http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(3): 544–545 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.874758

RAPID COMMUNICATION

Abatacept management during the perioperative period in patients with rheumatoid arthritis: report on eight orthopaedic procedures

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Keiichiro Nishida1,2, Yoshihisa Nasu3, Kenzo Hashizume2, Ryuichi Nakahara2, Masatsugu Ozawa2, Ryozo Harada2, Takahiro Machida2, and Toshihumi Ozaki2 1Department of Human Morphology, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, 2Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, and 3Department of Orthopaedic Surgery, Kurashiki Sweet Hospital, Kurashiki City, Okayama, Japan

Keywords Abatacept, Rheumatoid arthritis, Orthopaedic surgery, Surgical site infection, Delayed wound healing History Received 18 March 2013 Accepted 3 April 2013 Published online 13 April 2013

T cell activation occurs early in the inflammatory process of rheumatoid arthritis (RA) [1]. Abatacept is a fusion protein of T-lymphocyte-associated antigen 4 (CTLA-4) and immunoglobulin and suppresses T cell activation in RA by binding to CD80/86 co-stimulatory antigens, thereby blocking interaction with CD28 [1, 2]. Abatacept was approved by the Japanese Ministry of Health, Labour and Welfare in 2010 as the fifth biologic agent for the treatment of RA, and favorable tolerability and efficacy have been reported in Japanese patients with RA [3–5]. Surgical-site infections (SSIs) are the major concern in orthopaedic surgery for RA patients treated with biologic agents. Most national guidelines suggest withholding biologic agents prior to surgery and restarting them postoperatively if there is no evidence of infection or delayed wound healing. To date, information is limited to the management of tumor necrosis factor blockers, and there is no available data to support the optimal management of abatacept during the perioperative period [6]. We retrospectively reviewed the cases of seven patients who underwent eight orthopaedic surgical procedures at Okayama University Hospital and Kurashiki Sweet Hospital after discontinuation of abatacept. The patients’ characteristics are summarized in Table 1. All patients were women, aged 44–78 (average 66.8) years, and all were sero-positive and had been receiving treatment with abatacept at 500 mg/month for over 3 months. No patients had diabetes mellitus as a preoperative complication. Table 2 summarizes the pathology, type of surgery and postoperative events, including SSI, delayed wound healing and flare-up of the disease. Eight orthopaedic procedures were performed, including Correspondence to: Keiichiro Nishida, Department of Human Morphology, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Tel: ⫹81-86-235-7273; Fax: ⫹81-86-223-9727. E-mail: [email protected]

minor surgeries such as metatarsal bone osteotomy, tenosynovectomy, implant removal and wrist and finger arthroplasties, as well as major surgeries such as total knee arthroplasty. The average pre-operative abatacept discontinuation period was 15.9 days, stitches were removed on average 16.1 days after surgery and the total perioperative discontinuation period of abatacept was 33.1 days on average. Oral disease-modifying anti-rheumatic drugs were not stopped perioperatively, and all patients received antimicrobial prophylaxis for 2 days after surgery. We did not experience any postoperative infection, delayed wound healing, or flare-up of the disease among the current small number of patients. The perioperative management of patients using abatacept is a major concern among orthopaedic surgeons. Reported metaanalyses have not revealed a significant increase in the risk of serious infections during abatacept treatment in patients with RA [7]. However, surgery within the initial 3 months after first administration of abatacept should be avoided because adverse events, such as severe infections, are relatively frequent during this period [8]. Theoretically, a shorter discontinuation period before surgery may be associated with the risk of SSI and delayed wound healing, whereas long-term discontinuation of biologic agents may induce flare-up of the disease. Our report is the first to describe management of RA patients who underwent surgery during abatacept treatment. The pharmacokinetics of the serum concentration of abatacept after treatment discontinuation in patients with RA have not been reported. The mean half-life of abatacept when administered at a dose of 10 mg/kg is reportedly 13.1 days, with a range of 8–25 days [6]. The guidelines from the Japan College of Rheumatology for abatacept (URL: http://www.ryumachi-jp. com/info/guideline_ABT_100930.html, in Japanese) suggest that treatment with abatacept should be withheld before any surgical procedures, taking the half-life of abatacept into consideration. Treatment may be re-started postoperatively if there is no evidence

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DOI 10.3109/14397595.2013.874758

Table 1. Patients’ background Case no. 1 2 3 1 4 5 6 7 Mean

Gender Female Female Female Female Female Female Female Female

Age (years) 77 45 78 78 44 73 76 63 66.8

Body weight (kg) 53 59 46 48 49 36 44 47 48.6

Disease duration (years) 18 16 13 19 20 9 15 19 16.1

RF + + + + + + + +

CRP (mg/dl) 0.83 2.12 1.00 1.22 0.39 0.34 0.04 0.17 0.8

DAS28-CRP 5.97 2.73 N.A. 6.47 1.39 2.76 2.75 3.66 3.7

PSL (mg/day) 2.5 4 5 2 3 2 2.5 3 3.0

MTX (mg/week) 0 6 6 6 2 2 0 0 2.8

Other DMARDs – – SASP 1,000 mg/day – – SASP 1,000 mg/day – –

ABT (mg/month) 500 500 500 500 500 500 500 500

RF Rheumatoid factor, CPR C-reactive protein, DAS28 28-joint Disease Activity Score, PSL predonisolone, MTX methotrexate, SASP sulfasarazine, DMARD disease-modifying anti-rheumatic drugs, ABT abatacept

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Table 2. Surgical procedures and drug discontinuation period

Case no. 1

Side Left

Pathology Hullux valgus

2

Right

Middle finger tenosynovitis

3a 1 4

– Left Right

5 6 7 Mean

Right Right Right

Infectious spondylitis (L4/L5) Hullux valgus (postoperative) 1–5th metacarpophalangeal joint destruction Wrist joint destruction Knee joint destruction Knee joint destruction

aCase

Procedure Osteotomy of 1st metatarsal bone Release of tendon sheath, synovectomy Irrigation, debridement Implant removal Silicon implant arthroplasty radio-lunate partial arthrodesis Total knee arthroplasty Total knee arthroplasty

Pre-operative discontinuation period (days) 21

Total discontinuation period (days) 34

Postoperative event None

20

35

None

8 19 13

– 28 37

None None None

16 18 12 15.9

33 35 30 33.1

None None None

No. 3 patient did not re-start the abatacept treatment

of infection and once wound healing is deemed satisfactory. Guidelines from the French Society for Rheumatology for prescribing abatacept in adults with RA also suggest the discontinuation of abatacept [6], but there is also no clear suggested protocol for perioperative management due to lack of information regarding potential delays in healing in abatacept-treated patients. Based on expert opinion, these guidelines suggest that the interval from the last abatacept infusion should be determined on a case-by-case basis, taking into account the type of surgery, patient-related factors, severity of the joint disease and degree of control achieved by treatment. We initially planned to stop the administration of abatacept for 3 weeks before surgery (Case 1, 2 and 6), but subsequently reduced the discontinuation period (Case 4, 5 and 7). In Case 3, surgery was performed 8 days after the last infusion, but this involved emergency surgery due to deep infection. The patient was not re-treated with abatacept. Because postoperative wound healing usually takes 10–14 days, abatacept treatment was re-started around 5 weeks after the last pre-operative infusion, resulting in less than a 1-week delay to the abatacept infusion schedule. During the same period (January 2011—December 2012), we performed 163 orthopaedic procedures for 370 joints in RA patients who do not receiving biologic agents. Average age and disease duration at the surgery was 63.1 years and 19.5 years, respectively. The average dose of prednisolone and methotrexate was 3.1 mg/day and 6.6 mg/week, respectively. We found SSI in three cases (1.8 %) and delayed wound healing in five cases (3.1 %). These data do not directly support the safe profile of abatacept during the perioperative period, and more data from larger prospective or retrospective multicenter studies are required to achieve better management of abatacept. In conclusion, we performed eight orthopaedic procedures safely with a 2- to 3-week treatment-free interval before surgery with abatacept. The results of our small study could contribute to better decision-making by surgeons regarding how long abatacept

should be withheld before surgery to minimize the risk of SSIs and delayed wound healing, as well as to avoid flare-up of RA.

Conflict of interest K.N. has received lecture fees from Bristol-Myers Squibb. The other authors declare no conflict of interest.

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