OP0014: Infectious Complications in Elective Surgery
OP0081: Characteristics of TB During Anti-TNF Therapy and Infuluence of Pre-Treatment Screening
OP0093: Impact of Screening for Latent TB Prior to Anti-TNF Therapy
OP0094: Serious Infection Rates and Anti-TNF Therapy

OP0014

OP0014 INFECTIOUS COMPLICATIONS IN ELECTIVE SURGERY IN RA PATIENTS IN THE ANTI-TNF ERA: A RETROSPECTIVE STUDY
A. A. Den Broeder, T. Schraven, E. De Jong, D. R. A. M. De Rooij, F. H. J. Van den Hoogen

Similar to a study presented at the American College of Rheumatology 2004 meetings, the authors attempt to answer the question of whether anti-TNF treatment is associated with increased postoperative infections in patients undergoing orthopedic surgery.

In this retrospective study, all RA patients who had elective surgery between January 2001 and September 2004 were included. When multiple operations occurred in one individual, each was considered as an independent event if the two operations were > 3 months apart and the latter operation was not a complication of the former.

Patients were sorted into 1 of 3 groups: 1) did not use anti-TNF, 2) used anti-TNF but stopped preoperatively, and 3) used anti-TNF but did not stop preoperatively. If the discontinuation of the TNF inhibitor before the operation was four half-life times of the drug (infliximab 36 days, etanercept 12 days and adalimumab 64 days), the patient was placed in group 2 and not group 3. Infections of < 30 days and between 30 days and 1 year were classified. Risk factors for postoperative infection were determined by logistic regression.

Results: The 474 patients had a total of 696 operations. The overall infection rate was 4% (28/696) with 20 of these requiring re-operation and a mean of 2 additional days in the hospital. When individual groups were evaluated, the infections broke down as follows:

Group 1: 3.5% (20/575)
Group 2: 8.3% (6/72)
Group 3: 4.0% (2/49)

Conclusion: Foot surgery, diabetes, and prednisone use are associated with increased postoperative infection rates, but the use of TNF inhibitors prior to elective surgery is not.

Editorial Comments: The decision on when or if to stop a TNF inhibitor prior to surgery is an important clinical problem. Perioperative infections are a significant cause of morbidity associated with orthopedic procedures. However, stopping drugs may result in a disease flare causing pain and difficulties with rehabilitation. The current study and the prior report from the Hopkins Arthritis Center are hampered by their retrospective design and small numbers. The overall rate of infection is 4% in this study. By contrast, the Hopkins study had an overall rate of 11%, raising questions on how infections were ascertained and defined. The Hopkins study did show an increased risk of infection with TNF inhibitors, this study did not.

The Hopkins study was not able to determine when the TNF inhibitor was stopped and it is possible that many of their patients received a TNF inhibitor very close to the perioperative period. In this study, the non-discontinuation group (group 3) was defined as patients who discontinued less than 4 half lives prior to surgery. In comparison to the Hopkins study, this study may have had more patients discontinuing early. We may not need to discontinue a TNF inhibitor 4 half lives prior to surgery to significantly reduce the risk of perioperative infection. At the present time it remains prudent to discontinue a TNF inhibitor prior to surgery. The length of time needed is not clear from the current studies and awaits further investigation.

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OP0081

OP0081 CHARACTERISTICS OF TUBERCULOSIS DURING ANTI-TNF TREATMENT IN RA PATIENTS IN THE NETHERLANDS AND INFLUENCE OF PRE-TREATMENT SCREENING AND TREATMENT
A. A. Den Broeder, H. Vonkeman, M. C. W. Creemers, E. De Jong, M. A. Van de Laar

An increased incidence of tuberculosis (TB) has been associated with the use of TNF inhibitors. Because of this association, pre-treatment screening has been encouraged. The purpose of this abstract was to assess the benefits of pre-screening and define the characteristics of anti-TNF related TB.

Questionnaires were sent to rheumatologists in the Netherlands to gather data on anti-TNF treatments and methods of pre-screening since 2000. Anti-TNF related TB in RA patients was followed up with a validation of medical records and physician reports.

Results: From the survey, 5338 anti-TNF treatments were reported: 48.2% with infliximab, 29.2% with etanercept, and 22.6% with adalimumab. Pre-treatment screening rates increased from 46% in 2000 to 100% in 2004.

There were 16 cases of TB reported, 6 pulmonary, 4 extrapulmonary, and 5 combined.

• 10/16 TB cases were inadequately screened prior to initiation of treatment: 8 had no PPD testing, 4 had no chest x-ray, and 2 had false negative x-rays.
• 2/16 were treated with isoniazid (INH) prophylaxis but still developed TB
• 3/16 had a new TB contact
• 10 patients recovered; 3 died; 3 unknown or ongoing
• 12 on infliximab, 3 on adalimumab, and 1 on etanercept

Conclusion: Anti-TNF therapy is associated with a higher incidence of TB, both pulmonary and extrapulmonary. However, pre-treatment screening, including a PPD and a chest x-ray, can reduce the risk of developing TB associated with TNF inhibition. Physicians need to be suspicious of TB when patients have complaints and/or an unexplained fever.

Editorial comment: This information adds strong support to the current recommendations for screening for latent TB in all patients prior to the initiation of anti-TNF therapy. It would be interesting to know the total number of patients who were given INH prophylaxis prior to therapy in order to determine the rate of INH failures in this population. It should be noted that patients received only 6 months of INH therapy, less than the current U.S. Center of Disease Control recommendation of 9 months.

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OP0093

OP0093 IMPACT OF SCREENING FOR LATENT TB PRIOR TO INITIATING ANTI-TNF THERAPY IN NORTH AMERICA AND EUROPE
J. L. Perez, H. Kupper, G. T. Spencer-Green

Similar in objective to abstract OP0081 above, Perez et al assess the effectiveness of pre-treatment screening and isoniazid (INH) prophylaxis on the incidence of latent TB in patients with rheumatoid arthritis (RA) treated with the anti-TNF agent, adalimumab.

A review of all data from patients enrolled in RA clinical trials with adalimumab through December 2004 was done. This review would include trials both before and after screening was implemented. Screening included a PPD, a chest x-ray in most patients, and a clinical interview. Patients having a positive PPD or those felt to be at risk for TB were given INH prophylaxis.

Results: Overall, a total of 11,439 patients (14,544 patient-years) with RA were treated with adalimumab. There were 7 patients in 534 pt-yrs (rate of 0.013/pt-yr) who developed TB prior to screening and INH prophylaxis being implemented. Following pre-treatment screening implementation, there were 27 reported cases of TB (rate of 0.0019/pt-yr). This represents an 85% reduction in the TB incidence rate following the implement pre-treatment screening. A higher rate of TB was found in Europe (0.0027) than that in North America (0.0008). In 6 of the 27 cases had a positive PPD and 4 were not given a PPD.

In reviewing all 34 cases of TB, the median time to develop TB after beginning TNF therapy was 167 days (range 14-1636). 56% were confirmed with cultures and 65% were extrapulmonary. Looking at the ReAct study patients, 4 of 712 patients identified by investigators as high risk for TB went on to develop TB in spite of INH prophylaxis.

Conclusion: The introduction of pre-treatment screening prior to initiation of anti-TNF therapy has reduced the incidence of TB by 85%. Therefore, confirming that patients should be screened for latent TB prior to treatment with any anti-TNF therapy. If TB risk is suspected, INH prophylaxis can reduce the rate of reactivation.

Editorial comment: This study as well as the prior abstract (OP0081) documents the value of screening and treatment for latent TB in patients undergoing anti-TNF therapy.

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OP0094

OP0094 SERIOUS INFECTION RATES IN PATIENTS RECEIVING BIOLOGIC THERAPY IN THE UNITED KINGDOM: RESULTS FROM THE BSR BIOLOGICS REGISTER (BSRBR)
W. G. Dixon, K. L. Hyrich, K. Watson, D. P. M. Symmons, A. J. Silman, . And the BSR Biologics Register

One potential serious adverse event with the use of anti-TNF agents is infection. This prospective review from the BSR Biologics Register (BSRBR) of patients in the United Kingdom treated with anti-TNF agents for rheumatic diseases looks at the incidence of serious infections among the various TNF agents.

A total of 6388 patients were identified, of which 2602 were treated with etanercept, 2871 with infliximab, and 915 with adalimumab. An infection was considered serious if the patient required intravenous antibiotics, was admitted to the hospital, died, or the infection was in any way life-threatening. Infections were ascertained by a consultant and follow up with patients was done every 6 months.

Results: The rates and sites of serious infection were similar for all three TNF inhibitors with lower respiratory tract infections being the most common.

Conclusion: In this prospective cohort, the incidence rate of serious infections while on anti-TNF agents is estimated to be between 50 and 65 cases per 1000 person years follow-up. No significant differences in rate and site of infection were found between etanercept, infliximab, and adalimumab.

Editorial comment: It is reassuring that the rates of serious infections reported in this real world study are similar to the rates seen in the long term clinical trials of the TNF inhibitors. The rate of 50-60 events per 1000 patient-years and the sites of infection is also similar to those reported in retrospective studies of RA in patients not treated with TNF inhibitors. While physicians and patients need to continue to be vigilant for signs and symptoms of infections, in the aggregate, the increased risk of serious infections associated with all three TNF inhibitors appears to be modest.

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