Rituximab therapy for Wegener's granulomatosis refractory to conventional treatment
Tratamiento con rituximab en la granulomatosis de Wegener refractaria a la terapia convencional
A.. Sánchez-Escuredoa, R.. Núñezb, M.. Ibernóna, E.. Martínezc, D.. Lópezd, M.. Navarroa, J.. Boneta, J.. Araa, R.. Romeroa
a Servicio de Nefrología, Hospital Germans Trias i Pujol, Badalona, Barcelona,
b Servicio de Medicina Interna, Hospital Germans Trias i Pujol, Badalona, Barcelona,
c Servicio de Inmunología, Hospital Germans Trias i Pujol, Badalona, Barcelona,
d Servicio de Anatomía Patológica, Hospital Germans Trias i Pujol, Badalona, Barcelona,
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"apellidos" => "Romero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Germans Trias i Pujol, Badalona, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Germans Trias i Pujol, Badalona, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Servicio de Inmunología, Hospital Germans Trias i Pujol, Badalona, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Germans Trias i Pujol, Badalona, Barcelona, " "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento con rituximab en la granulomatosis de Wegener refractaria a la terapia convencional" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10772_108_19867_en_10772_f1.jpg" "Alto" => 489 "Ancho" => 600 "Tamanyo" => 182379 ] ] "descripcion" => array:1 [ "en" => "Chest computerised tomography showing pulmonary bleeding" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">To the Editor, </span></p><p class="elsevierStylePara">The prognosis of Wegener’s granulomatosis (WG) has improved with current therapies, but there is still a group of patients refractory to treatment. We describe a case of a refractory WG patient that reached remission with plasmapheresis and rituximab therapy, but later developed colon adenocarcinoma.</p><p class="elsevierStylePara">Immunosuppressive agents are effective drugs, but they are not exempt from severe secondary effects, such as infections and neoplasias. Our patient received different immunosuppressive treatments, among which was rituximab, which is considered to be an effective drug, but its long-term safety profile is unknown. Clinical monitoring is important in patients that receive multiple immunosuppressant drugs, given that they have a high risk of developing malignant diseases.</p><p class="elsevierStylePara">We present the case of a 42-year-old man, diagnosed with WG in 2004 by a renal biopsy. Induction treatment with 6-methylprednisolone boli (50mg) IV for three consecutive days, followed by oral prednisone (1mg/kg/day) and oral cyclophosphamide at doses of 100mg/day (1.5mg/kg/day). After three months of treatment, the patient achieved clinical remission, and PR3-ANCA became negative. During the maintenance phase, cyclophosphamide was replaced with mycophenolate mofetil (720mg/12hr). In 2007, the patient suffered a relapse. Treatment with cyclophosphamide in intravenous boli at doses of 850mg (10mg/kg) was resumed, with oral prednisone (1mg/kg/day). Clinical manifestations remitted and PR3-ANCA became negative after two months of treatment. However, in January 2008, the patient was admitted with a second relapse with haemoptysis and renal failure. He was administered 1g of intravenous cyclophosphamide every three weeks together with oral prednisone (1mg/kg/day). The patient continued with clinical respiratory and renal problems despite having received an accumulated dose of cyclophosphamide of 16g and high doses of corticosteroids. He was therefore diagnosed with refractory Wegener’s granulomatosis. A second kidney biopsy was performed, which showed persistence of pauci-immune necrotising glomerulonephritis with an extracapillary reaction in 7% of the glomeruli, moderate interstitial fibrosis and tubular atrophy and glomerulosclerosis in 50% of all glomeruli. Given the haemoptysis’ respiratory clinical involvement (Figure 1), plasma refills were started every other day for 15 days and oral prednisone at a dose of 1mg/kg/day. After the plasma refills were finished, rituximab was administered (375mg/m<span class="elsevierStyleSup">2</span> a week) for four weeks. Treatment with rituximab was monitored, measuring B lymphocytes in peripheral blood through CD19, immunoglobulin levels and PR3-ANCA titre (Table 1). Respiratory symptoms improved and renal function stabilised (creatinine 3.6mg/dl). All inflammation markers decreased, PR3-ANCA became negative and no B lymphocytes were found in peripheral blood. Mycophenolate mofetil was started with low doses of prednisone as a maintenance treatment. In November 2008, he was admitted again for anaemia-inducing rectal bleeding and progressive chronic renal failure with no signs of vasculitis activity (negative PR3-ANCA). He was diagnosed with rectal adenocarcinoma and had to start on haemodialysis.</p><p class="elsevierStylePara">Ten months later, the patient remained on haemodialysis, with no signs of vasculitis, negative PR3-ANCA and CD19 in peripheral blood at 0%.</p><p class="elsevierStylePara">Treatment with cyclophosphamide and corticosteroids has improved the prognosis of vasculitis, achieving remission for between 70% and 90% of cases.<span class="elsevierStyleSup">1</span> Nonetheless, 10% of patients do not achieve remission or present with frequent relapses, and are considered to be refractory to treatment.<span class="elsevierStyleSup">2</span> Several alternative treatments have been described for cases of refractory WG, such as: infliximab, etanercept, 15-deoxyspergualin, leflunomide, anti-lymphocyte serum and rituximab. Unfortunately there are not enough studies that indicate the best alternative therapy.<span class="elsevierStyleSup">3</span></p><p class="elsevierStylePara">Rituximab is a chimeric monoclonal antibody against the CD20 antigen that is expressed on the B lymphocyte surface; its binding results in the elimination of B lymphocytes and inhibition of antibody synthesis.<span class="elsevierStyleSup">4</span> At present there are several studies on its effectiveness in some autoimmune diseases and its use has also been described in a series of patients with ANCA-positive vasculitis refractory to treatment, in which full remission rates of 75% have been observed.<span class="elsevierStyleSup">5</span> In most studies with cases of refractory vasculitis which used rituximab, it was used concomitantly with steroids or other immunosuppressive agents. Patients achieved clinical remission in an average time of 2-6 months and in most cases remission was achieved together with a B-lymphocyte depletion in peripheral blood and a significant reduction in ANCA titres. B-lymphocyte recovery in peripheral blood often occurs at an average of 9-11 months and this is a risk factor for relapses after the first rituximab cycle. Repeated rituximab doses have been described, both as a preventative measure when B lymphocytes are recovered, and in relapse cases. This also achieves high levels of remission.<span class="elsevierStyleSup">6</span> Many of the studies on rituximab treatment consider it to be a safe and effective drug. The most common secondary effects are related to drug infusion. Among other less common effects are: development of neutropaenia, infections, progressive multifocal leukoencephalopathy, reactivation of hepatitis, intestinal perforation and interstitial pneumonitis, but there are few data that relate it to neoplasia development.<span class="elsevierStyleSup">7</span> It is difficult to be able to obtain conclusions on the safety of rituximab to treat vasculitis, given that the studies published are of reduced size. Recently, a study was published comparing rituximab with cyclophosphamide in the induction phase for patients with ANCA-positive vasculitis. It observed 6 cases of solid organ neoplasia in the group treated with rituximab (2 cases of colon neoplasia), which represented 5% compared to the control group.<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">Our patient did not have any family or personal history of malignant diseases, but developed a colon adenocarcinoma. Patients who have accumulated high doses of cyclophosphamide are at risk of developing neoplasias, according to the literature.<span class="elsevierStyleSup">9</span> Our patient received high doses of cyclophosphamide, but we were not able to confirm that the colon neoplasia was only related with this treatment. We suggest that rituximab could have been involved in the development of the colon adenocarcinoma. We believe that clinical monitoring is important in patients that receive multiple immunosuppressive drugs, given that they have a high risk of developing malignant diseases.</p><p class="elsevierStylePara"><a href="grande/10772_108_19867_en_10772_f1.jpg" class="elsevierStyleCrossRefs"><img src="10772_108_19867_en_10772_f1.jpg" alt="Chest computerised tomography showing pulmonary bleeding"></img></a></p><p class="elsevierStylePara">Figure 1. Chest computerised tomography showing pulmonary bleeding</p><p class="elsevierStylePara"><a href="grande/10772_108_19868_en_10772_t1.jpg" class="elsevierStyleCrossRefs"><img src="10772_108_19868_en_10772_t1.jpg" alt="Evolution of biochemical parameters over time"></img></a></p><p class="elsevierStylePara">Table 1. Evolution of biochemical parameters over time</p>" "pdfFichero" => "P1-E523-S3023-A10772-EN.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10772_108_19867_en_10772_f1.jpg" "Alto" => 489 "Ancho" => 600 "Tamanyo" => 182379 ] ] "descripcion" => array:1 [ "en" => "Chest computerised tomography showing pulmonary bleeding" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10772_108_19868_en_10772_t1.jpg" "Alto" => 299 "Ancho" => 600 "Tamanyo" => 135315 ] ] "descripcion" => array:1 [ "en" => "Evolution of biochemical parameters over time" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "De Groot K, Harper L, Jayne D, Flores Suárez LF, Gregorini G. 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Malignancies in Wegener¿s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients.\u{A0}J Rheumatol 2008;35:1. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18925682" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003100000004/v0_201502091636/X2013251411052087/v0_201502091637/en/main.assets" "Apartado" => array:4 [ "identificador" => "35437" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor - Brief Case Reports" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003100000004/v0_201502091636/X2013251411052087/v0_201502091637/en/P1-E523-S3023-A10772-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411052087?idApp=UINPBA000064" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 6 | 16 |
| 2024 October | 87 | 36 | 123 |
| 2024 September | 81 | 28 | 109 |
| 2024 August | 99 | 82 | 181 |
| 2024 July | 40 | 27 | 67 |
| 2024 June | 100 | 47 | 147 |
| 2024 May | 72 | 35 | 107 |
| 2024 April | 47 | 37 | 84 |
| 2024 March | 50 | 27 | 77 |
| 2024 February | 39 | 33 | 72 |
| 2024 January | 31 | 25 | 56 |
| 2023 December | 32 | 38 | 70 |
| 2023 November | 46 | 35 | 81 |
| 2023 October | 114 | 37 | 151 |
| 2023 September | 291 | 35 | 326 |
| 2023 August | 253 | 34 | 287 |
| 2023 July | 95 | 41 | 136 |
| 2023 June | 154 | 26 | 180 |
| 2023 May | 81 | 46 | 127 |
| 2023 April | 82 | 26 | 108 |
| 2023 March | 47 | 19 | 66 |
| 2023 February | 35 | 25 | 60 |
| 2023 January | 36 | 27 | 63 |
| 2022 December | 63 | 37 | 100 |
| 2022 November | 60 | 36 | 96 |
| 2022 October | 107 | 47 | 154 |
| 2022 September | 43 | 46 | 89 |
| 2022 August | 53 | 38 | 91 |
| 2022 July | 37 | 42 | 79 |
| 2022 June | 59 | 40 | 99 |
| 2022 May | 52 | 25 | 77 |
| 2022 April | 67 | 62 | 129 |
| 2022 March | 63 | 44 | 107 |
| 2022 February | 79 | 50 | 129 |
| 2022 January | 34 | 34 | 68 |
| 2021 December | 72 | 37 | 109 |
| 2021 November | 40 | 36 | 76 |
| 2021 October | 47 | 41 | 88 |
| 2021 September | 29 | 33 | 62 |
| 2021 August | 45 | 35 | 80 |
| 2021 July | 42 | 32 | 74 |
| 2021 June | 27 | 29 | 56 |
| 2021 May | 45 | 32 | 77 |
| 2021 April | 78 | 52 | 130 |
| 2021 March | 57 | 35 | 92 |
| 2021 February | 52 | 13 | 65 |
| 2021 January | 34 | 16 | 50 |
| 2020 December | 26 | 21 | 47 |
| 2020 November | 33 | 14 | 47 |
| 2020 October | 30 | 19 | 49 |
| 2020 September | 27 | 6 | 33 |
| 2020 August | 42 | 11 | 53 |
| 2020 July | 43 | 13 | 56 |
| 2020 June | 22 | 17 | 39 |
| 2020 May | 43 | 8 | 51 |
| 2020 April | 32 | 20 | 52 |
| 2020 March | 37 | 11 | 48 |
| 2020 February | 48 | 22 | 70 |
| 2020 January | 73 | 18 | 91 |
| 2019 December | 68 | 22 | 90 |
| 2019 November | 64 | 14 | 78 |
| 2019 October | 35 | 10 | 45 |
| 2019 September | 42 | 23 | 65 |
| 2019 August | 17 | 16 | 33 |
| 2019 July | 42 | 26 | 68 |
| 2019 June | 37 | 14 | 51 |
| 2019 May | 52 | 17 | 69 |
| 2019 April | 104 | 40 | 144 |
| 2019 March | 52 | 19 | 71 |
| 2019 February | 38 | 13 | 51 |
| 2019 January | 47 | 26 | 73 |
| 2018 December | 97 | 42 | 139 |
| 2018 November | 114 | 19 | 133 |
| 2018 October | 127 | 6 | 133 |
| 2018 September | 87 | 18 | 105 |
| 2018 August | 64 | 14 | 78 |
| 2018 July | 61 | 15 | 76 |
| 2018 June | 54 | 8 | 62 |
| 2018 May | 53 | 15 | 68 |
| 2018 April | 59 | 4 | 63 |
| 2018 March | 59 | 8 | 67 |
| 2018 February | 39 | 4 | 43 |
| 2018 January | 64 | 7 | 71 |
| 2017 December | 50 | 10 | 60 |
| 2017 November | 52 | 6 | 58 |
| 2017 October | 33 | 9 | 42 |
| 2017 September | 37 | 10 | 47 |
| 2017 August | 28 | 8 | 36 |
| 2017 July | 39 | 21 | 60 |
| 2017 June | 69 | 24 | 93 |
| 2017 May | 48 | 6 | 54 |
| 2017 April | 37 | 7 | 44 |
| 2017 March | 36 | 10 | 46 |
| 2017 February | 31 | 9 | 40 |
| 2017 January | 43 | 9 | 52 |
| 2016 December | 57 | 9 | 66 |
| 2016 November | 92 | 12 | 104 |
| 2016 October | 100 | 8 | 108 |
| 2016 September | 131 | 7 | 138 |
| 2016 August | 176 | 8 | 184 |
| 2016 July | 157 | 9 | 166 |
| 2016 June | 120 | 0 | 120 |
| 2016 May | 136 | 0 | 136 |
| 2016 April | 83 | 0 | 83 |
| 2016 March | 62 | 0 | 62 |
| 2016 February | 85 | 0 | 85 |
| 2016 January | 81 | 0 | 81 |
| 2015 December | 114 | 0 | 114 |
| 2015 November | 78 | 0 | 78 |
| 2015 October | 74 | 0 | 74 |
| 2015 September | 70 | 0 | 70 |
| 2015 August | 61 | 0 | 61 |
| 2015 July | 68 | 0 | 68 |
| 2015 June | 24 | 0 | 24 |
| 2015 May | 61 | 0 | 61 |
| 2015 April | 9 | 0 | 9 |
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