Possible asthma phenotype associated with rheumatoid arthritis
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Key takeaways:
- The association between asthma and rheumatoid arthritis remains unknown.
- Eight of nine patients with asthma and rheumatoid arthritis had severe asthma.
- Two-thirds of patients had evidence of atopy.
A prospective chart review suggests a novel asthma phenotype associated with rheumatoid arthritis, with possible common causality, according to results published in The Journal of Allergy and Clinical Immunology: In Practice.
Successful treatment may require integrated therapeutic approaches, Richard P. Ramonell, MD, assistant professor, and Sally E. Wenzel, MD, professor, division of pulmonary, allergy and critical care medicine, department of medicine, University of Pittsburgh, and colleagues wrote.
An undefined association
“Asthma and rheumatoid arthritis (RA) are both prevalent diseases with well-defined immunological bases, with one often considered allergic (Type 2) and the other autoimmune (Type 1/Th1),” Ramonell and Wenzel told Healio in a joint statement.
But general opinion holds that allergic and autoimmune diseases do not occur together, they continued.
The anecdotal and unexpected observation of reasonable numbers of patients with concomitant asthma and RA diagnosis who were often severely affected by one disease or the other at a large specialty clinic prompted this case series.
“By examining the demographic, clinical and immunological features of asthmatic patients who developed RA, we aimed to raise awareness and begin characterizing this potentially unique disease phenotype for larger more controlled studies,” Ramonell and Wenzel said.
Despite the prevalence of asthma and rheumatoid arthritis, the researchers said, their relationship remains unclear as previous studies have found an inverse relationship between the diseases as well as positive associations.
“There are a couple of large epidemiologic studies that show inverse associations between generally mild asthma and autoimmune disease,” Ramonell and Wenzel said. “In many cases of mild asthma, the diagnosis itself may not be correct (30% of the time).”
But severe asthma has not been subject to similar studies, they continued.
“We hypothesized that longstanding severe asthma, itself a chronic inflammatory disease, often existing since childhood, may predispose some patients to develop autoimmune disease including RA,” Ramonell and Wenzel said.
Previous studies have similarly suggested that earlier lung inflammation caused by smoking or infections could alter proteins in ways that initiate antibody production of autoantibodies.
The researchers also hypothesized that if the inflammation that accompanies prolonged asthma produces conditions conducive to RA development, the mixed inflammatory environment may make the asthma more severe or difficult to treat.
Study design, results
The review included nine adults (median age 71 years; six women; seven white) with asthma with a confirmed asthma diagnosis followed by a confirmed RA diagnosis seen by a single physician between 2006 and 2023.
Eight patients had severe asthma based on European Respiratory Society and American Thoracic Society guidelines. Five patients developed asthma later in life, the researchers said, with a median age of onset of 28 years.
The median age for the onset of RA for the full cohort was 60 years, and the median time between the asthma and RA diagnoses was 20 years. Further, 67% of the patients had never smoked, and the median BMI was 28.5.
The review provided data for asthma treatment regiments before RA for three patients, which the researchers categorized as standard therapy, including high-dose inhaled corticosteroids and long-acting beta agonists, oral corticosteroids, biologics and azathioprine.
Ramonell and Wenzel called these findings that eight of nine patients had severe asthma that required oral corticosteroids or biologics for diseases control, as well as the 20-year median time between asthma and RA diagnoses, “striking.”
When the review was conducted, seven patients were using oral corticosteroids for their asthma, and one also was using them for RA. Additionally, seven had used biologics for their asthma, and seven had used immunosuppression for their RA.
The patients whose asthma was treated with biologics had generally mild RA, the researchers said, and they did not experience any clear improvements. Prior to the review, one patient had visited the ED for asthma as well.
“Most patients with severe asthma were found to have elevated biomarkers of type 2 inflammation, supporting the concomitant presence of different immune pathways,” Ramonell and Wenzel said.
Medians included 1,300 cells/µL for maximum absolute eosinophil count, 73.5 IU/mL for IgE level, and 33.5 ppb for fractional exhaled nitric oxide. The researchers classified six patients as atopic. Two of eight patients with CT imaging had mild bronchiectasis. There were no other pulmonary abnormalities.
The researchers also had pulmonary pathology data available from wedge resections for two patients who had video-assisted thorascopic surgery.
In one patient, findings were consistent with asthmatic small airway disease, but focal bronchiectasis with a segmental and lobular pattern of acute and fibrinous pneumonia that also was found was not consistent with asthma.
The other patient’s pathology was consistent with asthmatic granulomatosis, which the researchers said has been associated with autoimmunity.
Additionally, six of eight patients tested positive for anti-cyclic citrullinated peptide antibodies. Patients with asthma and detectable anti-citrullinated protein antibodies have greater risks for developing rheumatoid arthritis, according to a prior study, the researchers said.
Conclusions, next steps
The severe asthma, late-onset asthma and atopy prevalent in this cohort identify a potentially novel asthma phenotype associated with RA, the researchers said, suggesting possible common causality that may require integrated therapy.
“These findings suggest that asthma, particularly severe forms, may predispose some patients to developing autoimmune conditions like RA,” Ramonell and Wenzel said.
Previous investigations, including studies by these researchers, have identified a shared inflammatory milieu involving type 1 and type 2 immune pathways in subsets of patients with predominantly severe asthma.
“This case series identifies a potential consequence of coexisting chronic inflammatory programs and challenges the traditional view of type 1 and type 2 inflammatory pathways as being entirely distinct or inversely related,” Ramonell and Wenzel said.
Ramonell and Wenzel also encouraged physicians to consider screening their patients with severe asthma for RA, particularly those patients who develop arthralgias or arthritis.
“Early detection of RA, especially in patients already being treated with immunomodulators for asthma, may enable prompt intervention, potentially mitigating joint damage and systemic complications,” Ramonell and Wenzel said.
These findings also underscore the need for pulmonologists and rheumatologists to collaborate in treating patients with complex inflammatory conditions, they continued.
The researchers also called for more detailed epidemiologic studies to confirm these findings among well-characterized patients with severe asthma as well as more detailed studies to identify the putative mechanisms that connect these diseases.
“It is important to note a key limitation of this study is its small size and anecdotal association between the two conditions,” Ramonell and Wenzel cautioned.
Studies of additional genetic or environmental risk factors that set these patients apart from more typical asthma should accompany future research, Ramonell and Wenzell added.
“Mechanistic studies should identify potential immunologic links to determine how the inflammatory environment in asthma might predispose individuals to RA,” they said.
“If confirmed, these studies could lead to identification of novel biomarkers to identify subsets of asthma patients at risk for autoimmune disease or novel therapeutic strategies targeting shared pathways to improve outcomes for both diseases,” they .
Reference:
- Holers VM, et al. Nat Rev Rheumatol. 2018;doi:10.1038/s41584-018-0070-0.
For more information:
Richard P. Ramonell, MD, can be reached at ramonellrp@upmc.edu.
Perspective
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There are many papers now showing that asthma is a risk factor for RA. Conversely, RA also seems to be a risk factor for new onset asthma. The findings are significant due to the high prevalence of asthma.
We have had several controlled papers published showing that asthma is a risk factor for rheumatoid arthritis. Clinically, I also have treated many patients who have both conditions. Certainly, awareness of this association may be helpful for early recognition and diagnosis of RA.
Still, it is unclear how treatments and endotypes of asthma may impact RA risk and disease activity. Also, advanced biologic drugs are now being used for asthma. The safety of these drugs in combination with disease-modifying anti-rheumatic drugs should be studied. It is also possible asthma drugs may impact RA disease activity.
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Ramonell RP, et al. J Allergy Clin Immunol Pract. 2024;doi:10.1016/j.jaip.2024.12.015.
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