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SMOKING NOW LINKED TO RHEUMATOID ARTHRITIS AND LUPUS: AND MAKES TREATING THOSE DISEASES LESS EFFECTIVE
PHILADELPHIA – Cigarette smoking leads to rheumatic disease and makes treatment less successful, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Philadelphia, Pa.
Three recent studies show links between the development of rheumatoid arthritis, less successful treatment of rheumatoid arthritis and disease activity and damage in lupus – adding to the seemingly never-ending list of health risks related to cigarette smoking.
Two studies focused on the link between smoking and rheumatoid arthritis, which is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
Previous studies have established that smoking is a risk factor for RA. Two independent research teams out of Sweden recently looked at the role smoking plays in the development of RA and in the response to treatment of the disease.
The first study focused on the development of RA involved 172 patients—primarily women with a mean age of 63 years old at the time of diagnosis—who were included in a community-based health survey that took place between 1991 and 1996. Participants of the self-administered survey provided information on lifestyle factors (such as smoking, diet and level of formal education) and provided blood samples.
Researchers found that those who were smoking at the time of the survey were at increased risk for RA when compared to those who were not. Anti-CCP antibodies, which are highly specific for RA, occurred years before disease onset, and were associated with former, but not current smoking. Even in the absence of those antibodies, smoking increased the risk of developing the disease. The researchers concluded that in addition to inducing the immune phenotype that predisposes to RA, smoking may also be involved in events that trigger the disease.
“The main strength of this study is the fact that smoking and other life style factors were measured before disease onset”, says Carl Turesson, associate professor, Malmö University Hospital, Malmö, Sweden, and lead investigator in the study. “Our data confirm that smoking is a risk factor for RA, and provide further insight on the impact of smoking on disease mechanisms.”
Another group of researchers focused on what happens when people with RA smoke while being treated for the disease.
Just as in the first study, this team of researchers pulled information from a Swedish population-based study. They looked at the information of 1,756 RA patients and noted whether each person had never smoked, smoked in his or her past or was a current smoker at diagnosis (and the total amount which is measured by how many years with one cigarette pack per day a person has smoked, called a pack-year).
They were specifically looking to see if a patient had no response to methotrexate or anti-TNF therapy—two common treatments for RA–and how that related to his or her smoking activity.
The researchers found that smoking was associated with non-response to both methotrexate and anti-TNF therapy at the three months follow-up visit, which is a common time-point for evaluating whether the treatment is effective. Forty percent of current smokers did not respond to methotrexate (as compared to 28 percent of those who had never smoked); there was no evidence that the total amount smoked impacted this. For those on anti-TNF therapy, 40 percent of current smokers did not respond (as compared to 25 percent of those who had never smoked). Unlike those taking methotrexate, the lack of response to anti-TNF therapy correlated to the total number of pack-years of cigarettes smoked. When reviewed as one to 15, 16 to 30, and over 30 pack-years, researchers noticed a 31, 40 and 43 percent lack of response, respectively.
“The findings indicate that RA patients who smoke have increased risk of not getting better on the standard first line treatment for RA, namely methotrexate,” explains Saedis Saevarsdottir, MD, PhD; rheumatology unit, Karolinska University Hospital, Stockholm, Sweden, and lead investigator in the study. “Moreover, those who needed the immunologically designed anti-TNF drugs, which are now the second-line treatment of choice for those who do not respond to methotrexate, also risked having poor effect of this expensive medication if they smoked. As this study includes RA patients from a large area in Sweden that are followed from the diagnosis in a quality register with respect to their medication and disease activity, it is likely to reflect the real-life setting.”
The third study looked at how smoking could be associated with more disease activity as well as organ damage in people with systemic lupus erythematosus. Disease activity is a measure of SLE symptoms, signs and laboratory evaluation for ongoing immunological response and injury; whereas disease damage reflects irreversible organ injury.
Systemic lupus erythematosus, also called SLE or lupus, is a chronic inflammatory disease that can affect the skin, joints, kidneys, lungs, nervous system, and/or other organs of the body. The most common symptoms include skin rashes and arthritis, often accompanied by fatigue and fever. Lupus occurs mostly in women, typically developing in individuals in their twenties and thirties – prime child-bearing age.
Researchers pulled information from a study on health-related quality of life in 216 patients with lupus who had been seen in the rheumatology clinic of a U.S. hospital between September 2006 and April 2008. These patients were predominately African American females in their early 40s.
Fifteen percent of the patients were smoking at the time of the study. Researchers noted that smokers had greater lupus disease activity and damage than non-smokers. Specific differences seen in diseases activity included a greater number of patients with swelling and pain in more than two joints, and lower complements—a marker of ongoing immunological response—among smokers. Smokers also had greater numbers of patients with irreversible skin related changes from lupus. These results led researchers to conclude that smokers do have higher disease activity and damage to organs.
“We are strongly encouraging physicians to actively enquire about smoking history, especially in patients with lupus, since smoking is strongly associated with how active or inactive their lupus is and development of irreversible skin damage,” explains Ravikumar Patel, MBBS; researcher, department of medicine, section of rheumatology at Rush University Medical Center in Chicago, and lead author in the study. “Besides the well-known adverse effects of smoking, we are presenting additional reasons for lupus patients to actively consider quitting smoking."
These three studies reconfirm or add to the growing number of health risks associated with cigarette smoking.
The ACR is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with or at risk for arthritis and rheumatic and musculoskeletal diseases. For more information on the ACR’s annual meeting, see www.rheumatology.org/annual.
Editor’s Notes: All three of these studies will be presented during the ACR Annual Scientific Meeting in the Pennsylvania Convention Center. Dr. Turesson will present “Smoking and Anti-CCP Antibodies Predict Rheumatoid Arthritis” during the ACR Annual Scientific Meeting at 3:00 pm on Monday, October 19 in Room 103 A. Dr. Saevarsdottir will present “Smoking Is Associated with Non-Response to Methotrexate and to Anti-TNF Treatment in Patients with Rheumatoid Arthritis. Results From the Swedish EIRA Study” at 4:30 pm on Monday, October 19 in Room 103 A. Ravikumar Patel, MBBS will present “Is Cigarette Smoking Associated with Disease Activity and Damage in Patients with Systemic Lupus Erythematosus” at 3:15 pm on Tuesday, October 20 in Room 108 B.
Presentation Number: 1162
Smoking and Anti-CCP Antibodies Predict Rheumatoid Arthritis
Carl Turesson, MD, PhD, Department of Rheumatology, Section of Rheumatology, Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden
Ulf GB Bergström, Department of Rheumatology, Malmö University Hospital, Section of Rheumatology, Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden
Lennart Truedsson, Lund University Hospital, Section of MIG, Department of Laboratory Medicine, Lund, Lund University, Lund, Sweden
Olle Melander, Department of Medicine, Malmö University Hospital, Section of Medicine, Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden
Tore Saxne, M.D., PhD, Department of Rheumatology, Lund University Hospital, Section of Rheumatology, Department of Clinical Sciences, Lund, Lund University, Lund, Sweden
Lennart TH Jacobsson, PhD, Department of Rheumatology Malmö University Hospital, Section of Rheumatology, Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden
Purpose: Previous studies indicate that smoking is a predictor of rheumatoid arthritis (RA) and that anti-CCP antibodies may be detected in individuals who develop RA years before onset. Our purpose was to investigate circulating autoantibodies and their relation to smoking before the onset of RA.
Method: The study design was a nested case-control study. Between 1991 and 1996, subjects (n=30447; 12121 men and 18326 women) from a defined catchment area were included in a community based health survey. Information on life style factors was obtained using a self-administered questionnaire, and blood samples were stored from all participants. From this population, individuals who developed RA after inclusion were identified by linking the health survey database to a community based RA register and to local and national patient administrative registers. One control for each case, matched for sex, year of birth and year of screening, who was alive and free of RA when the index person was diagnosed with RA, was selected from the health survey. Anti-CCP antibodies, antibodies to mutated citrullinated vimentin (anti-MCV) and IgM RF were determined by ELISA.
Results: One hundred and seventy two patients (36 men/136 women, mean age at RA diagnosis 63 years, 67 % RF positive at diagnosis or later) were diagnosed with RA after inclusion in the health survey. The median time from inclusion to RA onset was 5 years (range 1-13). Current smoking was a predictor of RA (p<0.001). Serum was available from 169 cases and 168 controls. Pre-RA cases were more likely to be anti-CCP positive (>20 U/mL; 21.9 % vs 0.6 %; p<0.001), with similar patterns for anti-MCV and IgM RF, and among men and women when studied separately. All three antibodies were detected up to 10 years before disease onset. The median anti-CCP level for positive cases was 82 U/mL (interquartile range 36-170). Pre-RA cases screened 1-4 years before disease onset were more likely to be anti-CCP positive compared to those included 5 or more years before disease onset (28% vs 17%). There was no major difference in current smoking habits between anti-CCP positive and anti-CCP negative pre-RA individuals (38% vs 36% current smokers), but anti-CCP positive pre-RA cases were more likely to have a history of ever smoking (85% vs 61%; p=0.009). Current smoking was a predictor of RA in analysis restricted to anti-CCP negative subjects (odds ratio 1.88; 95 % CI 1.13-3.12).
Conclusion: Current smoking was not associated with anti-CCP antibodies occurring before the onset of RA, but previous smoking may have played a role in their development. Current smoking predicted RA in the absence of anti-CCP antibodies. This suggests that smoking may influence several distinct mechanisms in the pre-clinical phase of RA.
Disclosure: C. Turesson, None; U. G. Bergström, None; L. Truedsson, None; O. Melander, None; T. Saxne, None; L. T. Jacobsson, None.
Presentation Number: 635
Smoking Is Associated with Non-Response to Methotrexate and to Anti-TNF Treatment in Patients with Rheumatoid Arthritis. Results From the Swedish EIRA Study
Saedis Saevarsdottir, MD, PhD, Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden
Sara Wedrén, MD, PhD, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Maria Seddighzadeh, PhD, Rheumatology Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Johan Askling, MD, PhD, Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden
Leonid Padyukov, MD, PhD, Rheumatology Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Lars Alfredsson, PhD, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Lars Klareskog, MD, PhD, Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden
Purpose: Smoking is a well established risk factor for rheumatoid arthritis (RA), and the aim of this study is to evaluate whether smoking influences response to methotrexate (MTX) and anti-TNF therapy.
Method: Clinical data for patients participating in a Swedish population-based study of incident RA (Epidemiological Investigation of Rheumatoid Arthritis, EIRA), who have received routine care, where retrieved from the Swedish Rheumatology and Biologics Registers (SRR/ARTIS, n=1756). Cigarette smoking (never, past or current and pack-years), RF and anti-CCP positivity and the presence of the shared epitope allele (SE) was defined by standard procedures. The primary endpoint was non-response to MTX or anti-TNF therapy at 3 months according to the EULAR response criteria, which is defined as less than 0.6 DAS28 units improvement or DAS28>5.1. Clinical data and information about anti-CCP, RF and SE status were available for 815 out of 965 patients started on MTX monotherapy at baseline and for 320 out of 375 patients that had started anti-TNF therapy as the first biological treatment until the end of the follow-up period. The data were analysed using logistic regression with uni- and multivariate models and presented as odds ratios with 95% confidence interval (OR[95%CI]).
Results: Smoking was associated with non-response to both MTX and anti-TNF treatment. For MTX treatment, 40% of current smokers and 28% of never smokers were non-responders (OR 1.8[1.2-2.7]). However, no clear dose response effect was observed between number of pack-years and response. For anti-TNF therapy, 40% of current smokers and 25% of never-smokers were non-responders (OR 2.0[1.1-3.7]). Whether the patients had concurrent MTX therapy did not influence these findings. When the patients were grouped according to number of pack-years of cigarette smoking into 0, 1-15, 16-30 and >30 pack-years; the frequency of non-response to anti-TNF therapy was 25%, 31%, 40% and 43%, respectively (OR: Ref., 1.3[0.72-2.5], 2.0[1.0-4.0] and 2.3[1.0-5.4]). The risk associated with smoking was significant after adjustment for clinical co-variables, anti-CCP, RF and SE in a multivariate model.
Conclusion: Cigarette smokers had a higher risk of non-response to both MTX and to anti-TNF treatment in this population based study on incident RA receiving real-life care.
Disclosure: S. Saevarsdottir, None; S. Wedrén, None; M. Seddighzadeh, None; J. Askling, Wyeth, Schering-Plough, Abbott, 9 ; L. Padyukov, None; L. Alfredsson, None; L. Klareskog, None.
Presentation Number: 1931
Is Cigarette Smoking Associated with Disease Activity and Damage in Patients with Systemic Lupus Erythematosus?
Meenakshi Jolly, MD , Department of Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, IL
Ravikumar Patel, MBBS , Department of Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, IL
Rohit Aggarwal, MD , Rheumtology, John H. Stroger, Jr. Hospital of Cook County and Rush University Medical Center, Chicago, IL
Winston Sequeira, MD , Department of Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, IL
Joel A. Block, MD , Rheumatology, Rush University Medical Center, Chicago, IL
Purpose: To determine the effect of cigarette smoking on disease activity and cumulative organ damage in patients with systemic lupus erythematosus (SLE).
Method: The data were extracted from an ongoing prospective study on health related quality of life in patients with SLE. Consecutive consenting adult SLE patients seen in the rheumatology clinic at an academic hospital were enrolled from September 2006 to April 2008 and detailed clinical and demographic variables were collected from 216 enrolled SLE patients. Disease activity was evaluated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and cumulative organ damage was measured by the Systemic Lupus International Collaborating Clinics Damage Index (SLICC). Smoking was defined as present if the subject reported smoking at the time of the study. Chi-Square test was used to compare the categorical data and the Mann Whitney test was used for non parametric data between the cases ‘smoker’ and controls ‘non-smoker’. P < 0.05 was considered significant on one tailed test.
Results: The mean (±SD) age of participants was 42 ± 13 years and 93 % were females. The ethnic composition was: African American 60 %, Caucasian 20 %, Hispanic 14 % and Asian 6 %. Fifteen percent of subjects reported that they were “currently smoking” at the time of the study. The mean (± S.D, range) SLEDAI score was 6.3 (± 6.1, 0-35) and mean SLICC score was 1.9 (±1.9, 0-9). Smokers had greater overall disease activity than nonsmokers (mean ± S.D, median) (7.8 ± 7, 6 vs. 6 ± 6, 4; p 0.047). SLEDAI scores suggested that - presence of arthritis (33.3 % vs. 18.1 %, p 0.044) and low complement levels (45.4 % vs. 28.3 %, p 0.042) were more frequent among smokers than among nonsmokers. There were no statistically significant differences in other components of SLEDAI. There was no statistically significant difference in overall disease damage in between smokers and nonsmokers, but specifically from SLICC skin scarring/alopecia (34.3 % vs. 9.1 %, p 0.001) and skin extensive scarring/ panniculum (34.3 % vs. 6.8 %, p 0.001) were more frequent among the smokers than nonsmokers. There were no statistically significant differences in other components of SLICC.
Conclusion: Cigarette smoking is associated with greater disease activity and cumulative organ damage in SLE. Smoking cessation should be aggressively addressed among patients with SLE.
Disclosure: M. Jolly, None; R. Patel, None; R. Aggarwal, None; W. Sequeira, None; J. A. Block, None.