Brands of this drug
Flixabi, Inflectra, Remicade, Remsima, Zessly
Issues for surgery
Risk of perioperative flare in disease activity (potentially leading to an increase in glucocorticoid use) if omitted.
Risk of post-operative infection if continued.
Advice in the perioperative period
Elective surgery
Establish indication, dose frequency and brand of biosimilar (see Further information).
The Surgical Team and patient’s Rheumatologist / Dermatologist / Gastroenterologist along with the patient should be involved in the planning for elective surgery to balance the potential benefit of preventing post-operative infection by stopping infliximab against the risk of developing severe or unstable disease.
Modifiable risk factors for perioperative infection, such as glycaemic control and smoking should ideally be addressed prior to surgery.
Glucocorticoid use is associated with increased perioperative infection in a dose dependent manner. Where possible consider delaying elective surgery until patients taking infliximab can be managed on less than 15mg prednisolone (or equivalent).
Minor procedures
Consider continuing infliximab before low-risk surgery (i.e. surgery without a break in sterile technique, during which the respiratory, gastrointestinal, and genitourinary tracts are not entered) e.g. endoscopy, bronchoscopy, hysteroscopy, cystoscopy, breast biopsy, dermatologic or ophthalmological procedures.
All other procedures
For indications other than inflammatory bowel disease: Surgery should be scheduled to enable the patient to miss ONE dose (i.e., scheduling surgery for a minimum of 15 days after fortnightly subcutaneous infliximab, 29 days after administration of 4 weekly intravenous infliximab, 43 days after 6 weekly intravenous infliximab or 57 days after 8 weekly intravenous infliximab).
EXCEPT: -
If the Surgical Team deem the procedure to be of especially high infection risk, consider stopping 3-5 half-lives before surgery. Be mindful that a flare in disease activity may occur, which may result in glucorticoids being administered, further increasing the infection risk (see Further information).
For inflammatory bowel disease: consider continuing infliximab before surgical intervention for IBD. For non-IBD procedures (e.g. arthroplasty) decision is less clear (see Further information) - discuss with the Surgeon and Gastroenterologist as part of planning for surgery.
Patients taking narrow therapeutic index medication
Some manufacturers predict that stopping or starting biologic therapy may affect expression of cytochrome P450 enzymes, which theoretically may affect metabolism of other medicines the patient may be taking. Additional monitoring may be needed in patient’s taking concomitant narrow therapeutic medication e.g. phenytoin, warfarin, theophylline when stopping infliximab before surgery.
Emergency surgery
Withhold any doses due in the immediate post-operative period. Monitor closely for infection if patient has received a subcutaneous dose of infliximab in previous 2 weeks or an intravenous dose in previous 4 - 8 weeks.
Perioperative considerations
Control of body temperature and avoidance of blood transfusion may minimise the risk of infection.
Post-operative advice
If stopped, recommence post-operatively when there is evidence of wound healing, all sutures and staples are out, there is no significant swelling, erythema, or drainage, and there is no ongoing nonsurgical site infection. This is typically around 14 days post-operatively.
Interactions with common anaesthetic agents
None.
Interactions with other common medicines used in the perioperative period
None.
Further information
Indications, dosing frequency and half-life
Infliximab is used for Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. Intravenous doses are typically administered every 4 – 8 weeks, depending on indication, whereas subcutaneous maintenance doses are administered every fortnight. Infliximab has a half-life of 11.3 - 13.7 days when given subcutaneously and 8 - 9.5 days when given intravenously.
Biosimilar medication
Infliximab has several biosimilar brands which are considered to be therapeutically equivalent to the originator biological medicine within their authorised indications. However, biosimilar medicines must be prescribed by brand name to prevent inadvertent switching.
Rationale for recommendations - risk of infection versus risk of disease
Inflammatory arthritis
Currently there is limited evidence regarding the risk of infection in patients who continue biologic disease modifying anti-rheumatic drugs (bDMARDs), e.g. infliximab perioperatively. Several meta-analyses have been conducted; however, the methodology of the underpinning studies is not comparable with respect to confounding factors and stopping duration. Thus, recommendations from eminent societies are largely based on expert opinion.
The British Society for Rheumatology (BSR), American College of Rheumatology / American Association of Hip and Knee Surgeons (ACR / AAHKS) and German Society for Rheumatology (GSR) advise planning surgery in most patients for after one dose of infliximab has been missed when the nadir of the drug is at its lowest. This pragmatic approach seeks to minimise the stopping period and thus the risk of a perioperative flare in symptoms which would result in an increase in glucocorticoid use, which would further increase the risk of infection. However, they caveat that if surgery is associated with a very high risk of infection consideration should be given to stopping for 3-5 half-lives, but this must be balanced against the risk of perioperative flare.
Conversely the Australian recommendations suggest it may be possible to continue bDMARDs perioperatively (unless individuals have a high risk of infection or where impact of infection would be severe, when surgery should be timed as outlined above). Whilst there is little evidence to support or refute this recommendation, there may be more evidence for this once the PERISCOPE trial has been evaluated. This clinical trial involves randomising patients on bDMARDs for inflammatory arthritis to either continue or stop bDMARDs prior to elective orthopaedic surgery, including arthroplasty, however patient recruitment is just starting and publication is not anticipated until at least 2026.
Psoriasis
The evidence for risk of post-operative infection in patients with psoriasis is minimal and is often extrapolated from other populations. The American Academy of Dermatologists / National Psoriasis Foundation (ADD / NPF) advise biologics can safely be continued before minor surgery. However, unlike the rheumatology societies the British Association of Dermatologists and AAD / NPF are more cautious with their recommendations for other surgery, suggesting most patients should stop biologic therapy for a period of time equivalent to 3 - 5 half-lives before surgery or the length of the treatment cycle, whichever is longer. Given the lack of robust evidence that a longer interruption of treatment is beneficial this seems an overly cautious approach, and risks a perioperative flare, particularly with medications with a long half-life, such as infliximab, which is likely to necessitate glucocorticoid use and subsequently increase the risk of infection. Therefore, for simplicity, and in the absence of evidence to the contrary we have extrapolated the recommendations for rheumatology patients to this patient population.
Inflammatory bowel disease
Results from studies addressing the safety of perioperative continuation of biologics, e.g. infliximab are conflicting, both in terms of risk of infection and healing of bowel anastomoses. Potentially this is because confounding factors, including glucocorticoid use, were not always considered. More recently the PUCCINI study prospectively collected data from 955 abdominal operations in patients with ulcerative colitis and Crohn’s disease and confirmed that neither pre-operative exposure to TNF-alpha inhibitors nor detectable drug levels before surgery were associated with an increased risk of overall infectious complications or surgical site infections. Conversely, smoking, and glucocorticoid use were associated with an increased risk of infection. Largely based on the PUCCINI study the European Colitis and Crohn’s Organisation (ECCO) recommend biologics can be continued during the perioperative period for patients requiring surgical intervention for inflammatory bowel disease. The British Society of Gastroenterology also suggest that evidence to support pre-operative stopping prior to IBD surgery is lacking. If not appropriate to continue pre-operatively they recommend timing surgery to have as long a gap as possible between the last dose and surgery.
For non-IBD surgery, recommendations are less clear. It is suggested to consider the concurrent use of glucocorticoids and the risk of post-operative complications when deciding whether to continue biologics, or time surgery for mid-way through, or the end of a dose cycle. Figure 2 in Cohen et al (2023) may be a useful tool when weighing this decision.
References
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Al-Janabi, A. and Yiu, ZZN. Biologics in Psoriasis: Updated Perspectives on Long-Term Safety and Risk Management. Psoriasis (Auckl). 2022; 12:1-14 DOI:10.2147/PTT.S328575
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Buchbinder, R. Glennon, V. Johnston RV. et al. Australian recommendations on perioperative use of disease-modifying anti-rheumatic drugs in people with inflammatory arthritis undergoing elective surgery. Internal Medicine Journal. 2023,53:1248–1255 DOI.org/10.1111/imj.16073
Cohen, BL. Fleshner, P. Kane, SV. et al. Prospective cohort study to investigate the safety of preoperative tumor necrosis factor inhibitor exposure in patients with inflammatory bowel disease undergoing intra-abdominal surgery. Gastroenterology 2022. 163: 204-221. DOI: 10.1053/j. gastro.2022.03.057
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Summary of Product Characteristics – Remicade (infliximab) 100mg powder for concentrate for solution for infusion. Merck Sharp & Dohme (UK) Limited. Accessed via www.medicines.org.uk 29/01/24 [date of revision of the text December 2023]
Summary of Product Characteristics – Remsima (infliximab) 120 mg solution for injection in pre-filled pen. Celltrion Healthcare UK Limited. Accessed via www.medicines.org.uk 29/01/24 [date of revision of the text July 2022]