SAN FRANCISCO—With little clinical evidence to guide them, rheumatologists often struggle to select appropriate treatments for their patients with special issues, noted moderator Peter J. Embi, MD, MS, assistant professor of medicine at the University of Cincinnati, as he introduced presenters in the 2008 ACR/ARHP Annual Scientific Meeting session, “Practical Pharmacotherapy: Special Problems in Special Patient Populations.” Accordingly, he and co-moderator Michael H. Weisman, MD, director of the Division of Rheumatology at Cedars-Sinai Medical Center in Los Angeles, chose two knowledgeable presenters: Stephen A. Paget, MD, physician-in-chief and chairman of the Division of Rheumatology at the Hospital for Special Surgery (HSS) in New York; and Carl A. Laskin, MD, Rheumatic Disease Unit, University of Toronto, and director, LifeQuest Centre for Reproductive Medicine. Both offered guidance from their own experience.
Perioperative Care: A Balancing Act
In patients with arthritis undergoing joint replacements, physicians must balance the medications taken to control disease processes with the need to ensure optimal wound healing, Dr. Paget emphasized. Preventing flareups may help to ensure successful postsurgical rehabilitation. With nearly 1 million combined total knee and total hip replacements performed in the United States each year, these benefit–risk challenges are apt to increase.
At the HSS, rheumatologists are members of a multidisciplinary team. Decisions about continuing or withdrawing drug therapy are considered in the context of such questions as: Will the medications affect healing of soft tissues and bone? Will they increase the risk of infection? Will the medication improve overall short- and long-term outcome of the surgery—and does this effect differ with different types of surgery?
Dr. Paget combined a literature review with the HSS experience regarding use of antirheumatic therapies—nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs)—in the perioperative setting and included a discussion of bisphosphonates and osteoporosis medications. He acknowledged that some of his advice may not be within the comfort zone of some rheumatologists. For instance, he said, “At the HSS, we do not avoid or discontinue NSAIDs of any kind before surgery—except for spine surgery, where they carry a risk of non-union.” Perioperative aspirin is also usually continued for primary coronary prevention as well as pain management. Results with this approach have been uniformly positive, he said, with no increased incidence of bleeding problems.
Dr. Paget also presented practical guidance regarding perioperative steroid coverage for patients on chronic steroid therapies ranging from 5 mg or less per day to 5 to 7.5 mg per day. As corticosteroids may predispose the patient to wound healing problems, this risk must be carefully balanced with the need for stress doses, he said. Wound healing issues also surface in patients taking methotrexate. Most prospective and retrospective studies suggest that the drug can be continued during the perioperative period without impairing wound healing or increasing infection risk. However, patients with diabetes or a history of infection demand a different approach—for example, stopping the drug two weeks prior to surgery and resuming two weeks afterwards, providing there is good wound healing.
Perioperative strategies for other DMARDs, such as sulfasalazine, azathioprine, or mycophenolate mofetil (MMF), are usually keyed to the drugs’ half lives. For example, sulfasalazine is held one day prior to surgery and resumed three days afterward. Caution also dictates that biologics be held at least one dose cycle prior to surgery (one week for etanercept, two weeks for adalimumab, and six to eight weeks for infliximab), he noted, citing recommendations from the ACR and other major rheumatologic societies.
Dr. Paget concluded with a discussion of bisphosphonate use in the orthopedic surgery setting at HSS, where the drugs are stopped preoperatively before back surgery and sometimes held when treating new fractures. He also cited a study that showed that an annual infusion of zoledronic acid within 90 days of repair of a low-trauma hip fracture was associated with improved survival and a reduction in new fractures.1
Summing up, Dr. Paget proposed that rheumatologists should be the principal caregivers for their patients in the perioperative period, and that musculoskeletal perioperative medicine may be emerging as a unique subsubspecialty in the field of rheumatology.
Exercising Caution
Regarding medications for patients who are pregnant and breastfeeding—or for those who want to conceive—rheumatologists should peruse available data, make phone calls to relevant resources such as teratogen registries, and come to a decision before counseling their patients, advised Dr. Laskin. He noted that he enjoys “the good fortune” of being located next door to Toronto’s Hospital for Sick Children, a renowned teratogen and children’s research center that also sponsors the Motherisk Program (www.motherisk.org).
“When you finally do make that decision, make sure you counsel your patient appropriately,” he emphasized. “And please, do NOT tell your patient, ‘Well, it could be this, or it could be that; the choice is yours.’ Patients are not looking for that from you. You’re the expert; if you cannot come off the fence—and I know it’s hard—find somebody who can.”
Dr. Laskin urged his audience to view the Food and Drug Administration’s (FDA’s) Pregnancy Classification scheme as a series of traffic lights. “It’s not outstanding,” he says of the scheme, “but it’s the best we have.” In this model, Category A is a bright green light (okay to use in pregnant patients); Categories B and C are yellow lights (proceed with caution); Category D is a “stale” yellow light; and Category X is a red light (contraindicated and should not be used).
Decisions about Category X drugs are not controversial. For instance, methotrexate is an abortafacient and should be avoided for at least three cycles before attempting pregnancy. Dr. Laskin imparted some sobering advice about patients who become pregnant while still on the drug: “This becomes a difficult scenario about how best to advise these women. If it’s less than three months since they have stopped the drug, you have to put on the table the question of termination of the pregnancy.” Leflunomide falls under the same recommendations, he says, and mothers should not nurse while on either drug. Because there are minimal data on MMF, and the critical time for fetal exposure is between four and nine weeks gestation, Dr. Laskin recommends also discontinuing this drug at least six weeks before conception.
Due to risks of cleft palate and digit and eye abnormalities, cyclophosphamide (Category D) should be stopped two to three months prior to conception. Azathioprine is also a Category D drug, but Dr. Laskin’s personal belief is that the drug has a “great safety track record” during pregnancy. Breastfeeding while on the drug, however, is not recommended by the American Academy of Pediatrics (AAP).
The tumor necrosis factor (TNF)–alpha blockers (Category B) currently present a real conundrum for physicians, admitted Dr. Laskin. Until a recent case report of an association between TNF-alpha blockers and VATER syndrome abnormalities in an infant, physicians were still prescribing these medications with some confidence.2 His current advice: withdraw the drug two to three months before conception. In mothers with rheumatoid arthritis who are at high risk for postpartum flare, it’s advisable to reinstitute the drug following delivery. In these women, Dr. Laskin feels that breastfeeding is allowable, even though the AAP has not given TNF-alpha blockers its blessing. His rationale is that the drug’s protein molecules are likely to be digested in the neonate’s stomach.
Dr. Laskin believes that the cleft risk associated with corticosteroids (most are Category C) may be most serious in women exposed during the first trimester—and that the validated risk (3.4%) may not be that much higher than in the general population. “However,” he said, “although this is not a life-threatening defect, put yourself in the position [of the mother], where your baby is going to have one, two, or more surgical procedures to correct the clefting. This is a tough road, and it’s important that everyone be counseled appropriately.” In a study by Dr. Laskin and his colleagues, prednisone (the only Category B corticosteroid) was associated with premature birth, although all the infants were healthy.3 His conclusion: “A healthy mother is a healthy baby. If this woman needs the drug, then you need to keep them on it.”
References
- Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med. 2007;357:nihpa40967.
- Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: A causal relationship. J Rheumatol. 2006;33:1014-1017.
- Laskin CA, Bombardier C, Hannah ME, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med. 1997;357:148-153.
