Infliximab in the treatment of amyloidosis secondary to Crohn's disease
Utilidad del infliximab en el tratamiento de la amiloidosis secundaria en la enfermedad de Crohn
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The deposition of amyloid material in AA amyloidosis mainly affects the kidneys and the major clinical manifestations are proteinuria and renal failure. The progression of chronic kidney disease associated with amyloidosis secondary to CD in the absence of an effective treatment leads to high morbidity and mortality rates.<span class="elsevierStyleSup">1-3</span></p><p class="elsevierStylePara">However, anti-tumour necrosis factor-alpha (anti-TNFα) agents, infliximab in particular, have been successfully used in recent years to treat AA amyloidosis in some inflammatory rheumatic diseases<span class="elsevierStyleSup">4</span> and also in some cases of CD.<span class="elsevierStyleSup">5-8</span></p><p class="elsevierStylePara">We present the case of a patient simultaneously diagnosed with oligosymptomatic CD and AA renal amyloidosis, successfully treated with infliximab over 4 years with a good response and absence of complications.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CASE REPORT</span> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">A 33-year-old male was referred to the nephrology unit in late 2006 due to elevated serum creatinine (SCr) levels, 1.4mg/dl. He had no history or clinical manifestations of urological or kidney disease. Five years previously, his SCr had been measured at 0.9mg/dl.</p><p class="elsevierStylePara">At 18-years-old, he was diagnosed with iron-deficiency anaemia and gastro-oesophageal reflux. In the past 4 years he reported suffering from dysphagia and postprandial heaviness, without any other gastrointestinal manifestations; and mechanical back pain. He had no febrile episodes, joint inflammation, skin lesions, serositis, or problems with any other body organs or systems.</p><p class="elsevierStylePara">He had a family history of ankylosing spondylitis in several males on his father’s side; a paternal uncle was also diagnosed with stage 5 chronic kidney disease secondary to nephropathy caused by analgesic use.</p><p class="elsevierStylePara">Normal physical examination, blood pressure: 130/79mm Hg, body mass index: 21kg/m<span class="elsevierStyleSup">2</span>.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Diagnostic tests </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Blood test: SCr: 1.47mg/dl; MDRD-4 estimated glomerular filtration rate (eFGR): 59ml/min/1.73m<span class="elsevierStyleSup">2</span>; urea: 33mg/dl; ions, liver enzymes and lipids: normal. Total proteins, proteinogram, immunoglobulins and complement: normal. Negative rheumatoid factor. C-reactive protein (CRP): 13mg/l (normal value [NV]<10mg/l). Antinuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies and HLA-B27 histocompatibility antigens were negative. Iron parameters: serum iron: 25µg/dl (NV: 40-60); ferritin: 38ng/ml (NV: 20-300), transferrin saturation index: 12%. Vitamin B12: 181pg/ml (NV: 208-930) and folic acid: 3.3ng/ml (NV: 7.2-15).</p><p class="elsevierStylePara">Urine test: proteinuria: 200mg/24h; albuminuria: 47mg/24h, with no monoclonal free light chains. Normal urine sediment.</p><p class="elsevierStylePara">Chest and spine x-rays showed no significant alterations. Ultrasound scans of the abdomen, kidneys and urinary passages: normal. Analysis by the rheumatology department ruled out ankylosing spondylitis.</p><p class="elsevierStylePara">Repeat tests after two months showed: SCr: 1.64mg/dl; eFGR (MDRD-4): 52ml/min/1.73m<span class="elsevierStyleSup">2</span>; proteinuria: 316mg/24h; albuminuria: 163mg/24h. And 4 months later: SCr: 1.77mg/dl; eFGR (MDRD-4): 47ml/min/1.73m<span class="elsevierStyleSup">2</span>; proteinuria: 640mg/24h. The iron, vitamin B12 and folic acid deficiencies were partially corrected with oral supplements.</p><p class="elsevierStylePara">In light of the persistent gastrointestinal symptoms (dysphagia, dyspepsia) and suspected intestinal malabsorption (iron and vitamin deficiency), we decided to perform an endoscopy of the digestive tract and take biopsies. The main alterations found in the mucosa of the terminal ileum were compatible with CD: ulcerated villi, lymphoplasmacytic inflammation in the lamina propria, neutrophil infiltration (crypt abscesses) and epithelioid histiocyte granulomas. A deposit of material with staining characteristics (Congo red and immunohistochemical) of AA amyloidosis, and no signs of inflammation, was found in the rectal mucosa, in the blood vessel walls of the lamina propria.</p><p class="elsevierStylePara">A percutaneous renal biopsy was also performed in light of the unfavourable progression of the renal parameters (renal function and proteinuria), which showed: 7 glomeruli, 3 with virtually global glomerulosclerosis and the remaining 4 with small eosinophilic deposits in the hilum of the glomerulus; patchy areas of interstitial fibrosis; and eosinophilic deposits in the walls of the blood vessels that were larger and more intense than the glomerular ones. The deposits tested positive for Congo red with green birefringence under polarised light and immunohistochemical staining detected the presence of amyloid A protein. </p><p class="elsevierStylePara">In the subsequent evolution of this case, the patient had no symptoms or clinical signs suggestive of any other type of inflammatory, infectious or tumour disease, or familial Mediterranean fever.</p><p class="elsevierStylePara">With the diagnosis of CD and secondary AA amyloidosis, it was decided to pursue aetiological treatment of the CD based on intravenous infliximab at 5mg/kg every 2 months, azathioprine at 1-1.5mg/kg/day (for the first year only, suspended due to leukopenia) and renin-angiotensin-aldosterone system blockers. The renal parameters improved (Figure 1), as did the inflammatory markers (CRP: 5mg/l, and serum amyloid A protein <5mg/l), and are maintained after 4 years of monitoring. There have been no major complications of the CD or side effects from the medication.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Between 0.9% and 3% of patients with CD develop secondary amyloidosis,<span class="elsevierStyleSup">1-3 </span>a rate that is 2.5-3 times higher in men.<span class="elsevierStyleSup">1,2</span></p><p class="elsevierStylePara">The average time from the diagnosis of CD to the appearance of amyloidosis is 10-15 years<span class="elsevierStyleSup">1,2</span>; in exceptional cases, the diagnosis of both clinical entities occurs simultaneously<span class="elsevierStyleSup">2</span> and it has even been suggested that amyloidosis can precede CD in rare cases.<span class="elsevierStyleSup">9</span> In our patient, both entities were diagnosed at the same time, although minor and non-specific digestive manifestations had been present for several years. In the two longest studies published to date,<span class="elsevierStyleSup">1,2</span> two thirds of people with amyloidosis secondary to CD had previous suppurative complications (fistulas or abscesses), and half or more had extraintestinal manifestations; from which we can deduce that AA amyloidosis in CD can also develop in the absence of chronic infections or extraintestinal complications, as in our case. In line with the foregoing, it would appear that AA amyloid nephropathy can first appear as an early complication in CD and not necessarily be associated with a clinically manifest, extensive and aggressive disease.</p><p class="elsevierStylePara">The main objectives of secondary renal amyloidosis treatment are to induce and maintain the remission of the primary disease, prevent renal deposition of amyloid A proteins, and stop or reverse the progression of chronic kidney disease. The effect of intestinal resection to prevent or treat renal amyloidosis in DC is controversial,<span class="elsevierStyleSup">1,3</span> and the majority of authors advocate drug treatment as the treatment of choice. Drugs like colchicine, azathioprine and dimethyl sulfoxide can slow down the progression of amyloid nephropathy, but their effectiveness has not been fully demonstrated.<span class="elsevierStyleSup">3</span> Eprodisate, the first drug in a new class of compounds, inhibits amyloid protein polymerisation and deposition in tissues and slows down the decline in the glomerular filtration rate in AA amyloidosis patients, but it has little effect on proteinuria and survival.<span class="elsevierStyleSup">10</span></p><p class="elsevierStylePara">In recent years, the anti-TNFα agent infliximab has been used successfully to treat isolated cases of renal amyloidosis secondary to CD. We conducted a PubMed search with the words “systemic or secondary amyloidosis, Crohn’s disease, infliximab” and selected those cases published in English not associated with other rheumatic inflammatory or infectious diseases or with familial Mediterranean fever.<span class="elsevierStyleSup">5-8</span> The main clinical characteristics of the four cases found in addition to our own are summarised in Table 1. In all these cases, treatment with infliximab was started soon after the diagnosis with amyloidosis and was followed by rapid and maintained clinical improvement of the intestinal disease and the laboratory inflammatory parameters, a rapid decrease in proteinuria and improved renal function with no complications associated with the medication. One of these studies showed a decrease in the amyloid deposits in the intestinal mucosa after 5 years of treatment with infliximab.<span class="elsevierStyleSup">5</span></p><p class="elsevierStylePara">The most common adverse effects relating to ongoing infliximab use in patients with amyloidosis and rheumatic diseases are an increased susceptibility to infections and the drug’s loss of effectiveness.<span class="elsevierStyleSup">4</span> In cases of resistance or loss of effectiveness or adverse effects in patients with CD, another anti-TNFα, adalimumab, can be used as an alternative.<span class="elsevierStyleSup">11,12</span></p><p class="elsevierStylePara">It has been hypothesised that anti-TNFα agents can improve amyloid nephropathy in inflammatory diseases through two mechanisms: 1) by reducing the glomerular inflammation and the increase in the glomerular permeability to albumin induced by TNFα cytokines and interleukin-6; and 2) by reducing the synthesis of acute-phase proteins mediated by the same cytokines.<span class="elsevierStyleSup">4</span> Indeed, it has been demonstrated that the serum amyloid A protein level reached is a prognostic factor in AA amyloidosis; mean levels below 10mg/l are associated with a higher likelihood of regression of the amyloid deposits and higher survival rates.<span class="elsevierStyleSup">13</span></p><p class="elsevierStylePara">To conclude, AA renal amyloidosis can first appear as an early complication in patients with CD, even in those patients with a disease that presents mild clinical symptoms. It would appear appropriate to recommend renal function and urinary protein excretion tests for patients diagnosed with CD at the time of diagnosis and at regular intervals thereafter with a view to diagnosing and, where applicable, starting early treatment on any associated kidney disease. Infliximab could be a useful and effective tool in the early treatment of amyloidosis secondary to CD and provides encouraging prospects.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors affirm that they have no conflicts of interest related to the content of this article.</p><p class="elsevierStylePara"><a href="grande/11332_16025_30485_en_t1_11332.jpg" class="elsevierStyleCrossRefs"><img src="11332_16025_30485_en_t1_11332.jpg" alt="Evolution of the renal parameters of 5 patients with AA amyloidosis and Crohn’s disease treated with infliximab"></img></a></p><p class="elsevierStylePara">Table 1. Evolution of the renal parameters of 5 patients with AA amyloidosis and Crohn’s disease treated with infliximab</p><p class="elsevierStylePara"><a href="grande/11332_16025_30486_en_f1_11332.jpg" class="elsevierStyleCrossRefs"><img src="11332_16025_30486_en_f1_11332.jpg" alt="Evolution of serum creatinine and urinary protein excretion before and after treatment with infliximab "></img></a></p><p class="elsevierStylePara">Figure 1. Evolution of serum creatinine and urinary protein excretion before and after treatment with infliximab </p>" "pdfFichero" => "P1-E536-S3497-A11332-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438487" "palabras" => array:1 [ 0 => "Enfermedad de Crohn" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438489" "palabras" => array:1 [ 0 => "Amiloidosis secundaria" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec438491" "palabras" => array:1 [ 0 => "Infliximab" ] ] ] "en" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438488" "palabras" => array:1 [ 0 => "Crohn's disease" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438490" "palabras" => array:1 [ 0 => "Secondary amyloidosis" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec438492" "palabras" => array:1 [ 0 => "Infliximab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">La amiloidosis secundaria o AA es una grave complicación de la enfermedad de Crohn (EC) evolucionada para la que no se dispone de un tratamiento eficaz. Presentamos un caso excepcional de un varón de 33 años afecto de insuficiencia renal moderada y proteinuria, que fue diagnosticado simultáneamente de nefropatía amiloide AA y de EC oligosintomática. Fue tratado con infliximab, 5 mg/kg/8 semanas durante 4 años, azatioprina 1-1,5 mg/kg/día (primer año) y un bloqueante del sistema renina-angiotensina-aldosterona, sin complicaciones. El tratamiento se siguió de una reducción de la proteinuria, mejoría de la función renal y de los parámetros inflamatorios a lo largo del tiempo. A propósito de este caso revisamos la literatura médica y concluimos que infliximab puede ser de utilidad para el tratamiento precoz de la amiloidosis secundaria en la EC. </p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara">Secondary amyloidosis (AA) is a severe complication of progressed Crohn’s disease (CD) for which no effective treatment exists. We present the exceptional case of a 33 year-old male with moderate renal failure and proteinuria, who was simultaneously diagnosed with AA amyloid nephropathy and oligosymptomatic CD. He was treated with infliximab at 5mg/kg/8 weeks for 4 years, azathioprine at 1-1.5mg/kg/day (first year) and renin-angiotensin-aldosterone system blockers, with no complications. Treatment caused a decrease in proteinuria, improved renal function, and improved inflammatory parameters over time. Inspired by this case, we performed a review of the medical literature and found that infliximab could be a useful tool in the early treatment of amyloidosis secondary to CD.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11332_16025_30485_en_t1_11332.jpg" "Alto" => 1058 "Ancho" => 2168 "Tamanyo" => 453383 ] ] "descripcion" => array:1 [ "en" => "Evolution of the renal parameters of 5 patients with AA amyloidosis and Crohn’s disease treated with infliximab" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11332_16025_30486_en_f1_11332.jpg" "Alto" => 904 "Ancho" => 1001 "Tamanyo" => 148435 ] ] "descripcion" => array:1 [ "en" => "Evolution of serum creatinine and urinary protein excretion before and after treatment with infliximab" ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003200000003/v0_201502091613/X2013251412001215/v0_201502091614/en/main.assets" "Apartado" => array:4 [ "identificador" => "35422" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Case Reports" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003200000003/v0_201502091613/X2013251412001215/v0_201502091614/en/P1-E536-S3497-A11332-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251412001215?idApp=UINPBA000064" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 12 | 11 | 23 |
| 2024 October | 48 | 51 | 99 |
| 2024 September | 61 | 39 | 100 |
| 2024 August | 68 | 60 | 128 |
| 2024 July | 43 | 47 | 90 |
| 2024 June | 48 | 49 | 97 |
| 2024 May | 68 | 39 | 107 |
| 2024 April | 55 | 39 | 94 |
| 2024 March | 43 | 31 | 74 |
| 2024 February | 37 | 41 | 78 |
| 2024 January | 33 | 35 | 68 |
| 2023 December | 17 | 38 | 55 |
| 2023 November | 55 | 32 | 87 |
| 2023 October | 30 | 36 | 66 |
| 2023 September | 34 | 40 | 74 |
| 2023 August | 40 | 21 | 61 |
| 2023 July | 41 | 40 | 81 |
| 2023 June | 37 | 33 | 70 |
| 2023 May | 67 | 51 | 118 |
| 2023 April | 42 | 28 | 70 |
| 2023 March | 62 | 22 | 84 |
| 2023 February | 48 | 30 | 78 |
| 2023 January | 41 | 27 | 68 |
| 2022 December | 39 | 31 | 70 |
| 2022 November | 41 | 27 | 68 |
| 2022 October | 40 | 37 | 77 |
| 2022 September | 57 | 52 | 109 |
| 2022 August | 41 | 47 | 88 |
| 2022 July | 50 | 45 | 95 |
| 2022 June | 62 | 42 | 104 |
| 2022 May | 66 | 41 | 107 |
| 2022 April | 58 | 59 | 117 |
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| 2022 February | 66 | 53 | 119 |
| 2022 January | 77 | 35 | 112 |
| 2021 December | 36 | 46 | 82 |
| 2021 November | 32 | 50 | 82 |
| 2021 October | 47 | 51 | 98 |
| 2021 September | 38 | 50 | 88 |
| 2021 August | 40 | 44 | 84 |
| 2021 July | 81 | 43 | 124 |
| 2021 June | 34 | 27 | 61 |
| 2021 May | 74 | 51 | 125 |
| 2021 April | 78 | 70 | 148 |
| 2021 March | 76 | 55 | 131 |
| 2021 February | 76 | 31 | 107 |
| 2021 January | 36 | 29 | 65 |
| 2020 December | 40 | 26 | 66 |
| 2020 November | 26 | 17 | 43 |
| 2020 October | 30 | 21 | 51 |
| 2020 September | 32 | 8 | 40 |
| 2020 August | 31 | 14 | 45 |
| 2020 July | 50 | 10 | 60 |
| 2020 June | 66 | 18 | 84 |
| 2020 May | 61 | 17 | 78 |
| 2020 April | 43 | 20 | 63 |
| 2020 March | 43 | 13 | 56 |
| 2020 February | 36 | 19 | 55 |
| 2020 January | 48 | 17 | 65 |
| 2019 December | 55 | 23 | 78 |
| 2019 November | 49 | 22 | 71 |
| 2019 October | 26 | 12 | 38 |
| 2019 September | 40 | 20 | 60 |
| 2019 August | 41 | 8 | 49 |
| 2019 July | 52 | 27 | 79 |
| 2019 June | 105 | 29 | 134 |
| 2019 May | 75 | 25 | 100 |
| 2019 April | 114 | 43 | 157 |
| 2019 March | 68 | 25 | 93 |
| 2019 February | 42 | 31 | 73 |
| 2019 January | 63 | 34 | 97 |
| 2018 December | 127 | 41 | 168 |
| 2018 November | 164 | 21 | 185 |
| 2018 October | 100 | 17 | 117 |
| 2018 September | 84 | 24 | 108 |
| 2018 August | 69 | 19 | 88 |
| 2018 July | 84 | 24 | 108 |
| 2018 June | 71 | 15 | 86 |
| 2018 May | 70 | 16 | 86 |
| 2018 April | 103 | 7 | 110 |
| 2018 March | 90 | 9 | 99 |
| 2018 February | 87 | 10 | 97 |
| 2018 January | 74 | 6 | 80 |
| 2017 December | 113 | 12 | 125 |
| 2017 November | 76 | 15 | 91 |
| 2017 October | 68 | 12 | 80 |
| 2017 September | 86 | 12 | 98 |
| 2017 August | 64 | 41 | 105 |
| 2017 July | 70 | 32 | 102 |
| 2017 June | 83 | 30 | 113 |
| 2017 May | 92 | 30 | 122 |
| 2017 April | 81 | 31 | 112 |
| 2017 March | 67 | 35 | 102 |
| 2017 February | 105 | 20 | 125 |
| 2017 January | 46 | 25 | 71 |
| 2016 December | 106 | 5 | 111 |
| 2016 November | 147 | 19 | 166 |
| 2016 October | 194 | 11 | 205 |
| 2016 September | 285 | 4 | 289 |
| 2016 August | 334 | 7 | 341 |
| 2016 July | 263 | 15 | 278 |
| 2016 June | 185 | 0 | 185 |
| 2016 May | 163 | 0 | 163 |
| 2016 April | 141 | 0 | 141 |
| 2016 March | 132 | 0 | 132 |
| 2016 February | 141 | 0 | 141 |
| 2016 January | 157 | 0 | 157 |
| 2015 December | 163 | 0 | 163 |
| 2015 November | 119 | 0 | 119 |
| 2015 October | 128 | 0 | 128 |
| 2015 September | 122 | 0 | 122 |
| 2015 August | 108 | 0 | 108 |
| 2015 July | 107 | 0 | 107 |
| 2015 June | 48 | 0 | 48 |
| 2015 May | 64 | 0 | 64 |
| 2015 April | 14 | 0 | 14 |
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