|LETTER TO EDITOR
|Year : 2022 | Volume
| Issue : 2 | Page : 193-195
The changing paradigm of glucocorticoid therapy in antineutrophil cytoplasmic antibody-associated vasculitis
Kunal Chandwar1, Chandani Shah2, Puja Srivastava3
1 Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Neurology, SMS Hospital, Jaipur, Rajasthan, India
3 Department of Medicine, Smt NHL Municipal Medical College, Sardar Vallabhbhai Patel Institute of Medical Sciences and Research, Ahmedabad, Gujarat, India
|Date of Submission||18-Dec-2021|
|Date of Acceptance||21-Feb-2022|
|Date of Web Publication||19-Apr-2022|
Dr. Kunal Chandwar
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chandwar K, Shah C, Srivastava P. The changing paradigm of glucocorticoid therapy in antineutrophil cytoplasmic antibody-associated vasculitis. Indian J Rheumatol 2022;17:193-5
|How to cite this URL:|
Chandwar K, Shah C, Srivastava P. The changing paradigm of glucocorticoid therapy in antineutrophil cytoplasmic antibody-associated vasculitis. Indian J Rheumatol [serial online] 2022 [cited 2022 Jul 4];17:193-5. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/193/343500
Glucocorticoids (GCs) have been both a friend and a foe in the treatment of most immune-mediated inflammatory diseases, and ensuring the lowest possible GC dose has been among the most significant unmet needs for these patients.
Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) management has been extremely challenging, considering how difficult it is to douse the fire of inflammation in AAV.
There seems to be a broad consensus regarding rituximab being the drug of choice for induction and maintenance in severe AAV with background GC as recommended by the recent American College of Rheumatology (ACR) and vasculitis foundation (VF) guidelines. Clarity on GC dose and duration still eludes us largely. Recent trials have shown that lower doses of GC may be as efficacious as standard-dose (SD) protocol leading the ACR to recommend preferring low-dose (LD) GC protocol over SD GC protocol in their recent recommendations. What protocol of GC can be considered LD and how low a dose of GCs is good enough for optimum disease control is a question whose answer might not be as simple as it may seem.
Comparing different trials can sometimes be hazardous as different trials have different populations with inclusion and exclusion criteria differences. In this article, we have tried to compare the patient characteristics with the GC protocol in the recent trial [Table 1] to help decide how and when to use LD GC.
LoVAS (Low-dose Glucocorticoid Vasculitis Induction Study), ADVOCATE, and PEXIVAS (Plasma Exchange and Glucocorticoids for Treatment of Anti Neutrophil Cytoplasm Antibody Associated Vasculitis) trials proved that LD GC could be as good as SD in achieving remission. While patients in the LoVas trial were older, predominantly Myeloperoxidase (MPO) positive and had mild renal dysfunction, the trial was important to have used the lowest cumulative steroid doses for severe AAV management [Table 1]. Applicability in patients with more significant renal dysfunction, proteinase-3 positivity, and non-Japanese patients is unclear.
|Table 1: Characteristic of patients and glucocorticoid dose in recent and landmark trials|
Click here to view
ADVOCATE trial had patients with moderate renal dysfunction given 30 mg of avocapan (a recently FDA approved oral C5a inhibitor) compared to a LD steroid regimen; while the trial was transformative in providing a GC alternative in avocapan, the GC protocol used provided 70% response rate at 6 months. Cost of therapy, lack of knowledge about long-term side effects, and a protocol with disparities in the standard treatment provided can be critiqued, and the patients receiving avocapan were not necessarily steroid free.
PEXIVAS showed that LD GC could be equally good even in those sick enough to be candidates of plasma exchange. These patients were sicker and had the lowest baseline estimated glomerular filtration rate among most recent studies and yet proved definitively that LD GC protocol was equally effective as SD protocol in the sickest of the sick.
The scout trial used a low GC protocol to stop all GC by week 8. The response was similar to the RAVE (Rituximab in ANCA-Associated Vasculitis) trial but with a lower median Birmingham Vasculitis Activity Score (BVAS) of 5 and a higher relapse rate.
Another trial by Pepper et al. compared a 1-week GC protocol with a 2-week protocol in the background of rituximab along with cyclophosphamide. One would be skeptical of the regimen used as a combination of both rituximab and cyclophosphamide may be a dead-end option rather than a go too one, even if it offers a low cumulative steroid usage.
The steroid protocol to be used can be individualized to patient needs and vulnerabilities. A possible way to utilize GC in patients of severe AAV would be to prefer the LoVaS LD GC protocol for patients with mild renal dysfunction, MPO positivity and in those patients who are more likely to have adverse effects of GC like the elderly. Patients with moderate renal dysfunction who can follow the ADVOCATE protocol or use avocapan if availability and cost permit but going steroid-free even with avocapan might be a bold step to take, and those with severe renal dysfunction can and should be given the LD PEXIVAS protocol as recommended by the ACR/VF guidelines [Figure 1]. We might need studies comparing the three protocols and the correct dose post pulse to fine-tune our GC protocol, real-world data, and a more inclusive and diverse patient population (more Asian, African, and South American decent patients than Caucasians) might help generalize these globally. There is still debate on the right pulse GC dose– 15 mg/kg versus fixed-dose 500 mg or 1 g prednisolone equivalent for 3–5 days, and we need well-designed studies to answer the correct pulse dose and duration. What place does avocapan have in the therapy in terms of duration of therapy and concomitant steroid dose also needs answers as we go forward?
|Figure 1: Proposed protocol for glucocorticoid based on studies discussed|
Click here to view
The utopian dream of a zero-steroid regimen in AAV might turn out true with newer drugs and trials in the pipeline.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chung SA, Langford CA, Maz M, Abril A, Gorelik M, Guyatt G, et al.
2021 American College of Rheumatology/Vasculitis Foundation Guideline for the management of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 2021;73:1366-83.
de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al.
Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2009;150:670-80.
Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al.
Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al.
Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.
Walsh M, Merkel PA, Peh CA, Szpirt WM, Puéchal X, Fujimoto S, et al.
Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 2020;382:622-31.
Jayne DR, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021;384:599-609.
Furuta S, Nakagomi D, Kobayashi Y, Hiraguri M, Sugiyama T, Amano K, et al.
Effect of reduced-dose vs. high-dose glucocorticoids added to rituximab on remission induction in ANCA-associated vasculitis: A randomized clinical trial. JAMA 2021;325:2178-87.
Chandwar K, Kumar P, Dhakad U. Reduced-dose vs. high-dose glucocorticoids added to rituximab and remission induction in ANCA-associated vasculitis. JAMA 2021;326:1535.
Chandwar K. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021;384:e81.
Miloslavsky EM, Niles JL, Wallace ZS, Cortazar FB, Fernandes A, Laliberte K, et al.
Reducing glucocorticoid duration in ANCA-associated vasculitis: A pilot trial. Semin Arthritis Rheum 2018;48:288-92.
Pepper RJ, McAdoo SP, Moran SM, Kelly D, Scott J, Hamour S, et al.
A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 2019;58:260-8.