Down-titration strategies

This table contains the strategies used in randomised controlled trials and controlled clinical trials of biological and targeted synthetic DMARD down-titration in rheumatoid arthritis. It is not intended to be an exhaustive list of all possible strategies, but may assist clinicians to choose a strategy when considering down-titration with their patients.

Classification

Medicine

Dose reduction

Considerations

Tumour necrosis factor inhibitor

Adalimumab

Dose interval increase

  • 40 mg/2 weeks → Stepwise increase in dose interval by 50% every 3 months (complete stop at fourth step)1
  • 40 mg/2 weeks → Stepwise increase in dose interval every 3 months, to 40 mg/3 weeks then 40 mg/4 weeks (then stop)2
  • 40 mg/2 weeks → 40 mg/3 weeks3
  • Available in 40mg fixed dose pen/syringe

Tumour necrosis factor inhibitor

Certolizumab pegol

Dose interval increase

  • 200 mg/2 weeks → 200 mg/4 weeks4
  • Available in 200mg fixed dose pen/syringe

Tumour necrosis factor inhibitor

Etanercept

Dose reduction

  • 50 mg/week → 25 mg/week5,6

Dose interval increase

  • 50 mg/week → Stepwise increase in dose interval by 50% every 3 months (complete stop at fourth step)1
  • 25 mg/twice weekly → 25 mg/week7
  • 50 mg/ week → Stepwise increase in dose interval every 3 months, to 50 mg/10 days then 50mg/2 weeks (then stop)2
  • Available in 25mg and 50mg fixed dose syringes, and 50mg fixed dose pen

B-cell targeted therapy

Rituximab

Dose reduction

  • Two 1000 mg infusions, 2 weeks apart → One 1000 mg infusion8
  • Available in 500mg and 1000mg vials.
  • Although Mariette et al.8 utilised a dose reduction, it is also accepted clinical practice to extend the period between treatments to more than 6 months.9

T-cell co-stimulation modulator

Abatacept

Dose reduction

  • 10 mg/kg infusion/month → 5 mg/kg infusion/month10
  • Available in 250mg vials and 125mg fixed dose pen/syringe

Janus Kinase inhibitor

Baricitinib

Dose reduction

  • 4 mg for ≥15 months → 2 mg for ≥15 months11
  • Available in 2mg and 4mg tablets

Multiple

Tumour necrosis factor inhibitors (adalimumab, certolizumab etanercept, golimumab, infliximab)

T-cell co-stimulation modulator (abatacept)

Interleukin 6 receptor inhibitor (tocilizumab)

Dose reduction

  • Standard dosing → 50% dose reduction12

Dose interval increase

  • Standard dosing → Stepwise increase in dose interval every year (up to 3 years with complete stop at third step)13
  • Golimumab available in 50mg fixed dose pen/syringe
  • Infliximab available in 100mg vials
  • Tocilizumab available in 80mg, 200mg and 400mg vials, and in 162mg fixed dose pen/syringe
  1. Fautrel B, Pham T, Alfaiate T, et al. Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study). Ann Rheum Dis 2016; 75(1): 59-67.
  2. van Herwaarden N, van der Maas A, Minten MJ, et al. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 2015; 350: h1389.
  3. l'Ami MJ, Krieckaert CL, Nurmohamed MT, et al. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial. Ann Rheum Dis 2018; 77(4): 484-7.
  4. Weinblatt ME, Bingham CO, 3rd, Burmester GR, et al. A Phase III Study Evaluating Continuation, Tapering, and Withdrawal of Certolizumab Pegol After One Year of Therapy in Patients With Early Rheumatoid Arthritis. Arthritis Rheumatol 2017; 69(10): 1937-48.
  5. Smolen JS, Nash P, Durez P, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet 2013; 381(9870): 918-29.
  6. van Vollenhoven RF, Ostergaard M, Leirisalo-Repo M, et al. Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis 2016; 75(1): 52-8.
  7. Raffeiner B, Botsios C, Ometto F, et al. Effects of half dose etanercept (25 mg once a week) on clinical remission and radiographic progression in patients with rheumatoid arthritis in clinical remission achieved with standard dose. Clin Exp Rheumatol 2015; 33(1): 63-8.
  8. Mariette X, Rouanet S, Sibilia J, et al. Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non-inferiority randomised controlled trial. Ann Rheum Dis 2014; 73(8): 1508-14.
  9. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 2011; 70(6): 909-20.
  10. Westhovens R, Robles M, Ximenes AC, et al. Maintenance of remission following 2 years of standard treatment then dose reduction with abatacept in patients with early rheumatoid arthritis and poor prognosis. Ann Rheum Dis 2015; 74(3): 564-8.
  11. Takeuchi T, Genovese MC, Haraoui B, et al. Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study. Ann Rheum Dis 2019; 78(2): 171-8.
  12. El Miedany Y, El Gaafary M, Youssef S, et al. Optimizing therapy in inflammatory arthritis: prediction of relapse after tapering or stopping treatment for rheumatoid arthritis patients achieving clinical and radiological remission. Clin Rheumatol 2016; 35(12): 2915-23.
  13. Bejerano C, Oreiro N, Fernandez-Lopez C, et al. Clinical evaluation usefulness of standardized protocol strategies of dose reduction in patients with rheumatoid arthritis in clinical remission treated with biologic therapies. The optibio study [Abstract]. Arthritis Rheumatol 2016; (Suppl 10).