Residency · Residency · Rheumatology

Perioperative Management of DMARDs and Biologics

Introduction

Patients with rheumatic diseases frequently undergo elective surgical procedures, including joint replacement, hand surgery, and spine surgery, requiring careful perioperative medication management. The central challenge is balancing the risk of surgical site infection from continued immunosuppression against the risk of disease flare from withholding therapy. The 2022 ACR/AAHKS guideline for perioperative management provides evidence-based recommendations to guide these decisions. Optimal perioperative planning requires collaboration among the rheumatologist, surgeon, and anesthesiologist. Most recommendations in this field carry conditional strength due to the limited availability of randomized controlled trial data, with recommendations largely based on observational studies and expert consensus.

General Principles

Risk assessment for perioperative medication management should consider the type of surgery and its inherent infection risk, the patient's current disease activity, the specific medication and its pharmacokinetics, and patient comorbidities. The infection risk hierarchy ranges from joint replacement (highest) through spine surgery and soft tissue surgery to minor procedures (lowest). An often-underappreciated consideration is that uncontrolled disease activity itself increases surgical infection risk through elevated inflammatory markers, poor nutritional status, and immobility. The overarching goal is to perform surgery during a period of well-controlled disease activity while minimizing the duration of immunosuppressive risk exposure.

Conventional Synthetic DMARDs

Methotrexate

Methotrexate should be continued through surgery, a strong recommendation from the 2022 ACR guideline. The landmark Grennan trial published in 2001 demonstrated that continuing methotrexate perioperatively did not increase infection risk in rheumatoid arthritis patients undergoing elective orthopedic surgery, while withholding methotrexate significantly increased the risk of disease flare. Multiple subsequent studies have confirmed the safety of continuing methotrexate in the perioperative period. The usual dose should be continued, and while scheduling the dose to avoid the day of surgery is reasonable if convenient, it is not mandatory. The rationale for continuation is supported by methotrexate's short half-life of 6 to 8 hours and the anti-inflammatory benefit that reduces both perioperative flare and the infection risk associated with active disease.

Leflunomide

Leflunomide should be continued through surgery, a conditional recommendation from the 2022 ACR guideline. Despite its long half-life of 14 to 18 days, observational data suggest that continuation is safe in the perioperative setting. Cholestyramine washout (8 g three times daily for 11 days), which was previously recommended by some authorities, is no longer routinely recommended per the 2022 ACR guideline. Washout should be considered only in very high-risk settings, such as revision arthroplasty or patients with a history of prosthetic joint infection.

Hydroxychloroquine

Hydroxychloroquine should be continued through surgery, a strong recommendation. It provides minimal immunosuppression and carries no increased infection risk. Given its extremely long half-life, discontinuation provides no benefit and may increase the risk of disease flare, particularly in SLE patients.

Sulfasalazine

Sulfasalazine should be continued through surgery, a conditional recommendation. Its mild immunosuppressive effect and short half-life support safe continuation through the perioperative period, with rapid offset available if needed.

Apremilast

Apremilast should be continued through surgery, a conditional recommendation. As a PDE4 inhibitor, it is not immunosuppressive in the traditional sense and carries no increased infection risk in the surgical setting.

Biologic DMARDs

General Biologic Principles

The general approach to biologic DMARDs is to withhold them before surgery by scheduling the surgical procedure at the end of the dosing cycle, a conditional recommendation applicable to all biologics. Following surgery, biologics should be resumed when the wound is healing well, sutures or staples have been removed, and there are no signs of infection, which is typically approximately 14 days postoperatively. The specific timing for each biologic is determined by its dosing interval.

TNF Inhibitors

For infliximab, the last dose should be administered at week 0 with surgery scheduled at week 6 to 8, representing the end of the every-8-week dosing cycle. For adalimumab, the last dose is given at week 0 with surgery at week 2, the end of the every-2-week cycle. For etanercept, the last dose is given at day 0 with surgery at day 7 to 14, the end of the weekly dosing cycle. For certolizumab, the last dose is given at week 0 with surgery at week 2 to 4, the end of the every-2-to-4-week cycle. For golimumab, the last dose is given at month 0 with surgery at month 1, the end of the monthly cycle. All TNF inhibitors should be resumed approximately 2 weeks postoperatively.

IL-6 Receptor Inhibitors

For intravenous tocilizumab, surgery should be scheduled at the end of the every-4-week dosing cycle, at week 4. For subcutaneous tocilizumab, surgery should be at the end of the weekly cycle, at week 1 to 2. For sarilumab, surgery should be at the end of the every-2-week cycle, at week 2. A critically important consideration specific to IL-6 receptor inhibitors is that tocilizumab suppresses CRP production. This means that postoperative infection may not manifest with the expected CRP elevation, making clinical assessment rather than laboratory markers the primary tool for detecting surgical site infection in these patients.

T Cell Co-stimulation Blocker

For intravenous abatacept, surgery should be scheduled at the end of the every-4-week cycle, at week 4 to 5. For subcutaneous abatacept, surgery should be at the end of the weekly cycle, at week 1 to 2.

B Cell Depleting Agent

Rituximab presents the most complex timing challenge among biologic agents. Surgery should be scheduled at month 5 to 6 of the every-6-month dosing cycle, when B cell reconstitution begins. The immunosuppressive effect of rituximab is prolonged, as B cell depletion persists for months after administration. Immunoglobulin levels should be checked preoperatively, as hypogammaglobulinemia increases infection risk independently of other factors.

IL-17 Inhibitors

For secukinumab, surgery should be scheduled at the end of the every-4-week cycle, at week 4. For ixekizumab, surgery should similarly be scheduled at the end of the every-4-week cycle.

IL-12/23 and IL-23 Inhibitors

For ustekinumab, surgery should be scheduled at the end of the every-12-week cycle, at week 12. For guselkumab, surgery should be at the end of the every-8-week cycle, at week 8. For risankizumab, surgery should be at the end of the every-12-week cycle, at week 12. The longer dosing intervals of these agents mean that longer pre-surgical withholding periods may be necessary.

IL-1 Inhibitors

Anakinra has a uniquely short half-life of 4 to 6 hours and should simply be withheld the day before surgery, with resumption when the wound is healing well. For canakinumab, surgery should be scheduled at the end of the every-8-week cycle, at week 8.

<image>A comprehensive perioperative medication management timeline for rheumatic disease medications. Show a horizontal surgery timeline with "Surgery Day" at center. For each drug class, show when to take the last dose before surgery and when to resume after surgery: Methotrexate: Continue through surgery (green bar extending through surgery). Leflunomide: Continue through surgery (green bar). TNF inhibitors: Show individual timelines for each drug (infliximab: last dose 6-8 weeks pre-op; etanercept: 1-2 weeks; adalimumab: 2 weeks; certolizumab: 2-4 weeks). IL-6Ri (tocilizumab IV): last dose 4 weeks pre-op. Rituximab: last dose 5-6 months pre-op. JAK inhibitors: withhold 3-7 days pre-op. All biologics/tsDMARDs: Resume ~14 days post-op when wound healed. Use color coding: green = continue, yellow = time around dosing cycle, red = withhold for specific period. Include a note: "Schedule surgery at end of dosing cycle."</image>

Targeted Synthetic DMARDs (JAK Inhibitors)

Tofacitinib, Baricitinib, Upadacitinib

JAK inhibitors should be withheld 3 days before surgery, a conditional recommendation from the 2022 ACR guideline. Their short half-lives of 3 to 12 hours allow rapid offset of immunosuppressive effects. Resumption should occur when the wound is healing well, approximately 14 days postoperatively. The rationale for withholding is that JAK inhibitors suppress immune responses including wound healing cytokines, creating a theoretical infection risk that outweighs the benefit of continuation through surgery.

Other Immunosuppressive Agents

Mycophenolate Mofetil

Mycophenolate mofetil should be withheld 1 week before surgery, based on expert opinion, as less data are available than for traditional DMARDs. It should be resumed when wound healing is progressing well. Mycophenolate is commonly used in SLE, vasculitis, and myositis.

Azathioprine

The recommendation for azathioprine is to either continue or withhold 1 week before surgery, with variable guidance from different expert panels. Azathioprine generally carries a lower infection risk than biologic agents. Continuation should be considered in patients at high risk for disease flare, particularly those with SLE or vasculitis.

Cyclophosphamide

Cyclophosphamide should be withheld before surgery, a consensus recommendation based on its significant immunosuppressive effects and potential for delayed wound healing. Timing depends on the treatment regimen, whether intravenous pulse or oral daily. Coordination with the treating rheumatologist is essential for determining the appropriate withholding period and resumption plan.

Glucocorticoids

Glucocorticoids should be continued at the current dose, and they must not be abruptly discontinued, a strong recommendation. The traditional practice of administering supraphysiologic "stress dose" steroids perioperatively has been re-evaluated. The 2022 ACR/AAHKS guideline recommends continuing the current glucocorticoid dose without supplemental stress dosing unless hemodynamic instability occurs. Patients on chronic glucocorticoids (more than 5 mg prednisone daily for more than 3 months) have hypothalamic-pituitary-adrenal axis suppression and must continue their baseline dose. Stress-dose hydrocortisone at 50 to 100 mg intravenously should be reserved for hemodynamic instability or signs of adrenal crisis. Chronic glucocorticoid use at doses exceeding 10 mg of prednisone daily is an independent risk factor for surgical site infection; minimizing the dose preoperatively when clinically feasible is advisable.

Special Surgical Considerations

Total Joint Arthroplasty

Total joint arthroplasty carries the highest infection risk among common rheumatologic surgeries, with a prosthetic joint infection rate of approximately 1 to 2 percent. The 2022 ACR/AAHKS guideline strongly recommends withholding biologics per their respective dosing intervals before joint replacement. Standard perioperative antibiotic prophylaxis with cefazolin 2 g intravenously preoperatively is appropriate; no extended antibiotic course is needed for immunosuppressed patients. Rheumatoid arthritis patients require screening for cervical spine instability with flexion-extension lateral cervical spine radiographs before any surgery requiring intubation.

Spine Surgery

Cervical instability in rheumatoid arthritis represents a critical preoperative safety concern. Atlantoaxial subluxation is identified by an anterior atlantodental interval exceeding 3 mm, and a posterior atlantodental interval less than 14 mm is concerning for potential cord compression. Preoperative imaging with flexion-extension lateral cervical spine radiographs, with or without CT or MRI, is mandatory. Fiberoptic intubation should be used when cervical instability is present to avoid hyperextension of the neck.

Hand and Foot Surgery

Tendon reconstruction, synovectomy, and nerve decompression are common procedures in rheumatoid arthritis patients. These carry lower infection risk than total joint arthroplasty but should still be managed per medication guidelines. Timing the procedure during a period of well-controlled disease activity optimizes outcomes.

Perioperative Flare Management

The risk of disease flare when medications are withheld perioperatively is approximately 10 to 15 percent, depending on the underlying disease and specific medication. A rheumatoid arthritis flare may elevate CRP, impair wound healing, and reduce rehabilitation capacity. An SLE flare may trigger cytopenias, serositis, or nephritis. When a flare occurs postoperatively, immunosuppression should be restarted once the surgical team confirms adequate wound healing, with bridging glucocorticoid therapy as needed. Effective communication between the rheumatologist and surgeon is essential for coordinating the timing of medication withholding and resumption.

Dental Procedures

Minor dental procedures generally do not require medication changes. Major oral surgery, including extractions and implant placement, warrants consideration of withholding biologics per the dosing cycle with appropriate antibiotic prophylaxis per dental guidelines. For patients with prosthetic joints, the 2012 ADA/AAOS guideline change determined that prophylactic antibiotics are not recommended for dental procedures, reversing prior recommendations.

<image>A decision-support flowchart for perioperative medication management in rheumatic disease patients undergoing elective surgery. Start with "Patient with rheumatic disease scheduled for elective surgery." First decision: "Is disease well-controlled?" If no → optimize disease control before surgery; delay if possible. If yes → assess medication class: csDMARDs (MTX, LEF, HCQ, SSZ) → CONTINUE through surgery (all of them). Biologics → schedule surgery at end of dosing cycle; withhold 1 dosing interval before surgery. JAK inhibitors → withhold 3 days before surgery. Glucocorticoids → continue at current dose; no routine stress dosing. For ALL withheld medications: Resume ~14 days post-surgery when wound healed, sutures removed, no infection signs. Include a warning box: "Cervical spine screening (flexion/extension X-rays) mandatory for RA patients before any surgery requiring intubation."</image>

Key Clinical Pearls

• Methotrexate should be CONTINUED through surgery; stopping it increases flare risk without reducing infection risk
• Schedule surgery at the END of the biologic dosing cycle, not immediately after dosing
• Tocilizumab suppresses CRP; post-operative CRP may not rise appropriately with infection; use clinical assessment
• Rituximab requires the longest pre-surgical lead time (5-6 months) due to prolonged B cell depletion
• Routine "stress dose" steroids are NO LONGER recommended; continue the current GC dose
• Cervical spine instability screening is essential in RA patients before any surgery requiring general anesthesia

References

1. Goodman SM, et al. 2022 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients with Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. Arthritis Care Res. 2022;74(9):1399-1408.
2. Grennan DM, et al. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis. 2001;60(3):214-217.
3. George MD, et al. Risk of biologics and glucocorticoids in patients with rheumatoid arthritis undergoing arthroplasty: a cohort study. Ann Intern Med. 2019;170(12):825-836.
4. Scanzello CR, et al. Perioperative management of medications used in the treatment of rheumatoid arthritis. HSS J. 2006;2(2):141-147.
5. Figueroa-Parra G, et al. Perioperative management of disease-modifying antirheumatic drugs and biologicals in rheumatic diseases. Rheumatology. 2023;62(1):45-56.

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