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Page 10 of 14 Skopis et al. Vessel Plus 2020;4:30 I http://dx.doi.org/10.20517/2574-1209.2020.42

The role of RTX as a maintenance therapy of pulmonary granulomas in patients with GPA was described in
an observational cohort study in 2014. The study looked at 5 patients with a history of PR-3 ANCA positive
GPA who had pulmonary granulomas that were previously resistant to traditional immunosuppressive
treatments. These patients received RTX infusions in reduced dosing schedules and were monitored for
radiographic improvement of their pulmonary granulomas on chest x-ray (CXR) every 6 months for a total
of 18-38 months. The results revealed that prolonged B cell depletion following treatment with RTX was
effective in reducing both the size and number of pulmonary nodules in these patients for at least 18 months
[26]
after treatment .

Renal manifestations of AAV include necrotizing and rapidly progressive glomerulonephritis with crescent
[2]
formation, leading to rapid decompensation of renal function and acute renal failure . Renal involvement
in AAV is an extremely poor prognostic factor, and it is the most significant predictor of mortality in AAV
[27]
patients . The renal manifestations of AAV can occur without concomitant systemic vasculitis, an entity
known as renal limited AAV. Rituximab has been studied as an induction agent for patients with AAV and
2
severe renal disease. 37 patients with a history of AAV and a GFR < 20/mL/min/1.73 m were studied in
order to determine the safety and efficacy of RTX and glucocorticoids alone vs. RTX, glucocorticoids and
CYC as induction therapy in patients with AAV and severe renal disease. The study found that there was
no difference in outcomes between the two treatment groups, and that RTX and glucocorticoids alone were
[28]
as effective as RTX, CYC and glucocorticoids in treating AAV patients with severe renal disease . The
MAINRITSAN trial also included patients with renal associated AAV and displayed the superiority of RTX
[23]
to AZA in maintenance of disease remission in these patients .

[29]
[30]
Other manifestations of AAV successfully treated with RTX include refractory scleritis , orbital GPA ,
[32]
[31]
[33]
hypertrophic pachymeningitis in refractory GPA , ENT manifestations of GPA , and DAH .
ADVERSE EFFECTS OF RITUXIMAB
Hypogammaglobulinemia has been observed in patients receiving maintenance therapy with RTX, which
is of particular concern given the increased risk of developing serious infections when immunoglobulins
are low [23,24] . Literature detailing an ideal threshold immunoglobulin level at which to stop RTX in
order to prevent development of serious, life threatening infections has not been described. It has
been described that antibiotic prophylaxis is effective in preventing infections in patients who develop
hypogammaglobulinemia after RTX therapy. These patients should receive influenza and pneumococcal
vaccinations prior to the initiation of treatment in order to prevent infections .
[34]
Late onset neutropenia has been described in patients with rheumatic diseases who have received RTX
therapy, albeit this is a rare side effect. Several mechanisms have been proposed which could potentially
contribute to late onset neutropenia in patients with rheumatic diseases receiving RTX including increased
production of B lymphocytes which halts production of T cells and, infiltration of bone marrow and
peripheral blood by T-large granular lymphocytes [34,35] .

Progressive multifocal leukoencephalopathy (PML) has also been described in patients with GPA and MPA
receiving RTX treatment. A cumulative analysis conducted in 2018 which studied patients receiving RTX
for GPA or MPA between 2009 and 2015 showed that the confirmed number of cases of reported PML was
very low (< 1 case per 10,000), indicating that this is a rather rare adverse effect of the medication. Despite
its rarity, physicians should still be aware of the risk of development of PML in AAV patients receiving
treatment with RTX, as these patients have often previously received cytotoxic immunosuppressants which
are also known risk factors for development of PML .
[36]