Abatacept, Adalimumab, Anakinra, Baricitinib, Belimumab, Brodalumab, Certolizumab, Dupilumab, Etanercept, Golimumab, Guselkumab, Infliximab, Ixekizumab, Risankizumab, Rituximab, Sarilumab, Secukinumab, Tildrakizumab, Tocilizumab, Tofacitinib, Ustekinumab, Vedolizumab
[NB: These agents are also sometimes referred to as Disease Modifying Anti-Rheumatic Drugs (DMARDs) or ‘Biologics’]
Issues for Surgery
Risk of perioperative flare in disease activity if omitted.
Risk of post-operative infection if continued.
For baricitinib and tofacitinib – potential increased risk of venous thromboembolism (VTE) if continued.
Advice in the Perioperative period
For minor surgery it may be possible to continue these agents.
For most biologics, except rituximab and tocilizumab, surgery should be planned for when at least one dosing interval has elapsed for that drug1, 2. This is pragmatic advice as the nadir of the drug’s effect would be at the end of its dosing interval; hence the immunosuppressant effects of the drug will be at its lowest1. Refer to Figure 1 – Dosing intervals, recommendations for timing of surgery and half-lives of biologic therapies used in rheumatology – for advice on specific drugs.
However, if the Surgical Team deem the procedure to be of especially high infection risk, consider stopping 3-5 half-lives (if this is longer than one dosing interval) before surgery but be mindful that a flare in disease activity may occur, which may result in steroids being administered, further increasing the infection risk1 (see Further Information).
Figure 1: Dosing intervals, recommendations for timing of surgery and half-lives of biologic therapies used in rheumatology
For minor surgery (e.g. endoscopy, bronchoscopy, hysteroscopy, cystoscopy, breast biopsy, ophthalmologic or dermatologic procedures) consideration should be given to continuing these agents perioperatively4, 5 (especially adalimumab, etanercept or infliximab4).
If the decision is made to stop biologic therapy, the British Association of Dermatologists (BAD) advocate allowing 3 – 5 times the half-life of the drug or the length of treatment cycle (whichever is longer) between the last dose of therapy and the planned surgery3. However, others sources suggest this may be a cautious approach4, 5 (see Further Information). Refer to Figure 2– Dosing intervals and half-lives of biologic therapies used in dermatology for information on specific drugs.
Figure 2: Dosing intervals and half-lives of biologic therapies used in dermatology
Inflammatory Bowel Disease (IBD) Indications (e.g. Crohn’s Disease, Ulcerative Colitis)
There are no specific recommendations in the literature but if there is concern regarding infection risk it would be reasonable to follow the principles outlined above regarding timing surgery for when at least one dosing interval has elapsed for that drug and bearing in mind that if stopped for lengthy periods pre-operatively the risk of disease flare requiring steroid treatment is increased. Tofacitinib has a short half-life (3 hours); however, the duration of immunosuppression following cessation of treatment is not fully known; for rheumatology patients it is recommended to stop 7 days pre-operatively2 – it may be prudent to also follow this advice for IBD indications. Refer to Figure 3 – Dosing intervals and half-lives of biologic therapies used for Inflammatory Bowel Disease for information on specific drugs.
Figure 3: Dosing intervals and half-lives of biologic therapies used for Inflammatory Bowel Disease
Rituximab is also licensed for chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL)7 – this is outside the scope of this monograph. Advice should be sought from the patient’s Haematologist/Oncologist.
Patients who require emergency surgery while on a biologic should be closely monitored for infection8, 9, 10, 11.
The potential of preventing post-operative infections by stopping biologics should be balanced against the risk of perioperative flare in disease activity. For minor surgery it may be possible to continue these agents. If necessary, withhold any doses due in the immediate post-operative period.
Recommence biologics post-operatively when there is good wound healing (typically around 14 days), all sutures and staples are out, and there is no evidence of infection1, 2, 3, 4, 5.
Patient’s taking narrow therapeutic drugs e.g. phenytoin, warfarin
Stopping or starting biologic therapy, specifically with sarilumab, tocilizumab and possibly belimumab, may affect expression of cytochrome P450 enzymes, which theoretically may affect metabolism of the patient’s other drugs. Additional monitoring may be needed in patient’s taking narrow therapeutic agents e.g. phenytoin, warfarin when stopping biologic therapy before surgery12, 13, 14.
Interaction(s) with Common Anaesthetic Agents
None6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27.
Interaction(s) with other Common Medicines used in the Perioperative Period
Clarithromycin 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 controlled15.
Other biologic agents
None6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27
Venous Thromboembolism (VTE) Risk
Patients taking baricitinib and tofacitinib should receive adequate thromboprophylaxis when undergoing surgery, as these medications have been associated with an increased risk of VTE15, 20.
Tocilizumab is a very potent suppressor of acute phase response. Patients having intravenous (IV) or subcutaneous (S/C) tocilizumab might need close monitoring in the post-operative period as the conventional indicators for sepsis (fever and acute phase response) might not be reliable1.
Rationale for Recommendations - Risk of Infection versus Risk of Disease Flare
There is limited and conflicting data with regard to the risk of infection perioperatively in association with biologic therapy1.
Figure 1 was compiled from the BSR guidance which included biologic therapies approved by the National Institute for Health and Care Excellence (NICE) as of June 2016 for the treatment of Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) and Axial Spondyloarthritis (SpA) including Ankylosing Spondylitis (AS)1. Therapies approved by NICE after June 2016, such as secukinumab, sarilumab and the Janus Kinase inhibitors, were not included1; advice for these agents was taken from the American College of Rheumatology /American Association of Hip and Knee Surgeons guidance2 or in the case of baricitinib, ixekizumab and sarilumab extrapolated from the dosage interval and half-life of the drug12, 20, 23.
Pharmacokinetic data for Figure 2 was obtained from the BAD guidance3 but for brodalumab, guselkumab, risankizumab and tildrakizumab, which were not included in this guidance, information was taken from the manufacturer’s data sheets21, 22, 24, 27. Dupilumab exhibits nonlinear clearance therefore it is not possible to provide a half-life, however, serum concentrations fall below the lower limit of detection by 9 weeks for the 200mg fortnightly and 10-11 weeks for the 300mg fortnightly regimes6.
Inflammatory Bowel Disease
Pharmacokinetic data for Figure 3 was obtained from the BSR guidance3 with the exception of vedolizumab, which was taken from the manufacturer’s data sheet25.