Case report
Anakinra induces complete remission of nephrotic syndrome in a patient with familial Mediterranean fever and amyloidosis
Anakinra induce la remisión completa del síndrome nefrótico en un paciente con fiebre mediterránea familiar y amiloidosis
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Sevillano, Eduardo Hernandez, Esther Gonzalez, Isabel Mateo, Eduardo Gutierrez, Enrique Morales, Manuel Praga" "autores" => array:7 [ 0 => array:4 [ "nombre" => "Ángel M." "apellidos" => "Sevillano" "email" => array:1 [ 0 => "sevillano.am@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Eduardo" "apellidos" => "Hernandez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Esther" "apellidos" => "Gonzalez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Isabel" "apellidos" => "Mateo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Eduardo" "apellidos" => "Gutierrez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Enrique" "apellidos" => "Morales" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Manuel" "apellidos" => "Praga" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital Universitario 12 de Octubre, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anakinra induce la remisión completa del síndrome nefrótico en un paciente con fiebre mediterránea familiar y amiloidosis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1709 "Ancho" => 2360 "Tamanyo" => 107877 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient progress after starting treatment with anakinra. SAlb, serum albumin (g/dL); SCr, serum creatinine (mg/dL); proteinuria, 24<span class="elsevierStyleHsp" style=""></span>h proteinuria (g/24<span class="elsevierStyleHsp" style=""></span>h).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Familial Mediterranean fever (FMF) is a hereditary inflammatory disease with an autosomal recessive pattern.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> It is caused by mutations in the <span class="elsevierStyleItalic">MEFV</span> gene, which codes for the protein pyrin. The abnormal synthesis of this protein leads to the dysregulation of various pathways involved in the control of inflammation (such as synthesis of interleukin-1β, activation of nuclear factor κβ, and apoptosis),<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2,3</span></a> which produces a sustained inflammatory state in patients with the disease. Clinically, FMF manifests as recurrent self-limiting episodes of fever and polyserositis. This maintained inflammation can lead to secondary amyloidosis (AA), which is one of the most devastating complications of this disease.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4,5</span></a> Several studies have demonstrated the effectiveness of colchicine in the treatment of FMF, in reducing the frequency and severity of inflammatory episodes in affected patients and preventing the onset of AA.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">6,7</span></a> However, colchicine is not effective in patients with clinical manifestations of AA, particularly if there is renal amyloidosis.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">8,9</span></a> Anakinra, an interleukin-1β inhibitor, has been shown to be beneficial in the treatment of FMF, reducing the number of episodes of the disease.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> In this article we describe the first case of a patient with FMF and nephrotic syndrome (NS) secondary to AA with complete remission of NS after starting treatment with anakinra.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Clinical case</span><p id="par0010" class="elsevierStylePara elsevierViewall">We present the case of a 76-year-old man diagnosed in 1995 with FMF, on the basis of symptoms of recurrent, self-limiting episodes of abdominal pain and fever. Following this diagnosis, he was prescribed treatment with colchicine at a dose of 0.5<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h, and he remained asymptomatic in subsequent years. In November 2010, the colchicine was stopped by his general practitioner, after which the patient started to experience episodes of polyarthralgia, chest pain, and abdominal pain. In January 2011 the patient was referred to our centre for investigation. On examination in clinic, the patient was afebrile, with a blood pressure of 95/71<span class="elsevierStyleHsp" style=""></span>mmHg and a heart rate of 83 beats per minute. The only finding of note was mild ankle oedema. Investigations revealed a serum creatinine of 1.33<span class="elsevierStyleHsp" style=""></span>mg/dL, serum albumin of 2.14<span class="elsevierStyleHsp" style=""></span>g/dL, cholesterol of 285<span class="elsevierStyleHsp" style=""></span>mg/dL, and triglycerides of 295<span class="elsevierStyleHsp" style=""></span>mg/dL. Proteinuria was 6.1<span class="elsevierStyleHsp" style=""></span>g/day. Urinary sediment showed 15 red blood cells per field. Other investigation parameters, including leukocytes, platelets, and haemoglobin, were normal. Mantoux test was negative.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Given the suspicion that the patient was experiencing new episodes of FMF, he was restarted on colchicine, and a genetic study was performed, which showed the M694 V mutation in the <span class="elsevierStyleItalic">MEFV</span> gene. Due to the presence of NS, a renal biopsy was performed: on optical microscopy, amorphous deposits were seen at a glomerular and vascular level. The deposits were Congo red positive. Electron microscopy revealed the presence of randomly arranged, unbranched fibrils measuring 8–10<span class="elsevierStyleHsp" style=""></span>nm, characteristic of amyloidosis.</p><p id="par0020" class="elsevierStylePara elsevierViewall">After establishing a diagnosis of NS secondary to AA, the dose of colchicine was increased to 1<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h, and enalapril was started to reduce proteinuria. These measures led to arterial hypotension and a deterioration in renal function, therefore enalapril was stopped. The NS worsened, requiring an increased dose of diuretics to control oedema, therefore in February 2011 it was decided to start treatment with anakinra at a dose of 100<span class="elsevierStyleHsp" style=""></span>mg/day. Proteinuria began to decrease from the second month of treatment, and the patient had a partial remission of NS in the fifth month, as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. Complete remission of NS was achieved after 30 months of treatment (proteinuria<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>g/day). At the most recent follow-up (42 months after starting anakinra), proteinuria was 0.4<span class="elsevierStyleHsp" style=""></span>g/day, serum creatinine was 1.18<span class="elsevierStyleHsp" style=""></span>mg/dL, and serum albumin was 4<span class="elsevierStyleHsp" style=""></span>g/dL. The clinical progress of the patient has been good, with no new episodes of FMF. The patient has had no adverse effects related to the anakinra treatment.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">Secondary amyloidosis is a typical complication in patients with chronic inflammatory disorders.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> Familial Mediterranean fever is the classic hereditary inflammatory disease, and AA is one of its most important complications. The use of colchicine in FMF was increased after the publication of several studies demonstrating that it could prevent further episodes of the disease, and therefore reduce the risk of developing AA.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">7–9</span></a> Until colchicine was established as the first line treatment in patients with FMF, 60% of patients with this disease developed AA. Currently, thanks to the widespread use of colchicine, this prevalence has decreased to 7%.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> However, the effectiveness of colchicine is limited in patients with established amyloidosis.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> This limited response is particularly significant in patients with amyloidosis with renal involvement. Colchicine can stabilise or improve the condition when proteinuria is below the nephrotic range, but a poor response has been described in patients with established NS (proteinuria<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>3.5<span class="elsevierStyleHsp" style=""></span>g/day and albumin<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>g/dL).<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">9–11</span></a> In addition, some patients are intolerant (2–3%) or resistant (5–10%) to colchicine.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> In these patients, and in those with advanced AA, the therapeutic options are limited.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> As mentioned in the introduction, mutations in the gene coding for pyrin leads to an inappropriate activation of interleukin-1β, which seems to be key in the pathogenesis of FMF.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> This discovery means that interleukin-1β inhibitors are a therapeutic option in patients with this disease.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">10,12</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In the literature, 30 cases have been described of patients with FMF treated with anakinra. In 20 of them, there were no findings of AA, and treatment with anakinra was started because of a persistent inflammatory activity not controlled with colchicine.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">10,13–21</span></a> In the other 10 cases, renal amyloidosis was demonstrated. Of those 10 patients, 6 were on a long-term dialysis programme<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">22–25</span></a> and 2 had received a transplant<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">26,27</span></a> at the time of starting anakinra. These 8 patients were prescribed anakinra for the control of FMF inflammatory attacks. Only 2 patients<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">23,28</span></a> were treated with anakinra with the aim of controlling glomerular proteinuria secondary to AA, and neither of these cases were in the nephrotic range. Both cases had a good clinical outcome, with renal function and proteinuria remaining stable after starting anakinra. In the 30 cases described, anakinra reduced or stopped inflammatory episodes, and very few adverse events were reported.</p><p id="par0035" class="elsevierStylePara elsevierViewall">This is the first case described in the literature showing complete remission of NS secondary to amyloidosis secondary to FMF following treatment with anakinra. Starting anakinra prevented further episodes of the disease, and a progressive decrease in proteinuria, remaining below 0.5<span class="elsevierStyleHsp" style=""></span>g/day from 30 months (complete remission). Renal function also remained stable. Although a follow-up renal biopsy would have been very needed to corroborate a reduction in amyloid deposit in the kidney, given the good clinical progress in this patient, it was decided not to perform this procedure. Anakinra may be a safe, effective, therapeutic alternative in patients with AA secondary to FMF with significant renal involvement; without treatment, these patients would probably progress to end-stage renal failure. It is likely that early treatment could lead to better outcomes. However, the cost of the drug and its possible adverse effects (increased infections, particularly respiratory and tuberculosis, and neutropenia)<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> should influence appropriate patient selection before starting treatment is essential. More clinical information is needed to confirm our findings.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres821850" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec818793" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres821851" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec818794" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Clinical case" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-02-13" "fechaAceptado" => "2015-06-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec818793" "palabras" => array:4 [ 0 => "Familial Mediterranean fever" 1 => "Amyloidosis" 2 => "Colchicine" 3 => "Anakinra" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec818794" "palabras" => array:4 [ 0 => "Fiebre mediterránea familar" 1 => "Amiloidosis" 2 => "Colchicina" 3 => "Anakinra" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Renal amyloidosis is one of the most severe complications of familial Mediterranean fever (FMF). Colchicine has reduced the incidence of this complication, which now only appears in untreated, under-treated and resistant patients, but it is usually ineffective in patients with advanced amyloidosis. Here we report a patient with FMF and biopsy-proven amyloidosis who presented with nephrotic syndrome despite colchicine treatment. Anakinra (an interleukin-1β inhibitor) was started and a dramatic complete remission of nephrotic syndrome was observed in the following months. Anakinra can be an effective treatment for FMF patients with severe secondary amyloidosis.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La amiloidosis renal es una de las complicaciones más graves de la fiebre mediterránea familiar (FMF). La colchicina ha reducido la incidencia de esta complicación, que ahora solo aparece en pacientes no tratados, tratados de manera insuficiente o resistentes al fármaco. No obstante, la colchicina se ha mostrado poco eficaz en pacientes que inician el tratamiento cuando la amiloidosis ya está presente. En este trabajo presentamos el caso de un enfermo con FMF y amiloidosis renal secundaria diagnosticada mediante biopsia renal que desarrolló un síndrome nefrótico completo a pesar del tratamiento con colchicina. Por la mala evolución del cuadro se decidió iniciar tratamiento con anakinra (un inhibidor de la interleucina 1β). En los meses posteriores a la instauración del fármaco el enfermo presentó una mejoría progresiva del síndrome nefrótico, hasta alcanzar la remisión completa. La función renal permaneció estable. Los inhibidores de la interleucina 1β pueden ser un tratamiento efectivo de la FMF en pacientes con amiloidosis renal secundaria.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Sevillano ÁM, Hernandez E, Gonzalez E, Mateo I, Gutierrez E, Morales E, et al. Anakinra induce la remisión completa del síndrome nefrótico en un paciente con fiebre mediterránea familiar y amiloidosis. Nefrologia. 2016;36:63–66.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1709 "Ancho" => 2360 "Tamanyo" => 107877 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patient progress after starting treatment with anakinra. SAlb, serum albumin (g/dL); SCr, serum creatinine (mg/dL); proteinuria, 24<span class="elsevierStyleHsp" style=""></span>h proteinuria (g/24<span class="elsevierStyleHsp" style=""></span>h).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Familial Mediterranean fever: a critical digest of the 2012–2013 literature" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E.M. Eisenstein" 1 => "Y. Berkun" 2 => "E. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 9 | 13 |
| 2024 October | 49 | 39 | 88 |
| 2024 September | 51 | 21 | 72 |
| 2024 August | 86 | 62 | 148 |
| 2024 July | 59 | 29 | 88 |
| 2024 June | 61 | 45 | 106 |
| 2024 May | 53 | 37 | 90 |
| 2024 April | 58 | 26 | 84 |
| 2024 March | 45 | 25 | 70 |
| 2024 February | 42 | 35 | 77 |
| 2024 January | 36 | 19 | 55 |
| 2023 December | 28 | 26 | 54 |
| 2023 November | 33 | 32 | 65 |
| 2023 October | 33 | 26 | 59 |
| 2023 September | 43 | 28 | 71 |
| 2023 August | 30 | 26 | 56 |
| 2023 July | 63 | 25 | 88 |
| 2023 June | 35 | 18 | 53 |
| 2023 May | 59 | 24 | 83 |
| 2023 April | 42 | 10 | 52 |
| 2023 March | 47 | 18 | 65 |
| 2023 February | 46 | 17 | 63 |
| 2023 January | 39 | 28 | 67 |
| 2022 December | 58 | 30 | 88 |
| 2022 November | 72 | 33 | 105 |
| 2022 October | 84 | 45 | 129 |
| 2022 September | 38 | 28 | 66 |
| 2022 August | 51 | 47 | 98 |
| 2022 July | 33 | 43 | 76 |
| 2022 June | 39 | 38 | 77 |
| 2022 May | 35 | 26 | 61 |
| 2022 April | 41 | 50 | 91 |
| 2022 March | 50 | 47 | 97 |
| 2022 February | 54 | 38 | 92 |
| 2022 January | 64 | 34 | 98 |
| 2021 December | 54 | 42 | 96 |
| 2021 November | 39 | 29 | 68 |
| 2021 October | 60 | 45 | 105 |
| 2021 September | 51 | 34 | 85 |
| 2021 August | 39 | 40 | 79 |
| 2021 July | 74 | 34 | 108 |
| 2021 June | 56 | 23 | 79 |
| 2021 May | 46 | 40 | 86 |
| 2021 April | 103 | 44 | 147 |
| 2021 March | 134 | 28 | 162 |
| 2021 February | 104 | 21 | 125 |
| 2021 January | 57 | 18 | 75 |
| 2020 December | 67 | 18 | 85 |
| 2020 November | 43 | 16 | 59 |
| 2020 October | 64 | 24 | 88 |
| 2020 September | 40 | 15 | 55 |
| 2020 August | 42 | 16 | 58 |
| 2020 July | 34 | 11 | 45 |
| 2020 June | 40 | 13 | 53 |
| 2020 May | 38 | 10 | 48 |
| 2020 April | 38 | 27 | 65 |
| 2020 March | 33 | 15 | 48 |
| 2020 February | 42 | 23 | 65 |
| 2020 January | 45 | 20 | 65 |
| 2019 December | 54 | 23 | 77 |
| 2019 November | 47 | 24 | 71 |
| 2019 October | 56 | 15 | 71 |
| 2019 September | 43 | 18 | 61 |
| 2019 August | 23 | 20 | 43 |
| 2019 July | 36 | 22 | 58 |
| 2019 June | 39 | 14 | 53 |
| 2019 May | 44 | 13 | 57 |
| 2019 April | 68 | 37 | 105 |
| 2019 March | 49 | 15 | 64 |
| 2019 February | 35 | 15 | 50 |
| 2019 January | 31 | 15 | 46 |
| 2018 December | 256 | 40 | 296 |
| 2018 November | 496 | 24 | 520 |
| 2018 October | 513 | 19 | 532 |
| 2018 September | 230 | 16 | 246 |
| 2018 August | 62 | 21 | 83 |
| 2018 July | 84 | 14 | 98 |
| 2018 June | 97 | 16 | 113 |
| 2018 May | 144 | 12 | 156 |
| 2018 April | 216 | 9 | 225 |
| 2018 March | 221 | 7 | 228 |
| 2018 February | 156 | 9 | 165 |
| 2018 January | 118 | 6 | 124 |
| 2017 December | 156 | 6 | 162 |
| 2017 November | 70 | 21 | 91 |
| 2017 October | 36 | 8 | 44 |
| 2017 September | 31 | 8 | 39 |
| 2017 August | 38 | 11 | 49 |
| 2017 July | 33 | 9 | 42 |
| 2017 June | 49 | 11 | 60 |
| 2017 May | 43 | 9 | 52 |
| 2017 April | 34 | 9 | 43 |
| 2017 March | 33 | 14 | 47 |
| 2017 February | 35 | 4 | 39 |
| 2017 January | 20 | 7 | 27 |
| 2016 December | 42 | 10 | 52 |
| 2016 November | 66 | 20 | 86 |
| 2016 October | 80 | 17 | 97 |
| 2016 September | 109 | 4 | 113 |
| 2016 August | 126 | 2 | 128 |
| 2016 July | 142 | 11 | 153 |
| 2016 June | 127 | 0 | 127 |
| 2016 May | 187 | 0 | 187 |
| 2016 April | 171 | 0 | 171 |
| 2016 March | 135 | 0 | 135 |
| 2016 February | 94 | 0 | 94 |
| 2016 January | 55 | 0 | 55 |
| 2015 December | 36 | 0 | 36 |
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