What recent updates are available to guide decisions on use of immunosuppressant antirheumatic drugs perioperatively for orthopedic procedures?
Background:
Rheumatic disease (RD) is a blanket term used to describe a spectrum of autoimmune inflammatory disorders of unknown etiology that affect multiple systems in the body, most especially the soft tissues and articular cartilage of the musculoskeletal system.1 Systemic lupus erythematosus (SLE), inflammatory arthritis, spondyloarthritis (SpA), and polymyositis (PM) are just some of the numerous diseases that are categorized under the umbrella term of RD.2 Collectively, these disorders affect a substantial proportion of the population in the United States (US); the estimated prevalence of rheumatoid arthritis and axial SpA (the most common form of SpA) in the US are 0.5% and 0.9 to1.4%, respectively.3 Psoriasis affects 2 to 4% of the US population and approximately one-third of these patients will go on to develop PsA. Additionally, it has been estimated that approximately 200,000 adults in the US are affected by SLE.4
Despite significant advances in the management of RDs in recent times, including availability of disease-modifying antirheumatic drugs (DMARDs) and targeted agents to treat these conditions, joint damage will ultimately progress and many patients with these diseases will eventually require orthopedic surgery to relieve pain and restore joint function.5 Patients with rheumatoid arthritis are approximately twice as likely to require knee and hip arthroplasties than patients without rheumatoid arthritis, and similar rates have been documented for patients with other RDs such as SLE and SpA. Patients with RDs undergoing surgery are generally at a higher risk for procedural complications (eg, venous thromboembolism, acute kidney injury, cardiac complications, and infection) compared to the general population due to various factors including disease activity and severity; infection is of particular concern in patients receiving antirheumatic drugs, including nonbiologic DMARDs and targeted agents including Janus kinase (JAK) inhibitors and biologic DMARDs since these drugs further suppress the body’s ability to fight off infection.5,6 Other factors, such as patient age, presence of comorbid conditions such as diabetes, and hospital and surgeon experience with performing such surgeries are additive and can further contribute to an individual patient’s risk of postoperative infection.7
Infections associated with joint surgery, specifically prosthetic joint infections (PJI), occur in about 1.5% of patients with RDs within the first 1 to 2 years after surgery.7 These early infections typically occur as the result of delayed healing of the surgical site or infections introduced at the time of the procedure. While immunosuppressant medications are known to contribute to the risk of postoperative infection in patients with RDs, very few studies (often consisting of low quality evidence) have been conducted to guide clinicians as to whether these medications should be held or continued through surgery in patients undergoing orthopedic procedures.5,7 Therefore, the purpose of this FAQ is to review recent recommendations that have been published to guide the use of antirheumatic medications in patients with RDs undergoing total hip and knee arthroplasties.
Guideline Recommendations
The steady approval of new antirheumatic agents over time, coupled with the growing concern for increased risk of infection in orthopedic surgical patients taking these drugs, led the American College of Rheumatology (ACR) and the American Association of Hip and Knee Surgeons (AAHKS) to release comprehensive guidelines in 2017 for perioperative management of antirheumatic medications in patients undergoing orthopedic surgeries.8 Specifically, these recommendations were made for adult patients with rheumatoid arthritis, SpA (including ankylosing spondylitis and PsA), juvenile idiopathic arthritis, or SLE undergoing total knee and hip arthroplasties. In late 2022, these guidelines were updated to incorporate newly approved antirheumatic agents and more recent published literature.9 Table 1 below describes the initial 2017 ACR/AAHKS recommendations and highlights recent updates made in 2022 to incorporate newly approved medications and recent updates to the literature.
| Table 1. ACR/AAHKS guidelines for perioperative management of antirheumatic drugs in patients undergoing total hip and knee arthroplasties.8,9 | |||
|---|---|---|---|
| Patient population | Drug or drug class | Original recommendation (2017) | 2022 updates |
| JIA RA SpA (includes AS and PsA) SLE | Nonbiologic DMARDs | Continue treatment with methotrexate, leflunomide, hydroxychloroquine, and/or sulfasalazine Level of evidence: Low to moderate | Recommendation unchanged but now includes apremilast |
| JIA RA SpA (includes AS and PsA) SLE* | Biologic drugs | Withhold all current biologic agents prior to surgery and plan the surgery at the end of the specific medication’s dosing cycle Level of evidence: Low | *Patients with SLE have been excluded and are now discussed in separate recommendations (see below) Rituximab is specifically listed among biologic agents that should be withheld |
| JIA RA SpA (includes AS and PsA) | Tofacitinib | Withhold for at least 7 days prior to surgery Level of evidence: Low | Recommendation updated to include baricitinib and upadacitinib and shorten the time frame for withholding therapy to 3 daysa |
| Severe SLEb | Azathioprine Cyclosporine Methotrexate Mycophenolate mofetil Tacrolimus | Continue the current dose of these medications throughout the surgical period Level of evidence: Low | Recommendation updated to include mycophenolic acid (Myfortic), mizoribine, anifrolumab, and voclosporin |
| Belimumab Rituximab | New recommendation: Continue belimumab Plan surgery in the last month of the dosing cycle of rituximab |
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| Non-severe SLEc | Azathioprine Cyclosporine Tacrolimus | Withhold the current dose for 1 week prior to surgery Level of evidence: Low | Recommendation updated to include mycophenolate mofetil, mycophenolic acid, and mizoribine |
| Belimumab Rituximab | New recommendation: Withhold the usual dose of belimumab and rituximab prior to surgery | ||
| JIA RA SpA (includes AS and PsA) SLE | Antirheumatic therapy | Restart biologic therapy in patients for whom biologic therapy was withheld prior to undergoing THA or TKA once the wound shows evidence of healing (typically ~14 days), all sutures/staples are out, there is no significant swelling, erythema, or drainage, and there is no clinical evidence of nonsurgical site infections Level of evidence: Low | Recommendation generally unchanged; JIA removed from the list of patient populations |
| RA SpA (includes AS and PsA) SLE | Corticosteroids | Continue the current daily dose of corticosteroids rather than administering perioperative supra-physiologic doses (so-called “stress dosing") Level of evidence: Low | Recommendation unchanged |
| Abbreviations: AS=ankylosing spondylitis; CNS=central nervous system; DMARDs=disease-modifying antirheumatic drugs; JAK=Janus kinase; JIA=juvenile idiopathic arthritis; PsA=psoriatic arthritis; RA=rheumatoid arthritis; SLE=systemic lupus erythematosus; SpA=spondyloarthritis. THA=total hip arthroplasty; TKA=total knee arthroplasty. aDuration shortened based on new evidence suggesting a rapid reversal of immunosuppressive effects following discontinuation of tofacitinib; recommendations for other JAK inhibitors are based on the fact that they have similar half-lives to tofacitinib. This recommendation does not pertain to potential cardiac or venous thromboembolic risks associated with JAK inhibitors. bSevere SLE defined by severe organ manifestations: lupus nephritis, lupus of the CNS, severe hemolytic anemia, platelets <50,000/ml, vasculitis, including pulmonary hemorrhage, myocarditis, lupus pneumonitis, severe myositis, lupus enteritis, lupus pancreatitis, cholecystitis, lupus hepatitis, protein-losing enteropathy, malabsorption, orbital inflammation/myositis, severe keratitis, posterior severe uveitis/retinal vasculitis, severe scleritis, optic neuritis, anterior ischemic optic neuropathy. cNon-severe SLE includes patients not receiving treatment for the manifestations listed in footnote a. |
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All of the recommendations provided within Table 1 are conditional (the desirable effects of the recommendations probably outweigh the undesirable effects in most patients) due to the limitations of the available published data.8,9 As such, there may be certain clinical scenarios where an alternate approach is preferable. For example, the guidelines state that patients with a history of severe or recurrent infections or prior PJI may elect to withhold nonbiologic DMARDs prior to surgery and may elect to wait a longer period of time than is recommended in the guidelines to restart therapy (if held).9 All of the recommendations (with the exception of one) were also based on low quality evidence; the recommendation to continue nonbiologic DMARDs through surgery was based on low to moderate quality evidence.8,9 Most of the existing evidence, as well as new evidence supporting the updated 2022 recommendations was indirect and came from cohort studies (including pharmacoepidemiologic database studies) that did not include a comparator group. As such, clinical judgment should be applied to each specific patient to determine the best course of action for perioperative medication management based on patient-specific factors (ie, disease activity and severity, infection risk, severity of joint-related symptoms).
In addition to the overarching recommendations provided in Table 1 above, the 2022 guideline also provides recommendations for timing of surgery based on the last dose that a specific medication was administered (see table here).9 This table provides recommendations by drug name for all patients and separately provides recommendations for use of certain agents in patients with both non-severe and severe SLE.
Conclusion:
Patients with RDs are more likely to undergo orthopedic procedures including hip and knee arthroplasties; these patients are at an increased risk for postoperative infection both due to their disease itself and because of the immunosuppressant agents used to treat these inflammatory conditions. Recently updated guidelines from the ACR/AAHKS provide specific recommendations for continuing or withholding antirheumatic medications, including JAK inhibitors, nonbiologic DMARDs, and biologic agents, in patients with various rheumatic conditions who are undergoing total hip or knee arthroplasties. In general, nonbiologic DMARDs (including apremilast and the conventional synthetic DMARDS [hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine]) may be continued throughout the perioperative period but JAK inhibitors and biologic DMARDs should be withheld for some time prior to the procedure. While these recommendations are helpful when determining medication management for orthopedic surgical patients with RDs, they are based on low quality evidence and may not apply to every patient. Randomized controlled trials are necessary to further support these recommendations. Healthcare providers should continue to stay up to date with the latest available evidence pertaining to the use of existing and emerging antirheumatic medications in the orthopedic surgical population as it becomes available.
References:
- Bernstein EJ, Mandl LA. Changing incidence of orthopedic surgery in rheumatic disease: contributing factors. Curr Rheumatol Rep. 2013;15(10):365. doi:10.1007/s11926-013-0365-8
- Radu AF, Bungau SG. Management of rheumatoid arthritis: an overview. Cells. 2021;10(11):2857. doi:10.3390/cells10112857
- Mease PJ, Liu M, Rebello S, et al. Comparative disease burden in patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis: data from two Corrona registries. Rheumatol Ther. 2019;6(4):529-542. doi:10.1007/s40744-019-00172-9
- Centers for Disease Control and Prevention. Updated February 17, 2022. Accessed December 23, 2022. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/lupus.htm
- Goodman SM, Bass AR. Perioperative medical management for patients with RA, SPA, and SLE undergoing total hip and total knee replacement: a narrative review. BMC Rheumatol. 2018;2:2. doi:10.1186/s41927-018-0008-9
- Goodman S M, George M D. ‘Should we stop or continue conventional synthetic (including glucocorticoids) and targeted DMARDs before surgery in patients with inflammatory rheumatic diseases?’. RMD Open. 2020;6(2):e001214. doi:10.1136/rmdopen-2020-001214
- Goodman SM, Springer B, Guyatt G, et al. 2017 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. J Arthroplasty. 2017;32(9):2628-2638. doi:10.1016/j.arth.2017.05.001
- Goodman SM, Springer BD, Chen AF, 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 (Hoboken). 2022;74(9):1399-1408. doi:10.1002/acr.24893
Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
Adwoa Oduro
PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy
January 2023
The information presented is current as of November 16, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.