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American Journal of Gastroenterology C 2004 by Am. Coll. of Gastroenterology Published by Blackwell Publishing
ISSN 0002-9270 doi: 10.1111/j.1572-0241.2004.04039.x
Cigarette Smoking and Appendectomy are Risk Factors for Extraintestinal Manifestations in Ulcerative Colitis F. Manguso, M.D., Ph.D., M. Sanges, M.D., T. Staiano, M.D., S. Gargiulo, M.D., P. Nastro, M.D., D. Gargano, M.D., P. Somma, M.D., G. Mansueto, M.D., R. Peluso, M.D., R. Scarpa, M.D., F. P. D’Armiento, M.D., Ph.D, C. Astarita, M.D., F. Ayala, M.D., A. Renda, M.D., G. Mazzacca, M.D., and A. D’Arienzo, M.D. Departments of Gastroenterology, General Surgery, Pathology, Rheumatology, Dermatology, Federico II University, Naples; and Department of Clinical and Experimental Medicine, Allergology and Clinical Immunology, Second University of Naples, Italy
OBJECTIVE:
Two common factors, cigarette smoking and appendectomy, have been found to play a role in ulcerative colitis (UC). Data on their role in the development of extraintestinal manifestations (EIM) are scarce.
METHODS:
The relationship between cigarette smoking, appendectomy, and EIM was examined in a prospective study involving 535 (M/F = 319/216) consecutive UC patients followed up for 18 yr. We considered the major EIM: seronegative spondyloarthropathy, pyoderma gangrenosum/erythema nodosum, acute anterior uveitis, and primary sclerosing cholangitis. We excluded patients with a history of EIM or those colectomized before study entry, ex-smokers, and those who started to smoke during the course of UC.
RESULTS:
In UC patients, seronegative spondyloarthropathy and dermatologic complications were found increased in smokers (p < 0.0001; p = 0.001) or in subjects with appendectomy (p = 0.0003; p = 0.02), while acute anterior uveitis and primary sclerosing cholangitis did not differ. The Kaplan-Meier analysis showed 18-yr rates for EIM of 71% in smokers and 45% in nonsmokers (log-rank test, p = 0.0001), and of 85% in patients with appendectomy and 48% in those without (p = 0.0001). Cox proportional-hazard model showed that cigarette smoking and appendectomy are independent factors promoting EIM. In smokers with appendectomy the adjusted hazard ratio (3.197, 95% CI 1.529–6.684) was higher than in patients with appendectomy alone (2.617, 95% CI 1.542–4.442) or smoking alone (1.947, 95% CI 1.317–2.879).
CONCLUSIONS:
In UC patients, appendectomy and cigarette smoking are prognostic factors for the development of EIM. The unfavorable effect of cigarette smoking on EIM is additive to that of appendectomy.
INTRODUCTION Two common factors, cigarette smoking and appendectomy, have been found to play a protective role in ulcerative colitis (UC). The negative association between smoking and onset of UC has been a striking and firmly established epidemiological factor since 1976 (1–10). Moreover, even though studies on the effect of smoking on the clinical course of UC have produced conflicting results (11–17), a nicotine therapy has been proposed (18, 19). Several studies reported the effects of smoking and/or nicotine that probably are implicated in UC (19–21). In healthy subjects, smoking has been shown to suppress both humoral and cellular immunity (19). Furthermore, other studies have demonstrated in smokers an increased production of endogenous corticosteroids, an increased rectal blood flow, and the inhibition of oxygen free radical production by neutrophils (19). In vitro studies have demonstrated a decreased interleukin production and the re-
duction of circular muscle activity through the release of nitric oxide (19, 20). In UC patients, smoking has been shown to reduce eicosanoid production without remarkable effects on mucus production and the intestinal permeability (19). It is noteworthy that the “opposite” effect of smoking on UC may not apply to nicotine itself, as not all the effects of smoking are reproduced by nicotine alone (21). Early studies have suggested that appendectomy is uncommon in patients who develop UC or lessens the risk of developing the intestinal disease (22–35). Some observations have shown a lesser extent and a less severe course of the intestinal disease in patients with appendectomy (17, 24, 36–38). UC is associated with a variety of extraintestinal manifestations (EIMs), intended as reactive lesions and not secondary to treatment or to complications, and up to one-third of patients had experienced at least one EIM in their life. The reported prevalence of these complications in UC varies
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between studies, because a wide variety of populations, data collection, and diagnostic methods have been used. An arthritis affecting the spine and/or peripheral joints has been considered the most common EIM of UC (39). It is characterized by the absence of serum rheumatoid factor, the peripheral and axial form occurring in about 10–23% and about 10–15%, respectively (40, 41). Pyoderma gangrenosum and erythema nodosum are the most frequently observed dermatologic manifestations, seen in about 0.5–5% (41) and 1–9% (42) of UC patients, respectively. The most common form of ocular manifestation is the acute anterior uveitis, an inflammation of the anterior chamber including iritis, scleritis, and episcleritis. This condition is found in up to 5% of UC patients (42). Finally, hepatobiliary involvement is mainly represented by primary sclerosing cholangitis (PSC) and involves about 1–7.4% of UC patients (41, 43). The mechanisms responsible for the EIMs of UC are not clearly understood and probably are related to immunologic factors. It has been hypothesized that the inflamed colonic mucosa may be the source of immune responses for the inflammatory process in specific extracolonic organs (44, 45). In the rheumatologic field, some studies have focused on the association of the lymphoid surgery (appendectomy, tonsillectomy, and adenoidectomy) or smoking and joint involvement (46–51). Lymphoid surgery has been found positively (46, 47) or negatively (48) associated with rheumatoid arthritis, while in other studies no association was evidenced (49, 50). On the other hand, an interesting study linked smoking with a severe outcome of ankylosing spondylitis (51), suggesting the influence of smoking on seronegative spondyloarthritis that is frequently associated with UC. In the hepatologic field, smokers showed a decreased risk of PSC (43, 52, 53), and the inverse association between current smoking and PSC appeared to be independent of, and not secondary to the protective effect of smoking on UC (52). Interestingly, no beneficial effect of transdermal nicotine in patients with PSC has been reported (54). Finally, a study showed in UC patients with appendectomy an increased frequency of PSC (55), while in another no difference was found (43). The aim of this prospective study was to investigate whether smoking and appendectomy may influence the onset of EIMs in patients affected by UC.
MATERIALS AND METHODS We included in this study all consecutive UC patients who were current smokers or nonsmokers, observed at the Gastroenterology Unit between January 1984 and January 2002. We excluded patients with a history of EIMs or who had been colectomized before study entry, who were ex-smokers, and who started to smoke during the course of UC. Moreover, we also excluded patients without at least 1 yr of follow-up. Patients who underwent colectomy or appendectomy, and those who died or were lost during the follow-up were considered from the date of inclusion to that of colectomy, appendectomy, death, or last visit.
A smoker was defined as a patient who had regularly smoked tobacco (cigarettes, cigars, pipe) at least from diagnosis of UC until the end of the follow-up, a nonsmoker was a person who had never smoked, and an ex-smoker was defined as a person who had given up smoking. We chose not to include ex-smokers and to exclude from the final evaluation patients who changed smoking habits during the course of UC to avoid a possible misinterpretation of the results. In fact, it is reported that ex-smokers develop the intestinal disease soon after stopping, and stopping or starting smoking during UC may have any influence on the clinical course of the disease. At the first contact with our unit and during follow-ups patients’ history was recorded, including smoking habits, previous surgery, and EIMs. Data were obtained by personal interview with the aid of a health history questionnaire and physical examination. Previous surgery was confirmed by the evaluation of related record chart. Patients included in the study were clinically followed up regularly every year and endoscopically every 2 yr, in absence of flare-ups or complications. In this study we considered the major EIMs: seronegative spondyloarthropathy (SpA), pyoderma gangrenosum/erythema nodosum, acute anterior uveitis, PSC. The rheumatologic evaluation included the record of axial and/or peripheral articular symptoms. Subjects who were positive for inflammatory articular involvement underwent radiographic and scintiscan assay of the joints. In all cases, serum rheumatoid factor was also excluded. The diagnosis of articular involvement was based on a positive finding at clinical evaluation plus a positive radiographic and/or scintigraphic examination. In particular, the presence of axial involvement was defined on the basis of New York criteria (56), and the active sacroiliac involvement was defined on the basis of the sacroiliac/sacrum uptake ratio as suggested by Percy and Lentle (57). The diagnosis of peripheral articular involvement was made after the exclusion of other forms of arthritis (e.g., rheumatoid arthritis and osteoarthritis). Because the criteria for SpA appeared to be too restricted, new criteria for the classification were proposed in 1991 by the European Spondyloarthropathy Study Group (58). In our study to avoid underestimating the number of SpA and consequently the number of extraintestinal manifestations, all observations of arthritis made before 1991 were reviewed according to the new guidelines. Notwithstanding this, no patient observed from 1984 to 1991 was reclassified after the introduction of ESSG criteria. The dermatologic evaluation included the record of history for skin disorders and the examination for current specific diseases. In patients with an unclear diagnosis a skin biopsy was also performed. The ocular evaluation included the record of history and the examination for current specific disorders. In all cases the study included the slit-lamp examination. Other causes of conjunctivitis were also excluded (59). PSC was suspected in patients with serum biochemical tests showing cholestasis. Definite diagnosis of PSC was established by
Risk Factors for Extraintestinal Manifestations in Ulcerative Colitis
endoscopic retrograde cholangiopancreatography examination and/or results of liver biopsy. Statistical Analysis Continuous variables are presented as median and interquartile range (IQR) and compared by nonparametric means with the Mann-Whitney U test. For categorical variables the Pearson χ 2 test was performed, unless the exact test was required for frequency tables when more than 20% of the expected values were less than 5. Cumulative event rates were calculated by the Kaplan-Meier method, with the time to a first event as the outcome variable (60). The statistical significance of differences in outcome between the two groups was assessed with the log-rank test (61). In addition, covariateadjusted analyses of outcomes among patients with and without EIMs were performed with the Cox proportional-hazard model (62). For the selection of the variables to be included in the multivariate model, we chose p < 0.2 (which is a lax criterion) because variables may contribute to a multiple regression model in unforeseen ways, due to complex interrelationships among variables. Covariates included in the first analysis were appendectomy, smoking habits, and age at onset of UC. In the second analysis we included age at onset of UC as covariate, together with a categorical covariate where patients were classified in four groups: nonsmoking and no appendectomy (reference category), appendectomy alone, smoking alone, appendectomy, and smoking. Relative risks, expressed as hazard ratios (with 95% confidence intervals), were calculated with use of the Cox proportionalhazards model. All tests of significance were two-sided. A p value of 0.05 or less was considered significant. The SPSS software package for Windows (release 11.0.1–15 Nov 2001; SPSS Inc., Chicago, IL, USA) was used for statistical analysis.
RESULTS From 998 consecutive UC patients, 317 did not fulfill the inclusion criteria: 308 were ex-smokers and/or colectomized (5 patients) and/or suffering from EIMs (15 patients). From 681 patients who were considered eligible, the diagnosis of
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UC was made in our unit in 603 cases, whereas 78 patients were referred to our unit with a diagnosis made in other hospitals. In this second group, follow-up diagnostic procedures confirmed the diagnosis. At the end of the study period, 41 patients had changed their smoking habit and 105 patients were followed up for less than 1 yr. These patients were excluded from the final analysis. Of the 535 patients (M/F = 319/216) considered in this study, 120 (22%) (M/F = 71/49) were smokers, and 137 (26%) (M/F = 64/73) showed one or more EIMs. Fifty patients (9%) (M/F = 16/34) were appendectomized before the onset of UC, eight of them with the time of appendectomy close to the time of UC diagnosis. Acute appendicitis was diagnosed in 22 patients, 3 of them with perforated appendicitis, while absence or minimal inflammation was reported in 28. The median (IQR) follow-up was 11 (8) yr. During the follow-up, 42 patients were submitted to colectomy, no one was appendectomized, and 9 patients died: 4 from cardiovascular diseases, 3 from cancer, one from the complications of viral liver cirrhosis, and one in a car accident. Moreover, 112 patients were considered lost to follow-up. The characteristics of patients with and without EIMs are summarized in Table 1. The extension of disease is the maximum mucosa involvement endoscopically observed during the follow-up period. Smoking Habit Relevant data on smoker and nonsmoker patients are given in Table 2. The median age at the onset of UC and the distribution of sex, appendectomy, colectomy, and extension of the disease was not different in smokers and nonsmokers. Of the 120 smokers, 114 smoked exclusively cigarettes and 6 patients smoked cigarettes and occasionally pipes and cigars. EIM rates were found more significantly increased in smokers than in nonsmokers, in particular those involving joints and skin. No differences were found in the case of ocular and hepatobiliary involvement. The number of EIMs was significantly higher in smokers than in nonsmokers. In particular, we found that 21 (18%) smokers and 41 (10%) nonsmokers had one EIM, while 26 (22%) smokers and 49 (12%) nonsmokers experienced multiple EIMs during the course of UC. The median time between the onset of UC and the appearance of the first EIM was 11 yr with an IQR
Table 1. Characteristics of 535 UC Patients With and Without Extraintestinal Manifestations
Age at onset of UC (yr) Male sex Extension of disease Proctitis Proctosigmoiditis Left side Pancolitis Smokers Appendectomized Colectomized
Extraintestinal Manifestations (n = 137)
No Extraintestinal Manifestations (n = 398)
28 (17) 47
30 (20) 64
8 31 18 43 34 18 4
10 28 19 44 18 6 7
p Value 0.18 0.0003 0.85
0.0001
