Rheumatoid arthritis smoking

Rheumatoid arthritis smoking DEFAULT

The Harvard Gazette

A new study by investigators from Harvard-affiliated  Brigham and Women’s Hospital found a potential direct link between exposure to parental smoking during childhood and increased risk of seropositive rheumatoid arthritis (RA) later in life.

Researchers utilized established longitudinal data from 90,923 women in the Nurses’ Health Study II (NHSII) to elucidate the relationship between passive smoking exposure and incident RA. Passive exposure was broken down into three categories, including maternal smoking during pregnancy, parental smoking during childhood, and years lived with smokers since age 18. Even with personal smoking accounted for, passive exposure to parental smoking during childhood was found to increase risk of incident seropositive RA by 75 percent. Findings are published in Arthritis & Rheumatology.

“There has been intense interest in mucosal lung inflammation from personal smoking as a site of RA pathogenesis,” said senior author Jeffrey A. Sparks of the Department of Medicine at the Brigham. “But the majority of RA patients aren’t smokers, so we wanted to look at another inhalant that might precede RA.”

RA is an inflammatory disease characterized by arthritis at multiple joints and is associated with morbidity and mortality outcomes. Many people with RA have signs of lung inflammation, and while genetic and environmental factors contribute to risk of developing RA, smoking has long been implicated as a key RA risk factor. Personal (active) smoking is the most well-established environmental risk factor associated with RA, with passive smoking left relatively unexplored.

To link passive smoking and incident RA more conclusively, Sparks and colleagues used data from NHSII questionnaires collected biennially between 1989 and 2017 from 90,923 women aged 35-52 years. Researchers used participant medical records to confirm incident RA and serostatus. Statistical modeling was then used to estimate the direct effect of each passive smoking exposure on RA risk, as well as to control for other factors such as personal smoking.

A 75 percent higher risk of RA was found in individuals who experienced passive childhood exposure to parental smoking. This risk increased in participants who themselves became active smokers. Over the median follow-up of 27.7 years, 532 women in the cohort developed confirmed incident RA cases — the majority (352) of which were seropositive (positive for RA autoantibodies). Maternal smoking during pregnancy and years lived with smokers beyond age 18 showed no significant association with incident RA risk.

Although the all-female nurse participant pool led to high response rates and retention, the study is limited by the absence of men. The team intends to continue with longitudinal studies that encompass both men and women, as to provide critical insight into other rheumatoid conditions and even other autoimmune diseases.

“Our findings give more depth and gravity to the negative health consequences of smoking in relation to RA, one of the most common autoimmune diseases,” said lead and co-corresponding author Kazuki Yoshida of the Brigham’s Division of Rheumatology, Inflammation and Immunity. “This relationship between childhood parental smoking and adult-onset RA may go beyond rheumatology — future studies should investigate whether childhood exposure to inhalants may predispose individuals to general autoimmunity later in life.”

This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under award number K23 AR069688 to Jeffrey Sparks. This work was additionally supported by the Rheumatology Research Foundation R Bridge Award, and by the National Institutes of Health (award numbers L30 AR066953, K24 AR052403, R01 AR049880, R01AR057327, R01 AR119246, R01 HL034594, P30 AR070253, P30 AR072577, P30 AR069625, UM1CA186107, U01 HG008685, 1OT2OD026553, and R03 AR075886). Kazuki Yoshida was supported by the Rheumatology Research Foundation K Bridge Award, Brigham and Women’s Hospital Department of Medicine Fellowship Award, and K23 AR076453 (NIAMS). Nurses’ Health Study II was supported by the National Institutes of Health (U01 CA176726, R01CA67262, and U01 HL145386).

Sours: https://news.harvard.edu/gazette/story/2021/08/exposure-to-parental-smoking-increases-risk-of-rheumatoid-arthritis/

What You Should Know About Rheumatoid Arthritis (RA) and Smoking

There’s been a lot discovered about rheumatoid arthritis (RA) and its causes.

Studies have shown that smoking is a big risk factor in the development of RA, though the exact role that smoking plays in that development is unknown.

Researchers do think that smoking affects the way that your immune system functions, especially if you already have certain conditions that make it more likely that you’ll develop RA.

A also found that smoking may alter the way your body responds to some RA medications. The study found that poor response to certain drugs was often linked to the smoking habits of the participants.

Also, if your RA diagnosis requires surgery, smoking may increase your risk for complications. It can affect anesthesia and drug metabolism, as well as your heart rate, breathing, and blood pressure.

People who smoke are also at a higher risk for experiencing more severe RA symptoms and being less likely to recover from their symptoms.

What’s the connection between smoking and RA?

Here are some of the links between RA and smoking:

  • You are more likely to develop RA if you smoke. Studies show that environmental and hereditary factors are likely causes in the development of RA. Smoking is considered an environmental factor, meaning it puts you at a higher risk for RA.
  • You are less likely to respond to RA treatments if you smoke. Studies show that patients who are smokers are less likely to respond to anti- TNF-a drugs and to methotrexate, which are both RA treatments.
  • Smoking can make symptoms worse if you have RA. Smoking can cause RA pain to intensify, and it can cause the RA to spread and inflame other parts of your body. Smoking can also lead to other health complications that could worsen your RA.
  • Women are more likely to develop RA if they smoke. A study found that women who smoke daily could increase their risk for developing RA by more than double.

Smoking may be a calming mechanism, and it may help to distract you from the pain of RA, but in addition to worsening your RA symptoms, smoking can lead to a number of other health problems.

If you’re a person who smokes, you may want to consider quitting to help reduce your risk for health complications.

How can I quit smoking?

Tobacco is addictive, so making the decision to quit smoking can be difficult and emotional.

Here are some tips you can follow to help you on your journey:

  • Speak with your doctor. You may be able to quit cold turkey, but many smokers can’t. Your doctor can talk with you about the different options that are available. There are focus groups related to quitting, and there are also medications available with and without a prescription that can help you quit.
  • Decide what type of smoking cessation plan you want to follow. Having a plan can help you stay prepared for things like cravings and withdrawals, as well as allow you to set realistic expectations for yourself and stay motivated throughout your process.
  • Pick the day that you plan to quit. Picking a day to quit is a key step in the process. If you pick a day that’s too soon, you may not have enough time to prepare. But if you pick a day too far away, that leaves the opportunity to change your mind about quitting.
  • Tell your friends and loved ones that you’re trying to quit. This may be helpful for them so that they aren’t doing things like smoking around you and offering you cigarettes. It may be helpful for you because it could potentially give you much-needed support.
  • Find other activities to distract yourself from smoking. For example, you can keep gum with you to chew on when the urge to smoke strikes. You can also try picking up new hobbies to distract yourself from urges.
  • Know what to expect. Because nicotine is a drug, your body will go through withdrawal. You may feel depressed, restless, cranky, anxious, frustrated, or mad. You may be unable to sleep, or you might gain weight. Talk with your doctor about available resources to help address and cope with your withdrawal symptoms.
  • Don’t give up if you relapse. It may take several tries before you can fully kick the habit. If your first plan doesn’t work, try a different one. You may relapse several times before you finally quit, but that’s OK.

More about RA

RA is a type of inflammatory arthritis, which means that the body’s immune system mistakenly attacks the joints. This causes the synovial tissue cells, or the soft tissue that lines the inside of the joints, to divide, thicken, and swell.

The thickening of synovial tissues can lead to pain and inflammation in the joints. Inflammatory arthritis is unlike other forms of arthritis, such as osteoarthritis, which is a result of wear and tear of your joints.

RA affects about 1.5 million people in the United States. The disease is more prevalent — nearly three times — among people assigned female at birth than those assigned male.

RA can affect almost any joints in your body, including:

  • feet
  • hands
  • wrists
  • elbows
  • knees
  • ankles

If you have RA, warmth and swelling in your joints is common, but these symptoms might go unnoticed.

You’re also likely to experience tenderness and pain in your joints. You may feel stiff in the morning for more than 30 minutes, or you may have joint pain and swelling for several weeks.

Usually, more than one joint is affected. RA commonly affects smaller joints, such as those present in the hands and feet.

In addition to the joints, RA can also have negative effects on other parts of your body. Other common symptoms of RA include:

Currently, there’s no cure for RA. Medication can be used to treat the disease, but severe cases can result in loss of mobility or the development of joint deformities.


Quitting smoking can help with your RA, including helping improve your quality of life and potentially enabling you to reduce your RA medications. Quitting may also be beneficial for those around you.

The American Lung Association lists smoking as the leading cause of preventable death.

Secondhand smoke can be just as harmful, so it’s important to think about the safety of your kids, other family members, and friends.

If you’re struggling to quit, help is available.

Your doctor can tell you about nearby smoking cessation programs, as well as other resources, and work with you to create the best plan for you.

Sours: https://www.healthline.com/health/ra-and-smoking
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What is the relationship between smoking and rheumatoid arthritis?

Both rheumatoid arthritis (RA) and smoking cause inflammation in the body. This has led some researchers to investigate whether smoking may cause or exacerbate RA.

RA is an autoimmune disease in which the immune system mistakenly attacks healthy cells within the body. This results in inflammation in the joints as well as other body tissues and organs.

This article explores the link between smoking and RA and provides tips on how to quit smoking. It also outlines some other risk factors for RA.

Can smoking cause RA?

Doctors do the cause of RA. However, research supports the notion that certain environmental factors may activate genes that predispose a person to the condition. Smoking cigarettes is one such risk factor.

Both RA and smoking chronic inflammation within the body. The inflammatory effects of smoking may contribute to the development of RA or may add to the inflammatory effects of preexisting RA.

Authors of a 2018 study identified an association between smoking and a higher likelihood of developing RA. However, this was only the case among people who had smoked more than a pack of cigarettes per day for 2.5 years or more, or the equivalent number of cigarettes over fewer years.

A involving 230,732 women found a correlation between smoking and the occurrence of RA. The study also found that quitting smoking decreased a person’s risk of RA. The longer a person had been a nonsmoker, the lower was their risk of developing the condition.

Moreover, in a 2017 study, researchers identified a link between secondhand smoke exposure and a worsening of RA symptoms among women with RA. The researchers suggest that smoke exposure might somehow trigger RA, such as by activating genes that predispose a person to the condition.

Despite all these findings, the link between smoking and RA remains complex. Not all smokers develop RA, and not all people with RA smoke.

Instead, it is likely that smoking is one of many environmental risk factors that may increase the likelihood of RA occurring in susceptible individuals.

Smoking with RA

Smoking may increase the risk of RA complications in people who already have the condition.

A outlines a possible link between RA and hearing loss. According to the review, smoking can cause inflammation of the blood vessels, which may further increase the risk of hearing loss in people with RA.

Smoking also increases the risk of cardiovascular diseases that can limit a person’s ability to exercise.

Since physical activity plays an important role in the management of RA, smoking may negatively affect the prognosis of the condition.

How to quit smoking

Quitting smoking can be very challenging. This is because the nicotine in cigarettes is highly addictive, and it takes time for the body and mind to adapt to absence of nicotine.

People who have recently stopped smoking may experience withdrawal symptoms, such as:

People can try the to increase their odds of quitting smoking:

  • Plan a quit date in advance: Planning a quit date allows a person time to prepare for quitting. Where possible, people should plan to quit at a time of low stress, and should try to ensure they have adequate support in place. This may be in the form of a quit-smoking program, supportive friends and family, or engaging activities or hobbies.
  • Quit completely rather than just cutting back: Quitting completely allows nicotine to leave the body faster. Withdrawal will happen more immediately, but it will also end more quickly. smokers who quit outright rather than cut back have higher rates of success.
  • Consider joining a program to quit smoking: The right quit-smoking program offers support and reassurance that may make it easier for a person to quit the habit.
  • Ask a doctor about medication: Medication can help ease some withdrawal symptoms, such as depression and anxiety.
  • Plan a distraction: Engaging in an enjoyable activity can distract from thoughts about smoking and can make cravings easier to manage. Examples of such activities include gardening, walking a dog, or meeting up with a friend.

Outlook and prognosis of RA if a person smokes

The course of RA, including its progression, will differ from person to person. However, smoking generally worsens the prognosis of individuals with the condition.

Smoking inflammation that adds to the chronic inflammation due to RA. This can lead to a worsening of preexisting RA symptoms.

RA is a chronic condition that can worsen over time. However, medication can help a person manage it and slow its progression.

suggests that smoking could reduce the effectiveness of certain RA drugs.

As such, people should notify a doctor if they smoke. The doctor will be able to recommend the most appropriate RA treatment and can direct people to resources to help them quit smoking.


RA is a chronic autoimmune condition. A number of factors can contribute to the development of RA and to the worsening of its symptoms. Smoking is one such factor.

If people with RA who smoke quit smoking, they may notice some benefits, such as a reduction of severity of RA symptoms, and a better response to RA medication.

A doctor can help a person develop a quit-smoking plan and offer strategies to lower smoking-related health risks.

Sours: https://www.medicalnewstoday.com/articles/smoking-and-rheumatoid-arthritis
Smoking is a cause of Rheumatoid Arthritis

Smoking and Rheumatoid Arthritis

1. Scott D.L., Wolfe F., Huizinga T.W. Rheumatoid arthritis. Lancet. 2010;376:1094–1108. doi: 10.1016/S0140-6736(10)60826-4. [PubMed] [CrossRef] [Google Scholar]

2. Cooles F.A., Isaacs J.D. Pathophysiology of rheumatoid arthritis. Curr. Opin. Rheumatol. 2011;23:233–240. doi: 10.1097/BOR.0b013e32834518a3. [PubMed] [CrossRef] [Google Scholar]

3. Mongey A.B., Hess E.V. Drug and environmental effects on the induction of autoimmunity. J. Lab. Clin. Med. 1993;122:652–657. [PubMed] [Google Scholar]

4. Sopori M. Effects of cigarette smoke on the immune system. Nat. Rev. Immunol. 2002;2:372–377. doi: 10.1038/nri803. [PubMed] [CrossRef] [Google Scholar]

5. Harel-Meir M., Sherer Y., Shoenfeld Y. Tobacco smoking and autoimmune rheumatic diseases. Nat. Clin. Pract. Rheumatol. 2007;3:707–715. doi: 10.1038/ncprheum0655. [PubMed] [CrossRef] [Google Scholar]

6. Onozaki K. Etiological and biological aspects of cigarette smoking in rheumatoid arthritis. Inflamm. Allergy Drug Targets. 2009;8:364–368. doi: 10.2174/1871528110908050364. [PubMed] [CrossRef] [Google Scholar]

7. Ruiz-Esquide V., Sanmartí R. Tobacco and other environmental risk factors in rheumatoid arthritis. Reumatol. Clin. 2012;8:342–350. doi: 10.1016/j.reuma.2012.02.011. [PubMed] [CrossRef] [Google Scholar]

8. Hoovestol R.A., Mikuls T.R. Environmental exposures and rheumatoid arthritis risk. Curr. Rheumatol. Rep. 2011;13:431–439. doi: 10.1007/s11926-011-0203-9. [PubMed] [CrossRef] [Google Scholar]

9. Vessey M.P., Villard-Mackintosh L., Yeates D. Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception. 1987;35:457–464. doi: 10.1016/0010-7824(87)90082-5. [PubMed] [CrossRef] [Google Scholar]

10. Heliövaara M., Aho K., Aromaa A., Knekt P., Reunanen A. Smoking and risk of rheumatoid arthritis. J. Rheumatol. 1993;20:1830–1835. [PubMed] [Google Scholar]

11. Uhlig T., Hagen K.B., Kvien T.K. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J. Rheumatol. 1999;26:47–54. [PubMed] [Google Scholar]

12. Karlson E.W., Lee I.M., Cook N.R., Manson J.E., Buring J.E., Hennekens C.H. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals. Arthritis Rheumatol. 1999;42:910–917. doi: 10.1002/1529-0131(199905)42:5<910::AID-ANR9>3.0.CO;2-D. [PubMed] [CrossRef] [Google Scholar]

13. Criswell L.A., Merlino L.A., Cerhan J.R., Mikuls T.R., Mudano A.S., Burma M., Folsom A.R., Saag K.G. Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: Results from the Iowa Women’s Health Study. Am. J. Med. 2002;112:465–471. doi: 10.1016/S0002-9343(02)01051-3. [PubMed] [CrossRef] [Google Scholar]

14. Padyukov L., Silva C., Stolt P., Alfredsson L., Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheumatol. 2004;50:3085–3092. doi: 10.1002/art.20553. [PubMed] [CrossRef] [Google Scholar]

15. Costenbader K.H., Feskanich D., Mandl L.A., Karlson EW. Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am. J. Med. 2006;119:503.e1–9. doi: 10.1016/j.amjmed.2005.09.053. [PubMed] [CrossRef] [Google Scholar]

16. 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;69:70–81. doi: 10.1136/ard.2008.096487. [PubMed] [CrossRef] [Google Scholar]

17. Di Giuseppe D., Discacciati A., Orsini N., Wolk A. Cigarette smoking and risk of rheumatoid arthritis: A dose-response meta-analysis. Arthritis Res. Ther. 2014;16:R61. doi: 10.1186/ar4498.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

18. Krishnan E., Sokka T., Hannonen P. Smoking-gender interaction and risk for rheumatoid arthritis. Arthritis. Res. Ther. 2003;5:R158–R162. doi: 10.1186/ar750.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

19. Stolt P., Bengtsson C., Nordmark B., Lindblad S., Lundberg I., Klareskog L., Alfredsson L. EIRA study group: Quantification of the influence of cigarette smoking on rheumatoid arthritis: Results from a population based case-control study, using incident cases. Ann. Rheum. Dis. 2003;62:835–841.[PMC free article] [PubMed] [Google Scholar]

20. Pryor WA., Stone K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann. N. Y. Acad. Sci. 1993;686:12–28. doi: 10.1111/j.1749-6632.1993.tb39148.x. [PubMed] [CrossRef] [Google Scholar]

21. Kalpakcioglu B., Senel K. The interrelation of glutathione reductase, catalase, glutathione peroxidase, superoxide dismutase, and glucose-6-phosphate in the pathogenesis of rheumatoid arthritis. Clin. Rheumatol. 2007;27:141–145. doi: 10.1007/s10067-007-0746-3. [PubMed] [CrossRef] [Google Scholar]

22. Barr J., Sharma C.S., Sarkar S., Wise K., Dong L., Periyakaruppan A., Ramesh G.T. Nicotine induces oxidative stress and activates nuclear transcription factor kappa B in rat mesencephalic cells. Mol. Cell. Biochem. 2007;297:93–99. doi: 10.1007/s11010-006-9333-1.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

23. Cheng X.L., Zhang H., Guo D., Qiao Z.D. Upregulation of Fas and FasL expression in nicotine-induced apoptosis of endothelial cells. Methods Find. Exp. Clin. Pharmacol. 2010;32:13–18. doi: 10.1358/mf.2010.32.1.1428742. [PubMed] [CrossRef] [Google Scholar]

24. Bijl M., Horst G., Limburg P.C., Kallenberg C.G. Effects of smoking on activation markers, Fas expression and apoptosis of peripheral blood lymphocytes. Eur. J. Clin. Investig. 2001;31:550–553. doi: 10.1046/j.1365-2362.2001.00842.x. [PubMed] [CrossRef] [Google Scholar]

25. Imirzalioĝlu P., Uckan S., Alaaddinoĝlu E.E., Haberal A., Uckan D. Cigarette smoking and apoptosis. J. Periodontol. 2005;76:737–739. doi: 10.1902/jop.2005.76.5.737. [PubMed] [CrossRef] [Google Scholar]

26. Peng S.L. Fas (CD95)-related apoptosis and rheumatoid arthritis. Rheumatology (Oxford) 2006;45:26–30. doi: 10.1093/rheumatology/kei113. [PubMed] [CrossRef] [Google Scholar]

27. Genestier L., Paillot R., Fournel S., Ferraro C., Miossec P., Revillard J.P. Immunosuppressive properties of methotrexate: Apoptosis and clonal deletion of activated peripheral T cells. J. Clin. Investig. 1998;102:322–328. doi: 10.1172/JCI2676.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

28. Mizushima N., Kohsaka H., Miyasaka N. Ceramide, a mediator of interleukin 1, tumour necrosis factor α, as well as Fas receptor signalling, induces apoptosis of rheumatoid arthritis synovial cells. Ann. Rheum. Dis. 1998;57:495–499. doi: 10.1136/ard.57.8.495.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

29. Holt P.G., Keast D. Environmentally induced changes in immunological function: Acute and chronic effects of inhalation of tobacco smoke and other atmospheric contaminants in man and experimental animals. Bacteriol. Rev. 1977;41:205–216.[PMC free article] [PubMed] [Google Scholar]

30. Reynolds H.Y. Bronchoalveolar lavage. Am. Rev. Respir. Dis. 1987;135:250–263. [PubMed] [Google Scholar]

31. Bracke K., Cataldo D., Maes T., Gueders M., Noël A., Foidart J.M., Brusselle G., Pauwels R.A. Matrix metalloproteinase-12 and cathepsin D expression in pulmonary macrophages and dendritic cells of cigarette smoke-exposed mice. Int. Arch. Allergy Immunol. 2005;138:169–179. doi: 10.1159/000088439. [PubMed] [CrossRef] [Google Scholar]

32. Liu Y., Aryee M.J., Padyukov L., Fallin M.D., Hesselberg E., Runarsson A., Reinius L., Acevedo N., Taub M., Ronninger M., et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol. 2013;31:142–147. doi: 10.1038/nbt.2487.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

33. Wang H., Yu M., Ochani M., Amella C.A., Tanovic M., Susarla S., Li J.H., Wang H., Yang H., Ulloa L., et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–388. doi: 10.1038/nature01339. [PubMed] [CrossRef] [Google Scholar]

34. Raitio A., Tuomas H., Kokkonen N. Levels of matrix metalloproteinase-2, -9 and -8 in the skin, serum and saliva of smokers and non-smokers. Arch. Dermatol. Res. 2005;297:242–248. doi: 10.1007/s00403-005-0597-1. [PubMed] [CrossRef] [Google Scholar]

35. Xue M., McKelvey K., Shen K., Minhas N., March L., Park S.Y., Jackson C.J. Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation. Rheumatology (Oxford) 2014 doi: 10.1093/rheumatology/keu254. [PubMed] [CrossRef] [Google Scholar]

36. Ferson M., Edwards A., Lind A., Milton G.W., Hersey P. Low natural-killer-cell activity and immunoglobulin levels associated with smoking in human subjects. Int. J. Cancer. 1979;23:603–609. doi: 10.1002/ijc.2910230504. [PubMed] [CrossRef] [Google Scholar]

37. Shegarfi H., Naddafi F., Mirshafiey A. Natural killer cells and their role in rheumatoid arthritis: Friend or foe? Sci. World J. 2012 doi: 10.1100/2012/491974.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

38. Kawada T. Smoking-induced leukocytosis can persist after cessation of smoking. Arch. Med. Res. 2004;35:246–250. doi: 10.1016/j.arcmed.2004.02.001. [PubMed] [CrossRef] [Google Scholar]

39. Johnson J.D., Houchens D.P., Kluwe W.M., Craig D.K., Fisher G.L. Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: A review. Crit. Rev. Toxicol. 1990;20:369–395. doi: 10.3109/10408449009089870. [PubMed] [CrossRef] [Google Scholar]

40. Cozen W., Diaz-Sanchez D., Gauderman J.W. Th1 and Th2 cytokines and IgE levels in identical twins with varying levels of cigarette consumption. J. Clin. Immunol. 2004;24:617–622. doi: 10.1007/s10875-004-6247-0. [PubMed] [CrossRef] [Google Scholar]

41. Arnson Y., Shoenfeld Y., Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J. Autoimmun. 2010;34:J258–265. doi: 10.1016/j.jaut.2009.12.003. [PubMed] [CrossRef] [Google Scholar]

42. Yoshida Y., Tanaka T. Interleukin 6 and rheumatoid arthritis. Biomed. Res. Int. 2014 doi: 10.1155/2014/698313.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

43. Klimiuk P.A., Fiedorczyk M., Sierakowski S., Chwiecko J. Soluble cell adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) in patients with early rheumatoid arthritis. Scand. J. Rheumatol. 2007;36:345–350. doi: 10.1080/03009740701406460. [PubMed] [CrossRef] [Google Scholar]

44. Klimiuk P.A., Sierakowski S., Latosiewicz R., Cylwik J.P., Cylwik B., Skowronski J., Chwiecko J. Soluble adhesion molecules (ICAM-1, VCAM-1, and E-selectin) and vascular endothelial growth factor (VEGF) in patients with distinct variants of rheumatoid synovitis. Ann. Rheum. Dis. 2002;61:804–809. doi: 10.1136/ard.61.9.804.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

45. Gibbons L.J., Hyrich K.L. Biologic therapy for rheumatoid arthritis: Clinical efficacy and predictors of response. BioDrugs. 2009;23:111–124. doi: 10.2165/00063030-200923020-00004. [PubMed] [CrossRef] [Google Scholar]

46. Benedetti G., Miossec P. Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis. Eur. J. Immunol. 2014;44:339–347. doi: 10.1002/eji.201344184. [PubMed] [CrossRef] [Google Scholar]

47. Harrison O.J., Foley J., Bolognese B.J., Long E., III, Podolin P.L., Walsh P.T. Airway infiltration of CD4+ CCR6+ Th17 type cells associated with chronic cigarette smoke induced airspace enlargement. Immunol. Lett. 2008;121:13–21. doi: 10.1016/j.imlet.2008.07.011. [PubMed] [CrossRef] [Google Scholar]

48. Wegner N., Lundberg K., Kinloch A., Fisher B., Malmström V., Feldmann M., Venables P.J. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol. Rev. 2010;233:34–54. doi: 10.1111/j.0105-2896.2009.00850.x. [PubMed] [CrossRef] [Google Scholar]

49. Klareskog L., Stolt P., Lundberg K., Källberg H., Bengtsson C., Grunewald J., Rönnelid J., Harris H.E., Ulfgren A.K., Rantapää-Dahlqvist S., et al. 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 Rheumatol. 2006;54:38–46. doi: 10.1002/art.21575. [PubMed] [CrossRef] [Google Scholar]

50. Gregersen P.K., Silver J., Winchester R.J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheumatol. 1987;30:1205–1213. doi: 10.1002/art.1780301102. [PubMed] [CrossRef] [Google Scholar]

51. Mattey D.L., Dawes P.T., Clarke S. Relationship among the HLA-DRB1 shared epitope, smoking, and rheumatoid factor production in rheumatoid arthritis. Arthritis Rheumatol. 2002;47:403–407. doi: 10.1002/art.10514. [PubMed] [CrossRef] [Google Scholar]

52. Viatte S., Plant D., Raychaudhuri S. Genetics and epigenetics of rheumatoid arthritis. Nat. Rev. Rheumatol. 2013;9:141–153. doi: 10.1038/nrrheum.2012.237.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

53. Zeilinger S., Kühnel B., Klopp N., Baurecht H., Kleinschmidt A., Gieger C., Weidinger S., Lattka E., Adamski J., Peters A., et al. Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One. 2013;8:e63812. doi: 10.1371/journal.pone.0063812.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

54. Wu S., Luo H., Xiao X., Zhang H., Li T., Zuo X. Attenuation of collagen induced arthritis via suppression on Th17 response by activating cholinergic anti-inflammatory pathway with nicotine. Eur. J. Pharmacol. 2014;735:97–104. doi: 10.1016/j.ejphar.2014.04.019. [PubMed] [CrossRef] [Google Scholar]

55. Van Maanen M.A., Lebre M.C., van der Poll T., LaRosa G.J., Elbaum D., Vervoordeldonk M.J., Tak P.P. Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis Rheumatol. 2009;60:114–122. doi: 10.1002/art.24177. [PubMed] [CrossRef] [Google Scholar]

56. Zhou Y., Zuo X., Li Y., Wang Y., Zhao H., Xiao X. Nicotine inhibits tumor necrosis factor-α induced IL-6 and IL-8 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Rheumatol. Int. 2012;32:97–104. doi: 10.1007/s00296-010-1549-4. [PubMed] [CrossRef] [Google Scholar]

57. Yu H., Yang Y.H., Rajaiah R., Moudgil K.D. Nicotine-induced differential modulation of autoimmune arthritis in the Lewis rat involves changes in interleukin-17 and anti-cyclic citrullinated peptide antibodies. Arthritis Rheumatol. 2011;63:981–991. doi: 10.1002/art.30219.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

58. Vesperini V., Lukas C., Fautrel B., Le Loet X., Rincheval N., Combe B. Association of tobacco exposure and reduction of radiographic progression in early rheumatoid arthritis: Results from a French multicenter cohort. Arthritis Care Res. (Hoboken) 2013;65:1899–1906. doi: 10.1002/acr.22057. [PubMed] [CrossRef] [Google Scholar]

59. Jiang X., Alfredsson L., Klareskog L., Bengtsson C. Smokeless tobacco (moist snuff) use and the risk of developing rheumatoid arthritis: Results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) case-control study. Arthritis Care Res. (Hoboken). 2014 doi: 10.1002/acr.22325. [PubMed] [CrossRef] [Google Scholar]

60. MacGregor A.J., Snieder H., Rigby A.S., Koskenvuo M., Kaprio J., Aho K., Silman A.J. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheumatol. 2000;43:30–37. doi: 10.1002/1529-0131(200001)43:1<30::AID-ANR5>3.0.CO;2-B. [PubMed] [CrossRef] [Google Scholar]

61. Bang S.Y., Lee K.H., Cho S.K., Lee H.S., Lee K.W., Bae S.C. Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status. Arthritis Rheumatol. 2010;62:369–377. [PubMed] [Google Scholar]

62. Wagner C.A., Sokolove J., Lahey L.J., Bengtsson C., Saevarsdottir S., Alfredsson L., Delanoy M., Lindstrom T.M., Walker R.P., Bromberg R., et al. Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP-negative rheumatoid arthritis: Association with cigarette smoking and HLA-DRB1 “shared epitope” alleles. Ann. Rheum. Dis. 2014 doi: 10.1136/annrheumdis-2013-203915.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

63. Gregersen P.K. Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. Immunol. Rev. 2005;204:74–86. doi: 10.1111/j.0105-2896.2005.00243.x. [PubMed] [CrossRef] [Google Scholar]

64. Taylor L.H., Twigg S., Worthington J., Emery P., Morgan A.W., Wilson A.G., Teare M.D. Metaanalysis of the association of smoking and PTPN22 R620W genotype on autoantibody status and radiological erosions in rheumatoid arthritis. J. Rheumatol. 2013;40:1048–1053. doi: 10.3899/jrheum.120784. [PubMed] [CrossRef] [Google Scholar]

65. Keenan B.T., Chibnik L.B., Cui J., Ding B., Padyukov L., Kallberg H., Bengtsson C., Klareskog L., Alfredsson L., Karlson E.W. Effect of interactions of glutathione S-transferase T1, M1, and P1 and HMOX1 gene promoter polymorphisms with heavy smoking on the risk of rheumatoid arthritis. Arthritis Rheumatol. 2010;62:3196–3210. doi: 10.1002/art.27639.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

66. Mikuls T.R., Levan T., Gould K.A., Yu F., Thiele G.M., Bynote K.K., Conn D., Jonas B.L., Callahan L.F., Smith E., et al. Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans. Arthritis Rheumatol. 2012;64:655–664. doi: 10.1002/art.33408.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

67. Kristiansen M., Frisch M., Madsen H.O., Garred P., Jacobsen S. Smoking and polymorphisms of genes encoding mannose-binding lectin and surfactant protein-D in patients with rheumatoid arthritis. Rheumatol. Int. 2014;34:373–380. doi: 10.1007/s00296-013-2904-z. [PubMed] [CrossRef] [Google Scholar]

68. Bartok B., Firestein G.S. Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis. Immunol. Rev. 2010;233:233–255. doi: 10.1111/j.0105-2896.2009.00859.x.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

69. Huber L.C., Distler O., Tarner I., Gay R.E., Gay S., Pap T. Synovial fibroblasts: Key players in rheumatoid arthritis. Rheumatology (Oxford) 2006;45:669–675. doi: 10.1093/rheumatology/kel065. [PubMed] [CrossRef] [Google Scholar]

70. Buchan G., Barrett K., Turner M., Chantry D., Maini R.N., Feldmann M. Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: Prolonged production of IL-1 alpha. Clin. Exp. Immunol. 1988;73:449–455.[PMC free article] [PubMed] [Google Scholar]

71. Shizu M., Itoh Y., Sunahara R., Chujo S., Hayashi H., Ide Y., Takii T., Koshiko M., Chung S.W., Hayakawa K., et al. Cigarette smoke condensate upregulates the gene and protein expression of proinflammatory cytokines in human fibroblast-like synoviocyte line. J. Interferon Cytokine Res. 2008;28:509–521. doi: 10.1089/jir.2007.0081. [PubMed] [CrossRef] [Google Scholar]

72. Adachi M., Okamoto S., Chujyo S., Arakawa T., Yokoyama M., Yamada K., Hayashi A., Akita K., Takeno M., Itoh S., et al. Cigarette smoke condensate extracts induce IL-1-beta production from rheumatoid arthritis patient-derived synoviocytes, but not osteoarthritis patient-derived synoviocytes, through aryl hydrocarbon receptor-dependent NF-kappa-B activation and novel NF-kappa-B sites. J. Interferon Cytokine Res. 2013;33:297–307. doi: 10.1089/jir.2012.0107. [PubMed] [CrossRef] [Google Scholar]

73. Hyrich K.L., Watson K.D., Silman A.J., Symmons D.P. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2006;45:1558–1565. doi: 10.1093/rheumatology/kel149. [PubMed] [CrossRef] [Google Scholar]

74. Söderlin M.K., Petersson I.F., Geborek P. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug. Scand. J. Rheumatol. 2012;41:1–9. doi: 10.3109/03009742.2011.599073. [PubMed] [CrossRef] [Google Scholar]

75. Tamaki A., Hayashi H., Nakajima H., Takii T., Katagiri D., Miyazawa K., Hirose K., Onozaki K. Polycyclic aromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor. Biol. Pharm. Bull. 2004;27:407–410. doi: 10.1248/bpb.27.407. [PubMed] [CrossRef] [Google Scholar]

76. Finkel T., Deng C.X., Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009;460:587–591. doi: 10.1038/nature08197.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

77. Niederer F., Ospelt C., Brentano F., Hottiger M.O., Gay R.E., Gay S., Detmar M., Kyburz D. SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance. Ann. Rheum. Dis. 2011;70:1866–1873. doi: 10.1136/ard.2010.148957. [PubMed] [CrossRef] [Google Scholar]

78. Engler A., Niederer F., Klein K., Gay R.E., Kyburz D., Camici G.G., Gay S., Ospelt C. SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts. J. Mol. Med. 2014;92:757–767. doi: 10.1007/s00109-014-1139-0. [PubMed] [CrossRef] [Google Scholar]

79. Ling S., Cline E.N., Haug T.S., Fox D.A., Holoshitz J. Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheumatol. 2013;65:618–626. doi: 10.1002/art.37814.[PMC free article] [PubMed] [CrossRef] [Google Scholar]

80. Santoro M.G. Heat shock factors and the control of the stress response. Biochem. Pharmacol. 2000;59:55–63. doi: 10.1016/S0006-2952(99)00299-3. [PubMed] [CrossRef] [Google Scholar]

81. Ospelt C., Camici G.G., Engler A., Kolling C., Vogetseder A., Gay R.E., Michel B.A., Gay S. Smoking induces transcription of the heat shock protein system in the joints. Ann. Rheum. Dis. 2014;73:1423–1426. [PubMed] [Google Scholar]

82. Mattey D.L., Brownfield A., Dawes P.T. Relationship between pack-year history of smoking and response to tumor necrosis factor antagonists in patients with rheumatoid arthritis. J. Rheumatol. 2009;36:1180–1187. doi: 10.3899/jrheum.081096. [PubMed] [CrossRef] [Google Scholar]

83. Abhishek A., Butt S., Gadsby K., Zhang W., Deighton C.M. Anti-TNF-alpha agents are less effective for the treatment of rheumatoid arthritis in current smokers. J. Clin. Rheumatol. 2010;16:15–18. doi: 10.1097/RHU.0b013e3181ca4a2a. [PubMed] [CrossRef]

Sours: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284707/

Arthritis smoking rheumatoid

Rheumatoid arthritis and smoking: putting the pieces together

Arthritis Research & Therapyvolume 11, Article number: 238 (2009) Cite this article

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Besides atherosclerosis and lung cancer, smoking is considered to play a major role in the pathogenesis of autoimmune diseases. It has long been known that there is a connection between rheumatoid factor-positive rheumatoid arthritis and cigarette smoking. Recently, an important gene–environment interaction has been revealed; that is, carrying specific HLA-DRB1 alleles encoding the shared epitope and smoking establish a significant risk for anti-citrullinated protein antibody-positive rheumatoid arthritis. We summarize how smoking-related alteration of the cytokine balance, the increased risk of infections (the possibility of cross-reactivity) and modifications of autoantigens by citrullination may contribute to the development of rheumatoid arthritis.


It has long been known that there is a connection between seropositive rheumatoid arthritis (RA) and smoking. The exact underlying mechanism, however, has only been speculated.

Cigarette smoking is one of the major environmental factors suggested to play a crucial role in the development of several diseases. Disorders affecting the great portion of the population, such as atherosclerosis, lung cancer or cardiovascular diseases, are highly associated with tobacco consumption. More recently, it has been reported that smoking is involved in the pathogenesis of certain autoimmune diseases such as RA, systemic lupus erythematosus, systemic sclerosis, multiple sclerosis and Crohn's disease.

Firstly, Vessey and colleagues described an association between hospitalization due to RA and cigarette smoking, which was an unexpected finding of their gynecological study [1]. Since then several population-wide case–control and cohort studies have been carried out [2]. For example, a population-based case–control study in Norfolk, England showed that ever smoking was associated with a higher risk of developing RA [3]. Only an early Dutch study from 1990 involving female RA patients (control patients with soft-tissue rheumatism and osteoarthritis) reported that smoking had a protective effect in RA, albeit they only investigated recent smoking and their controls were not from the general population [4]. Investigations have elucidated that many aspects of RA (rheumatoid factor (RF) positivity, severity, and so forth) can be linked to smoking. Recent data suggest that cigarette smoking establishes a higher risk for anti-citrulli-nated protein antibody (ACPA)-positive RA. In the present paper we attempt to give a thorough review of this field, concerning the main facts and hypotheses in the development of RA in connection with smoking.

Smoking and immunomodulation

Smoking in general

Smoking is considered to have a crucial role in the pathogenesis of many diseases and, as a significant part of the population smokes, it is one of the most investigated and well-established environmental factors. Cigarette smoke represents a mixture of 4,000 toxic substances including nicotine, carcinogens (polycyclic aromatic hydrocarbons), organic compounds (unsaturated aldehydes such as acrolein), solvents, gas substances (carbon monoxide) and free radicals [5]. Many data suggest that smoking has a modulator role in the immune system contributing to a shift from T-helper type 1 to T-helper type 2 immune response; pulmonary infections are increased, immune reactions against the invasion of microorganisms are depleted (see below), and (lung) tumor formation is augmented.

Exposure to cigarette smoke results in the depression of phagocytic and antibacterial functions of alveolar macrophages (AMs) (Table 1) [6, 7]. Although AMs from smokers are able to phagocytose intracellular bacteria, they are unable to kill the bacteria – which consequently implies the deficiency of these cells in smokers [8]. Cigarette smoke condensate, administered to mice, leads to a decrease in primary antibody response [9]. Chronic smoking results in T-cell anergy by impairing the antigen receptor-mediated signaling [10].

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Smoking induces a decline in TNF production, which is supported by several data in the literature. In the work of Higashimoto and colleagues, in vivo exposure to tobacco smoke caused a significant decrease in the production of TNFα by AMs after lipopolysaccharide (LPS) stimulation. In vitro exposure of AMs to tobacco smoke extracts (water-soluble extracts) also caused a drop in the secretion of TNFα with stimulation of LPS [11].

Owing to chronic smoking, AMs from rats significantly increase the generation of superoxide anion and release high amounts of TNFα after smoking sessions; when challenged with LPS, however, even though a more pronounced cytokine secretion can be found, it is not as marked as in the control groups [12]. It therefore seems that macrophages of experimental animals are activated, but at the same time are somehow depressed, and respond less to LPS.

In line with the abovementioned observations, the capacity of AMs of healthy smokers to release TNFα, IL-1 and IL-6 is significantly decreased [13, 14].


Data on alterations of macrophage functions by nicotine (such as pinocytosis, endocytosis, microbial killing and reducing TNFα secretion induced by LPS) date back more than 40 years [6]. It is known that various kinds of immune cells carry nicotinic and muscarinic acetylcholine receptors (T cells and B cells), through which the nervous system and also the immune system itself can modulate and coordinate the proliferation, differentiation and maturation of immune cells [10]. It is suggested that the major portion of acetylcholine in the circulating blood originates from T-cell lines. The thymic epithelium as well as T cells in the thymus express nicotinic acetylcholine receptor, as do mature lymphocytes [10]. Chronic smoking leads to T-cell anergy, while its acute effects are primarily mediated via the activation of the hypothalamic–pituitary–adrenal axis [10, 15]. The nicotinic acetylcholine receptor is involved in the suppression of antimicrobial activity and cytokine responses (downregulation of IL-6, IL-12, and TNFα, but not that of the anti-inflammatory cytokine IL-10) of AMs [16].

In recent work of Borovikova and colleagues, acetylcholine significantly attenuated the release of cytokines (TNF, IL-1 and IL-6, but not anti-inflammatory IL-10) in LPS-induced human macrophage cultures [17]. Particularly the α7 subunit, mediated by the inhibition of NF-κB, has a role in the alteration of cytokine responses [18]. Nicotine also affects the quality of antigen presentation: in mature dendritic cells, nicotine exposure decreases the production of proinflammatory T-helper type 1 IL-12, and decreases the capacity of dendritic cells to induce antigen-presenting cell-dependent T-cell responses. Other reports contradict this, however, suggesting that the effect of nicotine on mature dendritic cells is proinflammatory in nature. Moreover, nicotine alters various neutrophil functions; for example, attenuates super-oxide anion production [10].

All of these data suggest an immunosuppressive effect of nicotine on the immune system, inhibiting various functions of almost all immune cell types.

Other organic compounds

Hydroquinone is found in high concentrations in cigarette smoke, causing prominent suppression in the production of IL-1, IFNγ and TNFα in human peripheral blood macrophages [19]. Hydroquinone seems to also significantly inhibit IFNγ secretion in lymphocytes in a dose-dependent manner. In addition, hydroquinone treatment results in the reduction of IFNγ secretion in effector CD4+ T cells and T-helper type 1-differentiated CD4+ T cells. These findings provide evidence that hydroquinone may suppress immune responses and contribute to the increased incidence of microbial infections caused by cigarette smoking [20].

Besides hydroquinone, other organic compounds are also present in cigarette smoke. Certain data suggest that unsaturated aldehydes such as acrolein and crotonaldehyde, contained in the aqueous phase of cigarette smoke extract, can evoke the release of neutrophil chemoattractant IL-8 and TNFα in human macrophages [21], which can be inhibited by N-acetyl-cysteine or glutathione monoethyl ester. Endogenous unsaturated aldehydes are found in high amounts in chronic obstructive pulmonary disease patients and are involved in the promotion of inflammation, so the exogenous analogues in smoke may have similar effects impeded by glutathione derivates.

Oxidative stress

Chronic smoking as a repetitive trigger causes marked oxidative stress in the body [5], which might be responsible for a constant inflammatory process. High amounts of exogenous free radicals contained in smoke can react to endogenous nitrogen monoxide, producing the harmful peroxy nitrite and decreasing the protective effect of nitrogen monoxide. Smoke also induces the production of endogenous free radicals; for example, reactive oxygen species (peroxide, superoxide, hydroxyl ion). Oxidative free radicals can lead to a wide variety of damages in cells via lipid peroxidation as well as via the oxidation of DNA and proteins, resulting in apoptosis. Several enzymes (for example, α1-protease inhibitor) containing redox-sensitive amino acids (cysteine or methionine) in their catalytic site can lose their activity or can undergo conformational changes. This may cause a higher susceptibility for degradation or may challenge the equilibrium of proteases/protease inhibitors.

The oxidant/antioxidant imbalance may activate redox-sensitive transcription factors such as NF-κB and activator protein-1, which regulate the genes of proinflammatory mediators (IFNγ) and protective antioxidants [22]. Normally, TNF can lead alternatively to activation of NF-κB or to apoptosis, depending on the metabolic state of the cell. Nicotine, as mentioned above, reduces TNF release of AMs and consequently promotes less NF-κB activation through TNF; however, the increased oxidative stress would permit and contribute to NF-κB activation.

In accordance with this observation, mild exposure to cigarette smoke can induce NF-κB activation in lymphocytes through the increase in oxidative stress and the reduction in the intracellular glutathione levels [23]. Vapor-phase cigarette smoke can increase the detachment of alveolar epithelial cells and decrease their proliferation. Furthermore, these cells show a higher susceptibility for smoke-induced cell lysis. Reduced glutathione seems to protect against the effects of cigarette smoke exposure, and the depletion of intracellular glutathione, produced by smoke condensates, enhances cell injury [24]. It is intriguing that there is a strong association between RA, smoking and the GSTM1 (the enzyme involved in glutathione production) null genotype [25]. The polymorphisms of receptor activator of NF-κB (see below) have also been linked to RA [26], which indicates that free radicals in smoke may contribute to the pathological chain of RA development.

Dong and colleagues have reported in MCF7 cells (human breast adenoma line) that estrogen enhances peptidyl arginine deiminase (PAD) type 4 (see information about PADs below) expression via the estrogen receptor alpha → activator protein-1 pathway [27]. Chromatin immunoprecipitation and siRNA assays have also revealed that activator protein-1 is a cis-acting factor bound to the promoter of PAD4. These data suggest that free radicals in cigarette smoke might influence PAD expression via the activation of redox-sensitive factors in the respiratory tract.

It is noteworthy that PAD enzyme isoforms contain highly conserved cysteine in their active site, which plays a crucial role in the catalysis process. It has been shown that agents acting on cysteine sulfhydryl groups via binding them covalently can inactivate the enzyme, while reduced compounds can enhance its activity [28]. Free radicals in smoke produce an oxidative milieu, which may promote the formation of disulfide groups in the active site of the enzyme and may also have a disadvantageous impact on PAD. On the contrary, PAD expression and activity are increased in the lungs of smokers [29] – the explanation for this might be that PAD is originally located intracellularly, and citrullinated proteins may be released into the extracellular matrix after apoptosis.

Anti-estrogenic effect

Another striking phenomenon is the estrogen–smoke interaction in regulating PAD genes. PAD2 expression is increased in bronchoalveolar lavage of smokers, compared with nonsmokers [29]. The expression of PAD2 and PAD4 is also elevated in the synovium of RA patients. The expression of PAD (type 4) enzymes is dependent on estrogens [27]. Smoking, however, has an anti-estrogenic effect through the formation of inactive 2-hydroxy catechol estrogens [30], which would counteract PADs.

These statements suggest that the anti-estrogenic effect of smoking may not have as much importance as its other pleiotropic roles (immunomodulation, activation of redox-sensitive factors, and so forth) in the contribution to the development of ACPA + RA considering the estrogen dependence of the PAD enzyme.

Elevation of serum fibrinogen

Fibrinogen is mainly involved in blood coagulation and inflammation. The Framingham Study has revealed that smokers have higher levels of serum fibrinogen [31]. The citrullinated form of fibrin can be found in RA synovial tissue co-localizing with citrullinated autoantibodies [32]. It has been reported that the polymerization of citrullinated fibrinogen catalyzed by thrombin is impaired, suggesting that the function and antigenicity of citrullinated proteins are somewhat altered, which may potentially contribute to proinflammatory responses and autoimmune reactions in the joints [33].

Smoking and aspects of RA


Genetics of RA

RA is considered to have a complex etiology: both genetic and environmental factors contribute to the disease development [26, 34, 35]. The genetic component of RA is widely investigated [36]: the strongest gene association is considered to be the one with the human leukocyte antigen (HLA) region, particularly the HLA-DRB1 genes accounting for about two-thirds of the genetics of RA. Certain HLA-DRB1 alleles (DRB1*0401, DRB1*0404, DRB1*0405, DRB1*0408, DRB1*0101, DRB1*102, DRB1*1001 and DRB1*1402), encoding the so-called shared epitope (SE) at amino acid positions 70 to 74 in the third hypervariable region of the DRB1 molecule, are associated with a higher susceptibility for RA [26].

Another significant association of RA is with the polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene. PTPN22 is an intracellular protein expressed in hematopoietic cells; it sets the threshold of T-cell receptor signaling [37]. PTPN22 is therefore likely to be a general risk factor for the development of autoimmunity. Certain functional variants (for example, R620W, 1858 C/T) of PTPN22 have been shown to confer a moderate risk for seropositive RA [38]. In addition, a significant interaction between PTPN22 and smoking (>10 pack-years) has been observed in a case–control study [39]. Other studies, however, have failed to confirm this observation.

Association studies implicate the role of several other genes, including TNF receptor 2 (TNFR2), solute carrier family 22, member 4 (SLC22A4), runt-related transcription factor 1 (RUNX1) and the receptor activator gene of NF-κB (TNFRSR11A) [26]. Furthermore, PADI4 polymorphisms have been found to confer a risk for RA only in Japanese and Korean populations, but not European populations [40].

RA therefore can be divided into two subsets of disease entities (ACPA-positive RA and ACPA-negative RA), which are likely to be genetically distinct: HLA-DRB1 SE alleles and PTPN22 are restricted to ACPA-positive RA, while genes such as interferon regulatory factor 5 (IRF-5) and C-type lectin seem to confer risk for ACPA-negative RA [26].

Genetics of smoking

Smoking as a chronic habit is genetically determined to some extent. The major candidate genes associated with smoking are those of cytochrome P450 enzymes, which play a substantial role in nicotine metabolism, and also those of dopamine receptors influenced by nicotine in the mesocorticolimbic dopaminergic reward pathways of the brain. A significant linkage was found between the ever–never smoking trait and chromosome 6 [41], which is associated with the HLA genes. A Hungarian group has determined the polymorphisms of the MHC class III genes in coronary artery disease patients versus healthy individuals with defined smoking habits [41]. A significant association between ever smoking (past and current smokers) and a specific MHC haplotype (the TNF2 allele of the promoter of TNFα) has been observed. More attempts were made to find a correlation between TNF promoter polymorphisms and RA, although most of them failed [42]. These results suggest that genes (MHC classes) determining different aspects of smoking behavior do not seem to predispose for RA; that is, the genetics of these two entities, the habit and the disease are unlikely to have a similar genetic root.

Smoking is a risk factor for RA in shared epitope carriers

According to a Swedish population-based case–control study, there is a gene–environment interaction between smoking and the HLA-DRB1 SE genotype [43]. The relative risk of RA was extremely high in smokers carrying single SE alleles (7.5) or double SE alleles (15.7). Nevertheless, neither smoking nor SE alleles, nor the combination of these factors, have increased the risk of developing seronegative RA [43]. The case–control study of the Iowa Women's Health Study involving postmenopausal women has indicated a strong positive association of smoking, SE positivity and GSTM1 null genotype with RA [25].

Smoking, seropositivity and disease activity

Smoking and seropositivity

A Finnish population screening has showed an association between RF and smoking, but they have not investigated RA [44]. In another study, a positive correlation was observed between smoking and RF levels; particularly, IgA RF was found to account for more severe disease [45]. Smoking confers risk for only the seropositive form of RA [46], suggesting that the two disease entities may have different pathomechanisms.

Certain studies support the fact that there is an association between smoking and RA only in men, but not in women [47] –-yet many other reports contradict this suggestion [48]. A case–control study from Sweden has found that smokers of both sexes have an increased risk of developing seropositive RA but not seronegative RA [49].

Smoking intensity and RA

Many attempts have been made to clarify how smoking history (duration of smoking in years or the intensity of smoking per day) influences the development of RA.

A population-based case–control study of RA in the United States showed that women with 20 pack-years or more of smoking (number of pack-years = number of cigarettes smoked per day × number of years smoked/20) had a relative risk for RA compared with never-smokers [48]. Similarly, a study of female health professionals has showed that women smoking ≥ 25 cigarettes/day for more than 20 years (>25 pack-years) experienced an increased risk of RA [50]. A strong association has been found between RA and heavy cigarette smoking (history of 41 to 50 pack-years), but not with smoking itself [51]. The smoking intensity (number of cigarettes/day), however, was not associated with RA after adjusting for duration of smoking, which suggests that it is the duration of smoking and not the intensity that confers risk for RA. Yet, in a prospective female cohort in

Iowa, both factors of smoking were found to be associated with RA, and were observed only in current smokers and in those ever-smokers who quit 10 years or less prior to the study [52]. Similarly, in the prospective Nurses Health Study both smoking intensity and duration were directly related to risk of RA, with prolonged increased risk after smoking cessation [53]. A case–control study of Sweden has reported that the increased risk for RA is established after a long duration of smoking (≥ 20 years; the intensity was moderate) and might be sustained for several years (10 to 20 years) after smoking cessation [49].

To summarize, it seems that both smoking duration and intensity may be associated with the development of RA. The duration might be more decisive (≥ 20 years), however, and at least 10 years of smoking cessation is needed to reduce the RA risk.

RA is characterized by antibodies including RF and ACPA. These data may indicate that a long duration of smoking with appropriate intensity may cause permanent immunomodulation and subsequent antibody production of memory cells, resulting in a steady state of pathological antibodies. After an unspecified time (about 10 years) of smoking cessation, these cells may disappear from the body.

Smoking and disease severity

Clinical evaluations of patients at the University of Iowa have revealed that cigarette smoking (especially ≥ 25 pack years) was significantly associated with RF positivity, radiographic erosions and nodules [54]. In another study there was a correlation between heavy smoking (≥ 20 pack-years) and rheumatoid nodules, a higher Health Assessment Questionnaire score, a lower grip strength and more radiological joint damage, suggesting the adverse effect of smoking on progression, life quality and functional disability [55]. Some reports support that smoking can increase extraarticular manifestations (rheumatoid nodules, interstitial pulmonary disease, rheumatoid vasculitis) [56–58].

In the work of Manfredsdottir and colleagues, a gradual increase in disease activity was observed from never, former and current smokers defined by the number of swollen and tender joints and the visual analogue scale for pain, but smoking status did not influence the radiological progression [59]. In a cohort of Greek patients with early RA, cigarette smoking was associated with increased disease activity and severity in spite of the early treatment [60]. Only one study found reduced radiographic progression and generally more favorable functional scores among heavy smokers [61]. The recent results of Westhoff and colleagues have revealed that smoking does not influence the Disease Activity Score or radiographic scores, yet smokers need higher doses of disease-modifying antirheumatic drugs, which may indicate reduced potency of these drugs due to smoking or higher disease activity that can be controlled by only high doses of drugs [62].

One can conclude that smoking influences the course of RA in a negative way, although its extent differs in the various studies. Therefore it is essential to draw patients' attention to the expected beneficial effect of smoking cessation.

Smoking and anti-cyclic citrullinated proteins

Recent data have revealed that smoking is highly associated with ACPA-positive RA (Table 2). The evaluation of incident cases of arthritis (undifferentiated arthritis and RA) has revealed that tobacco exposure increases the risk of anti-cyclic citrullinated protein (anti-CCP) antibodies (see information about anti-CCPs below) only in SE-positive patients [63]. In a national case–control study, tobacco smoking was related to an increased risk of anti-CCP-positive RA [64]. The investigation of consecutive sera of RA patients in a rheumatology clinic has shown that anti-CCP titers were associated with tobacco exposure [65].

Full size table

In a case–control study involving patients with early-onset RA, Klareskog and colleagues found that previous smoking is dose-dependently associated with occurrence of anti-CCPs in RA patients. A major gene–environment interaction was also observed between smoking and HLA-DR SE genes: the presence of double copies of SE alleles confers about 20-fold risk for anti-CCP-positive RA in smokers [66]. A nationwide case–control study involving known and recently diagnosed RA patients conducted in Denmark has also proved strong gene–environment effects: there was an increased risk for anti-CCP-positive RA in heavy smokers with homozygote SE alleles [67].

In the study of the Leiden Early Arthritis Clinic, the HLA-DRB1*0401, HLA-DRB1*0404, HLA-DRB1*0405 or HLA-DRB1*0408 SE alleles conferred the highest risk of developing anti-CCP antibodies, and the smoking-SE interaction was highest in cases of HLA-DRB1*0101 or HLA-DRB1*0102 and HLA-DRB1*1001 SE alleles [68]. The same clinic has confirmed that anti-CCP-positive RA patients, who are current or former tobacco smokers, show a more extensive anti-CCP isotype usage compared with nonsmoker anti-CCP-positive patients; these observations were also valid for SE-negative RA patients [69]. In a French population of RA patients (one-half of them were multicase families), the presence of at least one SE allele (especially the DRB1*0401 allele) was related to the presence of anti-CCP antibodies [70]; smoking was associated with anti-CCP antibodies only in the presence of SE, and the cumulative dose of cigarette smoking was linked to the anti-CCP antibody titers.

A case-only analysis of three North American RA cohorts – RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, from the National Inception Cohort of Rheumatoid Arthritis Patients, and from the Study of New Onset Rheumatoid Arthritis (SONORA) – has shown an association between smoking and anti-CCP in the NARAC and the National Inception Cohort, but not in the SONORA [71]. The SE alleles correlated with anti-CCP in all cohorts. Only the analysis of the NARAC cohort provided some evidence, however, for gene–environment interaction between smoking and SE alleles in anti-CCP-positive RA. In a study of African Americans with recent onset of RA, there was no association between smoking, anti-CCP antibody, IgM-RF or radiographic erosions [72]. A recent report comparing three large case–control studies – the Swedish Epidemiological Investigation of Rheumatoid Arthritis study, the NARAC study, and the Dutch Leiden Early Arthritis Clinic study – has reinforced the previous results [73]; namely, the association of smoking, HLA-DRB1 SE alleles and anti-CCP-positive RA. No interaction was found between PTPN22 R620W and smoking, however, indicating that smoking may have disadvantageous effects only in genetically susceptible individuals (for example, those carrying SE genes).

To conclude, these data suggest there may be an association between smoking, SE alleles and ACPA-positive RA. Further environmental and genetic factors (because the studies involving Americans show a more complex picture of RA risk factors), however, should also be considered.

Anti-citrullinated protein antibodies and citrullination

A long time ago RA sera were revealed to specifically react to filaggrin (found physiologically in keratin), which has been proven to be a citrullinated protein; however, light has been shed on the importance of citrullinated proteins only in recent years. Commercial kits are nowadays available to detect ACPAs: these antibodies react to synthetic CCPs – hence the name anti-CCPs. ACPAs are markedly specific for RA – only a small percentage of the general population carries them [74]. Antibodies (for example, anti-filaggrin) against citrullinated proteins – such as vimentin, fibrinogen, type II collagen, alfaenolase – usually arise several years prior to disease onset [74].

Citrullination is catalyzed by PADs dependent on a high calcium concentration. Five PAD isoforms (PAD1, PAD2, PAD3, PAD4 = 5, PAD6) are currently distinguished. Proteins lose specific positive charges through deimination (arginine → citrulline) and can change conformation, becoming more susceptible for degradation [75]. Physiologically, citrullination takes place in the epidermis and the central nervous system. Pathologically, an increased citrullination has been observed in the lining and sublining of joints and also in extraarticular regions in RA [74]. Citrullination is not specific for RA, however – other rheumatologic diseases with synovitis, including inflammatory osteoarthritis, reactive arthritis, undifferentiated arthritis, gout and even trauma, show the presence of citrullinated proteins [76]. The highly specific ACPAs are therefore the results of factors other than local inflammation, involving genetic and environmental factors. Only PAD2 and PAD4 isotypes are expressed in the synovium of RA patients (and also other arthritides) [77]. Their sources are probably inflammatory cells; for example, dying human macrophages and lymphocytes produce citrullinated vimentin, which, if released into the extracellular matrix of RA synovium, can specifically react with sera of RA patients.

Anti-citrullinated protein antibodies, smoking and other autoimmune diseases

Anti-CCPs are highly specific for RA, but they are found in 5 to 13% of patients with psoriatic arthritis [78] and also a minority of patients with primary Sjögren syndrome have an elevated anti-CCP titer, which is linked to the presence of synovitis [79]. Whether smoking confers a risk for the development of anti-CCPs in otherwise healthy individuals has not been investigated, but increased protein citrullination can be seen in the bronchoalveolar lavage of healthy smokers [29].

Smoking is associated with several autoimmune diseases such as systemic lupus erythematosus, primary biliary cirrhosis or multiple sclerosis, where similar gene–environment interactions may exist – the knowledge gained from research into these diseases could also help in the understanding of RA. For example, Moscarello and colleagues have proposed that citrullinated myelin basic proteins may have a crucial role in the pathogenesis of multiple sclerosis [80]: as in RA due to citrullination, myelin basic protein may become more susceptible for degradation by metalloproteases. In primary biliary cirrhosis, celiac disease or systemic lupus erythematosus, antibodies against self-enzymes involved in protein modification (deamidation, carboxylation, glycolysation) also exist, like the anti-PAD antibodies in RA (see later).

The connection of smoking, lung cancer, TNF and RA

It is well known that smoking has a pivotal role in the development of lung cancer. Smoke contains several carcinogens, leading to severe DNA damage via adduct formation and subsequently altered gene function. Contact-mediated cytostasis of tumor cells is also decreased by AMs of smokers [13]. As mentioned in a previous section, components in smoke have significant immune modulator effects (they alter the functions of T cells and B cells, macrophages, dendritic cells and neutrophils) on several acting points involving the reduction of the production of TNFα. Apart from the direct cytotoxic effects of TNFα against tumors, its antitumor activities may involve activation of different neutrophil functions, alteration of endothelial cell functions and increased production of IL-1. As a consequence, the inhibition of TNFα (as an anti-tumor agent) via smoke components may contribute to (lung) cancer formation besides the crucial effects of direct carcinogens found in smoke.

In the pathogenesis of RA, TNFα plays a key role considering the joint and bone damage. Increased levels of TNFα can be measured at the sites of inflammation. Moreover, transgenic mice expressing high levels of TNFα develop RA-like arthritis. In an animal model of collagen-induced arthritis, the inhibition of TNFα led to the amelioration of disease course. Later, extensive multicentric studies proved the beneficial effect of TNF blockage in RA [81], and nowadays TNF antagonists are widely used. In RA patients who smoke, an elevated ratio of TNFα/soluble TNF receptor released from activated T cells can be seen – which may contribute to the increased TNFα activity observed in RA. The ratio is related to the extent of smoking – sustained even after smoking cessation – proving why smoking intensity and duration have an impact on the development and course of RA [82].

Considering the TNFα-lowering effect of cigarette smoking, one could also suggest that TNFα should have beneficial effects on RA, even though the opposite is probably true. Other pleiotropic factors (oxidative stress, infections, citrullination) of smoke components rather than the TNF antagonism alone, evoked by nicotine, may therefore be the main susceptibility factors of disease development. To support this hypothesis, in both types of inflammatory bowel disease (ulcerative colitis and Crohn's disease), in which smoke has an opposite role, TNF antagonists are beneficial and are crucial components of the therapeutic repertoire.

Nowadays, three TNF antagonists exist – etanercept, a soluble fusional receptor; infliximab, a chimeric monoclonal antibody; and adalimumab, a completely human monoclonal antibody – and two other TNF antagonists (certolizumab and golimumab) are in clinical development. There are concerns about using biological agents, however, as the incidence of malignancies, especially lymphomas, may be increased compared with the normal population.

The increased proliferative drive of immune cells resulting in autoantibody formation and disease severity rather than TNF antagonism or disease-modifying antirheumatic drugs (methotrexate) seems to be responsible for the elevated lymphoma risk, which is supported by the recent analysis of the Swedish Biologics Register [83]. On the contrary, a previous meta-analysis of randomized trials of anti-TNF therapy has revealed a dose-dependent increased risk of malignancies in RA patients treated with anti-TNF antibodies [84]. In conclusion, patients treated with TNF antagonists should be closely followed regarding malignancies.

RA, infection and citrullination

Data suggest that smoking has immunosuppressive effects through the various substances contained in cigarette smoke, among which nicotine has the most substantial role (Figure 1). Nicotine can enter the bloodstream through the alveolar compartment-endothelial barrier, and then may reach different parts of the body, including lymphoid tissues, where it may have systemic immunomodulator effects and may act through the nicotinic receptors of the autologuous nervous system. Owing to immunosuppression evoked by smoke, infections are increased not only in the respiratory tract but in other regions of the body.

Complex role of smoking in the pathogenesis of rheumatoid arthritis. ACPA, anti-citrullinated protein antibody; AP-1, activator protein-1; EBV, Epstein–Barr virus; HQ, hydroquinone; IRF-5, interferon regulatory factor 5; nACh, nicotinic acetylcholine; PAD, peptidyl arginine deiminase; PADI4, gene of peptidyl arginine deiminase type 4; PTPN22, protein tyrosine phosphatase nonreceptor 22; RA, rheumatoid arthritis; RF, rheumatoid factor; SE, shared epitope.

Full size image

Superantigens of specific bacteria (Streptococcus, Staphylococcus) and viruses (Epstein–Barr virus (EBV)) bypass the processing of antigen-presenting cells through directly binding to MHC II molecule T-cell receptors outside the conventional antigen-specific variable chains, initiating massive T-cell activation (up to 20% of total). In addition, they may utilize not only the T-cell receptor pathways but also other pathways [85]. A wide repertoire of T cells may be activated due to superantigens, and also those cells reactive to citrullinated proteins or autodeiminated PADs (see below) in the respiratory tract. In line with this knowledge, specific bacteria and viruses have been incriminated in the pathogenesis of RA – one of which is EBV. Pratesi and colleagues found that sera from RA patients can react to citrullinated EBV nuclear antigen [86], which suggests previous EBV infection (superantigen) and also the presence of parallel citrullination – which might be induced by chronic smoking, as the amount of citrullinated proteins is increased in the bronchoalveolar lavage of smokers. The role of EBV in the RA pathogenesis is supported by several other data: the anti-EBV titer is elevated in RA patients; certain EBV antigens share similarities with synovial self-autoantigens providing the possibility of viral cross-reactivity; the gp110 glycoprotein in EBV contains a copy of SE; cell-mediated responses against EBV proteins were found in the synovial fluid of RA patients; and EBNA-1 can undergo citrullination, and the virus can induce antibody formation against citrullinated proteins [87].

Another explanation for the primary steps towards RA might be bacterial/viral cross-reactivity with autoantigens, as in the case of EBV. On the one hand, Porphyromonas gingivalis causing periodontitis has a functional PAD enzyme, which is quite similar to human PADs, and subsequently the infection may stimulate antibody production against the human PADs as well [88]. The incidence of periodontitis is elevated due to smoking [89], so the body might be exposed to a more increased burden of P. gingivalis causing a constant antigen trigger compared with nonsmokers. Autoantibodies against PAD4 enzymes are specific markers of RA, they exist in about 40% of RA patients, and they account for more severe disease course. Polymorphisms in the PADI4 gene (only in certain populations) may influence the immune response to PAD4 enzyme, potentially contributing to disease propagation [90]. It is also reported that PADs can autodeiminate themselves, due to which the structure of the molecule might be changed profoundly and new epitopes may arise. Furthermore, the modified citrullinated proteins and PAD may create an altered molecule complex like the tissue transglutaminase and deaminated gluten in celiac disease, which may result in autoimmune reaction in genetically prone subjects.

On the other hand, emerging data suggest there might be a connection between RA and Proteus mirabilis. These data are supported by the following observations. There is an increased incidence of urinary tract infections (especially P. mirabilis) in RA patients [91]. Furthermore, Ebringer and Rashid have found sequence homology between certain HLA alleles associated with RA and hemolysins of P. mirabilis. They also identified another homology between type XI collagen and Proteus urease enzyme, yet they have failed to show common motifs between P. urease and RA-targeted synovial structures even though active RA patients have elevated IgG and IgM antibodies against Proteus [91]. Consequently, due to infections, cross-reactivity might arise against auto-structures of joints.

Similarly, CD19+ B cells capable of secreting antibodies reactive to type II collagen are present in both RA patients and in healthy subjects. In RA patients, however, the cells accumulate in the inflamed joints, suggesting that they have been activated due to certain factors (possibly superantigens or cross-reactivity) [92].

It is known that synovitis in general, also in nonautoimmune rheumatic diseases, is marked by citrullinated proteins, although the presence of ACPAs is specific for RA, and is likely to be the result of many tolerance-breaking immune steps. Neeli and colleagues have found that LPS-induced neutrophils can produce marked citrullination of histones, which then can be identified as the components of extracellular chromatin traps [93]. Bacterial invasion can provide the perfect background for neutrophil activation and subsequent release of highly autoantigenic citrullinated histones in the respiratory tract.

Besides common environmental factors, intrapersonal and interpersonal psychological factors may also contribute to RA pathogenesis. To support this hypothesis, RA patients with an elevated daily stress level (daily hassles, interpersonal conflicts) have poorer outcome and more erosions, while major stress (major negative life events) might ameliorate the disease course. Long-lasting (chronic) minor stress may lead to proinflammatory responses via short-lived surges of hormones and neurotransmitters, yet major stress might lead to massive, long-lived release of stress-axe mediators of the hypothalamic–pituitary–adrenal axis (norepinephrine, cortisol, and so forth), resulting in anti-inflammatory responses [94]. Smoking might sustain a constant minor stress in the body via its addictive nature, and subsequently may lead to neurohumoral immunomodulation.

To summarize, if the constellation of genetic factors – for example, HLA-DRB1 as it has a higher affinity to bind citrullinated form of proteins [95], and perhaps other loci in different populations such as the North American population – and of environmental factors – smoking, concomitant infections (cross-reactivity, molecular mimicry) and also general stressors (psychological as well) – is created, there is a possibility for autoimmune disease development.

As citrullination is considered one of the crucial steps in the development of RA, and also as ACPAs seem to be involved in the progression of RA, new pharmaceutical agents targeting PADs have been investigated: PAD inhibitors including F-amidine (the most potent known inhibitor), paclitaxel and 2-chloroacetamidine [40]. Their clinical utilization is a little controversial, however, as ACPAs can appear several years prior to the development of RA, and at the time when healthcare professionals are able to interfere with the pathological processes of their patients, the vicious circle of the autoimmune process has already started, and may be sustained by factors other than citrullination. Moreover, we know little about the physiological functions of PADs – so their inhibition may involve serious disturbances in the cells, such as apoptosis [96].

Conclusion and future directions

The connection of smoking, anti-citrullinated antibodies and RA is unambiguously proven by several studies and reports. Consequently, it is essential to inform patients about the hazardous role of smoking in the development and progression of RA. Moreover, as the autoimmune diseases in general cause accelerated atherosclerosis due to constant inflammation, and increase the cardiovascular risk, it is important for patients to understand smoking cessation is required as much as taking disease-modifying antirheumatic drugs or biologics to achieve remission and better life quality.

Although we have an effective therapeutic repertoire for RA, we cannot reverse the developed joint deformity in advanced stages, so the initiation of the early treatment prior to bone and joint damage has great importance. To achieve this early initiation, we need to better understand the pathogenesis of the disease and the interaction of risk factors, and also to develop better diagnostic tools on the basis of this information.


anti-citrullinated protein antibody

alveolar macrophage

cyclic citrullinated peptide

Epstein–Barr virus

human leukocyte antigen




North American Rheumatoid Arthritis Consortium

nuclear factor

peptidyl arginine deiminase

protein tyrosine phosphatase nonreceptor 22

rheumatoid arthritis

rheumatoid factor

shared epitope

small interfering RNA

Study of New Onset Rheumatoid Arthritis

tumor necrosis factor.


  1. 1.

    Vessey MP, Villard-Mackintosh L, Yeates D: Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception. 1987, 35: 457-464.

    CASArticlePubMed Google Scholar

  2. 2.

    Heliovaara M, Aho K, Aromaa A, Knekt P, Reunanen A: Smoking and risk of rheumatoid arthritis. J Rheumatol. 1993, 20: 1830-1835.

    CASPubMed Google Scholar

  3. 3.

    Symmons DP, Bankhead CR, Harrison BJ, Brennan P, Barrett EM, Scott DG, Silman AJ: Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case–control study in Norfolk, England. Arthritis Rheum. 1997, 40: 1955-1961.

    CASArticlePubMed Google Scholar

  4. 4.

    Hazes JM, Dijkmans BA, Vandenbroucke JP, de Vries RR, Cats A: Lifestyle and the risk of rheumatoid arthritis: cigarette smoking and alcohol consumption. Ann Rheum Dis. 1990, 49: 980-982.

    PubMed CentralCASArticlePubMed Google Scholar

  5. 5.

    Costenbader KH, Karlson EW: Cigarette smoking and autoimmune disease: what can we learn from epidemiology?. Lupus. 2006, 15: 737-745.

    CASArticlePubMed Google Scholar

  6. 6.

    Green GM, Carolin D: The depressant effect of cigarette smoke on the in vitro antibacterial activity of alveolar macrophages. N Engl J Med. 1967, 276: 421-427.

    CASArticlePubMed Google Scholar

  7. 7.

    Ortega E, Barriga C, Rodriguez AB: Decline in the phagocytic function of alveolar macrophages from mice exposed to cigarette smoke. Comp Immunol Microbiol Infect Dis. 1994, 17: 77-84.

    CASArticlePubMed Google Scholar

  8. 8.

    King TE, Savici D, Campbell PA: Phagocytosis and killing of Listeria monocytogenes by alveolar macrophages: smokers versus nonsmokers. J Infect Dis. 1988, 158: 1309-1316.

    ArticlePubMed Google Scholar

  9. 9.

    Nguyen Van Binh P, Zhou D, Baudouin F, Martin C, Radionoff M, Dutertre H, Marchand V, Thevenin M, Warnet JM, Thien Duc H: Modulation of the primary and the secondary antibody response by tobacco smoke condensates. Biomed Pharmacother. 2004, 58: 527-530.

    CASArticlePubMed Google Scholar

  10. 10.

    de Jonge WJ, Ulloa L: The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol. 2007, 151: 915-929.

    PubMed CentralCASArticlePubMed Google Scholar

  11. 11.

    Higashimoto Y, Shimada Y, Fukuchi Y, Ishida K, Shu C, Teramoto S, Sudo E, Matsuse T, Orimo H: Inhibition of mouse alveolar macrophage production of tumor necrosis factor alpha by acute in vivo and in vitro exposure to tobacco smoke. Respiration. 1992, 59: 77-80.

    CASArticlePubMed Google Scholar

  12. 12.

    Pessina GP, Paulesu L, Corradeschi F, Luzzi E, Tanzini M, Aldinucci C, Di Stefano A, Bocci V: Chronic cigarette smoking enhances spontaneous release of tumour necrosis factor-alpha from alveolar macrophages of rats. Mediators Inflamm. 1993, 2: 423-428.

    PubMed CentralCASArticlePubMed Google Scholar

  13. 13.

    Yamaguchi E, Itoh A, Furuya K, Miyamoto H, Abe S, Kawakami Y: Release of tumor necrosis factor-alpha from human alveolar macrophages is decreased in smokers. Chest. 1993, 103: 479-483.

    CASArticlePubMed Google Scholar

  14. 14.

    Sauty A, Mauel J, Philippeaux MM, Leuenberger P: Cytostatic activity of alveolar macrophages from smokers and nonsmokers: role of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. Am J Respir Cell Mol Biol. 1994, 11: 631-637.

    CASArticlePubMed Google Scholar

  15. 15.

    Singh SP, Kalra R, Puttfarcken P, Kozak A, Tesfaigzi J, Sopori ML: Acute and chronic nicotine exposures modulate the immune system through different pathways. Toxicol Appl Pharmacol. 2000, 164: 65-72.

    CASArticlePubMed Google Scholar

  16. 16.

    Matsunaga K, Klein TW, Friedman H, Yamamoto Y: Involvement of nicotinic acetylcholine receptors in suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella pneumophila infection by nicotine. J Immunol. 2001, 167: 6518-6524.

    CASArticlePubMed Google Scholar

  17. 17.

    Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000, 405: 458-462.

    CASArticlePubMed Google Scholar

  18. 18.

    Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ: Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003, 421: 384-388.

    CASArticlePubMed Google Scholar

  19. 19.

    Ouyang Y, Virasch N, Hao P, Aubrey MT, Mukerjee N, Bierer BE, Freed BM: Suppression of human IL-1β, IL-2, IFN-γ, and TNF-α production by cigarette smoke extracts. J Allergy Clin Immunol. 2000, 106: 280-287.

    CASArticlePubMed Google Scholar

  20. 20.

    Choi JM, Cho YC, Cho WJ, Kim TS, Kang BY: Hydroquinone, a major component in cigarette smoke, reduces IFN-γ production in antigen-primed lymphocytes. Arch Pharm Res. 2008, 31: 337-341.

    CASArticlePubMed Google Scholar

  21. 21.

    Facchinetti F, Amadei F, Geppetti P, Tarantini F, Di Serio C, Dragotto A, Gigli PM, Catinella S, Civelli M, Patacchini R: α,β-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages. Am J Respir Cell Mol Biol. 2007, 37: 617-623.

    CASArticlePubMed Google Scholar

  22. 22.

    Nguyen C, Teo JL, Matsuda A, Eguchi M, Chi EY, Henderson WR, Kahn M: Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma. Proc Natl Acad Sci USA. 2003, 100: 1169-1173.

    PubMed CentralCASArticlePubMed Google Scholar

  23. 23.

    Hasnis E, Bar-Shai M, Burbea Z, Reznick AZ: Cigarette smoke-induced NF-κB activation in human lymphocytes: the effect of low and high exposure to gas phase of cigarette smoke. J Physiol Pharmacol. 2007, 58 (Suppl 5): 263-274.

    PubMed Google Scholar

  24. 24.

    Lannan S, Donaldson K, Brown D, MacNee W: Effects of cigarette smoke and its condensates on alveolar cell injury in vitro. Am J Physiol. 1994, 266: L92-L100.

    CASPubMed Google Scholar

  25. 25.

    Criswell LA, Saag KG, Mikuls TR, Cerhan JR, Merlino LA, Lum RF, Pfeiffer KA, Woehl B, Seldin MF: Smoking interacts with genetic risk factors in the development of rheumatoid arthritis among older Caucasian women. Ann Rheum Dis. 2006, 65: 1163-1167.

    PubMed CentralCASArticlePubMed Google Scholar

  26. 26.

    Bowes J, Barton A: Recent advances in the genetics of RA susceptibility. Rheumatology (Oxford). 2008, 47: 399-402.

    CASArticle Google Scholar

  27. 27.

    Dong S, Zhang Z, Takahara H: Estrogen-enhanced peptidylarginine deiminase type IV gene (PADI4) expression in MCF-7 cells is mediated by estrogen receptor-alpha-promoted transfactors activator protein-1, nuclear factor-Y, and Sp1. Mol Endocrinol. 2007, 21: 1617-1629.

    CASArticlePubMed Google Scholar

  28. 28.

    Méchin MC, Sebbag M, Arnaud J, Nachat R, Foulquier C, Adoue V, Coudane F, Duplan H, Schmitt AM, Chavanas S, Guerrin M, Serre G, Simon M: Update on peptidylarginine deiminases and deimination in skin physiology and severe human diseases. Int J Cosmet Sci. 2007, 29: 147-168.

    ArticlePubMed Google Scholar

  29. 29.

    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, 67: 1488-1492.

    CASArticlePubMed Google Scholar

  30. 30.

    Baron JA, La Vecchia C, Levi F: The antiestrogenic effect of cigarette smoking in women. Am J Obstet Gynecol. 1990, 162: 502-514.

    CASArticlePubMed Google Scholar

  31. 31.

    Kannel WB, D'Agostino RB, Belanger AJ: Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham Study. Am Heart J. 1987, 113: 1006-1010.

Sours: https://arthritis-research.biomedcentral.com/articles/10.1186/ar2751
QD53 - Smoking \u0026 RA


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