Granulomatosis with polyangiitis (GPA) is a necrotizing vasculitis of the medium and small blood vessels, which can be fatal. Without proper treatment, approximately 80% of cases do not survive more than a year. In particular, rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage (DAH) are well-known life-threatening conditions in GPA. Rituximab is a chimeric monoclonal antibody directed against CD20 and recommended for the induction of remission in severe active GPA.[2,3] Plasma exchange (PE) may be considered for treating RPGN when the serum creatinine level is >5.6 mg/dl or in the setting of life-threatening DAH.[4,5] Concurrent use of rituximab and PE has been reported in antibody-mediated rejection after kidney transplantation or in thrombotic thrombocytopenic purpura. However, no case reports or studies have discussed the efficacy of rituximab plus concurrent plasma exchange for treating GPA. We report a case of GPA with diffuse non-infectious endocarditis, DAH, and RPGN, which was treated successfully with rituximab and PE combination therapy.
The institutional review board approved the study. Written informed consent was obtained from the patient for publication of the case.
2 Case presentation
A 23-year-old woman presented to our emergency room with fever, abdominal pain, vomiting, and diarrhea, which manifested after eating raw fish 3 days ago. Laboratory examination revealed mild anemia (hemoglobin (Hb) 11.5 g/dl) and elevated levels of erythrocyte sedimentation rate (ESR) (74 mm/hour) and C-reactive protein (CRP) (13.79 mg/dl). Blood chemistry results, including renal function, were within reference ranges. Abdominal computed tomography (CT) showed no specific findings except heterogeneous enhancement of the spleen. Colonoscopy showed hemorrhagic colitis (Fig. 1A) and she was admitted on suspicion of infectious colitis. Administration of intravenous antibiotics was ineffective. Three days after admission, the patient developed episcleritis and erythematous macules and violaceous subcutaneous nodules on the fingers (Fig. 1B), palms (Fig. 1C), and soles (Fig. 1D) which appeared similar to Janeway lesions or Osler nodes. Transesophageal echocardiogram (TEE) revealed mitral valve vegetation with mild regurgitation mimicking infective endocarditis (Fig. 1E). However, the blood culture did not yield any pathogens. The skin biopsy showed diffuse perivascular chronic inflammatory cell infiltration consistent with leukocytoclastic vasculitis (Fig. 1F).
Ten days after admission, the patient presented with blood-tinged sputum and respiratory distress (respiratory rate, 44 breaths/minute; oxygen saturation, 90% on 1 L/minute oxygen). The Hb level abruptly declined to 6.4 g/dl. Chest imaging showed reticular opacity on X-ray (Fig. 2A) and diffuse ground-glass opacity in both lung fields on CT (Fig. 2D). Bronchoscopy and bronchoalveolar lavage indicated DAH. Moreover, serum creatinine levels rapidly increased from 0.8 to 6.1 mg/dl. In addition, the patient developed proteinuria (urine protein to creatinine ratio [UPC] 1.28) and microscopic hematuria. The patient underwent renal biopsy and skin punch biopsy. Histopathologic findings revealed pauci-immune crescentic glomerulonephritis with renal granuloma (Fig. 3) and leukocytoclastic vasculitis of the skin. The test result for antineutrophil cytoplasmic antibody (ANCA) against proteinase 3 was positive (3.8 IU/ml; reference range <2.0 IU/ml), whereas test results for myeloperoxidase-ANCA and antinuclear antibodies were negative. We started methylprednisolone pulse therapy (1 g daily for 3 days) after making a diagnosis of GPA with non-infectious endocarditis, DAH, and RPGN (Fig. 4). However, no clinical improvement was observed. After initiating PE every other day, creatinine levels began to slowly decline, but DAH continued to worsen (Fig. 2B). Based on continued DAH progression, combined rituximab with PE therapy was considered.
We performed PE every 2 to 3 days for 5 consecutive sessions in total. Rituximab (375 mg per square meter of body-surface area) was administered once weekly for 4 weeks. The first dose of rituximab was administered the day after the first PE treatment. Two consecutive sessions of PE were performed after the first and second dose of rituximab, respectively. After the second dose of rituximab was administered, there was a significant decrease in alveolar hemorrhage and blood transfusion was no longer required. Chest X-ray and CT findings improved (Fig. 2C and E). Laboratory data, including serum creatinine and hemoglobin, were also notably improved. Mitral valve vegetation disappeared in follow-up TEE. The dosing schedules of rituximab and PE and the patient's clinical course according to therapy are summarized in Fig. 4A. The patient's general condition continued to improve dramatically over the following days.
The patient was discharged with a prescription of prednisolone 50 mg/day, azathioprine 50 mg/day, and trimethoprim/sulfamethoxazole (for pneumocystis pneumonia prophylaxis). Creatinine was 0.7 mg/dl and Hb was 9.2 g/dl on discharge. Prednisolone was tapered to 10 mg/day in the outpatient clinic. Azathioprine was changed to tacrolimus with or without mycophenolate mofetil (MMF) because of persistent mild proteinuria. However, GPA remained stable with low-dose prednisolone and immunosuppressants over a 5-year follow-up period. However, after the 5-year follow-up, rituximab was re-administered (375 mg/m2 once per week, for 4 weeks) as creatinine increased to 1.2 mg/dl and UPC rose to 1.21. MMF was discontinued to prepare for pregnancy and renal function remained stable at the 6-year follow-up (Fig. 4B).
While there are several reports on the concurrent use of rituximab and PE to treat other autoimmune diseases,[6,7] there is no standard regimen for this combination, including the dosage of the drug, the order of administration, and the interval between doses. The efficacy and safety of rituximab plus concurrent PE after kidney transplantation have previously been shown. However, no previous reports have discussed this combination for treating GPA, except one case of de novo ANCA-associated vasculitis which developed after kidney transplant. In the de novo ANCA-associated vasculitis case, contrary to our case, the additional PE had a therapeutic effect when the serum creatinine continued to rise despite rituximab therapy.
Our patient presented life-threatening complications of GPA, including hemorrhagic colitis, non-infectious endocarditis, DAH, and RPGN, in a short period of time. In particular, acute renal failure and DAH have been associated with an increased risk of early mortality. Due to the rapid progression of the disease, we considered more aggressive treatments to achieve clinically significant improvement. Another consideration was that the patient, a young woman, wanted to preserve her fertility and refused intravenous cyclophosphamide pulse therapy. As expected, renal function started to improve after initiating PE. However, DAH continued to deteriorate despite treatment with PE, and for this reason combination therapy with rituximab was considered. We cannot exclude the possibility that the patient's recovery could have been obtained by rituximab monotherapy. However, we also cannot exclude the possibility that the cessation of PE may have allowed the re-accumulation of the pathologic antibody, resulting in a rebound phenomenon. As a result, we decided to use concurrent treatment with rituximab and PE and achieved rapid clinical improvement.
PE can remove all solutes in the plasma, including drugs. Therefore, a major concern of this combination therapy is that rituximab may be removed during PE. It is possible to eliminate rituximab and reduce its clinical efficacy if PE is performed shortly after rituximab administration. It has been reported that 50% of rituximab was removed when it was administered <3 days prior to PE. As such, some authors recommended infusing rituximab 48 to 72 hours before the first PE treatment. However, in our case, 2 sessions of PE were done within 24 to 96 hours after the first and second dose of rituximab, but clinical improvement became far more pronounced after the second dose of rituximab. This may be because rituximab had a faster therapeutic effect before it was removed by PE. Rituximab binds to its target as soon as it is administered and immediately initiates cytolysis to induce effective B-cell depletion within 4 days. A study in macaques showed that rituximab administration depleted peripheral blood circulating CD19+/CD20+ cells within 24 hours. Due to the rapid effect of rituximab we therefore assumed that PE did not interfere with rituximab's immunosuppressive effects and could also provide an additional therapeutic effect by removing residual harmful antibodies.
Concurrent therapy with rituximab and PE can be considered in severe GPA refractory to standard therapy, which rapidly progresses to a life-threatening condition, or in young patients who wish to preserve fertility. However, no substantial evidence or treatment guidelines exist regarding the optimal dosing schedule of rituximab plus concurrent PE treatment. This case study suggests that the use of rituximab and concurrent PE may represent a promising combination for severe and refractory GPA. However, further studies are needed to confirm the efficacy and optimal dosing schedule for this combination therapy.
Conceptualization: Yeon-Ah Lee.
Data curation: Sang Wan Chung.
Supervision: Yeon-Ah Lee.
Writing – original draft: Ran Song.
Writing – review & editing: Yeon-Ah Lee.
Yeon-Ah Lee orcid: 0000-0001-8007-9131.
. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J 1958;2:265–70.
. Stone JH, Merkel PA, Spiera R, et al. Rituximab
versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221–32.
. Jones RB, Tervaert JW, Hauser T, et al. Rituximab
versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211–20.
. Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 2003;42:1149–53.
. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange
or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007;18:2180–8.
. Aglieco F, Manickaratnam S, Bona R, et al. A case report
of refractory warm autoimmune hemolytic anemia treated with plasmapheresis and rituximab
. Ther Apher Dial 2008;12:185–9.
. Darabi K, Berg AH. Rituximab
can be combined with daily plasma exchange
to achieve effective B-cell depletion and clinical improvement in acute autoimmune TTP. Am J Clin Pathol 2006;125:592–7.
. Ahmed T, Senzel L. The role of therapeutic apheresis in the treatment of acute antibody-mediated kidney rejection. J Clin Apher 2012;27:173–7.
. Sagmeister MS, Weiss M, Eichhorn P, et al. Case report
: de novo ANCA-associated vasculitis after kidney transplantation treated with rituximab
and plasma exchange
. BMC Nephrol 2018;19:270.
. Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol 2008;26:S94–104.
. Puisset F, White-Koning M, Kamar N, et al. Population pharmacokinetics of rituximab
with or without plasmapheresis in kidney patients with antibody-mediated disease. Br J Clin Pharmacol 2013;76:734–40.
. Jasti S, Coyle T, Gentile T, et al. Rituximab
as an adjunct to plasma exchange
in TTP: a report of 12 cases and review of literature. J Clin Apher 2008;23:151–6.
. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (Rituximab
) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 1997;90:2188–95.
. Schroder C, Azimzadeh AM, Wu G, et al. Anti-CD20 treatment depletes B-cells in blood and lymphatic tissue of cynomolgus monkeys. Transpl Immunol 2003;12:19–28.