Hold the immunomodulators for surgery? Maybe yes, maybe no

SCOTTSDALE, ARIZ. – When patients on immunosuppressive therapies need surgery, the risks of disease flare and compromised postoperative recovery and rehabilitation must be weighed against the risk of increased infections and impaired wound healing.

"I’m not sure that there is necessarily a right answer, but I think most people would stop biologic [agents] beforehand," Dr. Paul Grant said at a meeting on perioperative medicine sponsored by the University of Miami.

The decision whether to suspend a disease-modifying antirheumatic drug before surgery may depend on the individual drug and on the patient, said Dr. Grant, director of perioperative and consultative medicine at the University of Michigan Health System in Ann Arbor.

For example, it appears to be safe for patients on methotrexate to continue on therapy during elective orthopedic surgery. Evidence for this comes from a randomized clinical trial in which patients with rheumatoid arthritis (RA) were assigned to either continue on methotrexate (MTX) or suspend taking it for 2 weeks before and 2 weeks after surgery. The study also contained a control of patients with RA who were not on MTX (Ann. Rheum. Dis. 2001;60:214-7).

The investigators found that there were no significant differences in early complication rates or in complications up to 1 year of follow-up between patients who suspended or remained on MTX. Patients who stayed on the drug had significantly lower rates of RA flare.

Additionally, two systematic reviews, one looking at eight studies echoes the findings of the aforementioned randomized trial, and the other looking at four studies, in which the reviewer concluded that "continued MTX therapy appears to be safe perioperatively and seems also to be associated with a reduced risk of flares (Clin. Exp. Rheumatol. 2009;27:856-62) (Clin. Rheumatol. 2008;27:1217-20).None of the examined papers addresses the issue of safety in connection with comorbidities, age, or high doses of methotrexate."

"The bottom line here is that methotrexate should be continued for most surgeries. I think it might be reasonable to hold it in certain situations, for example if the patient has pretty bad kidney or liver disease, or if it’s surgery to treat a major infection," Dr. Grant said.

TNF-alpha antagonists

In contrast, the data on tumor necrosis factor–alpha (TNF-alpha) antagonists are fuzzier, with limited and conflicting information on perioperative use of these agents (etanercept, infliximab, adalimumab, certolizumab, golimumab).

"The major concern with these drugs is infection," Dr. Grant said. He pointed to a meta-analysis published in JAMA in 2006, which showed that taking the drugs doubled the risk of serious infections in general. The study did not specifically look at perioperative use of TNF-alpha antagonists (JAMA 2006;295:2275-85).

A retrospective cohort studyof 127 patients with RA who were undergoing various orthopedic procedures found that there were no differences in surgical site infections but more cases of wound dehiscence in patients who continued on the drugs, compared with those who interrupted their use perioperatively (Clin. Exp. Rheumatol. 2007;25:430-6).

A second, prospective study in 31 patients with RA undergoing foot/ankle surgery found that there were no significant differences in infection or healing between patients who interrupted therapy and those who did not (Foot Ankle Clin. 2007;12:509-24).

Other studies and systematic reviews in patients with RA or Crohn’s disease generally found no significant differences in serious infection rates, but they did detect a higher incidence of skin and soft-tissue infections among patients on anti-TNF-alpha agents vs. other disease-modifying antirheumatic drugs.

The risk of infections tends to be highest at the start of therapy with a TNF-alpha antagonist and stopping therapy is more likely to result in RA flares among patients with established disease, compared with those in the early stages of RA. Therefore, TNF blocker therapy should be restarted as soon as possible after surgery to prevent flare, Dr. Grant said.

The American College of Rheumatology and British Society of Rheumatology recommend holding TNF-alpha antagonists for one dosing cycle before major surgery. For etanercept (Enbrel), that translates to a 1-week before surgery hold, for infliximab (Remicade) 6-8 weeks, and for adalimumab (Humira) 2 weeks. These agents should also be held for 10-14 days after surgery or until wound healing is satisfactory.

"It’s probably safe to continue these medications for minor surgeries," Dr. Grant said.

Other agents

The anti-CD20 agent rituximab (Rituxan) – currently used to treat RA, vasculitis, hematologic malignancies, and other conditions – has a lower risk for bacterial infections than does TNF-alpha antagonists and has been shown to be safe in patients with a history of recurrent bacterial infections.

"Hydroxychloroquine (or Plaquenil) is felt to be safe during the preoperative period. It is recommended to continue this medication without stopping," Dr. Grant said.