There is a Connection between Rheumatoid Arthritis (RA) and Smoking – what are the Reasons?
That smoking is unhealthy really isn’t a secret any more. However, it may be less well known that smoking is especially damaging to patients with rheumatoid arthritis (RA) or people with a genetic predisposition towards this autoimmune disease.
Until a few years ago, a coherent explanation of how smoking triggers the break in immunotolerance and why tobacco smoke promotes the onset of autoimmune disease was still missing. A group of Swedish researchers has found one of the missing links in the pathogenic chain between tobacco smoke and rheumatoid arthritis (Makrygiannakis et al., 2008). The scientists from the Karolinska Institute in Stockholm showed that cigarette smoke is directly involved in the development of rheumatoid arthritis.
Citrullination: tobacco smoke alters proteins
If the corresponding genetic predisposition is in place, contaminants in smoke lead to the activation of a certain enzyme called peptidylarginine deiminase type 2 (PAD2, PAD-2). This enzyme activation leads to a biochemical change in the body’s own proteins, this change is called citrullination. Five PAD types have been described to date. It has been demonstrated that two of them (PAD2 and PAD4) occur in the synovial membranes of RA patients, where they play a critical role in the inflammation of the joints.
Citrullination is actually a physiological process of the cell metabolism, occurring in epidermal cells or nerve cells, for example. It regularly occurs in apoptosis, programmed cell death. Citrullination of the body’s own proteins is also observed in “normal” inflammatory processes. The enzymatic deimination of arginine leads to the formation of the amino acid citrulline.
This post-translational modification leads to a change in the structure of the protein. This forms neoepitopes, which are falsely recognized as foreign by the immune systems of RA patients. These persons form antibodies against the altered proteins, which leads to the onset of rheumatoid arthritis. Incidentally, these pathological autoantibodies are exactly the antibodies recommended as ACPAs for the diagnosis of rheumatoid arthritis (ACPAs = antibodies against citrullinated protein/peptide antibodies, anti-citrullinated protein/peptide antibodies).
PAD inhibitors: novel drugs for rheumatoid arthritis?
Citrullination of native proteins by the various peptidylarginine deiminases (PAD) is a critical step in the pathogenesis of rheumatoid arthritis. This would suggest that inhibition of citrullination through drugs would be a good approach for treatment. According to the latest literature, various PAD inhibitors are currently being researched.
However, scientists warn against excessive premature celebration of these new drugs for treating rheumatoid arthritis, because ACPAs can appear years before the onset of RA. This means that the autoimmune disease is often in full swing by the time the first clinical symptoms appear. By this time, the disease is probably being sustained by completely differently processes and factors instead of citrullination; it is thus not certain that this new approach for the treatment of RA will work.
In addition, very little is currently known about the physiological significance of peptidylarginine deaiminases. Their deactivation by PAD inhibitors could have potentially fatal consequences for cell metabolism and the balance in the human body.
Scientific studies: smoking and rheumatoid arthritis (RA)
Studies and scientific research establishing the relationship between tobacco consumption and the onset of rheumatoid arthritis are many. The review Rheumatoid Arthritis and Smoking: Putting the Pieces Together, by Hungarian authors Zsuzsanna Baka, Edit Buzás, and György Nagy, gives a very good overview of the relevant studies and the facts as they are currently understood (free article download on Arthritis Res Ther, accessed on April 30th, 2010).
Cigarette smoking over a sufficiently long time and at a sufficient intensity clearly leads to enduring immunomodulation. As a consequence, memory cells continually produce pathological antibodies like rheumatoid factors (RF) and ACPAs, as described by Zsuzsanna Baka, Edit Buzás, and György Nagy in their review.
After the patients quit smoking, it still takes several years for these long-lived cells to be cleared from the body. This is in agreement with the observation that the risk of getting RA for former smokers only decreases noticeably after about ten years of abstinence.
On the whole, it can also be concluded that both the duration of tobacco consumption and the number of cigarettes smoked daily influence the risk of developing rheumatoid arthritis. However, the length of time over which cigarettes were consumed is clearly more significant; the risk of becoming ill increases markedly after 20 years.
Not yet included in the review study from Hungary is a recent meta-analysis on the subject published early this year in the Annals of the Rheumatic Diseases and available online a year earlier. For this meta-analysis in Ann Rheum Dis, the Japanese authors looked at over 400 scientific publications on the subject of smoking and rheumatism from the last forty years. In the end they used 16 of these studies in their analysis.
Higher risk for long-term smokers, increased risk with genetic predisposition
The conclusions of the meta-analysis are not really surprising and fit the image drawn by previous studies on the subject of smoking and rheumatism: “Smoking is a risk factor for RA […] It is especially strongly associated with RA for RF positive males and both male and female heavy smokers”, the authors conclude (LinkOut to the abstract on Ann Rheum Dis, accessed 30th April 2010). The connection between smoking and rheumatoid arthritis seems to be well and truly proven. A quick overview of the results of the Japanese meta-analysis is provided in a news release from Reuters Health (accessed 30th April 2010).
“Hands off the cigarettes” should especially apply to those with a genetic predisposition toward rheumatic disease. The strongest genetic risk factor identified for rheumatoid arthritis (RA) is the “shared epitope” (SE) of the HLA-DRB1 allele (see also the blog post by my colleague Friederike Hammar: Genetics of RA susceptibility, April 7th, 2010). Smokers with the “shared epitope” genetic marker on both alleles have twenty times the risk of developing rheumatoid arthritis, as reported by Klareskog and co-workers in a 2006 study (free article download).
Smokers require more medication
Those patients who already have rheumatoid arthritis are also not doing themselves any favours by smoking cigarettes. Aside from the increased risk of tumours, and damage to the heart, lungs, and blood vessels, smoking RA patients require more anti-rheumatic drugs than non-smokers.
Precisely speaking, this means that the chance that the number of inflamed, tender, and swollen joints can be reduced by treatment to alleviate pain is only about half as good for smokers as non-smokers. This according to Dr. Edmund Edelmann, president of the Bundesverband der Deutschen Rheumatologen (BDRh, Association of German Rheumatolgists) on the web site Rheumatologen im Netz (LinkOut to the news release [German] accessed 30th April, 2010).
Smokers also require significantly more of the classical basic medications (disease modifying anti-rheumatic drugs, DMARDs) and the genetically engineered biologicals used in the treatment of rheumatoid arthritis. Cigarette consumption appears to weaken the effects of these drugs. It is also possible that tobacco smoke increases the disease activity of rheumatoid arthritis, causing the afflicted to require more medications.
As the quantity of medication used increases, so does the risk of side effects for the treatment. According to more recent studies, the quantity of drugs needed for adequate treatment decreases when RA patients stop smoking.
Abhishek A, Butt S, Gadsby K, Zhang W, Deighton CM. Anti-TNF-alpha agents are less effective for the treatment of rheumatoid arthritis in current smokers. J Clin Rheumatol. 2010 Jan;16(1):15-8. – LinkOut to the abstract
Baka Z, Buzás E, Nagy G. Rheumatoid arthritis and smoking: putting the pieces together. Arthritis Res Ther. 2009; 11(4): 238. Review. – free article download
Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Méchin MC, Vincent C, Nachat R, Yamada M, Takahara H, Simon M, Guerrin M, Serre G. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum. 2007 Nov;56(11):3541-53 – free article download
Karlson EW, Chang S-C, Cui J, Chibnik LB, Fraser PA, Vivo I de, Costenbader KH. Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann Rheum Dis 2010;69:54-60 – free article download
Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, Rönnelid J, Harris HE, Ulfgren AK, Rantapää-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006 Jan;54(1):38-46. Research Article. – free article download
Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR. Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry 2006 Oct 3;45(39):11727-36. – free article download
Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, Grunewald J, Skold CM, Klareskog L, Catrina AI. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008 Oct;67(10):1488-92. – abstract
Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010 Jan;69(1):70-81. Review. – abstract
Westhoff G, Rau R, Zink A. Rheumatoid arthritis patients who smoke have a higher need for DMARDs and feel worse, but they do not have more joint damage than non-smokers of the same serological group. Rheumatology (Oxford). 2008 Jun;47(6):849-54. – free article download
Author of this article: Tobias Stolzenberg
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