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EADV 2020 | Controversies: Can We Stop Biologics in Complete Responders?

Biologics 2020

Presented by Lars Iverson MD, DMSc, and Stefano Piaserico MD, PhD

A report from the 29th Congress of the European Academy of Dermatology and Venereology

Biologics in psoriasis have been generally continued in patients who respond well, but is uninterrupted therapy required to adequately control the disease?

YES: Dr. Lars Iverson argued that interruption or cessation of biologic therapy is possible in certain patients, and is already tolerated well for various reasons; real world examples include cessation for surgery, pregnancy, and payer reimbursement policies. Furthermore, a systematic review of intermittent biologic use for psoriasis found that interruption and re-initiation was associated with continued efficacy in 60-95% of patients, though most studies were on TNF-inhibitors and relapse definition varied.25

Patient-specific predictors may be paramount in the decision to interrupt therapy. A study 202 patients on ustekinumab who clinically responded and then had treatment withdrawn found the following significant predictors of relapse via multivariate regression analyses. Positive response (unlikely to relapse) included the biologic naïve, high PASI response during treatment, and use of other immunosuppressants once off ustekinumab. Negative response (likely to relapse) was seen in positive family history of psoriasis, renal disease, and extended time to achieve PASI-50 after initiation.

Rheumatology and gastroenterology literature further support this theme, suggesting that short disease duration (early intervention) and low disease activity can predict maintained remission after cessation of TNF-inhibitors (TNFi) in rheumatoid arthritis.26

In summary, early disease intervention and effective treatment response appears to predict which patients may be candidates for interrupted therapy; achieving a ‘deep remission’ early in the course can guide further management.27

NO: Dr. Piaserico supported continued use of biologics given safety and efficacy of long-term use.

First, biologics do not carry the cumulative toxic effects that many traditional systemic medications do. From intermittent treatment with these medications, we know that relapse of psoriasis is almost inevitable, and this relapse is surprisingly more frequent than in psoriatic or rheumatoid arthritis.28-30

In a study of 270 patients on TNFi, 50% relapsed over 6 months after withdrawal with mean relapse of 2.7 (etanercept), 3.8 (adalimumab), and 2.5 (infliximab) months.31  Cardinal trials of newer biologics also showed high relapse rates including secukinumab (84% relapse by week 52),32  brodalumab (94% relapse, median 56 days),33  ixekizumab (87% relapse, median 143 days).34  Though IL-23 inhibitors appear to have a more durable response, median relapse rates range from 15-30 weeks.35,36

Additionally, anti-drug antibodies may form, there is risk of response-loss upon restarting therapy (especially with TNFi), and an increased incidence of infusion reactions upon restarting could affect compliance.37 Though the COVID-19 pandemic did cause some physicians to alter biologic management, fortunately the evolving data suggest biologic safety, and various dermatology associations recommend against stopping biologics in healthy patients.38-40

Lastly, controlling the systemic inflammation in psoriasis appears to mitigate the metabolic and cardiovascular dysfunction and comorbidities, and even the European Society of Cardiology recommends specialists treat at-risk conditions aggressively.41,42 It would therefore be unwise remove or interrupt biologic therapy, at least until more definitive data emerge.

Therapeutics Pearls:

  • Classical systemic psoriasis agents are effective and have known safety profiles. They should be considered among first-line treatments in patients without contraindications.
  • IL-17 and IL-23 targeted therapies both provide exceptional skin clearance. Though IL-23 is more effective, IL-17 response appears more rapid and is promising in treating psoriatic arthritis. IL-23 blockade suppresses only pathogenic Th17 cells, which allows its use in IBD.
  • Biologic selection should be customized to each individual patient to consider comorbidities, contraindications, and goals. Growing registry data, and subsequent trials, are improving our ability to choose the correct biologic for each patient.
  • Cessation or interruption of biologic therapy may be appropriate in some patients, specifically in those who were treated early and achieved excellent response. However, psoriasis relapse is common with biologic cessation, and strict long-term disease control with biologics may diminish systemic comorbidity risk.
References

References

1.     Korman NJ, Malatestinic W, Goldblum OM, et al. Assessment of the benefit of achieving complete versus almost complete skin clearance in psoriasis: a patient’s perspective. J Dermatolog Treat. Published online June 1, 2020:1-7.

2.     Barker J, Hoffmann M, Wozel G, et al. Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (Restore1). Br J Dermatol. 2011;165(5):1109-1117.

3.     Warren RB, Mrowietz U, von Kiedrowski R, et al. An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (Metop): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10068):528-537.

4.     Gyulai R, Bagot M, Griffiths CEM, et al. Current practice of methotrexate use for psoriasis: results of a worldwide survey among dermatologists. J Eur Acad Dermatol Venereol. 2015;29(2):224-231.

5.     Friedman B, Cronstein B. Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine. 2019;86(3):301-307.

6.     Yan K, Xu W, Huang Y, et al. Methotrexate restores the function of peripheral blood regulatory T cells in psoriasis vulgaris via the CD73/AMPK/mTOR pathway. Br J Dermatol. 2018;179(4):896-905.

7.     Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP. Methotrexate is a jak/stat pathway inhibitor. PLoS One. 2015;10(7):e0130078. 

8.     Lee J-H, Youn J-I, Kim T-Y, et al. A multicenter, randomized, open-label pilot trial assessing the efficacy and safety of etanercept 50 mg twice weekly followed by etanercept 25 mg twice weekly, the combination of etanercept 25 mg twice weekly and acitretin, and acitretin alone in patients with moderate to severe psoriasis. BMC Dermatol. 2016;16(1):11.

9.     Borghi A, Corazza M, Bertoldi AM, Caroppo F, Virgili A. Low-dose acitretin in treatment of plaque-type psoriasis: descriptive study of efficacy and safety. Acta Derm Venereol. 2015;95(3):332-336.

10.  Chen W, Zhang X, Zhang W, Peng C, Zhu W, Chen X. Polymorphisms of SLCO1B1 rs4149056 and SLC22A1 rs2282143 are associated with responsiveness to acitretin in psoriasis patients. Sci Rep. 2018;8(1):13182.

11.  Berry W, Daniel BS, Baker C, Foley P. Real world experience using Ciclosporin in psoriasis: Efficacy and toxicity in the Australasian Psoriasis Registry. Australas J Dermatol. Published online May 4, 2020.

12.  Mrowietz U, Szepietowski JC, Loewe R, et al. Efficacy and safety of LAS41008 (Dimethyl fumarate) in adults with moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm® - and placebo-controlled trial (Bridge). Br J Dermatol. 2017;176(3):615-623.

13.  Pathirana D, Ormerod AD, Saiag P, et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2009;23 Suppl 2:1-70.

14.  Blauvelt A, Reich K, Tsai T-F, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: Results from the CLEAR study. J Am Acad Dermatol. 2017;76(1):60-69.e9.

15.  Egeberg A, Bryld LE, Skov L. Drug survival of secukinumab and ixekizumab for moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2019;81(1):173-178.

16.  Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392(10148):650-661.

17.  Blauvelt A, Papp K, Gottlieb A, et al. A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 12-week efficacy, safety and speed of response from a randomized, double-blinded trial. Br J Dermatol. 2020;182(6):1348-1358.

18.  Reich K, Armstrong AW, Langley RG, et al. Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (Eclipse): results from a phase 3, randomised controlled trial. Lancet. 2019;394(10201):831-839.

19.  McInnes IB, Behrens F, Mease PJ, et al. Secukinumab versus adalimumab for treatment of active psoriatic arthritis (Exceed): a double-blind, parallel-group, randomised, active-controlled, phase 3b trial. Lancet. 2020;395(10235):1496-1505.

20.  Smolen, J., Nash, P., & Tahir, H. (2019, November 12). A Head-to-Head Comparison of Ixekizumab and Adalimumab in Biologic-Naïve Patients with Active Psoriatic Arthritis: Efficacy and Safety Outcomes from a Randomized, Open-Label, Blinded Assessor Study Through 52 Weeks. Retrieved November 01, 2020, from https://acrabstracts.org/abstract/a-head-to-head-comparison-of-ixekizumab-and-adalimumab-in-biologic-naive-patients-with-active-psoriatic-arthritis-efficacy-and-safety-outcomes-from-a-randomized-open-label-blinded-assessor-study-th/

21.  Ivanov S, Lindén A. Interleukin-17 as a drug target in human disease. Trends Pharmacol Sci. 2009;30(2):95-103.

22.  Patel DD, Kuchroo VK. Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity. 2015;43(6):1040-1051.

23.  Wilkinson N, Tsakok T, Dand N, et al. Defining the therapeutic range for adalimumab and predicting response in psoriasis: a multicenter prospective observational cohort study. J Invest Dermatol. 2019;139(1):115-123.

24.  Dand N, Duckworth M, Baudry D, et al. HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis. J Allergy Clin Immunol. 2019;143(6):2120-2130.

25.  Al-Hammadi A, Ruszczak Z, Magariños G, et al. Intermittent use of biologic agents for the treatment of psoriasis in adults. J Eur Acad Dermatol Venereol. Published online July 8, 2020.

26.  Tanaka Y, Takeuchi T, Mimori T, et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (Remission induction by remicade in ra) study. Ann Rheum Dis. 2010;69(7):1286-1291.

27.  Chiu H-Y, Hui RC-Y, Tsai T-F, et al. Predictors of time to relapse following ustekinumab withdrawal in patients with psoriasis who had responded to therapy: An eight-year multicenter study. J Am Acad Dermatol. Published online January 28, 2019.

28.  Kennedy NA, Warner B, Johnston EL, et al. Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis. Aliment Pharmacol Ther. 2016;43(8):910-923.

29.  Bots SJ, Kuin S, Ponsioen CY, et al. Relapse rates and predictors for relapse in a real-life cohort of IBD patients after discontinuation of anti-TNF therapy. Scand J Gastroenterol. 2019;54(3):281-288.

30.  Mangoni AA, Al Okaily F, Almoallim H, et al. Relapse rates after elective discontinuation of anti-TNF therapy in rheumatoid arthritis: a meta-analysis and review of literature. BMC Rheumatol. 2019;3:10.

31.  Stinco G, Balato N, Buligan C, et al. A multicenter retrospective case-control study on Suspension of TNF-inhibitors and Outcomes in Psoriatic patients (STOP study). G Ital Dermatol Venereol. 2019;154(4):392-399.

32.  Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014;371(4):326-338.

33.  Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175(2):273-286.

34.  Umezawa Y, Torisu-Itakura H, Morisaki Y, et al. Long-term efficacy and safety results from an open-label phase III study (Uncover-j) in Japanese plaque psoriasis patients: impact of treatment withdrawal and retreatment of ixekizumab. J Eur Acad Dermatol Venereol. 2019;33(3):568-576.

35.  Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76(3):418-431.

36.  Blauvelt A, Leonardi CL, Gooderham M, et al. Efficacy and safety of continuous risankizumab therapy vs treatment withdrawal in patients with moderate to severe plaque psoriasis: a phase 3 randomized clinical trial. JAMA Dermatol. 2020;156(6):649-658.

37.  Barker J, Hoffmann M, Wozel G, et al. Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (Restore1). Br J Dermatol. 2011;165(5):1109-1117.

38.  Gadarowski MB, Balogh EA, Bashyam AM, Feldman SR. Examining recommendations for the use of biologics and other systemic therapies during COVID-19: a review and comparison of available dermatology guidelines and patient registries. J Dermatolog Treat. Published online October 30, 2020:1-5.

39.  Piaserico S, Gisondi P, Cazzaniga S, Naldi L. Lack of evidence for an increased risk of severe Covid-19 in psoriasis patients on biologics: a cohort study from northeast Italy. Am J Clin Dermatol. 2020;21(5):749-751.

40.  Gisondi P, Piaserico S, Luigi N, et al. Incidence rates of hospitalization and death from COVID-19 in patients with psoriasis receiving biological treatment: a Northern Italy experience. J Allergy Clin Immunol. Published online November 5, 2020. (Europ Heart Journal, 2017).

41.  Osto E, Piaserico S, Maddalozzo A, et al. Impaired coronary flow reserve in young patients affected by severe psoriasis. Atherosclerosis. 2012;221(1):113-117.

42.  European Heart Journal (2012) 33, 1635–1701 doi:10.1093/eurheartj/ehs092

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