|Year : 2019 | Volume
| Issue : 1 | Page : 4-6
Is rituximab “The Wonder Drug” for antineutrophil cytoplasmic antibodies-associated vasculitis?
Saket Jha, GSRSNK Naidu, Aman Sharma
Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||14-Mar-2019|
Dr. Aman Sharma
Professor, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
|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
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. 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. 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. 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., 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.,
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. 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. Despite treatment with methotrexate and azathioprine for remission maintenance, the relapse rates hover around 35%. Cyclophosphamide as remission maintenance agent has a lower relapse rate; however, as stated above, it is associated with significant toxicity. 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., 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., Clinical manifestations such as ENT manifestation, pulmonary, and renal are more common than granulomatous manifestations such as pachymeningitis and orbital pseudotumor., The disease manifestations also vary with ethnic background. Indian population has higher number of PR3-positive disease, in contrast to Chinese population which has predominant MPA-positive disease. 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. On the contrary, evidence is divided in granulomatous pathology like orbital pseudotumor and pachymeningitis.,,
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. 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.
Apart from being a potent remission induction and maintenance agent, rituximab has also been used in pregnant patients presenting with GPA.
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.
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