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.
Risk of venous thromboembolism (VTE), particularly if continued - see Further information.
Advice in the perioperative period
Elective surgery
Establish indication and dose frequency (see Further information).
Check liver function test (LFTs) pre-operatively if not recently checked.
The Surgical Team and patient’s Rheumatologist / 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 tofacitinib 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 tofacitinib can be managed on less than 15mg prednisolone (or equivalent).
Minor procedures
Consider continuing tofacitinib 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.
Ensure adequate thromboprophylaxis if continued (see Further information).
All other procedures
Surgery should be scheduled to enable the patient to miss THREE days of tofacitinib (i.e., scheduling surgery for 4 days after last dose of tofacitinib).
EXCEPT:-
If the Surgical Team deem the procedure to be of especially high infection risk, consider stopping 7 days before surgery. However, a flare in disease activity may occur, which may result in glucocorticoids being administered, further increasing the infection risk.
Emergency surgery
Consider withholding any doses due in the immediate post-operative period to reduce risk of VTE and infection. Monitor closely for infection and postoperative VTE.
Ensure adequate thromboprophylaxis (see Further information).
Patients presenting with new onset abdominal signs and symptoms
Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation. If diagnosed, stop tofacitinib and discuss with Specialist – see Further information.
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 once wound healing stable – discuss with Surgical Team. To prevent relapse consideration should be given to restarting tofacitinib 3 - 5 days after surgery if no concerns. Ideally treatment interruption should not exceed 14 days (see Further information).
If post-operative bloods indicate haemoglobin, neutrophils or lymphocytes below normal range consult product literature as treatment interruption may be required – discuss with Specialist.
If postoperative VTE, or infection, develops discontinue tofacitinib and discuss with Specialist.
Interactions with common anaesthetic agents
None.
Interactions with other common medicines used in the perioperative period
Clarithromycin, and potentially erythromycin, is predicted to increase exposure to tofacitinib (via CYP3A4 inhibition). The manufacturer advises tofacitinib dose reduction with this combination; however, they also advise interruption of tofacitinib in patients who develop serious infections until the infection is controlled.
Further information
Indications and dosing frequency
Tofacitinib is used for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. This is an oral formulation and doses are administered twice daily if the immediate-release preparation or once daily if the modified-release preparation.
Venous thromboembolism (VTE) risk
Ensure patients receive adequate thromboprophylaxis when undergoing surgery as serious VTE events have been observed in patients taking tofacitinib. In a randomised post authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose-dependent increased risk for VTE was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors. It is not known if pre-operative cessation of tofacitinib reduces the VTE risk back to baseline.
Diverticulitis
Diverticulitis and gastrointestinal perforations have been reported in clinical trials with tofacitinib. It should be used with caution in patients with diverticular disease or a history of diverticulitis, or who are taking non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids or opioids due to the risk of gastrointestinal perforation.
Rationale for recommendations - risk of infection versus risk of disease
Inflammatory arthritis
Tofacitinib is known to increase the risk of serious infections, particularly in the elderly, hence use is not recommended in patients over 65 years old unless there is no suitable alternative. Tofacitinib has a short half-life; approximately 3 hours for the immediate-release formulation and 6 hours for the modified-release formulation. However, changes in C-reactive protein (CRP) do not fully reverse within 2 weeks after discontinuation prompting concerns that the duration of pharmacodynamic activity is longer than the half-life. This initially led to the American College of Rheumatology / American Association of Hip and Knee Surgeons (ACR / AAHKS) recommending stopping 7 days pre-operatively, however, they have since revised their guidance and recommend stopping 3 days prior to arthroplasty (with the caveat that a longer cessation period may be considered if history of infections or previous prosthetic joint infection). This aligns with the recommendations from the German Society for Rheumatology. The change in advice is attributed to a sub-study which showed a rapid increase in disease activity after discontinuing tofacitinib with patients experiencing flares within 2 weeks, sooner than with TNF inhibitors.
Whilst the ACR / AAHKS do not distinguish between targeted DMARDs (e.g. tofacitinib) and biologic DMARDs in their restarting advice (i.e. usually 14 days post-operatively) the German Society for Rheumatology advise resuming treatment earlier, due to the much shorter half-life and risk of flare. They recommend recommencing when wound conditions are stable possibly at 3 - 5 days post-operatively and ideally treatment interruption should not exceed 14 days.
Ulcerative colitis
Currently there is very limited data on the perioperative safety of tofacitinib in patients with IBD; the single study available reported an increase in the number of venous thromboembolic events and recommended prolonged use of thromboprophylaxis. Cohen et al recommend stopping JAK inhibitors three days prior to surgery which aligns with the recommendations by rheumatology societies. Their recommendations for restarting JAK inhibitors vary from 3 days to 14 days post-operatively depending on the clinical situation. Figure 2 and 3 in Cohen et al may be useful tools when weighing this decision.
References
Albrecht, K. Poddubnyy, D. Leipe, J. et al. 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
Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed 31st January 2024]
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:10.1016/j.cgh.2023.01.042.
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
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed 31st January 2024]
Kaine, J. Tesser, J. Takiya, L. Re-establishment of efficacy of tofacitinib, an oral JAK inhibitor, after temporary discontinuation in patients with rheumatoid arthritis. Clin Rheumatol. 2020; 39(7):2127-2137 doi:10.1007/s10067-020-04956-1
Moreira P, Correia A, Cerquerira M, Gil M. Perioperative management of disease-modifying antirheumatic drugs and other immunomodulators. ARP Rheumatol. 2022; 3:218-224.
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
Summary of Product Characteristics – XELJANZ (tofacitinib) 5 mg film-coated tablets. Pfizer Limited. Accessed via www.medicines.org.uk 31/01/24 [date of revision of the text November 2023]
Tofacitnib. 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 24th May 2024]