Cytokine Modulators (Immunosuppressants)


 

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


Elective Surgery 

Rheumatology Indications 
The Surgical Team and patient’s Rheumatologist should be involved in the planning for elective surgery1. The potential prevention of post-operative infection by stopping biologics should be balanced against the risk of perioperative flare in disease activity1 (see Further Information).

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 1Dosing 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

Dermatology Indications
The Surgical Team and patient’s Dermatologist should be involved in the planning for elective surgery. Balance the potential benefit of preventing post-operative infection by stopping biologic therapy against the risk of developing severe or unstable disease3, 4, 5.

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 2Dosing 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)
The decision to continue should be made on an individual patient basis in conjunction with the Surgical Team and the patient’s specialist.

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

 

Other Indications
Dupilumab is also licensed for asthma6 – this is outside the scope of this monograph. Advice should be sought from the patient’s Respiratory specialist.

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.

Emergency Surgery

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.

Post-operative Advice

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


Tofacitinib

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


  Further Information


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 

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.

Rheumatology
The British Society for Rheumatology (BSR) guidance acknowledges that previous studies suggested biologic agents should be stopped for a period of time equivalent to 3-5 half-lives before surgery; however, for those drugs with long half-lives this is likely to lead to potentially significant (and possibly irreversible) decline in disease control and major flare1. This often requires steroid therapy and the associated risks of this may exceed those of the biologics. Hence the pragmatic advice to time surgery for when one dosing interval has elapsed as this will coincide with the nadir of the drug’s effect and therefore the immunosuppressant effects of the drug will be at its lowest1.

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.

Dermatology
Biologic agents can safely be continued 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 procedures4, 5. The British Association of Dermatologists advise biologic agents should be stopped for a period of time equivalent to 3-5 half-lives before surgery3; however very few studies have been conducted in patients with psoriasis and most recommendations are extrapolated from studies in patients with rheumatoid arthritis or inflammatory bowel disease, which may not be appropriate4. Withholding these drugs for extended periods of time, in the absence of a well-established risk could be considered a conservative approach4; particularly as a retrospective study with limited sample size found no significant difference in post-operative risk of infection and delayed wound healing between those patients who continued and those who stopped biologic therapy, including those undergoing major surgery. Moreover, interrupting biologic therapy perioperatively was associated with a significant (P = 0.003) risk of flare of psoriasis28. It has also been suggested that consideration should be given to commencing alternative treatment e.g. methotrexate or ciclosporin to prevent disease flare in patients who stop biologic agents for prolonged periods4.

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
Patients with Crohn’s Disease have an increased rate of perioperative complications compared to the general surgical population; pre-operative use of corticosteroids is an established risk factor, however, the effect of biologic therapy on perioperative complications is less clear. The individual studies have heterogenous populations and different definitions of perioperative biologic use make meta-analysis challenging. Meta-analyses have found an increased risk of perioperative complications, specifically infections, in patients on pre-operative biologic therapy and possibly an increased risk of anastomotic complications29.

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.

 

  References


  1. Holroyd CR, Seth R, Bukhari M et al. The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis. Rheumatology. 2019; 58(2):e3-e42
  2. Goodman S, Springer B, Guyatt G et al. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guidelines for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. Arthritis Care & Research. 2017; 69(8):1111-1114
  3. British Association of Dermatologists. Guidelines for biologic therapy for psoriasis 2017. Accessed via www.bad.org.uk 24/05/2019
  4. Choi Y, Debbaneh M, Weinberg J et al. From the Medical Board of the National Psoriasis Foundation: Perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2016; 75:798-805
  5. Menter A, Strober B, Kaplan D et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. Journal of the American Academy of Dermatology 2019; 80(4):1029-1072
  6. Summary of Product Characteristics – Dupixent® (dupilumab) 300 mg solution for injection in pre-filled syringe. Sanofi Genzyme. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text August 2019]
  7. Summary of Product Characteristics – MabThera® (rituximab) 1400mg Solution for Subcutaneous Injection. Roche Products Limited. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text February 2019]
  8. Summary of Product Characteristics – Humira® (adalimumab) 40mg solution for injection in pre-filled pen. AbbVie Ltd. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text November 2018]
  9. Summary of Product Characteristics – Cimzia® (certolizumab pegol) 200mg solution for injection in pre-filled pen. UCB Pharma Ltd. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text March 2019]
  10. Summary of Product Characteristics – Simponi® (golimumab) 100mg solution for injection in pre-filled syringe. Merck Sharp & Dohme LImited. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text March 2019]
  11. Summary of Product Characteristics – Remicade® (infliximab) 100mg poweder for concentrate for solution for infusion. Merck Sharp & Dohme Limited. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text April 2019]
  12. Summary of Product Characteristics – Kevzara® (sarilumab) 150mg solution for injection in pre filled pen. Sanofi Genzyme. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text August 2017]
  13. Summary of Product Characteristics – RoActemra® (tocilizumab) 162mg Solution for Injection in Pre-Filled Pen. Roche Products Limited. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text January 2019]
  14. Summary of Product Characteristics – Benlysta® (belimumab) 120 mg powder for conentrate for solution for infusion. GlaxoSmithKline UK. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text July 2019]
  15. Summary of Product Characteristics – XELJANZ® (tofacitinib) 10 mg film-coated tablets. Pfizer Limited. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text July 2019]
  16. Summary of Product Characteristics – ORENCIA® (abatacept) 125mg solution for injection (pre-filled syringe). Bristol-Myers Squibb Pharmaceuticals Limited. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text April 2019]
  17. Summary of Product Characteristics – Enbrel® (etanercept) 25mg solution for injection in pre-filled pen. Pfizer Limited. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text April 2019]
  18. Summary of Product Characteristics – Cosentyx® (secukinumab) 150mg solution for injection in pre-filled pen. Novartis Pharmaceuticals UK Ltd. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text November 2018]
  19. Summary of Product Characteristics – STELARA® (ustekinumab) 45mg solution for injection in pre filled syringe. Janssen-Cilag Ltd. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text January 2019]
  20. Summary of Product Characteristics – Olumiant® (baricitinib) 2mg Film-Coated Tablet. Eli Lilly and Company Limited. Accessed via www.medicines.org.uk 24/05/2019 [date of revision of the text October 2018]
  21. Summary of Product Characteristics – Kyntheum® (brodalumab) 210 mg powder Solution for Injection. Leo Laboratories Limited. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text September 2017]
  22. Summary of Product Characteristics – Tremfya® (guselkumab) 100 mg solution for injection in pre-filled pen. Janssen-Cilag Ltd. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text August 2019]
  23. Summary of Product Characteristics – Taltz® (ixekizumab) 80 mg solution for injection in pre-filled pen. Eli Lilly and Company Limited. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text August 2019]
  24. Summary of Product Characteristics – Skyrizi® (risankizumab) 75 mg solution for injection in pre-filled syringe. AbbVie Ltd. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text August 2019]
  25. Summary of Product Characteristics – Entyvio® (vedolizumab) 300 mg powder for concentrate for solution for infusion. Takeda UK Ltd . Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text March 2019]
  26. Summary of Product Characteristics – Kineret® (anakinra) 100 mg solution for injection in a pre-filled syringe. Swedish Orphan Biovitrum Ltd. Accessed via www.medicines.org.uk 03/09/2019 [date of revision of the text March 2019]
  27. Summary of Product Characteristics – Ilumetri® (tildrakizumab) 100 mg solution for injection in pre-filled syringe. Almirall Limited. Accessed via www.medicines.org.uk 23/09/2019 [date of revision of the text September 2018]
  28. Bakkour W, Purssell H, Chinoy H et al. The risk of post-operative complications in psoriasis and psoriatic arthritis patients on biologic therapy undergoing surgical procedures. J Eur Acad Dermatol Venereol. 2016; 30(1):86-91
  29. Wong D, Roth E, Feuerstein J et al. Surgery in the age of biologics. Gastroenterol Rep (Oxf). 2019; 7(2):77-90.