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performed in patients undergoing THA or TKA. We abstracted data from a systematic review of literature that included systematic reviews and meta-analyses of biologic agents versus placebo (and occasionally versus control treatment including nonbiologic DMARDs) in nonsurgical patients, which revealed that the risk of serious infections was increased with biologic agents, with most odds/ hazards/risk ratios ;1.5 (range 0.61–8.87) and a higher risk of serious adverse events with most odds/hazards/risk ratios ;1.5 (range 0.33–2.54) (41–87). Our systematic review did not provide ample evidence that would support a differential risk of serious infection among available biologic agents (41–87). Because avoiding infection was significantly more important to patients than flares in the postoperative period, the Panel did not support separating biologic agents regarding infection risk in the perioperative period until further studies clarify and establish differences in risk (41–87). The literature review also revealed that the risk of postoperative infection complications after total joint arthroplasty (TJA) was increased in patients with RA nearly 2-fold, and deep infection complications increased by 1.5-fold (2,56); in SLE, overall postoperative complications were increased 1.3-fold, and septicemia by 2-fold (8), although medication use at the time of surgery was not always reported. In addition, a systematic review, meta-analysis, and network meta-analysis revealed that infection risk for biologic agents is strongly associated with high-dose therapy (higher dose than the standard) and may not be associated with low-dose biologic agents (42), so serum half-life may not correspond to the duration of the immunosuppressant effect. The dosing cycle was therefore chosen as more relevant in determining the withholding interval (88–91) and timing the surgery at the end of the dosing interval at the nadir of the drug effect. With regard to patients with SLE, a systematic review of literature that included systematic reviews and metaanalyses of rituximab versus placebo (and occasionally versus control treatment including nonbiologic DMARDs) in nonsurgical patients with RA and SLE revealed the risk of serious infections with rituximab with a range of RRs from 0.66 to 0.73 (41,45), and a risk for all serious adverse events with a range of RRs from 0.85 (95% CI 0.62–1.17) to 0.89 (95% CI 0.7–1.14) (59,92). However, most data were indirect and the Panel considered these medications to be similar to tumor necrosis factor inhibitors used for the treatment of RA, which usually have a risk of infection. Moreover, rituximab is not approved by the US Food and Drug Administration (FDA) for treatment of SLE, and belimumab, although FDA-approved for use in SLE, has not been studied in manifestations of severe SLE (e.g., 1116 Goodman et al lupus nephritis), so the Panel recommended withholding these medications prior to surgery and planning the surgery for the end of the dosing cycle, due to the risk of infection and the paucity of data supporting perioperative benefit in SLE (93–95). Observational studies reveal that patients with severe or active SLE have a higher risk of adverse events after surgery, but there is no approved role for these biologic agents for patients with severe SLE, including perioperative risk mitigation. SLE manifestations of rash and synovitis are the common clinical indications for belimumab (95,96), and are not thought to increase perioperative risk. There is no direct evidence, however, linking perioperative infection risk to the use of these biologic agents, and little is known about the association of surgical risk with biologic agents for patients with SLE. Since the duration of the immunologic effects of these drugs does not correspond to the serum level, the Panel based the recommendation on the dosing interval (88–91). The Patient Panel did not include patients with SLE, and they were reluctant to vote on SLE medication management strategies because they were uncertain about the value SLE patients would place on flares, which might be organ-threatening, compared to infection risk. As an example, using this guideline, patients treated with adalimumab, routinely dosed at 2-week intervals, would plan their surgery in week 3, while patients treated with infliximab, when dosed every 8 weeks, would schedule their surgery in the week after the first withheld dose during week 9. Patients treated with rituximab every 6 months would schedule their surgery, when possible, at the week after the first withheld dose during month 7. Patients with SLE receiving belimumab, which is given every 4 weeks, would schedule their surgery during week 5. 3. RA, SpA including AS and PsA, or JIA Withhold tofacitinib for at least 7 days prior to surgery in patients with RA, SpA including AS and PsA, or JIA undergoing THA or TKA (Table 2). This recommendation was based on indirect evidence from systematic reviews and meta-analyses of tofacitinib versus placebo (and occasionally versus control treatment including nonbiologic DMARDs) in nonsurgical patients showing that the risk of serious infections was increased with tofacitinib, with an incidence rate of 2.91 (95% CI 2.27–3.74) (97) and higher risk of all infections, with an RR of 5.7 (95% CI 1.8–18.1) (48). Although this drug has an extremely short serum half-life, little is known about the
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