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A number of genetic and environmental factors have been implicated in the etiology of rheumatoid arthritis (RA). The only well-established environmental risk factor is tobacco smoking, which has been shown in a number of studies to be associated with increased RA risk [ 1 – 4 ]. Associations between RA and factors such as diet [ 5 – 7 ], coffee intake [ 8 – 10 ], alcohol [ 11 – 13 ], and body mass index [ 12 – 14 ] have also been studied, but the evidence to suggest a causal role of these factors is inconclusive. A widespread theory is that one or more infectious agents might act as initiator in the pathogenesis of RA by having antigens similar to host antigens, a mechanism referred to as molecular mimicry [ 15 ], but the evidence in favor of any particular microbe is weak. Because RA is approximately three times as common in women as in men, sex hormones and reproductive factors have been suggested as potentially involved in the etiology [ 16 – 18 ]. Furthermore, a sexually transmitted agent with a higher male-to-female than female-to-male transmission rate might theoretically explain the female predominance in RA, but only few studies have examined sexual behavior and venereal diseases as possible risk factors [ 19 , 20 ].
One possible explanation for conflicting results in etiologic studies might be that risk factors differ between subtypes of RA. It was recently demonstrated that smoking is selectively associated with rheumatoid factor (RF)-positive RA [ 21 ] or with RA positive for anti-cyclic citrullinated peptide (CCP) antibodies [ 22 , 23 ]. Also, coffee consumption has been found to be selectively associated with RF-positive RA, although the association diminished considerably after adjustment for tobacco smoking [ 9 ]. Further supporting the existence of etiologically distinct subtypes of RA, recent case-control studies have shown that measures of low socioeconomic status are predominantly associated with risk of RF-positive RA [ 24 , 25 ]. The aim of the present study was to evaluate both new and previously hypothesised non-genetic risk factors in serologically defined subgroups of anti-CCP-positive and anti-CCP-negative RA.
Materials and methods.
Patients with RA and controls.
The study was conducted as a frequency-matched case-control study. Patients with RA diagnosed within the previous 5 years were identified in rheumatology and internal medicine departments throughout Denmark, which has a predominantly Caucasian population of approximately 5.2 million inhabitants. To be included, patients had to be diagnosed with RA between ages 18 and 65 years and fulfill the American College of Rheumatology (ACR) 1987 classification criteria for RA [ 26 ] between August 1998 and July 2003. Information about date of diagnosis, defined as the date when the RA diagnosis was clinically confirmed by a rheumatologist, and cumulative fulfillment of the ACR 1987 classification criteria for RA was obtained from medical records by a rheumatologist at each department or by the project coordinator (MP) and a rheumatologist (MK) from the study team.
Controls who were frequency-matched by gender and birth year were randomly selected from the Danish population by means of the Civil Registration System, a national database that keeps track of all demographic changes in Denmark [ 27 ]. Using identical invitation letters to cases and controls, we aimed at a 1:1 case-control ratio for women and a 1:2 case-control ratio for men, but all invited subjects who agreed to participate were included. A higher number of controls per case among men was chosen in order to enhance statistical power in analyses of RA in men.
The questionnaire was tested in a pilot experiment comprising 50 patients with RA and 50 controls whose data are not included in this report. Three trained female medical students carried out all interviews between September 2002 and February 2004. Bimonthly meetings were held to ensure that all interviews were conducted in a uniform manner. Interviews were conducted as computer-assisted telephone interviews, and answers were entered directly into a database. Logical tests were built into the program to keep data entry errors at a minimum. Each telephone interview took approximately half an hour and included questions about a wide range of exposure and confounder variables, including level of education, age at menarche, parity, spontaneous abortions, breastfeeding, age at menopause, use of oral contraceptive pills and hormone replacement therapy, marital status, lifetime number of sexual partners of opposite sex, age at first sexual intercourse, lifetime number of anal-intercourse partners of opposite sex, lifetime number of same-sex sexual partners (male study participants only), lifetime number of prostitute visits (male study participants only), histories of venereal diseases (including chlamydia, genital herpes, acuminate condylomas, gonorrhea, and syphilis), smoker status, pack-years smoked (one pack-year equivalent to 20 cigarettes per day for 1 year with one cigarette equivalent to 1 g, one cheroot to 3 g, and one cigar to 4 g of tobacco), coffee, alcohol, and wine consumption 10 years before interview, frequency of fish intake as a hot meal or on bread (at least once a week, 1–3 times a month, less than once a month) 10 years before interview, intake of fish oil (ever/never), vegetarian diet (ever/never), body mass index at age 20 years and 10 years before interview, level of physical activity at work and during leisure time 10 years before interview, pets in childhood and in adulthood, histories of mononucleosis, hay fever, atopic dermatitis, asthma before age 45 years, stomach or duodenal ulcer, heavy diarrhea of at least 4 days’ duration, type I diabetes, thyroid disease, periodontal disease, urinary tract infection, cancer, blood transfusion, tonsillectomy, adenoidectomy, appendectomy, splenectomy, and schizophrenia among first-degree relatives.
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