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 Table of Contents  
EDITORIAL
Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 4-6

Is rituximab “The Wonder Drug” for antineutrophil cytoplasmic antibodies-associated vasculitis?


Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication14-Mar-2019

Correspondence Address:
Dr. Aman Sharma
Professor, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.254190

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How to cite this article:
Jha S, Naidu G, Sharma A. Is rituximab “The Wonder Drug” for antineutrophil cytoplasmic antibodies-associated vasculitis?. Indian J Rheumatol 2019;14:4-6

How to cite this URL:
Jha S, Naidu G, Sharma A. Is rituximab “The Wonder Drug” for antineutrophil cytoplasmic antibodies-associated vasculitis?. Indian J Rheumatol [serial online] 2019 [cited 2019 Apr 25];14:4-6. Available from: http://www.indianjrheumatol.com/text.asp?2019/14/1/4/254190



Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) are clubbed under antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) in the Chapel Hill Consensus Conference 2012 nomenclature system.[1] There has been a paradigm shift in the management of AAV during the last decade.

Before the advent of cyclophosphamide in the 1970s, AAV was virtually a death sentence.[2] The use of oral cyclophosphamide did bring down the mortality significantly, but this came at a cost of higher side effects including risk of malignancies. This issue was addressed by several randomized controlled trials and the landmark CYCLOPS study. It showed that pulse cyclophosphamide is as good as oral cyclophosphamide with some risk of minor relapses which did not result in higher mortality.[3] Methotrexate and mycophenolate mofetil could not stand the test of time with their use restricted to remission induction in only mild limited variety of AAV.[4],[5] There was a dire need of a new drug, as the relapse rates of AAV were still high. There were significant proportion of patients with refractory disease or patients in whom cyclophosphamide could not be used either because of drug toxicity or fertility issues. RAVE and RITUXIVAS were two back to back trials published in 2010 which established rituximab as a potent remission induction agent.[6],[7]

RAVE trial showed rituximab to be noninferior to cyclophosphamide and had a sustained response at 18 months. In addition, rituximab performed better in patients with relapsing disease. It is important to note that this study excluded patients with severe lung (diffuse alveolar hemorrhage) and renal (creatinine >4 mg/dl) involvement. RITUXIVAS also showed rituximab to be noninferior to cyclophosphamide, and both drugs showed similar response rates at 24 months. Cyclophosphamide, however, was used in both arms in RITUXIVAS study. Apart from systemic involvement, rituximab has proved its worth against other agent for limited ear, nose, and throat (ENT) involvement.[8] Some of these manifestations though limited could be life-threatening, like subglottis stenosis.

AAV is notorious for its frequent relapses in more than 50% of cases.[9] Despite treatment with methotrexate and azathioprine for remission maintenance, the relapse rates hover around 35%.[10] Cyclophosphamide as remission maintenance agent has a lower relapse rate; however, as stated above, it is associated with significant toxicity.[11] Data from retrospective studies and RAVE trial paved the path of rituximab as maintenance agent. MAINRITSAN 1 and MAINRITSAN 2 trials have established the role of rituximab as an effective maintenance agent.[12],[13] Guillevin et al. compared fixed-dose rituximab and azathioprine in MAINRITSAN 1, which showed sustained remission with rituximab than azathioprine. The relapse rates were 5% in rituximab arm and 25% in azathioprine arm at 28 months. The fixed schedule of rituximab was challenged in MAINRITSAN 2 by tailored schedule. Patients in one arm were given scheduled rituximab at 6 months. In the other arm, rituximab was given if there was a twofold rise in PR3 titers or there were clinical signs of relapse. There was no significant difference in the relapse rate in either schedule, and the patients in the PR3 monitored arm received less number of rituximab infusions.

Treating refractory disease is still a challenge. Rituximab has shown promising results in this subset; however, the evidence is mostly from uncontrolled studies.[14],[15] Clinical manifestations such as ENT manifestation, pulmonary, and renal are more common than granulomatous manifestations such as pachymeningitis and orbital pseudotumor.[16],[17] The disease manifestations also vary with ethnic background.[18] Indian population has higher number of PR3-positive disease, in contrast to Chinese population which has predominant MPA-positive disease.[17] Rituximab may behave differently with pattern of disease manifestation. There is robust data for effective remission in patients with active vasculitis involving pulmonary, renal, and ENT manifestation.[19] On the contrary, evidence is divided in granulomatous pathology like orbital pseudotumor and pachymeningitis.[20],[21],[22]

The current study is a 24-month prospective observational study of 21 relapsing/refractory AAV patients. Rituximab resulted in remission in 16 cases with pulmonary as the dominant organ involvement followed by eye which included cases of scleritis and orbital pseudotumor.[23] The result of this study is in synchrony with other studies which shows rituximab as an efficient remission induction and maintenance agent in relapsing/refractory disease. It would be interesting to know as to how many patients out of this group received innovator and how many received biosimilar rituximab.

In our experience of 184 GPA patients, 56 patients received biomimic rituximab. Forty-five patients received rituximab for remission induction (primary induction in 20 and reinduction in 25) and 43 for remission maintenance. There were altogether 15 relapses in 13 patients and 7 deaths. Disease activity and sepsis were attributed to cause of death in 4 and 3 patients, respectively.[24]

Apart from being a potent remission induction and maintenance agent, rituximab has also been used in pregnant patients presenting with GPA.[25]

Treatment with rituximab has signaled the beckoning of a new era in the management of AAV. The fatal disease is now a chronic manageable disease. In addition to a primary induction and maintenance agent, this drug is useful in difficult to manage, relapsing/refractory disease. Various questions still remain such as ideal dose for remission maintenance, use of combination therapy especially in patients with refractory disease, and the optimal duration of remission maintenance. With this area, being a hotbed of research, we are sure that we would get some of the answers very soon.



 
  References Top

1.
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65:1-11.  Back to cited text no. 1
    
2.
Novack SN, Pearson CM. Cyclophosphamide therapy in Wegener's granulomatosis. N Engl J Med 1971;284:938-42.  Back to cited text no. 2
    
3.
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.  Back to cited text no. 3
    
4.
Stone JH, Tun W, Hellman DB. Treatment of non-life threatening Wegener's granulomatosis with methotrexate and daily prednisone as the initial therapy of choice. J Rheumatol 1999;26:1134-9.  Back to cited text no. 4
    
5.
Han F, Liu G, Zhang X, Li X, He Q, He X, et al. Effects of mycophenolate mofetil combined with corticosteroids for induction therapy of microscopic polyangiitis. Am J Nephrol 2011;33:185-92.  Back to cited text no. 5
    
6.
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.  Back to cited text no. 6
    
7.
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.  Back to cited text no. 7
    
8.
Lally L, Lebovics RS, Huang WT, Spiera RF. Effectiveness of rituximab for the otolaryngologic manifestations of granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken) 2014;66:1403-9.  Back to cited text no. 8
    
9.
Walsh M, Flossmann O, Berden A, Westman K, Höglund P, Stegeman C, et al. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2012;64:542-8.  Back to cited text no. 9
    
10.
Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008;359:2790-803.  Back to cited text no. 10
    
11.
Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, et al. Arandomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36-44.  Back to cited text no. 11
    
12.
Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371:1771-80.  Back to cited text no. 12
    
13.
Charles P, Terrier B, Perrodeau É, Cohen P, Faguer S, Huart A, et al. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: Results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2018;77:1143-9.  Back to cited text no. 13
    
14.
Cartin-Ceba R, Golbin JM, Keogh KA, Peikert T, Sánchez-Menéndez M, Ytterberg SR, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): Ten-year experience at a single center. Arthritis Rheum 2012;64:3770-8.  Back to cited text no. 14
    
15.
Ayan G, Esatoglu SN, Hatemi G, Ugurlu S, Seyahi E, Melikoglu M, et al. Rituximab for anti-neutrophil cytoplasmic antibodies-associated vasculitis: Experience of a single center and systematic review of non-randomized studies. Rheumatol Int 2018;38:607-22.  Back to cited text no. 15
    
16.
Sharma A, Lakshman AB, Nampoothiri RV, Verma RK, Rathi M, Naidu GS, et al. Pulmonary and ear, nose and throat (ENT) involvement in ANCA-associated Vasculitis at diagnosis-experience from a tertiary care centre in North India. J Assoc Physicians India 2017;65:40-7.  Back to cited text no. 16
    
17.
Sharma A, Naidu GS, Rathi M, Verma R, Modi M, Pinto B, et al. Clinical features and long-term outcomes of 105 granulomatosis with polyangiitis patients: A single center experience from North India. Int J Rheum Dis 2018;21:278-84.  Back to cited text no. 17
    
18.
Naidu GS, Misra DP, Rathi M, Sharma A. Is granulomatosis with polyangiitis in Asia different from the West? Int J Rheum Dis 2019;22 Suppl 1:90-4.  Back to cited text no. 18
    
19.
Charles P, Guillevin L. S3. Rituximab for ANCA-associated vasculitides: The French experience. Presse Med 2013;42:534-6.  Back to cited text no. 19
    
20.
Sharma A, Kumar S, Wanchu A, Lal V, Singh R, Gupta V, et al. Successful treatment of hypertrophic pachymeningitis in refractory Wegener's granulomatosis with rituximab. Clin Rheumatol 2010;29:107-10.  Back to cited text no. 20
    
21.
Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B, et al. Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): Comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis 2012;71:327-33.  Back to cited text no. 21
    
22.
Lower EE, Baughman RP, Kaufman AH. Rituximab for refractory granulomatous eye disease. Clin Ophthalmol 2012;6:1613-8.  Back to cited text no. 22
    
23.
Rituximab in Relapsed/Refractory Antineutrophil Cytoplasmic Antibody Associated Vasculitis: A SingleCenter Prospective Observational Study. Indian J Rheumatol 2019;14:12-16.  Back to cited text no. 23
    
24.
Sharma A, Mittal S, Naidu G, Jha S, Rathi M, Sharma V, et al. Efficacy and safety of biomimic rituximab in granulomatosis with polyangiitis – Experience from a single tertiary care centre in India [abstract]. Arthritis Rheumatol 2018;70 Suppl 10.  Back to cited text no. 24
    
25.
Singh P, Dhooria A, Rathi M, Agarwal R, Sharma K, Dhir V, et al. Successful treatment outcomes in pregnant patients with ANCA-associated vasculitides: A systematic review of literature. Int J Rheum Dis 2018;21:1734-40.  Back to cited text no. 25
    




 

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