Letter to the Editor
Successful use of azathioprine in glucocorticoid refractory immune amegakaryocytic thrombocytopenia of lupus
El uso exitoso de azatioprina en la trombocitopenia amegacariocítica inmune glucocorticoide refractaria del lupus
Latika Guptaa, Vikas Guptaa,
, Krushna Chandra Panib, Navkirti Mittalc, Vikas Agarwala
Corresponding author
a Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
b Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
c Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Consequently, evidence for its treatment is limited to case reports.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–3</span></a> Here we report successful use of azathioprine in this setting.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 48-year-old woman presented with polyarthralgia involving bilateral small and large joints, low-grade fever, and easy fatigability of eight years duration. She had Raynaud phenomenon but no skin rashes, oral ulcers, sicca symptoms or photosensitivity. The examination was unremarkable except for minor pedal edema.</p><p id="par0015" class="elsevierStylePara elsevierViewall">For last two months, her creatinine had been elevated (3.3<span class="elsevierStyleHsp" style=""></span>mg/dL). She had bland sub-nephrotic proteinuria and bilateral shrunken kidneys on sonography. She had been having intermittent thrombocytopenia in the past. Platelet count was 80,000/mm<span class="elsevierStyleSup">3</span> at her first presentation. She had never been worked up for lupus before, given the mild and intermittent nature of her arthralgia, and non-specific symptoms. Anti-nuclear antibody was positive by immunofluorescence in a speckled pattern. Anti-double-stranded DNA antibody was more than 300<span class="elsevierStyleHsp" style=""></span>IU/mL, complement levels were normal and Direct Coombs test was negative. She was initiated on 0.25<span class="elsevierStyleHsp" style=""></span>mg/kg prednisone and hydroxychloroquine with a diagnosis of systemic lupus erythematosus. She came back a week later with high-grade fever. This time she had thrombocytopenia of (10,000/mm<span class="elsevierStyleSup">3</span>) and lymphopenia (300/mm<span class="elsevierStyleSup">3</span>). The diagnostic possibilities considered were lupus disease activity, Macrophage Activation Syndrome (MAS) and viral fever. Serology for Dengue and Epstein–Barr virus were negative, as was polymerase chain reaction for Cytomegalovirus. Hemoglobin of 11.6<span class="elsevierStyleHsp" style=""></span>g/dL, normal aspartate transaminase (16<span class="elsevierStyleHsp" style=""></span>IU/L), alanine transaminase (21<span class="elsevierStyleHsp" style=""></span>IU/L), and coagulation parameters made MAS unlikely. A bone marrow biopsy revealed reduced megakaryocytes with preserved erythroid and myeloid precursors, and plasma cell infiltrate in the interstitium. It ruled out myelophthisis from infiltrative disorders such as myelofibrosis, infections and neoplasia. She was not on any drug that could cause thrombocytopenia, nor had any evidence of exposure to toxins. Thus, with a background of lupus, she was diagnosed as having immune-mediated amegakaryocytic thrombocytopenia. Initially, she was administered intravenous methylprednisolone at a dose of 1<span class="elsevierStyleHsp" style=""></span>g daily for three days and then, intravenous immunoglobulin at a dose of 1<span class="elsevierStyleHsp" style=""></span>g/kg daily for two days. The platelet count rose to 80,000/mm<span class="elsevierStyleSup">3</span> over the next seven days, but the rise was ill sustained, necessitating the addition of another immunosuppressant. The literature on therapeutic options in this setting is limited to occasional reports of Cyclosporine, Rituximab, and Eltrombopag. Due to the presence of end-stage renal disease as well as cost considerations, azathioprine (AZA) was considered. The dose was gradually escalated from 25<span class="elsevierStyleHsp" style=""></span>mg/day to 125<span class="elsevierStyleHsp" style=""></span>mg/day. Platelet counts stabilized at >100,00/mm<span class="elsevierStyleSup">3</span> by two months. The patient has done well over 3 years after initiating AZA, without further thrombocytopenia or new organ involvement related to lupus.</p><p id="par0020" class="elsevierStylePara elsevierViewall">It has been long believed that bone marrow aplasia in lupus is an exception rather than the rule.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Recent series have described aplasia in 10–50% of biopsies from lupus patients, suggesting it may be more common than previously thought.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,6</span></a> In amegakaryocytic thrombocytopenia, the pathogenesis is believed to be immune-mediated. Antibodies to the thrombopoietin receptor (c-Mpl) can block signaling on megakaryocytes, thereby halting maturation of platelets in the bone marrow.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">7,8</span></a> T-cells in lupus have inhibitory effects on Colony forming unit-Monocyte (CFU-M).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> Change in T helper to suppressor cell ratio was one of the earliest cited reasons for impaired megakaryopoiesis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> The infiltration of plasma cells in the bone marrow in our patient is surrogate for immune-mediated pathogenesis, though we haven’t substantiated this by the antibody or in vitro T cell assays.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Since there is evidence of a role of both cell-mediated and humoral factors in the pathogenesis of this entity in lupus, azathioprine may be a good choice when other therapies fail or cannot be used. In our knowledge, literature on the use of AZA in this setting is limited to a single case report.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> With successful treatment in our patient, we suggest that azathioprine should be added to the armamentarium to treat this rare entity.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0030" class="elsevierStylePara elsevierViewall">None to report.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interests</span><p id="par0035" class="elsevierStylePara elsevierViewall">None to report.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interests" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful treatment of amegakaryocytic thrombocytopenia with anti-CD20 antibody (rituximab) in a patient with systemic lupus erythematosus" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. 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Yoshinari" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/BF01451051" "Revista" => array:6 [ "tituloSerie" => "Clin Rheumatol" "fecha" => "1998" "volumen" => "17" "paginaInicial" => "219" "paginaFinal" => "222" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9694056" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0100" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful treatment of amegakaryocytic thrombocytopenia with azathioprine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Chang" 1 => "T.C. Tang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000328031" "Revista" => array:6 [ "tituloSerie" => "Acta Haematol" "fecha" => "2011" "volumen" => "126" "paginaInicial" => "135" "paginaFinal" => "137" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21701159" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000001600000003/v1_202006131316/S2173574320300575/v1_202006131316/en/main.assets" "Apartado" => array:4 [ "identificador" => "8400" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000001600000003/v1_202006131316/S2173574320300575/v1_202006131316/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574320300575?idApp=UINPBA00004M" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 7 | 11 |
| 2024 October | 27 | 27 | 54 |
| 2024 September | 30 | 17 | 47 |
| 2024 August | 52 | 37 | 89 |
| 2024 July | 36 | 26 | 62 |
| 2024 June | 49 | 35 | 84 |
| 2024 May | 42 | 33 | 75 |
| 2024 April | 36 | 19 | 55 |
| 2024 March | 31 | 23 | 54 |
| 2024 February | 36 | 27 | 63 |
| 2024 January | 26 | 16 | 42 |
| 2023 December | 26 | 32 | 58 |
| 2023 November | 31 | 25 | 56 |
| 2023 October | 30 | 22 | 52 |
| 2023 September | 82 | 34 | 116 |
| 2023 August | 35 | 14 | 49 |
| 2023 July | 23 | 21 | 44 |
| 2023 June | 30 | 19 | 49 |
| 2023 May | 28 | 17 | 45 |
| 2023 April | 16 | 7 | 23 |
| 2023 March | 41 | 24 | 65 |
| 2023 February | 39 | 17 | 56 |
| 2023 January | 25 | 18 | 43 |
| 2022 December | 41 | 23 | 64 |
| 2022 November | 40 | 27 | 67 |
| 2022 October | 43 | 27 | 70 |
| 2022 September | 29 | 22 | 51 |
| 2022 August | 24 | 28 | 52 |
| 2022 July | 23 | 46 | 69 |
| 2022 June | 20 | 33 | 53 |
| 2022 May | 20 | 37 | 57 |
| 2022 April | 35 | 36 | 71 |
| 2022 March | 25 | 50 | 75 |
| 2022 February | 24 | 33 | 57 |
| 2022 January | 38 | 40 | 78 |
| 2021 December | 29 | 37 | 66 |
| 2021 November | 21 | 45 | 66 |
| 2021 October | 27 | 38 | 65 |
| 2021 September | 21 | 40 | 61 |
| 2021 August | 22 | 32 | 54 |
| 2021 July | 16 | 22 | 38 |
| 2021 June | 16 | 39 | 55 |
| 2021 May | 28 | 39 | 67 |
| 2021 April | 77 | 76 | 153 |
| 2021 March | 54 | 25 | 79 |
| 2021 February | 17 | 19 | 36 |
| 2021 January | 19 | 21 | 40 |
| 2020 December | 22 | 21 | 43 |
| 2020 November | 23 | 17 | 40 |
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