Dr. Ayman El - Gendy

Head of Dermatology Department , Saudi Airline

Abstract

Psoriasis is a common, chronic inflammatory skin disorder that occurs worldwide and the prevalence differs significantly between different people and regions. In this report, we present a case with severe psoriasis with PASI 35 (psoriasis area and severity index), who had poor response to topical preparations and phototherapy, secondary failure to TNFα antagonists (etanercept and adalimumab), ustekinumab, as well as failure to response to secukinumab regimen. Switching the patient to ixekizumab after failure to respond to secukinumab, remarkably ixekizumab, an interleukin (IL) 17A inhibitor provided almost complete psoriasis clearance (90% improvement) after 12 weeks of treatment. The patient then discontinued ixekizumab for two months due to surgical intervention (abdominoplasty) and regained PASI 90 response one month after retreatment.

Introducation

Psoriasis is a common, chronic, noncommunicable skin disease. The reported prevalence of psoriasis in countries ranges between 0.09% and 11.43%, making psoriasis a serious global problem with at least 100 million individuals affected worldwide and among different ethnic groups (Kim et al. 2019; WHO 2016). It can arise at any age, and is most common in the age group 50–69. Along with the progress in understanding psoriasis pathogenesis, highly targeted and effective therapies have since developed with the perspective not only to improve but to clear psoriasis (Ronholt and Iversen 2017). Recent advances in biologic agents have considerably expanded the treatment options for patients with psoriasis including Ixekizumab (Loft et al. 2019). Ixekizumab (Taltz®) is a subcutaneously administered, humanized anti-interleukin (IL) 17A monoclonal antibody indicated for the treatment of adults with moderate to severe plaque psoriasis (Syed 2017). In this report, we present a case with severe psoriasis with PASI 35, who failed to respond to topical preparations, phototherapy, TNFα antagonists (etanercept and adalimumab), ustekinumab, as well as secukinumab, and was finally treated with ixekizumab for 12 weeks.

Case Presentation

A 44-year-old woman was referred to our clinic with a history of severe psoriasis (PASI 35) for many years and several admissions to the hospital because of the psoriasis. The patient has a past medical history of obesity, hypertension, hyperlipidemia and no family history of psoriasis or other dermatologic diseases. Multiple therapies were attempted, including topical preparations and phototherapy, TNFα antagonists (etanercept and adalimumab), and ustekinumab. Systemic treatments were not introduced due to comorbidities of psoriasis. Given the poor response to earlier treatments, the patient started treatment with secukinumab 300mg as per label. After 12 weeks, absolute PASI score 75 response was reached. However, after 32 weeks, the patient started to lose the response with the reappearance of psoriasis severely. Considering the failure of this rescue treatment, the patient initiated ixekizumab with the recommended induction and maintenance dose as per label (160 mg at first week, then 80 mg/ 2 weeks). At a follow-up visit 2 weeks later, the patient achieved PASI 75 and at week 12, we observed almost complete resolution (PASI 90 response) (Figure 1). After 12 weeks of treatment, the patient maintained a good response, without any safety issues. The patient then discontinued ixekizumab for two months due to surgical intervention (abdominoplasty) and regained PASI 90 response one month after retreatment.

Discussion

In this case we found that switching to ixekizumab after failure to respond to secukinumab led to a significant clinical improvement, even though both agents are IL-17A inhibitors. This is concurred with a report that presented that 88.2 % of secukinumab non-responder patients reached PASI 75 response at week 12 after switching to ixekizumab, irrespective of the reason or timing of secukinumab discontinuation (Georgakopoulos et al. 2018). Loss of efficacy of biological therapies in patients with psoriasis is a well-known event. Biological switching is common in clinical practice, especially in tumour necrosis factor-a and interleukin (IL)-12/23 inhibitor treatment. In our case, switching the patient to ixekizumab after failure to respond to secukinumab, remarkably ixekizumab provided almost complete psoriasis clearance (90% improvement) after 12 weeks of treatment. However, the reason for the cure of ixekizumab after the failure to respond to secukinumab with the same mechanism of action is not well established. Even though ixekizumab and secukinumab having the same mechanism of action, it does not mean that they are biologically equivalent or have the similar clinical outcomes. Slight variances in the properties of an antibody, such as affinity, specificity, and solubility, may have a large influence in terms of efficacy. Reports from previous studies also stated that secukinumab had the lowest drug survival among all the biologics (Azevedo and Torres 2018). Hypothetical explanations for this different clinical outcome include a very high binding affinity of ixekizumab tohuman IL-17A (KD<3pM), compared to secukinumab (KD between 60370pM, average approximately 200pM) (Liu et al. 2016). Furthermore, the difference in the binding affinity to human IL-17A/F heterodimer may also have medical influence, as ixekizumab binds to human IL-17A/F heterodimer with high affinity (KD<3pM) whereas secukinumab affinity is considerably lower (KD ~2000pM) (Liu et al. 2016). This appears significant since IL-17A/F heterodimer and IL-17A homodimers signal through the same IL -17 receptor A/receptor C complex (IL-17RA/RC), (Glatt et al. 2018). Moreover, IL-17A/F heterodimer is a two-faced cytokine closely mimicking IL-17A as well as IL-17F. Furthermore, emerging evidence suggests that IL-17F contributes to chronic tissue inflammation beyond IL-17A alone (Azevedo and Torres2018). Although continuous treatment of psoriasis is recommended for optimal long-term management of the disease, treatment may need to be interrupted in routine clinical practice. The duration of remission following treatment withdrawal is variable. In our case, the patient discontinued ixekizumab for two months due to surgical intervention (abdominoplasty) and regained PASI 90 response one month after retreatment. Findings from one study had stated that most patients who were withdrawn had disease relapse, and most of those patients seemed to recapture response after 24 weeks of treatment. ( Blauvelt et. al. 2017).

Conclusion

In this case study, the patient responded favorably to ixekizumab, which opens the possibility of using new biologic agents and individualized therapy in patients with psoriasis.

Lessons Learned

1. Time: 12 weeks.

2. Failure: patient failed to respond to topical preparations, phototherapy, TNFα antagonists (etanercept and adalimumab), ustekinumab, and secukinumab regimen.

3. Success: Ixekizumab, an interleukin 17A inhibitor provided almost complete psoriasis clearance (90% improvement) after 12 weeks of treatment. If necessary to interrupt therapy during routine clinical practice, retreatment with ixekizumab is safe and effective.

References

Azevedo A, Torres T. The successful treatment with ixekizumab in a multi-failure psoriasis patient.Dermatol Online J. 2018 Sep 10; 24(9). Georgakopoulos JR, Phung M, Ighani A, Yeung J.Efficacy and safety of switching to ixekizumab in secukinumab nonresponders with plaque psoriasis: A multicenter retrospective study of interleukin 17A antagonist therapies. J Am Acad Dermatol. 2018 Jul; 79(1):155-157. Glatt S, Baeten D, Baker T, et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo- Lessons Learned controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann 1. Time: 12 weeks. 2. Failure: patient failed to respond to topical preparations, phototherapy, TNFα antagonists (etanercept and adalimumab), ustekinumab, and secukinumab regimen. 3. Success: Ixekizumab, an interleukin 17A inhibitor provided almost complete psoriasis clearance (90% improvement) after 12 weeks of treatment. If necessary to interrupt therapy during routine clinical practice, retreatment with ixekizumab is safe and effective. Rheum Dis. 2018 Apr; 77(4):523-532. Kim BR, Kang D, Kang M, et al. Risk of acute infections in patients with psoriasis: A nationwide population-based cohort study.J Am Acad Dermatol. 2019 Nov 5. pii: S0190- 9622(19)32996-2. doi: 10.1016/j.jaad.2019.10.072. World Health Organization, Global Report on Psoriasis, World Health Organization, 2016 Liu L, Lu J, Allan BW, et al. Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A.J Inflamm Res. 2016 Apr 19;9:39- 50. Loft ND, Vaengebjerg S, Halling-Sønderby AS, et al, Adverse events with IL-17 and IL-23 inhibitors for psoriasis and psoriatic arthritis: a systematic review and meta-analysis of phase III studies.J Eur Acad Dermatol Venereol. 2019 Nov 13. doi: 10.1111/jdv.16073. Rønholt K, Iversen L.Old and New Biological Therapies for Psoriasis.Int J Mol Sci. 2017 Nov 1; 18(11). pii: E2297. Syed YY.Ixekizumab. A Review in Moderate to Severe Plaque Psoriasis.Am J Clin Dermatol. 2017 Feb; 18(1):147-158. Blauvelt A, Papp KA, Sofen H et al. Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis. J Eur Acad Dermatol Venereol 2017; 31: 1004– 1013
Categories: Dermatology

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