Case and Research Letters
Schnitzler Syndrome With Response to Anakinra Monotherapy: 7 Years of Follow-up
Síndrome de Schnitzler con respuesta a anakinra en monoterapia: 7 años de seguimiento
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Hidalgo-García, E. García-Fernández, L. Palacio-Aller, P. Gonzalvo" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Y." "apellidos" => "Hidalgo-García" "email" => array:1 [ 0 => "yhidalgog@yahoo.es" ] "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" => "E." "apellidos" => "García-Fernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "L." "apellidos" => "Palacio-Aller" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "P." "apellidos" => "Gonzalvo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Central de Asturias, Oviedo, España" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital de Cabueñes, Gijón, España" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital de Cabueñes, Gijón, España" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital de Cabueñes, Gijón, España" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de Schnitzler con respuesta a anakinra en monoterapia: 7 años de seguimiento" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1106 "Ancho" => 2450 "Tamanyo" => 360514 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A and B, Urticarial rash of fleeting pink edematous papules and plaques on the trunk and limbs, with no desquamation.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Schnitzler syndrome is a rare entity, with around 250 cases reported to date.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> It is characterized by the presence of an urticarial rash associated with a monoclonal gammopathy, together with recurrent episodes of fever, joint pain, generalized bone pain, lymphadenopathy, hepatosplenomegaly, and bone changes.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,3</span></a> Although its etiology and pathogenesis remain unknown, an excellent response to interleukin (IL)<span class="elsevierStyleHsp" style=""></span>1 inhibitors has been observed, and absence of a response should lead us to reconsider the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A 63-year-old woman with no family history of interest and who reported undiagnosed bone and joint pain since 2001, was seen in 2007 for an 18-month history of fleeting, slightly pruritic skin lesions on her trunk and limbs, with no fever or other associated systemic symptoms. She had not identified any etiological or pathogenic agents.</p><p id="par0015" class="elsevierStylePara elsevierViewall">There were no relevant findings on examination and she presented a good general state of health. Dermographism was negative. No goiter, palpable peripheral lymph nodes, or hepatosplenomegaly were detected.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Complete blood count, erythrocyte sedimentation rate, general biochemistry including electrolytes, liver and kidney function tests, antinuclear antibodies, complement (C3 and C4), thyrotropin, protein electrophoresis, immunoglobulin (Ig) levels (IgG, IgA, IgM, IgE), and tumor markers were normal or negative. No abnormal findings were detected on plain chest x-ray or abdominopelvic ultrasound. C-reactive protein was 87.5.</p><p id="par0025" class="elsevierStylePara elsevierViewall">With a diagnosis of chronic idiopathic urticaria, treatment was started with oral antihistamines with a poor response. In January 2009, the patient developed recurrent spikes of fever that lasted 2 to 3 days and were associated with intense generalized bone pain and the appearance on her trunk and limbs of well-defined, edematous pink lesions that resolved in less than 24<span class="elsevierStyleHsp" style=""></span>hours leaving no residual lesion (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, A and<span class="elsevierStyleHsp" style=""></span>B). Skin biopsy revealed a superficial and deep perivascular infiltrate formed of neutrophils, affecting the interstitium (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A), with leukocytoclasia without vasculitis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). In addition, a focal neutrophilic infiltrate was observed around the eccrine glands, both at the level of the epidermis and around the dermal duct.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Blood tests revealed neutrophil leukocytosis and elevation of the acute phase reactants. Antinuclear antibodies, C3, C4, ferritin, rheumatoid factor, serology for hepatitis B and C viruses, and cryoglobulins remained normal or negative. In September 2009, a monoclonal IgM-κ band of 2.61 was detected (upper limit of normal, 2.30), enabling us to make a diagnosis of Schnitzler syndrome.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Sequential treatment was started with colchicine, 100<span class="elsevierStyleHsp" style=""></span>mg/d, oral prednisone, 0.5<span class="elsevierStyleHsp" style=""></span>mg/kg/d, dapsone, 50<span class="elsevierStyleHsp" style=""></span>mg/d, and methotrexate, 15<span class="elsevierStyleHsp" style=""></span>mg/wk, with no improvement. In 2010, the patient commenced treatment with subcutaneous anakinra, 100<span class="elsevierStyleHsp" style=""></span>mg/d, leading to complete resolution of all her symptoms, including the nonspecific bone pain, within a week of starting treatment. The acute phase reactants normalized and no complications have arisen. At the time of writing, the monoclonal IgM-κ band persisted at levels between 2.40 and 2.85. Attempts to withdraw anakinra have led to immediate recurrence of the patient's symptoms, and she is currently asymptomatic on subcutaneous anakinra at a dose of 100<span class="elsevierStyleHsp" style=""></span>mg every 48<span class="elsevierStyleHsp" style=""></span>hours.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The first case of Schnitzler syndrome was reported in 1972 by Liliana Schnitzler. It is now considered the paradigm of acquired or late-onset autoinflammatory diseases.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> The diagnostic criteria were proposed by Lipsker et al.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> in 2001 and are still used with minor modifications made at the expert meeting in Strasbourg in 2012. It is a diagnosis of exclusion.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The presence of an urticarial rash is an obligate criterion for the diagnosis of Schnitzler syndrome.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Histologically, the syndrome is included in the group of neutrophilic urticarial dermatoses, and leukocytoclasia is a constant finding.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,7</span></a> Involvement of the eccrine ducts by the neutrophils, as found in our patient, has been reported as an epiphenomenon, and the presence of an intraepidermal neutrophilic infiltrate has recently been proposed as a marker of the neutrophilic dermatoses.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,8</span></a> Vasculitis is observed in 20% of cases,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> but this is questioned by some authors<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> who have critically reviewed biopsies and a number of literature reports and have found no clear evidence of vasculitis.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The other major diagnostic criterion is the presence of a monoclonal IgM-κ band, observed in 90% of cases,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> although an IgG variant has also been described.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> The minor diagnostic criteria include fever, joint pain and arthritis, bone pain, palpable lymphadenopathy, hepatosplenomegaly, elevation of the erythrocyte sedimentation rate, leukocytosis, and x-ray changes.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The two main complications reported during the course of the disease are AA amyloidosis and lymphoproliferative disorders. These develop in approximately 10% of patients.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Although the etiology and pathogenesis of Schnitzler syndrome remain unknown, the rapid response of the majority of patients to anakinra, an IL-1 receptor inhibitor, and more recently to canakinumab, an IL-1β inhibitor, would suggest a pivotal role for this interleukin in the etiology and pathogenesis of the disease and a relationship with cryopyrine-associated periodic syndromes.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8,9</span></a> A mutation in the <span class="elsevierStyleItalic">NLRP3</span> gene has been detected in some cases; that study was not performed in our patient. Although patient follow-up of up to 35 years has been reported, the relatively recent introduction of anakinra to the treatment of this disease means we cannot yet determine if it will reduce the frequency of blood dyscrasias, although a reduction in the frequency of amyloidosis is assumed.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3,10</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">We consider it important to report this case to draw attention to diagnostic difficulty of this syndrome and the need to follow-up atypical presentations, given the progressive appearance of symptoms and of alterations in the blood tests.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of Interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "Références" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Hidalgo-García Y, García-Fernández E, Palacio-Aller L, Gonzalvo P. Síndrome de Schnitzler con respuesta a anakinra en monoterapia: 7 años de seguimiento. Actas Dermosifiliogr. 2017;108:956–958.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1106 "Ancho" => 2450 "Tamanyo" => 360514 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A and B, Urticarial rash of fleeting pink edematous papules and plaques on the trunk and limbs, with no desquamation.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1244 "Ancho" => 3367 "Tamanyo" => 1330440 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A, Superficial and deep perivascular inflammatory infiltrate with involvement of the interstitium. Hematoxylin and eosin (H&E), original magnification<span class="elsevierStyleHsp" style=""></span>×20. B, Predominantly neutrophilic infiltrate with leukocytoclasia without vasculitis. H&E, original magnification<span class="elsevierStyleHsp" style=""></span>×40.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "Références" "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" => "Schnitzler's syndrome: Diagnosis, treatment and follow-up" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Simon" 1 => "B. Asli" 2 => "M. Braun-Falco" 3 => "H. de Koning" 4 => "J.P. Ferrand" 5 => "C. 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| año/Mes | Html | Total | |
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| 2023 Agosto | 56 | 19 | 75 |
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| 2023 Enero | 56 | 32 | 88 |
| 2022 Diciembre | 78 | 51 | 129 |
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| 2022 Agosto | 29 | 48 | 77 |
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| 2021 Diciembre | 54 | 44 | 98 |
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| 2021 Octubre | 50 | 56 | 106 |
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| 2021 Agosto | 69 | 37 | 106 |
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| 2020 Febrero | 1 | 1 | 2 |
| 2020 Enero | 4 | 0 | 4 |
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| 2019 Noviembre | 4 | 0 | 4 |
| 2019 Octubre | 1 | 0 | 1 |
| 2019 Septiembre | 10 | 0 | 10 |
| 2019 Agosto | 4 | 0 | 4 |
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| 2019 Mayo | 4 | 1 | 5 |
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| 2019 Marzo | 5 | 0 | 5 |
| 2019 Enero | 1 | 0 | 1 |
| 2018 Diciembre | 3 | 0 | 3 |
| 2018 Noviembre | 1 | 0 | 1 |
| 2018 Octubre | 2 | 0 | 2 |
| 2018 Septiembre | 3 | 0 | 3 |
| 2018 Febrero | 34 | 6 | 40 |
| 2018 Enero | 40 | 9 | 49 |
| 2017 Diciembre | 158 | 34 | 192 |
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