A Guide To Perioperative Management Of The Rheumatoid Patient

Reportedly 64 percent of infections that occur in patients with RA occur in the foot and ankle. In order to minimize the risks of infection and other potential complications with podiatric surgery in this patient population, this author reviews the literature and offers insights on whether medications for RA should be withdrawn, continued or modified during the perioperative period.

   Increasingly, the treatment of rheumatoid arthritis includes the utilization of immunosuppressive therapeutic agents. The effectiveness of disease modifying agents in reversing the progression of rheumatoid arthritis (RA) is illustrated by the reduced frequency with which patients with RA undergo surgery for bone and joint deformities.

   Louie and Ward demonstrated that in the state of California, rates of joint surgery for the treatment of RA declined in the 1990s and have continually diminished since that time.1 The authors concluded that the favorable long-term outcomes for the treatment of rheumatoid arthritis with newer agents have resulted in a decreased need for bone and joint surgery in patients afflicted with this disease.

   The patient with RA generally suffers with multiple joint involvement. Perioperative considerations include systemic factors as well as local factors. The patient with RA who is undergoing surgery has an associated increased rate of complications and generally has a less predictable outcome due to the effects of the disease. These patients may also have a significantly prolonged recovery in comparison to those without RA undergoing the same procedure.

   In addition to the usual medical evaluation, which would precede any surgical procedure, and careful evaluation of the entire lower extremity, physicians must assess disease activity as well as the medications utilized to treat the rheumatoid arthritis.

   Many of the complications associated with rheumatoid arthritis may be associated with the medications utilized to treat the disease rather than the disease process itself. For example, Hansen wondered if “surgeons have been much more pessimistic and therefore nihilistic about rheumatoid foot deformities than these conditions warrant.”2 He goes on to note “in fact, compromised healing is due not to the intrinsic disease but to the effects of anti-arthritic drugs such as steroids or methotrexate on healing.”

   Authors have reported a significant incidence of infectious disorders in patients with RA not undergoing surgery.3 The increased rate of infections may be due to soft tissue atrophy in combination with pressure-induced ulceration secondary to rheumatoid foot deformity. Infection may also be a direct result of the increased utilization of immunosuppressive agents for the treatment of RA. Sixty-four percent of infections occurring in a patient with RA occur in the foot and ankle.3

   Nassar and Cracchiolo noted that in general, surgery for patients with RA for the correction of foot deformity was successful.4 They also noted the frequent occurrence of complications due to the disease process itself and medications utilized to treat the disease. Complications are also due to the fact that patients with RA frequently require multiple operations and not infrequently require complicated procedures due to advanced deformity, according to the authors.

An Overview Of Pharmacologic Agents For Rheumatoid Arthritis

When it comes to the preoperative evaluation, patients should consider the medications the patient is taking for RA and their potential to affect wound healing adversely or increase postoperative sepsis. Here is a list of the general classes of medications physicians utilize to treat RA.5
• Aspirin
• Leflunomide (Arava, Sanofi Aventis)
• Intramuscular gold therapy such as sodium aurothiomalate
• B-cell depleting agents such as rituximab (Rituxan, Genentech)
•Azathioprine (Imuran, GlaxoSmithKline)
• T-cell costimulatory blocking agents such as abatacept (Orencia, Bristol-Myers Squibb)
• Sulfasalazine (Azulfidine, Pfizer)
• Tumor necrosis factor inhibitors such as infliximab (Remicade, Centocor Ortho Biotech) and etanercept (Enbrel, Amgen/Pfizer) and adalimumab (Humira, Abbott Laboratories)
• Interleukin inhibitors such as anakinra (Kineret, Biovitrum), atlizumab (Actemra, Roche)
• Hydroxychloroquine (Plaquenil, Sanofi Aventis)
• d-Penicillamine (Cuprimine, Merck) and Depen (Merck)
• Nonselective anti-inflammatory medications
• Selective anti-inflammatory medications

What The Literature Reveals About TNF-a Inhibitors

Given the increased incidence of infection associated with the utilization of disease-modifying medications (secondary to their immunosuppressive effects), researchers initially suggested discontinuing these medications in the perioperative period due to the potential of an increased incidence of perioperative sepsis.

   However, withdrawal of these medications is frequently associated with a flare in disease activity and recent studies have suggested that withdrawal of these agents in the perioperative period may not be required.

   Bibbo and Goldberg conducted a retrospective study of 31 patients.6 They demonstrated that wound healing and infectious complications were equivalent in patients undergoing foot and ankle surgery whether they were taking tumor necrosis factor alpha (TNF-a) inhibitors or receiving other agents for the treatment of RA.

   The comparator group in this study included patients receiving corticosteroids, methotrexate, leflunomide and anti-inflammatory medications.6 The authors concluded that the use of TNF-a inhibitors during the perioperative period is safe for patients with RA who are undergoing elective foot and ankle surgery as this does not increase the risks of non-healing or infection-related complications.

   Of course, we must balance the risk of postoperative sepsis against the exacerbation of disease that occurs during the perioperative period when immunosuppressive therapy ceases. Harle and colleagues suggest individualization in determining whether modifications to RA medications are necessary in the perioperative period.7 The authors note the lack of specific guidelines regarding immunosuppressive therapy in the perioperative setting. Furthermore, there is no evidence indicating that particular surgical procedures, such as foot surgery procedures, have a greater or lesser indication for maintenance or withdrawal of immunosuppressive therapy in the perioperative setting.

   Ruyssen-Witrand and co-workers reviewed 127 surgical procedures performed on patients receiving TNF-a inhibitors.8 The complication rate for orthopedic procedures was 13 percent with an infection rate of 6.5 percent. The authors observed that discontinuation of TNF-a therapy prior to surgery did not decrease the postoperative complication rate. Although the authors concluded that one should consider discontinuation of TNF-a therapy in the perioperative period, there was no indication of any significant reduction of complication risk when researchers discontinued such agents in their study.

   To the contrary, Kawakami and colleagues observed that the utilization of TNF-a inhibitors is associated with an increased risk of surgical site sepsis as well as deep vein thrombophlebitis in patients undergoing major orthopedic surgery.9 Authors noted a 12.5 percent infection rate in patients with RA on TNF-a therapy in comparison to a 2 percent infection rate in patients undergoing alternative treatment for RA.

Pertinent Insights On Methotrexate

Boerbooms and colleagues noted an increased infection rate in patients utilizing methotrexate for severe rheumatic disease.10 However, they did not study the incidence of infection in patients utilizing methotrexate in the perioperative period.

   Bibbo and co-workers reviewed 104 patients with RA who underwent reconstructive foot or ankle surgery.11 The authors assessed the presence of rheumatoid nodules and the effects of anti-inflammatory medication, steroids, methotrexate, hydroxychloroquine and gold. Overall, the study noted a 32 percent complication rate in the performance of 725 surgical procedures. The study authors did not find methotrexate to be associated with any increased risk of complications.

   Jain and co-workers examined the role of methotrexate and corticosteroids in 80 patients undergoing 129 surgical procedures of the hand and wrist for RA-associated disease.12 The authors noted that patients with both RA and diabetes demonstrated a higher risk of infection. The researchers concluded that surgeons may continue both corticosteroids and methotrexate in the perioperative period without risk of increased surgical site sepsis. However, Bridges and colleagues noted an increased incidence of wound dehiscence and infection in those patients utilizing methotrexate for the management of RA.13

   Loza and co-workers performed a systematic review of randomized control trials and high-quality cohort studies examining the utilization of methotrexate in the perioperative period.14 Two randomized controlled trials noted that the continuation of methotrexate was not associated with an increased risk of perioperative complications. Methotrexate also was associated with less disease exacerbation in the perioperative period.

   One retrospective study demonstrated that patients who continued on methotrexate demonstrated fewer cases of wound complication as well as less flare in the disease.14 Loza and colleagues concluded that continuation of methotrexate during the perioperative period is not associated with a significant risk of operative complications including infection.

   Similarly, Grennan and colleagues recommended continuation of methotrexate in the perioperative period.15 The authors were unable to demonstrate any increased risk of infection or other surgical complications when continuing methotrexate use through the perioperative period.

What You Should Know About Using Leflunomide

Leflunomide is a disease modifying anti-rheumatic drug utilized for the treatment of RA. The medication is a selective inhibitor of pyrimidine synthesis. Leflunomide has a long half-life. Accordingly, discontinuation of this medication would require a long duration. Discontinuation of leflunomide in the perioperative period is likely
not required.16

   However, studies have reported conflicting data. Fuerst and co-workers noted the risk of postoperative wound healing complications in patients undergoing leflunomide therapy was significantly higher than in patients undergoing alternative treatments with methotrexate.17 These authors reported a 40.6 percent complication rate in patients undergoing leflunomide therapy in comparison to a 13.6 percent complication rate in patients receiving methotrexate therapy. The study authors recommended interruption of perioperative leflunomide to avoid increased complication rates.

   There have been recommendations for interdiction of leflunomide two weeks prior to surgery.17 Conversely, Tanaka and colleagues reported no increased risk of infectious complications after surgery for patients with RA who continued leflunomide therapy.18

Should Patients Continue Using NSAIDs Perioperatively?

Surgeons frequently utilize aspirin for the management of joint inflammation and pain in patients with RA as it exerts both anti-inflammatory as well as analgesic properties. The utilization of aspirin is also common for prophylaxis in management of cardiovascular disease. Aspirin irreversibly binds to thromboxane A2, thereby inhibiting platelet aggregation. As a result, the continuation of aspirin therapy in the perioperative period may be associated with an increased risk of postoperative hemorrhage, hematoma and associated complications.

   There is no consensus in the literature as to when surgeons should discontinue aspirin prior to surgery for the management of RA associated pathology. However, one should consider discontinuation of aspirin therapy at least five days prior to surgery. There is an increased risk of excessive postoperative hemorrhage in patients who fail to discontinue aspirin therapy prior to surgery. There is a similar risk in patients who are taking concomitant antiplatelet medications as well as those who have coexisting hepatic dysfunction, renal dysfunction or additional hemostatic abnormalities.

   Non-selective anti-inflammatory medications reversibly inhibit thromboxane A2. Therefore, the inhibitory effect of the medications on platelet function is reversed with discontinuation of the medications. Authors have demonstrated that anti-inflammatory medication is associated with a significantly increased risk of excessive surgical bleeding.19,20

   Generally, one should discontinue non-selective anti-inflammatory medications five medication half-lives prior to surgery. For short acting anti-inflammatory medications such as ibuprofen, discontinuation of the medication one or two days prior to surgery is generally sufficient.

   Longer acting anti-inflammatory medications may require discontinuation between five and 15 days before surgery. For example, piroxicam (Feldene, Pfizer) or oxaprozin (Daypro, Pfizer) may require discontinuation up to 10 days prior to surgery whereas intermediate acting medications such as nabumetone (Relafen, GlaxoSmithKline) may require discontinuation five days prior to surgery.

   In general, selective COX-2 inhibitors do not affect platelets and generally do not require discontinuation prior to surgical intervention.21

What About Glucocorticoids?

It is important to maintain glucocorticoid therapy during the entire perioperative period. Discontinuation of glucocorticoids may result in a significant exacerbation of the RA disorder and may also result in significant physiologic consequences.

   Regulation of corticosteroid production occurs through the hypothalamic-pituitary-adrenal axis. The hypothalamus produces a corticotropin-releasing hormone, which regulates anterior pituitary gland secretion of the adrenocorticotropic hormone, which stimulates the production of cortisol by the adrenal cortex. When cortisol is present in adequate levels, negative feedback from the hypothalamus reduces anterior pituitary gland production of adrenocorticotropic hormone. This consequently reduces cortisol production by the adrenal gland.

   When it comes to surgery, cortisol levels are typically elevated during the time of the initial incision, during the surgical procedure itself, during the dispersal of anesthesia, during extubation and immediately following surgery.

   Generally, for podiatric surgical procedures less than one hour in length, particularly those performed with local anesthesia, local anesthesia with sedation, spinal anesthesia or a popliteal blockade, no supplementation is required for those patients receiving 5 mg per day or less of corticosteroids for management of RA. In general, when corticosteroid supplementation is required, this supplementation can occur over a relatively short period of time.

   For patients receiving large doses of corticosteroids or those presumed to have adrenocortical suppression, one may administer hydrocortisone 25 mg or methylprednisone (Medrol) 5 mg intravenously immediately prior to surgery. In those patients receiving large doses of corticosteroids or those presumed to have adrenocortical suppressiom, in whom a major procedure or prolonged general anesthesia is going to be required, one may administer hydrocortisone 50 to 75 mg or methylprednisone 10 to 15 mg intravenously the day of surgery and then rapidly taper the dosage over 48 hours.

Sulfasalazine And Hydroxychloroquine: What You Should Know

Sulfasalazine is a combination of sulfapyridine and aspirin like compounds. The medication may be associated with diminution in complete blood cell count. In general, one should consider withdrawal of the medication three or four days prior to surgery.

   Hydroxychloroquine is a less commonly utilized disease modifying anti-rheumatic medication. It is an anti-malarial medication. There is no indication that Plaquenil requires discontinuation in the perioperative period.

In Conclusion

The effect of disease modifying agents on surgical outcome is difficult to assess. There is conflicting data and a lack of specific guidelines regarding the perioperative utilization of disease modifying agents in ankle surgery as well as orthopedic procedures in general.

   In general, it would appear that in properly selected individuals, continuation of therapy throughout the perioperative period is associated with a decreased risk of disease flare and exacerbation. In properly selected individuals, the use of disease modifying agents is not associated with an increased delay in wound healing or septic complications.

   In those individuals in whom there is a perceived increased risk of infection, such as the patient with rheumatoid arthritis and concurrent immunosuppressive disorders such as diabetes, physicians should consider withdrawal of disease-modifying agents when appropriate. Also consider withdrawing such agents in those patients who have a history of prior foot or ankle sepsis, such as an ulcerated rheumatoid nodule or ulceration secondary to rheumatoid foot or ankle deformity.

   Similarly, when it comes to those patients undergoing major foot or ankle procedures such as total ankle replacement, ankle arthrodesis or triple arthrodesis, surgeons should consider withdrawal of immunosuppressive therapy when appropriate. However, given the existing paucity of recommended guidelines, the decision to withdraw disease-modifying agents during the perioperative period must occur on a case-by-case basis.

   One should likely discontinue aspirin and anti-inflammatory medications prior to surgery in order to reduce the risks of excessive hemorrhage and hematoma. Similarly, physicians should consider patients who are on glucocorticoid medications to be at risk for adrenocortical suppression.

   Dr. Jacobs is a Fellow of the American College of Foot and Ankle Surgeons, and the American Professional Wound Care Association. He is in private practice in St. Louis.

   For further reading, see “Treating Severe Deformity In Young Patients With Rheumatoid Arthritis” in the September 2003 issue of Podiatry Today, “What You Should Know About New Antirheumatic Medications” in the April 2005 issue or “Lower Extremity RA: Can Orthoses Have An Impact?” in the April 2006 issue.

References:

1. Louie GH, Ward MM. Changes in the rate of joint surgery among patients with rheumatoid arthritis in California 1983-2007. Ann Rheumatic Dis 2010; 69(5):868-871. 2. Hansen S. In (McGlamry ED, ed.): Textbook of Foot and Ankle Surgery. 3. Carl HD, Gelse K, Swoboda B. Bacterial infections of the rheumatoid foot. Z Rheumatol 2010; Epub ahead of print. 4. Nassar J, Cracchiolo III A. Complications in surgery of the foot and ankle in patients with rheumatoid arthritis. Clin Orthop Rel Res 2001; 391:140-152. 5. Matsumoto AK, Bathon J, Bongham III C. Rheumatoid arthritis treatment. http//www.hopkins-arthritis.org 6. Bibbo C, Goldberg JW. Infectious and healing complications after he elected orthopedic foot and ankle surgery during tumor necrosis factor-alpha inhibition therapy. Foot Ankle Int 2004; 25(5):331-335. 7. Harle P, Straub RH, Fleck M. Perioperative management of immunosuppression in rheumatic diseases-what to do. Rheum Int 2010; 30(8):999-1004. 8. Ruyssen-Witrand A, Gossec L, Salliot C, Luc M, Duclos M, Guignard S, Dougados M. Complication rates of 127 surgical procedures performed in rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exper Rheum 2007; 25(3):430-36. 9. Kawakami K, Ikari K, Kawamura K, et al. Complications and features after joint surgery in rheumatoid arthritis patient treated with tumor necrosis factor alpha blocker; perioperative interruption of tumor necrosis factor alpha blocker decreases complications? Rheumatology 2009; 49(2):341-7. 10. Boerbooms AM, Kerstens PJ, van Loenhout JW, Mulder J, Van de Putte LBA. Infections during low dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum 1995; 24(6):411-421. 11. Bibbo C, Anderson RB, Davis WH, Norton J. Rheumatoid nodules and postoperative complications. Foot Ankle Int 2003; 24(1):440-447. 12. Jain A, Witbreuk M, Ball C, Nanchal J. Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery. J Hand Surg 2002; 27(3):449-455. 13. Bridges Jr SL, Lopez-Mendez A, Han KH, Tracy IC, Alarcon GS. Should methotrexate be discontinued before he elected orthopedic surgery in patients with rheumatoid arthritis? J Rheum 1991; 18(7):984-988. 14. Loza E, Martinez-Lopez JA, Carmona L. A systematic review on the optimal management of the use of methotrexate in rheumatoid arthritis patients in the perioperative period to minimize perioperative morbidity and maintain disease control. Clin Exper Rheum 2009; 27(5):856-862. 15. Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery. Ann Rheum Dis 2001; 60(3): 214-270. 16. Pieringer H, Stuby U, Biesenbach G. Patients with rheumatoid arthritis undergoing surgery: How should we deal with antirheumatic treatment? Semin Arth Rheum 2007; 36(5):278-286. 17. Fuerst M, Mohl H, Baumgartel K, Ruther W. Leflunomide increases the risk of early healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery. Rheum Int 2006; 26(12):1138-42. 18. Tanaka N, Sakahashi H, Sato E, Hirose K, Ishima T, Ishii S. Examination of the risk of continuous leflunomide treatment on the incidence of infectious complications after joint arthroplasty in patients with rheumatoid arthritis. J Clin Rheum 2003; 9(2):115-118. 19. Robinson CM, Christie J, Malcolm-Smith M. Nonsteroidal antiinflammatory drugs, perioperative blood loss, and transfusion requirements in elective hip arthroplasty. J Arthroplasty 1993; 8(6):607-610. 20. Connelly CS, Panush RS. Should nonsteroidal anti-inflammatory drugs be stopped before elective surgery? Arch Int Med 1991; 151(10):1963-66. 21. Kelley JT, Conn DL. Perioperative management of the rheumatic disease patient. Bull Rheum Dis 2002; 51(6).