Rituximab in Granulomatosis with Polyangiitis: Challenging Equilibrium Between Therapeutic Efficacy and Iatrogenic Complications

Case Report

Austin J Nephrol Hypertens. 2014;1(1): 1003.

Rituximab in Granulomatosis with Polyangiitis: Challenging Equilibrium Between Therapeutic Efficacy and Iatrogenic Complications

Adele Mitrotti, Luigi Rossi, Francesca Indrio, Michele Rossini, Anna Maria Di Palma, Carlo Manno, Loreto Gesualdo and Vincenzo Montinaro*

Department of Nephrology, Dialysis and Transplant, University of Bari “Aldo Moro”, Italy

*Corresponding author: Vincenzo Montinaro, Department of Nephrology, Dialysis and Transplant, University of Bari “Aldo Moro”, Azienda Ospedaliero-Univesitaria Policlinico, Bari, Piazza G. Cesare, 11, 70124 Bari, Italy

Received: June 05, 2014; Accepted: June 30, 2014; Published: July 02, 2014


Background: Granulomatosis with Polyangiitis is a renal-pulmonary syndrome that is treated with aggressive immunosuppressive therapy including high dose corticosteroids, cyclophosphamide, and plasmapheresis. Rituximab is also effective in inducing remission. Excess of immune suppressors may provoke generalized infections. Ultimate objective of therapy is to find equilibrium between the aggressive disease and avoidance of severe adverse effects of immune suppressors.

Case presentation: We report a patient affected by rapidly evolving granulomatosis with polyangiitis, characterized by dialysis-dependent acute renal failure. The initial therapy based on high dose corticosteroids, oral cyclophosphamide and plasmapheresis was ineffective, while two infusions of 1 g of rituximab 15 days apart were effective in inducing remission. A few days after the second rituximab infusion, the patient presented cardiac arrest and tonic-clonic seizures and was admitted to the ICU. Brain MRI showed a severe and diffuse leukoencephalopathy that indicated a severe prognosis.

A progressive multifocal leukoencephalopathy (PML) was excluded, since JC virus in liquor resulted negative. After a few days from the ICU admission, the patient showed a rapid clinical improvement, and was discharged a few weeks later with a mild residual renal insufficiency and complete disappearance of the neurological signs and normalization of the brain MRI pattern.

Conclusion: In this case, it is uncertain whether the neurological and cardiac complications were a consequence of rituximab infusion or represented an evolution of the vasculitis. Anti-CD20 mab can be very effective in inducing remission of granulomatosis with polyangiitis; however, the exact dose regimen and interval between administrations need to be established.

Keywords: Granulomatosis with polyangiitis; Rituximab; adverse effects


Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasm antibody (ANCA)-associated small-vessel vasculitis that provokes a life-threatening renal-pulmonary syndrome and systemic involvement [1,2]. Remission can be achieved in a high percentage of cases by an aggressive immune suppressive therapy that includes high dose intravenous methylprednisolone followed by oral prednisone or intravenous methylprednisolone associated to either oral or intermittent intravenous cyclophosphamide (CYP) [3]. Intermittent intravenous CYP has the same efficacy on induction of remission compared to daily oral CYP; still it allows administering a lower cumulative dose and is associated to the same rate of leukopenia or infections as the daily oral CYP. However, there is a trend of a higher relapse rate with intravenous CYP compared to oral CYP, although the difference does not seem to be significant [4]. Therefore, especially in the nephrological practice of treating GPA, there is more confidence with oral CYP.

However, CYP can be used for a limited time, owing to its high toxicity. Maintenance of remission is attained with low dose oralsteroids and eitherazathioprine or methotrexate for a prolonged time; mycophenolate mofetil has proved to be less effective than azathioprine [5]. Nevertheless, in certain very aggressive forms, the immune suppressors do not act rapidly enough to halt the evolution of vasculitis or in some cases the disease flares are frequent and cannot be managed with CYP [6]. For these reasons, rituximab has been recently indicated as a potential alternative to CYP for induction and maintenance of remission of GPA [7]. Excessive immune suppression may also provoke invasive and life-threatening localized or systemic infections. Therefore, management of GPA requires a careful choice of the therapeutic regimen in order to establish equilibrium between the immune suppression and avoidance of potentially fatal complications.

We describe herein a case of GPA with an aggressive clinical course that was treated initially by oral CYP and, due to the rapidly deteriorating clinical conditions, with rituximab subsequently. The anti-CD20 treatment rapidly changed the disease course and induced remission, but was associated to severe, although reversible, cardiac and neurologic complications.

Case History

The patient was a 72 years old male, affected by hypertension that had underwent trans-ureteral resection of a bladder carcinoma 10 years before. In April 2013, a moderate renal insufficiency was detected (eGFR 44 ml/min/1.73 m2, according to CKD-EPI equation); other laboratory investigations were not performed. A month later, severe renal insufficiency supervened and was associated with fever, fatigue, dyspepsia, constipation and weight loss. Other relevant laboratory findings were anemia, hypoalbuminemia, proteinuria, HBs Ag positivity. The autoantibody evaluation by immunofluorescence assays showed positivity of c-ANCA, which was associated with anti-PR3 antibody to high titer by the ELISA assay (Table 1). The severe renal impairment required hemodialysis. After a week, renal biopsy was performed. Renal histopathologic alterations were characterized by diffuse extra capillary proliferation, crescents in various stages (cellular, fibrocellular and fibrous) and segmental fibrinoid necrosis of capillary loops. Interstitial lymphocytic and monocytic cell infiltrate was also present, associated to tubulitisand severe tubular damage. Finally, interstitial fibrosis was evident in 50% of the renal parenchyma. In consideration of the histological finding, an immunosuppressive therapy with high dose methylprednisolone bolus and oral CYP 100 mg per day was administered. Also, ten treatments of plasma exchange were performed. Given the positivity for HBs Ag, an antiviral treatment with Entecavir 0.5 mg every 72 hours was initiated. At this time point, chest CT showed bilateral diffuse parenchymal infiltrates in the upper lobes associated with calcified nodules in both lungs (Figure 1); clinically, the patient presented gross hematuria and hemoptysis; therefore, broad-spectrum antibiotics and antifungal therapy was initiated.