Perioperative Management of Immunosuppressive Medications for Rheumatoid Arthritis

Published:February 17, 2022DOI:https://doi.org/10.1016/j.jhsa.2021.09.038
      Operations in patients with rheumatoid arthritis are complicated by the fact that most drugs used in medical management have immunosuppressive mechanisms of action, including corticosteroids and conventional synthetic and biologic disease-modifying antirheumatic drugs. In deciding to continue or discontinue these medications perioperatively, surgeons must weigh the relative risk of infection from immunosuppression against the risk of rheumatoid arthritis symptom flares from reduced medical disease control. The objective of this article is to review the existing evidence regarding perioperative management of immunosuppressive rheumatoid arthritis medications, with a specific focus on relevance to hand and upper-extremity procedures.

      Key words

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      Disclosures for this Article

      Editors

      Dawn M. LaPorte, MD, has no relevant conflicts of interest to disclose.

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      All authors of this journal-based CME activity have no relevant conflicts of interest to disclose. In the printed or PDF version of this article, author affiliations can be found at the bottom of the first page.

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      Dawn M. LaPorte, MD, has no relevant conflicts of interest to disclose. The editorial and education staff involved with this journal-based CME activity has no relevant conflicts of interest to disclose.

      Learning Objectives

      Upon completion of this CME activity, the learner will understand:
      • The mechanism of action of drugs frequently used in the medical management of rheumatoid arthritis (RA).
      • The perioperative considerations and risks of different drugs used in the medical management of RA.
      • Current evidence and recommendations for management of different RA medications in patients undergoing elective hand surgery.
      Deadline: Each examination purchased in 2022 must be completed by January 31, 2023, to be eligible for CME. A certificate will be issued upon completion of the activity. Estimated time to complete each JHS CME activity is up to one hour.
      Copyright © 2022 by the American Society for Surgery of the Hand. All rights reserved.
      Rheumatoid arthritis (RA) is a progressive, inflammatory, autoimmune joint disease that causes synovial inflammation, destruction of articular cartilage, and periarticular bone erosion. RA affects between 0.5% to 1% of adults worldwide.
      • Aletaha D.
      • Smolen J.S.
      Diagnosis and management of rheumatoid arthritis: a review.
      In addition to symptomatic control with nonsteroidal anti-inflammatory drugs and systemic corticosteroids, medical management of RA relies on the use of disease-modifying antirheumatic drugs (DMARDs) that slow the rate of joint destruction. Care for the disease was further advanced with the introduction of biologic DMARDs (bDMARDs) that target specific molecules in the involved inflammatory pathways.
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      As a result of these improvements in medical management, rates of hand surgery for RA have declined in recent decades.
      • Gogna R.
      • Cheung G.
      • Arundell M.
      • Deighton C.
      • Lindau T.R.
      Rheumatoid hand surgery: is there a decline? A 22-year population-based study.
      However, hand and upper-extremity arthroplasties, synovectomies, tendon reconstructions, and muscle releases are still performed to alleviate the pain and loss of function associated with advanced disease.
      Operations in patients with RA are complicated by the fact that most drugs used in medical management have immunosuppressive mechanisms of action, including corticosteroids, conventional synthetic DMARDs (csDMARDs), and bDMARDs. In deciding to continue or discontinue these medications perioperatively, surgeons must weigh the relative risk of infection from immunosuppression against the risk of RA symptom flares from reduced medical disease control. In 2017, the American College of Rheumatology (ACR) and American Association of Hip and Knee Surgeons (AAHKS) released guidelines for perioperative management of RA medications.
      • Goodman S.M.
      • 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.
      However, these guidelines were designed to pertain only to patients undergoing total knee or total hip arthroplasty. The objective of this article is to review the existing evidence regarding perioperative management of immunosuppressive RA medications, with a specific focus on relevance to hand and upper-extremity procedures.

      Corticosteroids

      Over half of patients with established RA are prescribed systemic corticosteroids.
      • Crane M.M.
      • Juneja M.
      • Allen J.
      • et al.
      Epidemiology and treatment of new-onset and established rheumatoid arthritis in an insured US population.
      Chronic corticosteroid use is known to increase the risk of postoperative infection, and this risk may be dose-dependent.
      • George M.D.
      • Baker J.F.
      • Winthrop K.
      • et al.
      Risk of biologics and glucocorticoids in patients with rheumatoid arthritis undergoing arthroplasty: a cohort study.
      Perioperatively, the infectious risk of corticosteroid continuation must be balanced against the risk of intraoperative hemodynamic stability from hypothalamic-pituitary-adrenal axis suppression if steroids are withheld.
      Evidence suggests that patients on low-dose daily corticosteroids and undergoing minor surgeries may safely continue their baseline regimen throughout the surgical period without any need for stress-dose supplementation. A systematic review of studies assessing the need for stress-dose steroids in noncardiac surgery found overall low-quality evidence and no studies identifying a substantial difference in outcomes when stress-dose steroids were or were not given.
      • Groleau C.
      • Morin S.N.
      • Vautour L.
      • Amar-Zifkin A.
      • Bessissow A.
      Perioperative corticosteroid administration: a systematic review and descriptive analysis.
      Friedman et al
      • Friedman R.J.
      • Schiff C.F.
      • Bromberg J.S.
      Use of supplemental steroids in patients having orthopaedic operations.
      evaluated outcomes in 28 chronically corticosteroid-treated patients undergoing 35 hand surgeries while continuing their usual steroid with no planned stress-dose supplementation. The included patients used a mean dose of 10 mg prednisone daily for a mean of 7 years prior to surgery. No patient required exogenous steroids intraoperatively, and there were no instances of unexplained or unexpected hypotension, hyponatremia, or fever. Urine studies showed that 19/26 (73%) of patients had appropriately increased urinary cortisol following surgery, indicating an adequate adrenal response. Patients without increased urinary cortisol did not exhibit any clinical symptoms of abnormal adrenal function.
      • Friedman R.J.
      • Schiff C.F.
      • Bromberg J.S.
      Use of supplemental steroids in patients having orthopaedic operations.
      Due to the low quality of the current evidence and a dearth of studies stratifying patients by the individual risk of adrenal suppression, previous authors recommended intravenous administration of a stress dose of 50 mg hydrocortisone before incision for patients who do not fall into a low risk category.
      • Liu M.M.
      • Reidy A.B.
      • Saatee S.
      • Collard C.D.
      Perioperative steroid management: approaches based on current evidence.
      ,
      • MacKenzie C.R.
      • Goodman S.M.
      Stress dose steroids: myths and perioperative medicine.
      Risk is determined based on both the intensity of the operation and the patient’s baseline corticosteroid dose. Most hand surgeries are considered minor and are not expected to require supplementation. A stress dose may be needed for intermediate-intensity surgeries, such as total joint arthroplasty. For these higher-intensity surgeries, a baseline corticosteroid dose should be considered. Patients at low risk for adrenal suppression who do not require supplementation are those using corticosteroids for less than 3 weeks preoperatively and taking prednisone at ≤5 mg/day or ≤10 mg every other day or taking an equivalent drug.
      • Liu M.M.
      • Reidy A.B.
      • Saatee S.
      • Collard C.D.
      Perioperative steroid management: approaches based on current evidence.
      High-risk patients expected to require stress doses are those on >20 mg prednisone daily for more than 3 weeks or with clinical signs of Cushing syndrome. Intermediate-risk patients are those whose daily corticosteroid dose falls between these values.
      • Liu M.M.
      • Reidy A.B.
      • Saatee S.
      • Collard C.D.
      Perioperative steroid management: approaches based on current evidence.
      Intermediate-risk patients may undergo cosyntropin testing prior to surgery to evaluate their adrenal response. If supplemental intravenous corticosteroids are given, 25 mg intravenous hydrocortisone should be continued every 8 hours for 24 hours or until the patient is able to tolerate oral administration of the usual baseline medication.
      • Liu M.M.
      • Reidy A.B.
      • Saatee S.
      • Collard C.D.
      Perioperative steroid management: approaches based on current evidence.
      ,
      • MacKenzie C.R.
      • Goodman S.M.
      Stress dose steroids: myths and perioperative medicine.

      Synthetic DMARDs

      Conventional synthetic DMARDs

      The csDMARDs are a class of well-established medications that improve physical function in patients with RA and slow the progression of joint destruction.
      • Aletaha D.
      • Smolen J.S.
      Diagnosis and management of rheumatoid arthritis: a review.
      For many of the csDMARDs, the molecular targets and mechanisms of action that result in their benefit in RA have not yet been fully elucidated, and each drug may have multiple beneficial effects.
      Methotrexate is the most commonly used csDMARD and is considered the cornerstone of RA treatment.
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      ,
      • Crane M.M.
      • Juneja M.
      • Allen J.
      • et al.
      Epidemiology and treatment of new-onset and established rheumatoid arthritis in an insured US population.
      ,
      • Kim S.C.
      • Yelin E.
      • Tonner C.
      • Solomon D.H.
      Changes in use of disease-modifying antirheumatic drugs for rheumatoid arthritis in the United States during 1983–2009.
      It is often used in combination with corticosteroids, other csDMARDs, and bDMARDs, as doing so improves disease control compared to monotherapies.
      • Aletaha D.
      • Smolen J.S.
      Diagnosis and management of rheumatoid arthritis: a review.
      Methotrexate is safe to continue throughout the perioperative period, as it does not increase the infection risk and continuation may reduce postoperative RA flares. Grennan et al
      • Grennan D.M.
      • Gray J.
      • Loudon J.
      • Fear S.
      Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery.
      conducted a prospective randomized controlled trial of methotrexate continuation in patients with RA undergoing a variety of hand surgeries. Patients who continued methotrexate had lower rates of infection, other complications, and postoperative RA disease flares than both patients who discontinued methotrexate 2 weeks prior to surgery and patients with RA who had not received methotrexate.
      • Grennan D.M.
      • Gray J.
      • Loudon J.
      • Fear S.
      Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery.
      Similarly, Jain et al
      • Jain A.
      • Witbreuk M.
      • Ball C.
      • Nanchahal J.
      Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery.
      retrospectively reviewed outcomes of hand and wrist surgeries in which patients continued DMARDs perioperatively, and found no difference in postoperative wound infection rates between methotrexate users and nonusers and no influence of methotrexate dose on infection risks.
      Recommendations regarding perioperative management of leflunomide vary due to conflicting findings regarding postoperative complications. A randomized controlled trial of patients continuing leflunomide perioperatively or discontinuing use for 2 weeks before and 2 weeks after total joint arthroplasty found no difference in postoperative infection rates between the 2 groups (6.1% in those who continued vs 6.3% in those who discontinued).
      • 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.
      However, a prospective cohort study comparing patients continuing leflunomide or methotrexate perioperatively found a significantly higher infection rate in the leflunomide group (40.6% vs 13.1% in the methotrexate group).
      • Fuerst M.
      • Möhl H.
      • Baumgärtel K.
      • Rüther W.
      Leflunomide increases the risk of early healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery.
      Reviewing this evidence and considering the known infection risk with leflunomide use in nonsurgical patients, Goodman
      • Goodman S.M.
      Rheumatoid arthritis: perioperative management of biologics and DMARDs.
      recommended discontinuing leflunomide for 1 week preoperatively. Conversely, the ACR/AAHKS guidelines recommend continuing leflunomide throughout the perioperative period.
      • Goodman S.M.
      • 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.
      Limited evidence exists assessing the perioperative effects of other common csDMARDs, such as azathioprine, sulfasalazine, and hydroxychloroquine, individually. Studies of patients with RA continuing any of these csDMARDs during the perioperative period have not found an association with infection risks.
      • Jain A.
      • Witbreuk M.
      • Ball C.
      • Nanchahal J.
      Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery.
      ,
      • Scherrer C.B.
      • Mannion A.F.
      • Kyburz D.
      • Vogt M.
      • Kramers-De Quervain I.A.
      Infection risk after orthopedic surgery in patients with inflammatory rheumatic diseases treated with immunosuppressive drugs.
      • Barnard A.R.
      • Regan M.
      • Burke F.D.
      • Chung K.C.
      • Wilgis E.F.S.
      Wound healing with medications for rheumatoid arthritis in hand surgery.
      • Klifto K.M.
      • Cho B.H.
      • Lifchez S.D.
      The management of perioperative immunosuppressant medications for rheumatoid arthritis during elective hand surgery.
      One retrospective analysis suggested that sulfasalazine continuation decreases the likelihood of perioperative infection.
      • Den Broeder A.A.
      • Creemers M.C.W.
      • Fransen J.
      • et al.
      Risk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study.
      Thus, previous reviewers and the ACR/AAHKS guidelines recommend continuing these drugs at the current dose.
      • Goodman S.M.
      • 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.
      ,
      • Goodman S.M.
      Rheumatoid arthritis: perioperative management of biologics and DMARDs.
      While these drugs may be continued, surgeons should be aware that concurrent use of multiple csDMARDs has been associated with an increased risk of postoperative infection compared to monotherapy.
      • Scherrer C.B.
      • Mannion A.F.
      • Kyburz D.
      • Vogt M.
      • Kramers-De Quervain I.A.
      Infection risk after orthopedic surgery in patients with inflammatory rheumatic diseases treated with immunosuppressive drugs.
      ,
      • Menchaca-Tapia V.M.
      • Rodríguez E.M.
      • Contreras-Yáñez I.
      • Iglesias-Morales M.
      • Pascual-Ramos V.
      Adverse outcomes following hand surgery in patients with rheumatoid arthritis.

      Tofacitinib

      Unlike other csDMARDs, Tofacitinib (Xeljanz) has a specific molecular target, and thus has been classified as the first drug in a new category: the targeted synthetic DMARDs.
      • Aletaha D.
      • Smolen J.S.
      Diagnosis and management of rheumatoid arthritis: a review.
      ,
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      However, like the biologic agents, it is a second-line therapy indicated for RA refractory to csDMARD treatment. Tofacitinib has a short half-life and is a synthetic, small-molecule inhibitor of the Janus Kinase 1 and Janus Kinase 3 signaling pathways.
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      ,
      • Nishida K.
      • Harada R.
      • Nasu Y.
      • et al.
      The clinical course of patients with rheumatoid arthritis who underwent orthopaedic surgeries under disease control by tofacitinib.
      There is limited information on the impact of tofacitinib on outcomes in hand surgical populations. A small, retrospective case series of 11 hand surgeries in patients with RA treated with tofacitinib found no instances of surgical site infection (SSI) and one instance of delayed wound healing. However, patients had variable lengths of drug discontinuation prior to surgery.
      • Nishida K.
      • Harada R.
      • Nasu Y.
      • et al.
      The clinical course of patients with rheumatoid arthritis who underwent orthopaedic surgeries under disease control by tofacitinib.
      The ACR/AAHKS guidelines recommend withholding tofacitinib for 7 days prior to surgery, based on trials in nonsurgical patients and translational studies suggesting that immune responses return to normal within this time frame.
      • Goodman S.M.
      • 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.

      Biologic DMARDs

      Biologic DMARDs are targeted protein drugs that disrupt the action of a specific molecule or pathway involved in the pathogenesis of RA.
      • Aletaha D.
      • Smolen J.S.
      Diagnosis and management of rheumatoid arthritis: a review.
      ,
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      Biologics are indicated for patients who continue to have high disease activity and progressive joint destruction despite csDMARD treatment.
      • Aletaha D.
      • Smolen J.S.
      Diagnosis and management of rheumatoid arthritis: a review.
      These drugs are typically given in combination with csDMARDs, usually methotrexate. Tumor necrosis factor α (TNFα) inhibitors (TNFαi) were the first class of bDMARDs introduced for RA, and remain the most commonly used biologic drugs.
      • Crane M.M.
      • Juneja M.
      • Allen J.
      • et al.
      Epidemiology and treatment of new-onset and established rheumatoid arthritis in an insured US population.
      ,
      • Kim S.C.
      • Yelin E.
      • Tonner C.
      • Solomon D.H.
      Changes in use of disease-modifying antirheumatic drugs for rheumatoid arthritis in the United States during 1983–2009.
      Several other biologics with alternative molecular targets have also been adopted. Despite this variety of mechanisms, evidence in total joint replacement patients shows no difference in postoperative infection risks between the various bDMARDs.
      • George M.D.
      • Baker J.F.
      • Winthrop K.
      • et al.
      Risk of biologics and glucocorticoids in patients with rheumatoid arthritis undergoing arthroplasty: a cohort study.

      TNFαi

      Inhibition of TNFα disrupts multiple key inflammatory signaling pathways and reduces local bone destruction.
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      The most frequently prescribed TNFαi in patients with RA are etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humera).
      • Crane M.M.
      • Juneja M.
      • Allen J.
      • et al.
      Epidemiology and treatment of new-onset and established rheumatoid arthritis in an insured US population.
      ,
      • Kim S.C.
      • Yelin E.
      • Tonner C.
      • Solomon D.H.
      Changes in use of disease-modifying antirheumatic drugs for rheumatoid arthritis in the United States during 1983–2009.
      All TNFαi produce similar biomolecular effects and have been shown to have similar efficacy and safety profiles.
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      Individual studies of orthopedic patients have found conflicting results regarding the risks of continuing TNFαi perioperatively. A large, retrospective review by Scherrer et al
      • Scherrer C.B.
      • Mannion A.F.
      • Kyburz D.
      • Vogt M.
      • Kramers-De Quervain I.A.
      Infection risk after orthopedic surgery in patients with inflammatory rheumatic diseases treated with immunosuppressive drugs.
      of all hand surgeries in patients with inflammatory rheumatic diseases at a single institution found that bDMARD use within 3 months of surgery was associated with an increased infection risk (odds ratio, 2.54). Among those patients with a biologic dose within 3 months, the infection risk was substantially increased when surgery was performed within one administration interval of the biologic drug (odds ratio, 10.05).
      • Scherrer C.B.
      • Mannion A.F.
      • Kyburz D.
      • Vogt M.
      • Kramers-De Quervain I.A.
      Infection risk after orthopedic surgery in patients with inflammatory rheumatic diseases treated with immunosuppressive drugs.
      Conversely, Den Broeder et al
      • Den Broeder A.A.
      • Creemers M.C.W.
      • Fransen J.
      • et al.
      Risk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study.
      compared outcomes in patients with RA undergoing surgery within >4 (discontinuing) or ≤4 (continuing) drug half-lives of TNFαi administration, and found no difference in rates of SSIs. However, patients who continued treatment with TNFαi perioperatively were significantly more likely to have wound dehiscence.
      • Den Broeder A.A.
      • Creemers M.C.W.
      • Fransen J.
      • et al.
      Risk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study.
      Continuation of infliximab may not be associated with an increased infection risk. A large, claims-based analysis of Medicare patients undergoing total hip or knee arthroplasty found no difference in rates of serious infection or periprosthetic joint infection when surgery was performed within <4, 4 to 8 (1 dosing interval), 8 to 12, 12 to 16, or >16 weeks after the last infliximab infusion.
      • George M.D.
      • Baker J.F.
      • Hsu J.Y.
      • et al.
      Perioperative timing of infliximab and the risk of serious infection after elective hip and knee arthroplasty.
      Meta-analyses combining data from these investigations and others generally suggest that TNFαi use increases the infection risk and that the risk is higher if the drugs are not discontinued before surgery. Goodman et al
      • Goodman S.M.
      • Menon I.
      • Christos P.J.
      • Smethurst R.
      • Bykerk V.P.
      Management of perioperative tumour necrosis factor α inhibitors in rheumatoid arthritis patients undergoing arthroplasty: a systematic review and meta-analysis.
      showed that in patients undergoing total joint arthroplasty, a SSI was more likely when a TNFαi was given within 3 months of surgery (odds ratio, 2.47). The meta-analysis by Clay et al
      • Clay M.
      • Mazouyes A.
      • Gilson M.
      • Gaudin P.
      • Baillet A.
      Risk of postoperative infections and the discontinuation of TNF inhibitors in patients with rheumatoid arthritis: a meta-analysis.
      considered patients undergoing any hand surgery and found decreased risks of both overall complications (relative risk, 0.60) and SSIs specifically (relative risk, 0.62) when TNFαi were discontinued. Mabille et al
      • Mabille C.
      • Degboe Y.
      • Constantin A.
      • Barnetche T.
      • Cantagrel A.
      • Ruyssen-Witrand A.
      Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha.
      found a higher infection rate in orthopedic patients who continued biologic use in the perioperative period (6.63% vs 3.99%), but this difference was not significant. The findings of these meta-analyses are limited by the substantial variation in the biologic discontinuation periods used in the included studies and by differences in disease severity between patients treated with TNFαi or csDMARDs only.

      Other biologics

      Abatacept (Orenica) is a fusion protein of cytotoxic T-lymphocyte antigen 4 and immunoglobulin G1 that acts as a competitive inhibitor of CD28 at the CD80/CD86 T-cell receptor to disrupt the costimulation signal required for T-cell activation.
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      A case series of abatacept-treated patients with RA undergoing surgery at a mean of 5.3 weeks after the last infusion found that complications occurred in 6.7% of surgeries, with a longer duration of abatacept use being associated with a lower complication rate.
      • Latourte A.
      • Gottenberg J.E.
      • Luxembourger C.
      • et al.
      Safety of surgery in patients with rheumatoid arthritis treated by abatacept: data from the French Orencia in Rheumatoid Arthritis Registry.
      The complication rate in hand surgery cases (2.6%) was lower than the overall complication rate. A recent claims-based analysis of abatacept-treated patients with RA undergoing total joint arthroplasty suggests that the length of abatacept discontinuation may not have an impact on outcomes. The study found no difference in rates of postoperative hospital infections, periprosthetic joint infections, or 30-day readmission rates between patients who underwent surgery less or more than 4 weeks (1 dosing interval) after abatacept infusion.
      • George M.D.
      • Baker J.F.
      • Winthrop K.
      • et al.
      Timing of abatacept before elective arthroplasty and risk of postoperative outcomes.
      When surgery was performed within 2 weeks of infusion, patients had numerically, though not statistically significantly, higher rates of infection, periprosthetic joint infection, and readmission.
      Rituximab (Rituxan) is a monoclonal antibody against CD20 that depletes the peripheral B-cell population. Because of its long half-life and treatment effect, rituximab infusions are typically given every 6 months. A retrospective case-control study of 133 patients with RA treated with rituximab found that complications occurred following 8.5% of surgeries overall and 7.4% of hand surgeries, but there were no complications following 19 hand or wrist procedures. While there was no difference in the mean time between the last infusion and surgery in patients with and without complications (6.43 months vs 6.49 months, respectively), 66% of complications occurred when surgery was performed between 6 and 12 months after the last infusion.
      • Godot S.
      • Gottenberg J.E.
      • Paternotte S.
      • et al.
      Safety of surgery after rituximab therapy in 133 patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry.
      Tocilizumab (Actemra) is a humanized monoclonal clonal antibody against the interleukin-6 receptor. Outcomes of hand surgeries in patients with RA treated with tocilizumab have been reported in 2 case series. Momohara et al
      • Momohara S.
      • Hashimoto J.
      • Tsuboi H.
      • et al.
      Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre Tocilizumab in Perioperative Period (TOPP) study.
      reviewed 161 orthopedic operations, the majority of which were total joint arthroplasties, in patients who discontinued tocilizumab for 23.5 days prior to surgery on average. Postoperative SSIs occurred following 1.9% of operations and delayed wound healing occurred in 12.4%.
      • Momohara S.
      • Hashimoto J.
      • Tsuboi H.
      • et al.
      Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre Tocilizumab in Perioperative Period (TOPP) study.
      However, they found no association between either outcome and the length of tocilizumab discontinuation. RA flares occurred after surgery in 22.4% of cases and were more likely in patients with a longer interval between the last infusion and surgery (30.0 days in those with flares vs 21.6 in those without).
      • Momohara S.
      • Hashimoto J.
      • Tsuboi H.
      • et al.
      Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre Tocilizumab in Perioperative Period (TOPP) study.
      Morel et al
      • Morel J.
      • Locci M.
      • Banal F.
      • et al.
      Safety of surgery in patients with rheumatoid arthritis treated with tocilizumab: data from the French (Registry-Roactemra) Regate registry.
      reviewed 167 patients with RA undergoing any surgery from a prospectively collected registry of tocilizumab users. On average, surgery was performed 4.96 weeks after the last tocilizumab infusion. They found an overall complication rate of 8.6%, with the majority of complications being due to infection and only 1 patient experiencing a postoperative RA flare. No single factor, including the discontinuation interval, was found to be a significant risk factor for experiencing a complication in a multivariable analysis.
      • Morel J.
      • Locci M.
      • Banal F.
      • et al.
      Safety of surgery in patients with rheumatoid arthritis treated with tocilizumab: data from the French (Registry-Roactemra) Regate registry.
      Anakinra (Kineret) is a monoclonal antibody that binds to the interleukin-1 receptor.
      • Guo Q.
      • Wang Y.
      • Xu D.
      • Nossent J.
      • Pavlos N.J.
      • Xu J.
      Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies.
      Anakinra is among the least commonly prescribed bDMARDs for RA.
      • Crane M.M.
      • Juneja M.
      • Allen J.
      • et al.
      Epidemiology and treatment of new-onset and established rheumatoid arthritis in an insured US population.
      ,
      • Kim S.C.
      • Yelin E.
      • Tonner C.
      • Solomon D.H.
      Changes in use of disease-modifying antirheumatic drugs for rheumatoid arthritis in the United States during 1983–2009.
      Its effects on surgical outcomes have not been studied in a cohort of patients with RA. As anakinra is typically a daily medication, the ACR and AAHKS recommend surgery be performed on the second day following the last anakinra dose.
      • Goodman S.M.
      • 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.

      Evidence in Hand Surgery

      Hand surgeons face a challenge in interpreting the existing evidence on perioperative RA drug management and implementing current guidelines, because the majority of studies have evaluated patients undergoing total joint arthroplasty or other procedures not related to the hand or upper extremity. The evidence base for existing recommendations relies primarily on surgeries that may have higher baseline perioperative risks than the majority of hand and upper-extremity procedures.
      The few studies that have assessed hand surgery specifically suggest that the perioperative infection risk from DMARD continuation may be low. Jain et al
      • Jain A.
      • Witbreuk M.
      • Ball C.
      • Nanchahal J.
      Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery.
      retrospectively assessed the infection risks associated with perioperative continuation of csDMARDs and corticosteroids in 129 patients undergoing hand or wrist surgery. All medications were continued perioperatively. They found no differences in infection rates between methotrexate users and nonusers or between corticosteroid users and nonusers. The methotrexate dose, prednisolone dose, and use of other csDMARDs were also not associated with the likelihood of infection.
      • Jain A.
      • Witbreuk M.
      • Ball C.
      • Nanchahal J.
      Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery.
      Barnard et al
      • Barnard A.R.
      • Regan M.
      • Burke F.D.
      • Chung K.C.
      • Wilgis E.F.S.
      Wound healing with medications for rheumatoid arthritis in hand surgery.
      reviewed 28 patients with RA (35 hands, 140 wounds) undergoing metacarpophalangeal joint arthroplasty at a single center who continued csDMARDs and corticosteroids perioperatively, although the 4 patients using etanercept discontinued that medication 2 to 3 weeks preoperatively and resumed once all wounds were healed. They reported no serious complications and only 4 minor complications: 1 instance of delayed wound healing, 1 superficial infection, 1 RA flare, and 1 suture granuloma.
      • Barnard A.R.
      • Regan M.
      • Burke F.D.
      • Chung K.C.
      • Wilgis E.F.S.
      Wound healing with medications for rheumatoid arthritis in hand surgery.
      Menchaca-Tapia et al
      • Menchaca-Tapia V.M.
      • Rodríguez E.M.
      • Contreras-Yáñez I.
      • Iglesias-Morales M.
      • Pascual-Ramos V.
      Adverse outcomes following hand surgery in patients with rheumatoid arthritis.
      retrospectively reported outcomes from 130 hand surgeries in 96 patients who continued all RA medications perioperatively, and found that intensive treatment with concurrent use of ≥2 DMARDs and a corticosteroid was a significant predictor of postoperative complications, whereas less intensive regimens did not influence the complication rate. They did not distinguish between csDMARDs and bDMARDs in their analysis. Most recently, Klifto et al
      • Klifto K.M.
      • Cho B.H.
      • Lifchez S.D.
      The management of perioperative immunosuppressant medications for rheumatoid arthritis during elective hand surgery.
      compared complications in elective hand and upper-extremity procedures between 61 patients who continued all RA medications (including bDMARDs) and 27 patients with RA not taking any RA medications at the time of surgery. They considered bDMARDs to be continued if surgery occurred within 1 dosing interval. Among the patients continuing RA medications, 100% used at least 1 csDMARD, 31% used corticosteroids, and 5% used a bDMARD. Complication rates were higher in patients not taking any RA medications (19%) than those continuing medications perioperatively (5%), but this difference was not statistically significant. They concluded that patients undergoing elective hand surgery may safely continue RA medications without an increased risk of complications or unintended disease progression.

      Recommended Management Strategy

      Low-dose corticosteroids (≤5 mg/day) and csDMARDs are safe to continue throughout the perioperative period (Table 1). For most hand and upper-extremity procedures, planned perioperative stress-doses corticosteroids are not required. However, patients on high daily corticosteroid doses (>20 mg/day) or undergoing more intensive surgeries should be evaluated individually. Patients may continue their regular dose of csDMARDs, including methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, and azathioprine.
      Table 1Common Immunosuppressive Medications for rheumatoid arthritis and Recommended Management
      DrugMechanismTypical Dosing Regimen
      Goodman et al.4
      Continue or Withhold Perioperatively
      Goodman et al.4
      ACR/AAHKS Recommendation for Surgery Timing
      Goodman et al.4
      Evidence in Hand/Upper-Extremity Surgery
      CorticosteroidsInhibit inflammationDailyContinueStress dosing not requiredContinuation may not increase infection risk
      Jain et al.13
      Synthetic DMARDs
       HydroxychloroquineVariousDaily (1–2 doses)ContinueContinuation does not increase infection risk; use of ≥2 drugs with steroid may increase infection risk
      Jain et al.13
      ,
      Barnard et al,18 Menchaca-Tapia et al,21 and Klifto et al.19
       LeflunomideVarious; inhibits dihydroorotate dehydrogenase (pyrimidine synthesis)DailyContinue
       MethotrexateVarious; inhibits dihydrofolate reductase (purine synthesis)WeeklyContinue
       SulfasalazineVariousDaily (1–2 doses)Continue
       Tofacitinib (Xeljanz)Inhibits JAK1 and JAK3 signaling pathwaysDaily (1–2 doses)Withhold 7 days before surgery7 days after last doseNone
      Anti-TNFα bDMARDs
       Adalimumab (Humira)TNFα inhibitionWeekly or every 2 weeksWithhold 1 dosing intervalWeek 2 (weekly dosing) or week 3 (every 2 weeks dosing) after last doseNone
       Certolizumab (Cimzia)TNFα inhibitionEvery 2 weeks or every 4 weeksWithhold 1 dosing intervalWeek 3 (every 2 weeks dosing) or week 5 (every 4 weeks) after last doseNone
       Etanercept (Enbrel)TNFα inhibitionWeekly or twice weeklyWithhold 1 dosing intervalWeek 2 after last doseNone
       Golimumab (Simponi)TNFα inhibitionEvery 8 weeks (intravenous) or every 4 weeks (SQ)Withhold 1 dosing intervalWeek 9 (intravenous) or week (5) after last doseNone
       Infliximab (Remicade)TNFα inhibitionEvery 4, 6, or 8 weeksWithhold 1 dosing intervalWeek 5 (every 4 weeks dosing), week 7 (every 6 weeks), or week 9 (every 8 weeks) after last doseNone
      Other bDMARDs
       Abatacept (Orencia)Inhibits CD28/CTLA4 system; inhibits T-cell costimulationMonthly (intravenous) or weekly (SQ)Withhold 1 dosing intervalWeek 5 (intravenous) or week 2 (SQ) after last doseNone
       Anakinra (Kineret)IL-1 inhibitionDailyWithhold 1 dosing intervalDay 2 after last doseNone
       Rituximab (Rituxan)CD20 inhibition; depletes B cells2 doses 2 weeks apart every 4–6 monthsWithhold 1 dosing intervalMonth 7 after last doseNone
       Tocilizumab (Actemra)IL-6 inhibitionEvery 4 weeks (intravenous) or weekly (SQ)Withhold 1 dosing intervalWeek 5 (intravenous) or week 2 (SQ) after last doseNone
      CTLA-4, Cytotoxic T-lymphocyte antigen 4; IL, interleukin; SQ, subcutaneous.
      Goodman et al.
      • Goodman S.M.
      • 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.
      Jain et al.
      • Jain A.
      • Witbreuk M.
      • Ball C.
      • Nanchahal J.
      Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery.
      Barnard et al,
      • Barnard A.R.
      • Regan M.
      • Burke F.D.
      • Chung K.C.
      • Wilgis E.F.S.
      Wound healing with medications for rheumatoid arthritis in hand surgery.
      Menchaca-Tapia et al,
      • Menchaca-Tapia V.M.
      • Rodríguez E.M.
      • Contreras-Yáñez I.
      • Iglesias-Morales M.
      • Pascual-Ramos V.
      Adverse outcomes following hand surgery in patients with rheumatoid arthritis.
      and Klifto et al.
      • Klifto K.M.
      • Cho B.H.
      • Lifchez S.D.
      The management of perioperative immunosuppressant medications for rheumatoid arthritis during elective hand surgery.
      Due to the lack of specific evidence in hand surgery populations, we defer to current ACR/AAHKS guidelines regarding bDMARDs and tofacitinib. Because of studies in nonsurgical patients showing that the durations of the immunosuppressive effects of bDMARDs do not correspond to their serum half-lives, the ACR/AAHKS guidelines instead use the dosing cycle to determine the optimal timing for surgery. For all bDMARDs, they recommend scheduling surgery in the first week of the first withheld dose (eg, week 5 for a drug dosed every 4 weeks) of the patient’s typical dosing regimen, as this point represents the expected nadir of the drug effect.
      • Goodman S.M.
      • 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.
      Tofacitinib should be withheld for 7 days prior to surgery.
      • Goodman S.M.
      • 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.
      Biologics can be restarted when the surgical wound shows evidence of healing, all sutures or staples have been removed, and there are no signs of infection at the surgical site or systemically.
      • Goodman S.M.
      • 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.
      The decision to restart a bDMARD should be made in collaboration with the patient’s rheumatologist and clearly communicated to both the rheumatologist and the patient. A recent study found that after withholding bDMARDs for hand surgery, some patients did not restart medications for up to 3 months after surgery because of scheduling challenges and miscommunications.
      • Klifto K.M.
      • Cho B.H.
      • Lifchez S.D.
      The management of perioperative immunosuppressant medications for rheumatoid arthritis during elective hand surgery.
      Prolonged bDMARD discontinuation may increase the risk of experiencing an RA flare and unnecessary disease progression.

      Supplementary Data

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