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In the double blinded study, patients were randomized to receive anifrolumab (300mg monthly), an intensified regimen of 3 x 900mg doses followed by 300mg monthly, or standard of care therapy with mycophenolate mofetil and oral glucocorticoids.
Emerging evidence for the role of anifrolumab in active lupus nephritis has been provided by the recent phase II study (TULIP-LN by Jayne et al published recently in Annals of Rheumatic Disease).1 In this double blinded study, 147 patients were randomized 1:1:1 to receive either a base regimen of anifrolumab (300mg monthly), an intensified regimen of 3 x 900mg doses followed by 300mg monthly, or standard of care therapy with mycophenolate mofetil and oral glucocorticoids. In total, 45 patients received the base regimen of anifrolumab, 51 received the intensified regimen, and 49 received placebo plus standard of care treatment.
The primary endpoint utilized in this trial was a change in 24-hour urine protein creatinine ratio from baseline to week 52. Secondary endpoints included complete renal response (CRR) at week 52 and several additional endpoints assessing steroid tapering and stricter definitions of renal response were also included.
Unfortunately, in this case the primary endpoint was not met with no significant differences in 24-hour urinary protein/creatinine ratio (UPCR) at week 52. However, there were numeric but non-statistically significant improvements in CRR, CRR with UPCR ≤0.5 mg/mg, CRR with inactive urinary sediment and sustained glucocorticoid reductions in the intensified anifrolumab group relative to the standard of care group.1
Pharmacokinetic analysis revealed that anifrolumab exposure in the baseline regimen lupus nephritis group was approximately 50% that observed in non-renal SLE comparators. This was felt possibly to be due to renal loss associated with proteinuria in active nephritis patients. Further analysis by the authors suggested that the intensified anifrolumab regimen was necessary to achieve the desired clinical and serological impact on disease.
It is disappointing that the primary endpoint in this trial was not met, however there is cause for optimism. Robust pharmacokinetic and pharmacodynamic analysis carried out by the authors has yielded good data on the implications of active lupus nephritis on anifrolumab dosing in future work. Furthermore, the numerical improvements in key outcome measures such as sustained glucocorticoid reduction and CRR are encouraging. CRR represents a robust renal endpoint and steroid reduction is an outcome measure that matters to patients with immediate and long-term impacts on morbidity. Utilizing the intensified regimen of anifrolumab may in part address the dosing implications of lupus nephritis and may drive more robust positive findings in future work. Initial signs remain positive, but further work will clarify matters.
From a safety perspective the incidence of serious adverse events was comparable between the anifrolumab and control groups. Herpes-zoster (HZV) incidence was noted to be higher in the combined anifrolumab treated groups (16.7% vs 8.2%) which is in keeping with previous literature on the subject.2In a previous anifrolumab study, most cases of herpes zoster had been manageable with antiviral medication and had not necessitated cessation of anifrolumab.2 Patients with SLE are noted to be at higher risk of HZV infection even in the absence of anifrolumab therapy, in part due to their immunosuppressive therapy and the presence of multiorgan disease.2,3 Current EULAR guidance already recommends the consideration of HZV vaccination in high risk patients.3,4,5 With that in mind, clinicians should already be considering HZV vaccination in high-risk lupus nephritis patients, even in the absence of anifrolumab therapy. That said, it is encouraging to note that the onset of zoster infection in these patients did not generally necessitate cessation of anifrolumab therapy.
In summary, the role of anifrolumab is expanding and this work provides encouraging initial results and guidance for further research. Lupus nephritis care is expanding with new agents after a prolonged period of stagnation. However, the role anifrolumab must play in driving improved outcomes remains unclear. TULIP-LN was a relatively small study focused on illustrating proof of concept for this indication, however the outcomes from this work are likely to have significant implications in driving more definitive research in the future.
1. Jayne D, Rovin B, Mysler EF, Furie RA, Houssiau FA, Trasieva T, et al. Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Ann Rheum Dis [Internet]. 2022 Apr 1 [cited 2022 Apr 27];81(4):496–506. Available from: https://ard.bmj.com/content/81/4/496
2. Tummala R, Abreu G, Pineda L, Michaels MA, Kalyani RN, Furie RA, et al. Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials. Lupus Sci Med [Internet]. 2021 Feb 1 [cited 2022 Apr 27];8(1):e000464. Available from: https://lupus.bmj.com/content/8/1/e000464
3. Mok CC. Herpes zoster vaccination in systemic lupus erythematosus: the current status. https://doi.org/101080/2164551520181514228 [Internet]. 2018 Jan 2 [cited 2022 Apr 27];15(1):45–8. Available from: https://www.tandfonline.com/doi/abs/10.1080/21645515.2018.1514228
4. Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, Van Assen S, Bijl M, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis [Internet]. 2020 Jan 1 [cited 2022 Apr 27];79(1):39–52. Available from: https://ard.bmj.com/content/79/1/39
5. Merrill JT, Furie R, Werth VP, Khamashta M, Drappa J, Wang L, et al. Anifrolumab effects on rash and arthritis: impact of the type I interferon gene signature in the phase IIb MUSE study in patients with systemic lupus erythematosus. Lupus Sci Med [Internet]. 2018 Nov 1 [cited 2021 Jul 12];5(1):e000284. Available from: https://lupus.bmj.com/content/5/1/e000284