Treatment for Rheumatoid Arthritis and the Risk of Hospitalization for Pneumonia

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 54, No. 2, February 2006, pp DOI /art , American College of Rheumatology Treatment for Rheumatoid Arthritis and the Risk of Hospitalization for Pneumonia Associations With Prednisone, Disease-Modifying Antirheumatic Drugs, and Anti Tumor Necrosis Factor Therapy Frederick Wolfe, 1 Liron Caplan, 2 and Kaleb Michaud 3 Objective. Pneumonia is a major cause of mortality and morbidity in rheumatoid arthritis (RA). This study was undertaken to determine the rate and predictors of hospitalization for pneumonia and the extent to which specific RA treatments increase pneumonia risk. Methods. RA patients (n 16,788) were assessed semiannually for 3.5 years. Pneumonia was confirmed by medical records or detailed patient interview. Covariates included RA severity measures, diabetes, pulmonary disease, and myocardial infarction. Cox proportional hazards regression was used to determine the multivariable risk associated with RA treatments. Results. After adjustment for covariates, prednisone use increased the risk of pneumonia hospitalization (hazard ratio [HR] 1.7 [95% confidence interval ]), including a dose-related increase in risk (<5mg/day HR 1.4 [95% confidence interval ], >5 10 mg/day HR 2.1 [95% confidence interval ], >10 mg/day HR 2.3 [95% confidence interval ]). Leflunomide also increased the risk (HR 1.2 [95% confidence interval ]). HRs for etanercept (0.8 [95% confidence interval ]) and sulfasalazine (0.7 [95% confidence interval ]) did not Supported by Bristol-Meyers-Squibb. The National Data Bank for Rheumatic Diseases has received support from Abbott, Amgen, Bristol-Meyers-Squibb, Centocor, Merck, and TAP. 1 Frederick Wolfe, MD: National Data Bank for Rheumatic Diseases and University of Kansas School of Medicine, Wichita, Kansas; 2 Liron Caplan, MD: Washington University School of Medicine, St. Louis, Missouri; 3 Kaleb Michaud, MS: National Data Bank for Rheumatic Diseases, Wichita, Kansas, and Stanford University, Stanford, California. Address correspondence and reprint requests to Frederick Wolfe, MD, National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, 1035 N. Emporia, Suite 230, Wichita, KS fwolfe@arthritis-research.org. Submitted for publication February 27, 2005; accepted in revised form October 25, reflect an increased risk of pneumonia. HRs for infliximab, adalimumab, and methotrexate were not significantly different from zero. Conclusion. There is a dose-related relationship between prednisone use and pneumonia risk in RA. No increase in risk was found for anti tumor necrosis factor therapy or methotrexate. These data call into question the belief that low-dose prednisone is safe. Because corticosteroid use is common in RA, the results of this study suggest that prednisone exposure may have important public health consequences. Pneumonia due to infection is the leading cause of hospitalization in the US, excluding childbirth and psychosis (1). It is also one of the major causes of mortality in patients with rheumatoid arthritis (RA) (2). However, most of the interest in the pulmonary diseases associated with RA has been directed toward uncommon entities, including interstitial lung disease secondary to RA (3) and adverse pulmonary effects of specific treatments. Prior reports have putatively implicated injectable gold (4), penicillamine (5), sulfasalazine (6,7), methotrexate (8 10), infliximab (11), and leflunomide (12,13). Thus, while bacterial and viral causes of pneumonia predominate, they are rarely reported in research studies. The use of immunomodulatory drugs has sparked an interest in the infections that might result from treatment interventions. Methotrexate is suspected of conferring susceptibility to infectious pathogens (14 20), although most reports concern methotrexate pneumonitis, a hypersensitivity reaction (21). Low-dose prednisone is another commonly used treatment for RA, but there are no reported studies determining whether it is a risk factor for pneumonia in RA. Anti tumor necrosis 628

2 RA TREATMENT AND RISK OF PNEUMONIA 629 factor (anti-tnf) therapy has raised concern about a general risk of infection (22,23), but there is little evidence from clinical trials suggesting a real or substantial risk (24,25). Surprisingly, there have been no previous published studies of RA and pneumonia. We therefore undertook this study to 1) determine the rate of pneumonia in RA, 2) determine whether RA treatments increase the risk of hospitalization for infectionassociated pneumonia, and 3) estimate the degree of risk associated with each treatment. PATIENTS AND METHODS Patients and data collection. Patients in this study were participants in the National Data Bank for Rheumatic Diseases (NDB) longitudinal study of RA outcomes. NDB participants are recruited from the practices of US rheumatologists and are followed up prospectively with semiannual detailed, 28-page questionnaires, as previously described (26 28). This report concerns the status of 16,788 adult RA patients who completed questionnaires regarding their illness for up to 3.5 years beginning with events that occurred in first 6 months of 2001 and ending with events that occurred in the first 6 months of 2004, resulting in a mean SD followup time of years (median 2.5). Of these patients, 5,317 were enrolled as part of an infliximab safety registry and 1,852 as part of a leflunomide safety registry. Recorded demographic variables included sex, age, ethnic origin, education level, current marital status, and medical insurance type. Functional disability in this report was assessed by the Health Assessment Questionnaire (HAQ) (29,30). Information on pain, global disease severity, and fatigue was determined by visual analog scale (31), as well as the Rheumatoid Arthritis Disease Activity Index (RADAI) (32). Patients reported all medications, including dosage and frequency of use. Prednisone use was further characterized as mean daily dosage. The effect of comorbidity was assessed by a comorbidity score, which is the sum of 11 present or past comorbid conditions reported by the patient. Conditions include cancer, stroke, fracture, and renal, neurologic, endocrine, gastrointestinal, cardiovascular, pulmonary, genitourinary, and psychiatric problems. In addition, rates of specific conditions, including preexisting pulmonary disease, myocardial infarction, and diabetes, were determined. Patients report all hospitalizations. Hospitalizations for pneumonia were identified from patient descriptive reports, hospital records, physician reports, and mortality records. In hospital and mortality reports, pneumonia was confirmed by the presence of International Classification of Diseases, Ninth Revision codes , 136.9, and If records could not be obtained, we contacted the patient s physician and/or interviewed the patient with a structured, preplanned interview designed to address the reported condition. Comparison of patient reports with medical records indicated agreement in 94% of cases. Pneumonia cases also included deaths in which pneumonia was listed as a major cause on death records, provided that the death occurred in Table 1. Characteristics of the 16,788 RA patients* Demographics Age, mean SD years Male sex 22.8 Ethnic origin White, not of Hispanic origin 89.7 Black, not of Hispanic origin 4.8 Asian or Pacific Islander 1.0 American Indian or Alaskan native 1.1 Hispanic 3.0 Other 0.5 Education, years RA characteristics Disease duration, mean SD years Lifetime no. of DMARDs or biologic agents, mean SD HAQ (0 3), mean SD Semiannual direct medical costs, median dollars 7,024 Treatment Prednisone, all dosages 38.1 Daily dosage among prednisone users, mg Methotrexate 54.5 Hydroxychloroquine 17.7 Leflunomide 14.4 Sulfasalazine 5.7 Infliximab 36.9 Etanercept 12.8 Adalimumab 4.3 Comorbidity Smoking (ever) 54.2 Diabetes 10.1 Pulmonary disease (ever) 17.0 Myocardial infarction (ever) 8.2 Comorbidity index (0 11), mean SD Pneumonia-associated hospitalization 3.7 Pneumonia-associated death 0.4 * Except where indicated otherwise, data refer to values at last study observation. Except where indicated otherwise, values are the percent of patients. RA rheumatoid arthritis; DMARDs diseasemodifying antirheumatic drugs; HAQ Health Assessment Questionnaire. the 6-month period following the last NDB survey. We obtained information on deaths from family members and physicians, and also systematically screened the National Death Index (33,34) at yearly intervals for death information and causes of death. Statistical analysis. Predictors of first hospitalization for pneumonia were examined using Cox proportional hazards regression; all analyses satisfied the proportional hazard assumption based on Schoenfeld residuals. Patients reported events and treatments that occurred during the previous 6 months. Predictor treatment variables represented treatments being used at the start of the 6-month period in which pneumonia was assessed, while covariate values were those

3 630 WOLFE ET AL Table 2. Incidence rates of hospitalization for pneumonia among 9,619 nonregistry patients with rheumatoid arthritis Infections Exposure, years Incidence rate per 1,000 patient-years 95% confidence interval All patients , Sex Female , Male 83 4, Age, years , , , , , , determined at the close of the previous 6 month period. In the event of death, treatment variables were those in the 6-month period prior to the death. Approximately 8% of the fields coding previous history of pulmonary problems and previous history of myocardial infarction were missing; 0.6% were missing for diabetes history. To allow for all variables to be used in the multivariable analyses, we used the method of multiple imputation by chained equations to impute data to 5 data sets (35), according to the implementation method of Royston (36,37). We calculated incidence rates for the first hospitalization due to pneumonia beginning with each patient s enrollment in the NDB, using all patients. So that rates would be generalizable to community arthritis patients, we also calculated detailed incidence rates after excluding patients who were enrolled as part of pharmaceutical company sponsored safety registries. Cox regression analyses also included safety registry status as a dummy variable. However, in these multiple covariate analyses, safety registry status was not found to be a significant term. Analyses were performed using the Stata SE statistical package, version 8.2 (2003) (Stata, College Station, TX). P values less than 0.05 were considered significant. Ninety-five percent confidence intervals (95% CIs) were calculated, and all tests were 2-tailed. RESULTS At the time of the last assessment, prednisone and methotrexate were the most common treatments in this cohort during the previous 6 months (38.1% and 54.5%, respectively), followed by infliximab (36.9%), hydroxychloroquine (17.7%), and etanercept (12.8%) (Table 1). Among prednisone users, 66.9% received 5 mg/day, 23.4% received 5 10 mg/day, and 9.8% received 10 mg/day. The mean and median daily dosage of prednisone in the study cohort were 7.4 mg and 5.0 mg. On average, patients had been exposed to 3.3 disease-modifying antirheumatic drugs (DMARDs) or biologic agents, and the HAQ score was 1.1. Preexisting (pre-pneumonia) pulmonary disease had occurred in 17.0% of subjects. Diabetes was noted in 10.1%, and myocardial infarction in 8.2%. There were 749 hospitalizations for pneumonia that occurred in 644 patients in the full study cohort. The incidence density of pneumonia was 17 per 1,000 patient-years (95% CI ) for all patients, 19.2 per 1,000 patient-years for men (95% CI ), and 17.3 per 1,000 patient-years for women (95% CI ). For greater generalizability, we also conducted detailed incidence rate analyses of the 9,619 patients who were not part of the safety registries (Table 2). The incidence rate for pneumonia in this group was slightly lower than in the full cohort (14.7 per 1,000 patient-years Table 3. Univariable nontreatment predictors of pneumonia hospitalization* Variable Hazard ratio P 95% CI Demographics Age (per 10 years) Sex (male) Education level (years) Non-Hispanic white Comorbidity Smoking (ever) Diabetes Pulmonary disease (ever) Myocardial infarction (ever) Comorbidity score (0 11) RA characteristics RA duration (per 10 years) No. of previous DMARDs or biologic agents HAQ (0 3) * 95% CI 95% confidence interval (see Table 1 for other definitions). Comparison group is all other ethnic groups.

4 RA TREATMENT AND RISK OF PNEUMONIA 631 Table 4. Univariable treatment predictors of pneumonia hospitalization* Unadjusted Adjusted Variable Hazard ratio P 95% CI Hazard ratio P 95% CI Prednisone, all dosages No prednisone Prednisone 5 mg/day Prednisone 5 10 mg/day Prednisone 10 mg/day Methotrexate Hydroxychloroquine Leflunomide Sulfasalazine Infliximab Etanercept Adalimumab * 95% CI 95% confidence interval (see Table 1 for other definitions). Adjusted for age, sex, and for lagged variables of HAQ, pulmonary disease, diabetes, myocardial infarction, number of DMARDs or biologic agents, RA duration, smoking ever, education categories, safety registry membership, and prednisone usage (for nonprednisone variables). [95% CI ]). The rate was greater in men (17.9 per 1,000 patient-years [95% CI ]) than in women (13.8 per 1,000 patient-years [95% CI ]). The rate increased with age (Table 2). In the age group years, it reached its maximum (21.0 per 1,000 patient-years). Only 3% of pneumonia hospitalizations were attributed directly to nonviral, nonbacterial opportunistic infections. A number of demographic and clinical variables were associated with the risk of pneumonia, as seen in the covariate-specific disease associations presented in Table 3. For example, each 10-year increase in age was associated with a 30% increase in pneumonia risk. Pneumonia was also more common in those with less education. Comorbidity status predicted future pneumonia among those who had ever smoked (hazard ratio [HR] 1.3 [95% CI ]), were diabetic (HR 2.0 [95% CI ]), had a past myocardial infarction (HR 2.1 [95% CI ]), or had prior pulmonary disease (HR 3.8 [95% CI ]). Certain RA features were also associated with the risk of pneumonia. Risk was increased with increasing duration of RA (HR 1.1 per 10 years increase in RA duration [95% CI ]) and with each additional prior DMARD or biologic agent (HR 1.1 [95% CI ]). Among the most powerful predictors of hospitalization for pneumonia was functional status: a 1-unit increase in HAQ score had an HR of 2.0 (95% CI ). The effect of treatment variables on the risk of pneumonia varied according to the covariates in the model. Table 4 presents univariable associations unadjusted for covariates and associations adjusted for covariates. The addition of covariates mitigated the risk associated with treatment variables. In the adjusted analyses, use of prednisone increased the risk of pneumonia by 70% (HR 1.7 [95% CI ]) and leflunomide increased the risk by 30% (HR 1.3 [95% CI ], P 0.036), while persons receiving sulfasalazine had a reduced HR (0.7 [95% CI ], P Table 5. Multivariable predictors of pneumonia hospitalization* Variable Hazard ratio P 95% CI Treatment Prednisone Leflunomide Infliximab Adalimumab Methotrexate Hydroxychloroquine Etanercept Sulfasalazine Demographics Age (per 10 years) Sex (male 1) Smoking (ever) Comorbidity Pulmonary disease (ever) Myocardial infarction (ever) Diabetes RA characteristics HAQ (0 3) No. of previous DMARDs or biologic agents Duration of RA (years) * 95% CI 95% confidence interval (see Table 1 for other definitions). Also adjusted for categories of educational attainment and safety registry enrollment.

5 632 WOLFE ET AL 0.053). Etanercept use in this model was also associated with a marginally reduced HR (0.8 [95% CI ], P 0.051). In addition to a simple association of prednisone use with pneumonia, we also found a doserelated increase. Even dosages of 5mg/day were associated with pneumonia risk, in both the unadjusted model (HR 1.7 [95% CI ]) and the adjusted model (HR 1.4 [95% CI ]). Because drugs are often used concurrently, Table 5 recapitulates the adjusted analyses shown in Table 4, but includes all of the treatment variables simultaneously. In this model, treatment effects were weakened for all drugs except prednisone (HR 1.7 [95% CI ]). Of interest, most demographic, comorbidity, and RA-related variables remained significant in this multivariable model. DISCUSSION Despite the fact that infectious pneumonia ranks among the most common causes of death in RA, it has not yet been studied specifically in RA patients (2). Instead, most studies address noninfectious pulmonary complications of RA (such as interstitial lung disease), drug-related complications (such as hypersensitivity pneumonitis), or opportunistic pulmonary infections caused by unusual organisms. In our analyses, we confirmed that these types of infections were indeed rare, contributing only 3% of cases. Many of the pneumonia risk factors described in our model are consistent with findings of previous investigations conducted in non-ra populations and may reflect underlying biologic phenomena. Among these factors is preexisting pulmonary disease, which has been shown in more than 20 studies to greatly increase the risk of pneumonia (38 41). The pathophysiologic explanation for this finding is, however, incompletely understood. A number of studies have also established smoking history as a risk factor for pneumonia (42 45).The relevant mechanisms that have been proposed include decreased ciliary and respiratory epithelial function, as well as defects in cellular and humoral immunity (44,46). Interestingly, smoking entered the univariate model (Table 3), but was not predictive by multivariate analysis (Table 5) because of its correlation with preexisting pulmonary disease (which it may have caused). The proinflammatory cytokine TNF mediates the early response of mononuclear phagocytes to bacterial infections and may play an important role in lung disease. In particular, in endotoxin-reliant animal models of pneumonia, TNF production has been shown to be stimulated, which in turn contributes to inflammatory cell recruitment (47). Furthermore, bronchoalveolar fluid TNF levels may be higher in infected pulmonary lobes compared with the uninvolved lobes of patients with community-acquired pneumonia (48) (or may show a trend toward increased levels [49]). But despite the theoretical role of TNF in pneumonia, our study failed to demonstrate an increase in risk associated with any of the anti-tnf therapies (Table 5). Steroid exposure has rarely been addressed as a potential risk factor for pneumonia in the general population (38 41,44). To our knowledge, glucocorticoid dosage has not been demonstrated to be predictive of pneumonia risk in any previous study. However, we found a dose-related association between prednisone and pneumonia hospitalization in patients with RA (Tables 4 and 5). This relationship was evident even with average daily dosages of 5mg, and the association was robust to covariate control. The immunomodulatory effect of prednisone is facilitated through both genomic and nongenomic pathways. These actions have been recently summarized and involve an extensive cascade of transcriptional/ translational events, along with more rapid glucocorticoid receptor dependent and independent means (50). Given the broad spectrum of cellular mechanisms provoked by glucocorticoids (in relative contrast to the relatively specific actions of other DMARDs), it is perhaps not surprising that prednisone exhibited the strongest association with subsequent pneumonia. Prednisone use is common in RA and is therefore a potentially important health risk. In our study cohort, a substantial minority (38.1%) of patients were receiving prednisone. This prevalence would be reduced to 30.9% if the infliximab and leflunomide safety registry patients were excluded. Likewise, the removal of subjects from these 2 registries would reduce the prevalence of anti- TNF exposure to 32.3%. If the results of this study are correct, they may undermine the current belief that low-dose prednisone is safe. Given the prevalence of prednisone use, the findings of this investigation suggest a potentially important public health problem. Our data do not, and cannot, address the issue of net benefit. It is possible that discontinuing prednisone or not using prednisone in the first place might provoke equally undesirable adverse effects. It is noteworthy that we found no evidence of increased rates of pneumonia associated with methotrexate (Tables 4 and 5), which challenges the perception from earlier reports (14,15). We found a very slight

6 RA TREATMENT AND RISK OF PNEUMONIA 633 increased risk with leflunomide (HR 1.2 [95% CI ]) (Table 5). This compound, an inhibitor of de novo pyrimidine synthesis, retards the enzymatic activity of dihydroorotate dehydrogenase, thereby blocking T cell expansion. In addition, other pathways have recently been described, including inhibition of TNF-dependent NF- B activation of T cells (51,52). The relevance of these actions on the development of pneumonia has yet to be articulated. Finally, our results rule out the notion of an increased risk of pneumonia associated with sulfasalazine (HR 0.7 [95% CI ]). This marginally significant effect may or may not relate to sulfasalazine s known mechanisms of action (53,54). Although observational studies reflect actual clinical practice in the community, nonrandom assignment to therapy can confound the association between treatment and pneumonia unless all important covariates are controlled for. In the current study, we adjusted for differences in severity by the use of lagged covariates (Tables 4 and 5). The HAQ is usually thought of as the best predictor of hospitalization and long-term outcomes (28,55), and we included this variable in the model. We also included a count of the lifetime number of DMARDs or biologic agents used by patient, since the number of drugs is a measure of the lack of control of RA; furthermore, we included the duration of RA. HAQ disability and number of therapeutic agents were both found to be predictive of pneumonia risk. It is interesting to speculate whether known defects in immunity that parallel RA disease severity (such as mannosebinding lectin concentration) (56) might mediate this elevated risk. Although not included in the models whose results are shown in Tables 4 and 5, we examined a series of other covariates, including the RADAI, pain scores, and global severity. In the presence of the study covariates, these factors were not statistically significant and did not change the results of the analyses; therefore they were excluded from the analyses presented in Tables 4 and 5. In addition to direct estimates of arthritis severity, the inclusion of biologic agents in the analysis in Table 5 serves as a further adjustment for arthritis severity, since anti-tnf therapy is prescribed to patients whose arthritis is more severe. As demonstrated in Tables 3 and 5, demographic factors and the presence of pulmonary disease, cardiovascular disease, and diabetes also contribute to the risk of pneumonia, and we controlled for these factors. Even so, we may not have accounted for all covariate effects and we suggest that, ideally, a randomized controlled trial should be undertaken to confirm the findings of this study, particularly given the public health implications of our findings. In summary, our findings demonstrate a doserelated relationship between prednisone treatment and the risk of pneumonia in RA patients in the community. No increased risk was found with anti-tnf therapy or methotrexate. A slight increase in risk was found with leflunomide. Diabetes, prior myocardial infarction, and prior pulmonary disease also increase the risk of pneumonia. Because corticosteroid use is common in RA, the results of this study suggest that prednisone use may have important public health consequences. REFERENCES 1. Kozak LJ, Owings MF, Hall MJ. National Hospital Discharge Survey: 2001 annual summary with detailed diagnosis and procedure data. Vital Health Stat ;156: Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37: Du Bois RM, Well AU. The lung in rheumatic diseases. In: Hochberg M, Silman A, Smolen J, Weinblatt M, Weisman M, editors. Rheumatology. New York: Mosby; p Tomioka H, King TE. Gold-induced pulmonary disease: clinical features, outcome, and differentiation from rheumatoid lung disease. Am J Respir Crit Care Med 1997;155: Kay A. European League Against Rheumatism study of adverse reactions to D-penicillamine. Br J Rheumatol 1986;25: Ulubas B, Sahin G, Ozer C, Aydin O, Ozgur E, Apaydin D. Bronchiolitis obliterans organizing pneumonia associated with sulfasalazine in a patient with rheumatoid arthritis. Clin Rheumatol 2004;23: Hamadeh MA, Atkinson J, Smith LJ. Sulfasalazine-induced pulmonary disease. Chest 1992;101: Alarcon GS, Kremer JM, Macaluso M, Weinblatt ME, Cannon GW, Palmer WR, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis: a multicenter, case-control study. Ann Intern Med 1997;127: Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am 1997;23: Green L, Schattner A, Berkenstadt H. Severe reversible interstitial pneumonitis induced by low dose methotrexate: report of a case and review of the literature. J Rheumatol 1988;15: Kramer N, Chuzhin Y, Kaufman LD, Ritter JM, Rosenstein ED. Methotrexate pneumonitis after initiation of infliximab therapy for rheumatoid arthritis. Arthritis Rheum 2002;47: McCurry J. Japan deaths spark concerns over arthritis drug. Lancet 2004;363: Scott DL. Interstitial lung disease and disease modifying antirheumatic drugs. Lancet 2004;363: Boerbooms AM, Kerstens PJ, Vanloenhout JW, Mulder J, van de Putte LB. Infections during low-dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum 1995;24: Lemense GP, Sahn SA. Opportunistic infection during treatment with low dose methotrexate. Am J Respir Crit Care Med 1994; 150: Perruquet JL, Harrington TM, Davis DE. Pneumocystis carinii pneumonia following methotrexate therapy for rheumatoid arthritis [letter]. Arthritis Rheum 1983;26: Gutierrez-Urena S, Molina JF, Garcia CO, Cuellar ML, Espinoza

7 634 WOLFE ET AL LR. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 1996;39: Schnabel A, Burchardi C, Gross WL. Major infection during methotrexate treatment for rheumatoid arthritis. Semin Arthritis Rheum 1996;25: Hilliquin P, Renoux M, Perrot S, Puechal X, Menkes CJ. Occurrence of pulmonary complications during methotrexate therapy in rheumatoid arthritis. Br J Rheumatol 1996;35: Thomas E, Olive P, Mazyad H, Blotman F. Cytomegalovirusinduced pneumonia in a rheumatoid arthritis patient treated with low dose methotrexate. Clin Exp Rheumatol 1997;15: Schnabel A, Richter C, Bauerfeind S, Gross WL. Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis. Thorax 1997;52: Feltelius N, Fored M, Blomqvist P, Bertilsson L, Geborek P, Jacobsson LT, et al. Results from a nationwide post marketing cohort study of patients in Sweden treated with etanercept. Ann Rheum Dis 2005;64: Kroesen S, Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-tnf- therapy. Rheumatology (Oxford) 2003;42: Fleischmann R, Iqbal I, Nandeshwar P, Quiceno A. Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept. Drug Saf 2002;25: Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Dougados M, et al. Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases. Ann Rheum Dis 2003;62 Suppl 2:ii Wolfe F, Anderson J, Burke TA, Arguelles LM, Pettitt D. Gastroprotective therapy and risk of gastrointestinal ulcers: risk reduction by COX-2 therapy. J Rheumatol 2002;29: Wolfe F, Flowers N, Burke TA, Arguelles LM, Pettitt D. Increase in lifetime adverse drug reactions, service utilization, and disease severity among patients who will start COX-2 specific inhibitors: quantitative assessment of channeling bias and confounding by indication in 6689 patients with rheumatoid arthritis and osteoarthritis. J Rheumatol 2002;29: Michaud K, Messer J, Choi HK, Wolfe F. Direct medical costs and their predictors in persons with rheumatoid arthritis: a three-year study of 7,527 patients. Arthritis Rheum 2003;48: Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the Health Assessment Questionnaire, disability and pain scales. J Rheumatol 1982;9: Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23: Wolfe F, Hawley DJ, Wilson K. The prevalence and meaning of fatigue in rheumatic disease. J Rheumatol 1996;23: Stucki G, Liang MH, Stucki S, Bruhlmann P, Michel BA. A self-administered rheumatoid arthritis disease activity index (RA- DAI) for epidemiologic research: psychometric properties and correlation with parameters of disease activity. Arthritis Rheum 1995;38: Doody MM, Hayes HM, Bilgrad R. Comparability of National Death Index Plus and standard procedures for determining causes of death in epidemiologic studies. Ann Epidemiol 2001;11: Edlavitch SA, Baxter J. Comparability of mortality follow-up before and after the National Death Index. Am J Epidemiol 1988;127: Van Buuren S, Boshuizen HC, Knook DL. Multiple imputation of blood pressure covariates in survival analysis. Stat Med 1999;18: Royston P. Multiple imputation of missing values: update. Stat J 2005;5: Royston P. Multiple imputation of missing values. Stat J 2004;4: Farr BM, Bartlett CL, Wadsworth J, Miller DL, and the British Thoracic Society Pneumonia Study Group. Risk factors for community-acquired pneumonia diagnosed upon hospital admission. Respir Med 2000;94: Almirall J, Bolibar I, Balanzo X, Gonzalez CA. Risk factors for community-acquired pneumonia in adults: a population-based case-control study. Eur Respir J 1999;13: Koivula I, Sten M, Makela PH. Risk factors for pneumonia in the elderly. Am J Med 1994;96: Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk factors for acquiring pneumococcal infections. Arch Intern Med 1986;146: Almirall J, Gonzalez CA, Balanzo X, Bolibar I. Proportion of community-acquired pneumonia cases attributable to tobacco smoking. Chest 1999;116: Sherman CB. The health consequences of cigarette smoking: pulmonary diseases. Med Clin North Am 1992;76: Baik I, Curhan GC, Rimm EB, Bendich A, Willett WC, Fawzi WW. A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in US men and women. Arch Intern Med 2000;160: Paffenbarger RS Jr, Brand RJ, Sholtz RI, Jung DL. Energy expenditure, cigarette smoking, and blood pressure level as related to death from specific diseases. Am J Epidemiol 1978;108: Marcy TW, Merrill WW. Cigarette smoking and respiratory tract infection. Clin Chest Med 1987;8: Mizgerd JP, Lupa MM, Hjoberg J, Vallone JC, Warren HB, Butler JP, et al. Roles for early response cytokines during Escherichia coli pneumonia revealed by mice with combined deficiencies of all signaling receptors for TNF and IL-1. Am J Physiol Lung Cell Mol Physiol 2004;286:L Greene C, Lowe G, Taggart C, Gallagher P, McElvaney N, O Neill S. Tumor necrosis factor- -converting enzyme: its role in community-acquired pneumonia. J Infect Dis 2002;186: Kolsuz M, Erginel S, Alatas O, Alatas F, Metintas M, Ucgun I, et al. Acute phase reactants and cytokine levels in unilateral community-acquired pneumonia. Respiration 2003;70: Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action [revew]. Arthritis Rheum 2004;50: Urushibara M, Takayanagi H, Koga T, Kim S, Isobe M, Morishita Y, et al. The antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering with receptor activator of NF- B ligand stimulated induction of nuclear factor of activated T cells c1. Arthritis Rheum 2004;50: Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A ) blocks TNF-dependent nuclear factor- B activation and gene expression. J Immunol 1999;162: Smedegard G, Bjork J. Sulphasalazine: mechanism of action in rheumatoid arthritis. Br J Rheumatol 1995;34 Suppl 2: MacDermott RP. Progress in understanding the mechanisms of action of 5-aminosalicylic acid. Am J Gastroenterol 2000;95: Wolfe F, Michaud K, Gefeller O, Choi HK. Predicting mortality in patients with rheumatoid arthritis. Arthritis Rheum 2003;48: Graudal NA, Madsen HO, Tarp U, Svejgaard A, Jurik AG, Graudal HK, et al. The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 2000;43: