Lars Klareskog, MD, on the Study of Occupational Exposures and Risk of RA

Dr Lars Klareskog is professor with Division of Rheumatology, Department of Medicine, and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital (Solna), Stockholm, Sweden, where he specializes in the study of genetics in rheumatoid arthritis. Recently, Dr Klareskog and colleagues in his research group conducted a study on whether occupational inhalable agents present major risks in the development of rheumatoid arthritis, particularly among smokers and among those with a genetic predisposition to the disease.

Dr Klareskog agreed to answer a few questions about this study for the Rheumatology & Arthritis Learning Network.

--

RALN: What initiated your interest in looking at the effects of occupational inhalable exposures on the development of RA? 

Dr Klareskog: This is part of a long-standing interest in my and Professor Lars Alfredsson’s research group concerning the contributions of genes vs environment in the etiology of RA and other immune-mediated diseases. We were convinced early – in the mid ‘90s—that we have to investigate genes, environment, and immunity in one context and in good epidemiological materials to get close to the etiology of RA.

Therefore, we started at that time a case control study with new-onset RA and well matched healthy control individuals and asked all to respond to a big questionnaire on environmental exposures, including occupational exposures, smoking, and much more. We named this study Epidemiological Investigation of RA (EIRA) and have after that published more than 100 articles on gene-environment interactions leading to RA (see www.eirasweden.se).

One of the first results from this study was the finding of major gene-environment interactions between smoking and certain genetic variations in the transplantation antigens leading to the development of the major subset of RA— the subset characterized by presence of antibodies to citrullinated antigens (ACPA).

Through a number of additional studies from our group, which were replicated by others, we formulated what is today called the “mucosal hypothesis for an origin of RA, i.e., the concept that immune reactions typical for RA are first triggered at mucosal surfaces in the lung (and sometimes in the gums) and that this immunity may later be involved in causing RA. These findings and this working hypothesis have led us to investigate the influence also of a number of additional airway pollutants, and how these exposures interact with genetic variations and how together they influence immunity. As smoking is the most obvious airway pollutant, we always include smoking as an additional determinant of disease development.

With this background we used the extensive information we had collected in EIRA during many years of the influence of occupational airway environmental exposures on risk for RA. The results were even more striking than we had expected, as is seen in the publication you reference.

RALN: Your article in the Annals of Rheumatic Diseases specifically mentions your interest in assessing the interactions of these inhalables “with smoking and RA-risk genes, stratifying by presence of anticitrullinated protein antibodies (ACPA).” What the significance of the presence of these antibodies?

Dr Klareskog: The significance is that much evidence shows that the exposure to airway pollutants may cause citrullination as well as activation of antigen-presenting cells in the lung, so that immune reactions to citrullinated antigens may be formed in genetically susceptible individuals, and that this immunity may later contribute to the development of rheumatoid arthritis. The main significance of the data is that the occupational exposures may have a direct pathogenic role in the ACPA-positive subset of RA. 

RALN: Your study team estimated exposure to 32 inhalable agents. What were these agents? 

Dr Klareskog: They were all occupational exposures common in Sweden and in other industrial countries, and thus enough common to cay cause significant morbidity in RA. 

RALN:  Can you review the basic structure of your study?

Dr Klareskog: We investigated 4033 incident RA cases and 6485 matched controls in the EIRA case control study (described above). Genetic data were used to define Genetic Risk Score (GRS) or carrying any copy of human leucocyte antigen class II shared epitope (HLA-SE) alleles. Associations were identified with unconditional logistical regression models. Attributable proportion due to interaction was estimated to evaluate presence of interaction. 

RALN: What were your key findings? 

Dr Klareskog: A large number of occupational airway exposures were strongly associated with risk for RA, and this risk became very big when combined with smoking and presence of certain risk genes (odds ratios 18.22, 95% CI 11.77 to 28.19). Significant interactions were found between occupational inhalable agents and smoking/genetic factors (high GRS or HLA-SE) in ACPA-positive RA.

RALN: How could these findings apply in the clinical care of patients with RA? Would it be possible, for example, to use genetic testing to identify patients who are at increased risk from inhalable agents before they develop RA? 

Dr Klareskog: The findings provide additional arguments to advise anyone in the population not to smoke, and that this advice should be even more emphasized for relatives of patients with RA. Further, additional efforts are encouraged to reduce the level of airway occupational exposures even in countries with relatively high level of protection and awareness of the value of clean air. We do not advice to take genetic tests as this is not enough sensitive measure for risk for RA. 

RALN: Could reducing exposure to these agents among patients who have already developed RA reduce the risk of disease progression or severity?

Dr Klareskog: Most likely this is so, but we did not investigate this in the current study 

RALN: Do you have any further research planned?

Dr Klareskog: Yes, these studies encourage us to continue work to get a better understanding of how exposures to airways may trigger arthritis-inducing immunity, and how we may interfere with this process before onset of RA, thereby preventing the development of this disease.

Reference:
Tang B, Liu Q, Ilar A, et al. Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking. Ann Rheum Dis. 2023;82(3):316-323.