Images in Clinical Rheumatology
We might have the same mutation but my inflammasome beats your inflammasome: CINCA versus FCAS
Podríamos tener la misma mutación, pero mi inflamasoma vence al tuyo: CINCA versus FCAS
Mustafa Çakan
, Şerife Gül Karadağ, Nuray Aktay Ayaz
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Health Sciences University, Istanbul Kanuni Sultan Süleyman Research and Training Hospital, Clinic of Pediatric Rheumatology, Istanbul, Turkey
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(b) The view of the rash of FCAS patient.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Autoinflammatory diseases are a group of disorders primarily characterized by dysregulation of innate immunity.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> Inflammasomes are complex protein structures that are formed either spontaneously or after a trigger and produce caspase 1. Caspase 1 cleaves pro-IL-1β and pro-IL-18 to IL-1β and IL-18.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">1,2</span></a> Cryopyrin-associated periodic fever syndromes (CAPS) are a group of autoinflammatory disorders caused by mutations in the <span class="elsevierStyleItalic">NLRP3</span> gene.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> CAPS comprise three group of disorders: chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">1–4</span></a> CINCA is associated with the most severe phenotype in the spectrum of CAPS. The symptoms generally start in early infancy or even at birth. Fever, rash, arthropathy, central nervous system and ocular involvement are the main features of the disease. MWS is associated with moderate severity and characterized by attacks of fever, rash, arthralgia, arthritis and progressive sensorineural hearing loss. FCAS is considered as the least severe phenotype of CAPS and characterized by self-limited episodes of fever, rash, conjunctivitis, and arthralgia lasting less than 24<span class="elsevierStyleHsp" style=""></span>h, precipitated by generalized exposure to cold. Some patients may develop daily rash suggesting chronic inflammation.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">2,4,5</span></a> The significance of V198M sequence variant in the <span class="elsevierStyleItalic">NLRP3</span> gene is uncertain and considered as low penetrant mutation.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">6,7</span></a> Herein we present two cases at the extreme ends of the CAPS spectrum with V198M sequence variant in the <span class="elsevierStyleItalic">NLRP3</span> gene to demonstrate that V198M sequence variant, even though regarded as low penetrant mutation, may cause to CINCA phenotype.</p><p id="par0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Case 1</span>: A 16-month-old girl was consulted to pediatric rheumatology due to non-remitting fever for 3 weeks and persistence of high acute reactants (APR). She was born to non-consanguineous healthy parents at 29 weeks of gestation, 820<span class="elsevierStyleHsp" style=""></span>g, and was hospitalized for 3 months postnatally. She had two episodes of persistent unexplained fever, high APR [C-reactive protein (CRP): 108<span class="elsevierStyleHsp" style=""></span>mg/L, erythrocyte sedimentation rate (ESR): 88<span class="elsevierStyleHsp" style=""></span>mm/h] with sterile cultures. She had never been hospitalized after discharge until this event but was followed closely because of prematurity and insufficient physical development. She had three episodes of fever and rash attacks and two episodes of only rash lasting 1–2 weeks in a year. On physical examination she had frontal bossing, saddle nose, nystagmus, swelling of bilateral knees and ankles (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>a) and high APR (CRP: 299<span class="elsevierStyleHsp" style=""></span>mg/L, ESR: 140<span class="elsevierStyleHsp" style=""></span>mm/h). Cranial magnetic resonance imaging, eye examinations, and auditory screening tests have been done at the follow-up visits for prematurity and all were normal. After combining the medical history and physical findings we have suspected CINCA and <span class="elsevierStyleItalic">NLRP3</span> analysis showed heterozygous V198M sequence variant in exon 3. Anakinra 2<span class="elsevierStyleHsp" style=""></span>mg/kg/day was started and APR dramatically improved with resolution of the fever. But after a few months, APR started to increase gradually again without fever and anakinra dose was increased up to 8<span class="elsevierStyleHsp" style=""></span>mg/kg/day. Six months later anakinra was switched to canakinumab (2<span class="elsevierStyleHsp" style=""></span>mg/kg/month) due to painful injections. Under canakinumab treatment, although at some intervals had APR near to normal levels, inflammation was not controlled totally (CRP: 51<span class="elsevierStyleHsp" style=""></span>mg/L, ESR: 55<span class="elsevierStyleHsp" style=""></span>mm/h) and dose was increased gradually up to 12<span class="elsevierStyleHsp" style=""></span>mg/kg/month. She is being followed for 3.5 years and currently under monthly canakinumab (12<span class="elsevierStyleHsp" style=""></span>mg/kg/month) injections with normal APR and without further attacks. Neurological development of the patient is compatible with her age.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Case 2</span>: An 8-year-old girl was admitted to clinic with the complaint of non-pruritic rash for the last 9 months. Parents were non-consanguineous and healthy. The rash was waxing and waning spontaneously but sometimes was getting worse with accompanying myalgia, red eyes and subtle fever for a few days. She had been followed and investigated by dermatology and pediatric allergy departments and many anti-histaminic medications have been tried with no effect on the rash. The family did not associate the start of the rash with cold exposure but recalled that she was feeling unwell with more rashes after exposure to cold. She had discrete annular urticaria-like rashes most notable on the forehead and lower extremities (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>b) with normal examination otherwise. APR was mildly elevated (CRP 18<span class="elsevierStyleHsp" style=""></span>mg/L, ESR: 20<span class="elsevierStyleHsp" style=""></span>mm/h). The clinical picture of the patient was compatible with FCAS and <span class="elsevierStyleItalic">NLRP3</span> analysis showed heterozygous V198M sequence variant in exon 3. She is currently using canakinumab (2<span class="elsevierStyleHsp" style=""></span>mg/kg) every two months for the last 3 years and did not have any further attack since the first dose of canakinumab.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In conclusion, although CAPS patients have the same genetic disturbance and pathophysiology, CINCA patients seem to have a continuous activity of inflammasome. Early initiation of treatment with an IL-1 blocker (anakinra, canakinumab or rilonacept) is essential to control ongoing inflammation and prevent secondary amyloidosis in CAPS patient and very high doses of IL-1 blockers may be needed in the very young to control the overwhelming inflammation.</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0030" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">There is no conflict of interest associated with the manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-07-21" "fechaAceptado" => "2019-12-19" "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" => 1809 "Ancho" => 2508 "Tamanyo" => 487700 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(a) The view of the arthropathy and rash of CINCA patient. (b) The view of the rash of FCAS patient.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0040" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoinflammatory diseases: state of the art" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Georgin-Lavialle" 1 => "A. Fayand" 2 => "F. Rodrigues" 3 => "C. Bachmeyer" 4 => "L. Savey" 5 => "G. 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| 2024 Agosto | 47 | 31 | 78 |
| 2024 Julio | 38 | 30 | 68 |
| 2024 Junio | 40 | 59 | 99 |
| 2024 Mayo | 50 | 36 | 86 |
| 2024 Abril | 42 | 27 | 69 |
| 2024 Marzo | 44 | 27 | 71 |
| 2024 Febrero | 36 | 19 | 55 |
| 2024 Enero | 20 | 16 | 36 |
| 2023 Diciembre | 19 | 23 | 42 |
| 2023 Noviembre | 21 | 22 | 43 |
| 2023 Octubre | 29 | 28 | 57 |
| 2023 Septiembre | 61 | 40 | 101 |
| 2023 Agosto | 34 | 16 | 50 |
| 2023 Julio | 34 | 23 | 57 |
| 2023 Junio | 35 | 17 | 52 |
| 2023 Mayo | 39 | 24 | 63 |
| 2023 Abril | 29 | 9 | 38 |
| 2023 Marzo | 33 | 25 | 58 |
| 2023 Febrero | 43 | 26 | 69 |
| 2023 Enero | 31 | 16 | 47 |
| 2022 Diciembre | 46 | 22 | 68 |
| 2022 Noviembre | 40 | 30 | 70 |
| 2022 Octubre | 41 | 32 | 73 |
| 2022 Septiembre | 38 | 26 | 64 |
| 2022 Agosto | 37 | 37 | 74 |
| 2022 Julio | 30 | 36 | 66 |
| 2022 Junio | 37 | 30 | 67 |
| 2022 Mayo | 36 | 43 | 79 |
| 2022 Abril | 43 | 34 | 77 |
| 2022 Marzo | 32 | 36 | 68 |
| 2022 Febrero | 29 | 22 | 51 |
| 2022 Enero | 28 | 31 | 59 |
| 2021 Diciembre | 21 | 39 | 60 |
| 2021 Noviembre | 29 | 39 | 68 |
| 2021 Octubre | 45 | 48 | 93 |
| 2021 Septiembre | 33 | 37 | 70 |
| 2021 Agosto | 24 | 32 | 56 |
| 2021 Julio | 1 | 0 | 1 |
| 2021 Mayo | 1 | 0 | 1 |
| 2021 Marzo | 0 | 2 | 2 |
| 2021 Febrero | 3 | 4 | 7 |
| 2020 Noviembre | 1 | 0 | 1 |
| 2020 Junio | 1 | 2 | 3 |
| 2020 Mayo | 1 | 0 | 1 |
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