G, Rinaldi F. Prevalence of allergic respiratory diseases in patients with RA. Ann Rheum Dis. 2002;61:281.
- Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73:62-68.