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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 and dose frequency (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 ustekinumab 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 ustekinumab can be managed on less than 15mg prednisolone (or equivalent).

Minor procedures

Consider continuing ustekinumab 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 12 weeks and 1 day after administration of 12 weekly ustekinumab).

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 glucocorticoids being administered, further increasing the infection risk (see Further information).

For inflammatory bowel disease: consider continuing ustekinumab 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 ustekinumab before surgery.

Emergency surgery 

Withhold any doses due in the immediate post-operative period. Monitor closely for infection if patient has received a dose of ustekinumab in previous 12 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

After a dose at week 0 and 4 ustekinumab is administered every 12 weeks for plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. Whereas for Crohn’s disease and ulcerative colitis a loading dose is given at week 0, a further dose at week 8 and then ustekinumab is typically administered every 12 weeks, although if response is inadequate or response is lost the frequency of administration can be increased⁸. Ustekinumab has a half-life of approximately 21 days⁶.

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. ustekinumab 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)⁴ and German Society for Rheumatology (GSR)⁵ advise planning surgery in most patients for after one dose of ustekinumab 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 disease 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 populations¹². 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 ustekinumab, 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. ustekinumab 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 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

1. Albrecht, K. Poddubnyy, D. Leipe, J. et Perioperative management of patients with inflammatory rheumatic diseases: Updated recommendations of the German Society for Rheumatology. Zeitschrift fur Rheumatologie. 2022, 82: 1-11. Doi:10.1007/s00393-021-01150-9
   
   
2. 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
   
   
3. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed 1^st February 2024]
   
   
4. Buchbinder, R. Glennon, V. Johnston RV. et 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:10.1111/imj.16073
   
   
5. 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
   
   
6. Cohen, BL. Lincango, E. & Holubar, S. How to manage targeted immune suppressants (biologics and oral small-molecule drugs) perioperatively for inflammatory bowel disease and non-inflammatory bowel disease surgery. Clinical Gastroenterology and Hepatology. 2023; 21: 1148-1151 doi:1016/j.cgh.2023.01.042
   
   
7. Goodman, SM. Springer, BD. Chen AF. American College of Rheumatology and American Association of Hip and Knee Surgeons (AAHKS) 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. 2022;74(9):1399-1408 doi:10.1002/acr.24893
   
   
8. Holroyd, CR. Seth, R. Bukhari, M. et al. The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis. Rheumatology. 2019; 58:220-226 doi:10.1093/rheumatology/key207
   
   
9. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. Electronic version. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com [Accessed 1^st February 2024]
   
   
10. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed 1^st February 2024]
    
    
11. Lamb, CA. Kennedy, NA. Raine, T. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019.0:1–106 doi:10.1136/gutjnl-2019-318484
    
    
12. Menter, A. Strober, BE. Kaplan DH. et Derm Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol. 2019; 80:1029-1072 doi:10.1016/j.jaad.2018.11.057
    
    
13. Moreira P, Correia A, Cerquerira M, Gil M. Perioperative management of disease-modifying antirheumatic drugs and other immunomodulators. ARP Rheumatol. 2022; 3: 218-224
    
    
14. Pandit, H. & Mankia, K. PERI-operative biologic DMARD management: Stoppage or COntinuation during orthoPaEdic operations: The PERISCOPE trial. Protocol v1.0 (February 2023)
    
    
15. Sebastian, S. Segal, JP. Hedin, C. et al. ECCO Topical Review: Roadmap to Optimal Peri-Operative Care in IBD. Journal of Crohn’s and Colitis. 2023, 17:153-169 doi:10.1093/ecco-jcc/jjac129
    
    
16. Smith, CH. Yiu, ZZN. Bale, T. et al. British Association of Dermatologists guidelines for biologic therapy for psoriasis 2020: a rapid update. Br J Dermatol. 2020;183(4):628–637 doi:10.1111/bjd.19039
    
    
17. Summary of Product Characteristics – STELARA^® (Ustekinumab) 130 mg concentrate for solution for infusion. Janssen-Cilag Ltd. Accessed via medicines.org.uk 01/02/24[date of revision of the text July 2023]