Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation, pain, and swelling, primarily affecting the joints, occurring when the body’s immune system mistakenly attacks healthy tissue. Smoking is a significant modifiable risk factor that influences both the development and severity of RA. The toxic components in cigarette smoke interact negatively with the body’s immune processes.
Smoking’s Role in Rheumatoid Arthritis Onset
Smoking substantially increases the risk of developing RA, especially the form of the disease associated with specific autoantibodies. The initial immunological damage often begins in the lungs, which are constantly exposed to the toxic agents in tobacco smoke. These agents trigger a localized, chronic inflammatory event within the pulmonary tissue.
The smoke exposure promotes the production of enzymes called peptidylarginine deiminases (PADs) within the lungs. These PAD enzymes modify proteins by converting the amino acid arginine into citrulline, a process known as citrullination. This chemical alteration changes the structure of the body’s own proteins, making them appear foreign to the immune system.
In genetically predisposed individuals, particularly those carrying the HLA-DRB1 shared epitope, this process triggers the immune system to produce anti-citrullinated protein antibodies (ACPAs). ACPAs are highly specific hallmarks for RA, and their presence often precedes the clinical onset of joint symptoms by years. A meta-analysis showed that even a low lifetime exposure, such as 10 pack-years, is associated with a 26% increased risk of RA, with the risk rising dramatically for heavier smokers. The combination of a smoking history and certain genetic markers can increase the risk of RA by more than 20-fold compared to non-smokers without those genes.
How Smoking Worsens Existing Disease Activity
For patients already diagnosed with RA, continued smoking accelerates the disease process and leads to more severe clinical outcomes. Smokers with RA typically experience higher levels of systemic inflammation compared to non-smokers. This increased inflammatory burden results in higher disease activity scores, such as the DAS28, which measures tender and swollen joints and inflammatory markers.
Patients who smoke often report significantly more pain and have a greater number of swollen joints. The pro-inflammatory environment created by smoking includes elevated levels of inflammatory proteins like cytokines, which drive the joint and organ damage associated with RA. This heightened activity can result in faster radiographic progression, meaning more rapid joint destruction visible on X-rays.
Smoking is also strongly associated with extra-articular manifestations. For instance, smokers are more likely to develop rheumatoid nodules, which are firm lumps of tissue that form under the skin or near joints. Smoking also increases the risk of lung involvement in RA, which is a major contributor to mortality in these patients.
Interference with RA Treatment Efficacy
Smoking significantly compromises the effectiveness of medications used to manage RA, making it more challenging to achieve disease control. Smokers are less likely to achieve remission or low disease activity compared to non-smokers, even when receiving the same therapeutic regimen. This reduced response is observed across multiple drug classes, including conventional synthetic disease-modifying antirheumatic drugs (DMARDs).
Specifically, current smoking has been shown to predict an inadequate response to methotrexate, a first-line DMARD. Patients who smoke often require more aggressive medication combinations or higher doses to manage their symptoms. This lack of efficacy may be due, in part, to the effects of smoking on drug metabolism or the persistent pro-inflammatory state that dampens the drugs’ beneficial effects.
The interference is particularly pronounced with biological therapies, such as anti-tumor necrosis factor-alpha (anti-TNF-alpha) drugs and rituximab. Studies have shown that current smokers have substantially lower response rates to these advanced medications compared to those who have never smoked. For example, one study found that the percentage of current smokers who responded to anti-TNF-alpha treatment was significantly lower than never-smokers.
Benefits of Smoking Cessation for RA Patients
Quitting smoking offers clear and measurable benefits for individuals with or at risk of developing RA. For those who have not yet developed the disease, sustained smoking cessation helps reduce the risk of seropositive RA, although it may take several years to see the full reduction.
For patients already living with RA, stopping smoking can lead to a significant improvement in disease outcomes. Former smokers show levels of disease activity and inflammation that are similar to those who have never smoked. This reduction in inflammation often translates to less pain and improved physical function.
Crucially, smoking cessation enhances the effectiveness of RA treatments, including DMARDs and biologics. Quitting can improve a patient’s likelihood of achieving remission and a better response to their medication regimen. This leads to a slower rate of disease progression and reduced joint damage over time.