Enfermedad relacionada a IgG4. Serie clínica de pacientes chilenos / IGG4-related disease. Report of 52 patients

BACKGROUND: IgG4-related disease (IgG4 RD) is an immune-mediated fibro-inflammatory disorder, with tissue infiltration of IgG4+ plasma cells. It causes pseudotumors, tumors, and a wide spectrum of clinical manifestations. AIM: To report the clinical, laboratory, histopathological and treatment characteristics of a group of Chilean patients with IgG4 RD. MATERIAL AND METHODS: Review of medical records of 52 patients aged 18 to 76 years with IgG4 RD seen at six medical centers. RESULTS: Elevated IgG4 serum levels (> 135 mg/dl) were found in 18 of 44 (41%) patients. There was histological confirmation of the disease in 46 patients. The most common sites of involvement were lungs, eyes and kidneys. Eighteen (35%) patients had only one organ involved, 34 (65%) patients had two organs and 13 (25%) patients had three or more organs. The involvement of two organs was significantly more common in men (p < 0.05). In patients with only one organ involvement, the most frequent location was orbital and meningeal. All patients with kidney or lung disease had multiorgan involvement. All patients received corticosteroid therapy, 67% synthetic immunosuppressants, and 16% rituximab. CONCLUSIONS: ER-IgG4 can affect any tissue. Multiorgan involvement was more common in this series, with preference for lungs, eyes and kidneys. An excellent response to steroids is characteristic of the disease, but with a high relapse rate that requires additional immunosuppression.

Pacientes con compromiso orbitario y renal: Diagnósticos diferenciales poco frecuentes / Patients with orbitary and kidney commitment: Rare differential diagnoses

Se comunica una serie de tres casos clínicos que consultaron al servicio de Reumatología por compromiso orbitario y renal. Uno de ellos presentó pseudotumor orbitario con proteinuria en rango nefrótico; se realizó biopsia y se encontró infiltrado linfoplasmocitario denso y fibrosis estoriforme con inmunohistoquímica: 15 células IgG4+ por campo de alto poder y relación IgG/IgG4 ≤40%, concluyendo diagnóstico de enfermedad relacionada por IgG4. El segundo y tercer caso presentaron compromiso ocular con "ojos de mapache" y lesiones amarillentas en párpados, ambos con proteinuria >500 mg/24 h, con biopsia de piel rojo Congo positiva y birrefringencia verde manzana con luz polarizada. Se discuten distintos diagnósticos diferenciales poco frecuentes a tener en cuenta en estos pacientes.

A series of three cases that consulted the rheumatology service due to orbital and renal involvement is reported. One of them presented orbital pseudotumor with proteinuria in the nephrotic range, a biopsy was performed, finding dense lymphoplasmacytic infiltrate and storiform fibrosis with immunohistochemistry: 15 IgG4 positive cells per HPF and IgG/IgG4 ratio ≤40%, concluding diagnosis of IgG4 related disease. The second and third cases presented ocular involvement with raccoon eyes and yellowish lesions on the eyelids, both with proteinuria greater than 500 mg/24 h, with apple-green birefringence of amyloid on congo red staining. Different rare differential diagnoses to take into account in these patients are discussed.

Enfermedad relacionada con IgG4: reporte de un caso y revisión de la literatura / IgG4-related disease: a case report and literature review

Immunoglobulin G4 (IgG4-RD) -related disease is a regional or systemic fibroinflammatory disease of unknown etiology. It has a characteristic histopathological appearance of dense lymphoplasmacytic infiltrates with abundant IgG4 positive plasma cells, storiform fibrosis and obliterative phlebitis with the appearance of inflammatory swelling or swollen lesions. This entity frequently affects the pancreas, salivary glands, and lymph nodes, but it can compromise almost any structure in the human anatomy. This new disease entity includes a wide variety of diseases such as Mikulicz disease, autoimmune pancreatitis, Riedel's thyroiditis, interstitial nephritis, and retroperitoneal fibrosis. Glucocorticoid therapy can resolve clinical and pathologic abnormalities and impaired organ function. IgG4-RD was internationally recognized in 2011, and new evidence has accumulated on its pathogenesis, clinical characteristics, and treatment. However, much is still unknown about the behavior of IgG4 in vivo, the participation of this molecule in disease, and whether its role in IgG4-related disease is primary or secondary. The text below is based on a brief review of the most recent literature on this entity in relation to a clinical case.

Enfermedad relacionada con IgG4, según criterios ACR/EULAR 2019 sin evidencia de IgG4 en sangre / IgG4-related disease according to ACR/EULAR 2019 criteria without evidence of IgG4 in blood

INTRODUCCIÓN. La enfermedad relacionada con IgG4 es una patología fibroinflamatoria multiorgánica, de origen desconocido, que simula trastornos malignos, infecciosos e inflamatorios. Los criterios del American College of Rheumatology y la European League against Rheumatism 2019, son útiles para el diagnóstico diferencial de ésta enfermedad cuando se no se cuenta con evidencia de inmunoglobulina G4 en sangre. CASO CLÍNICO. Paciente hombre de 45 años de edad, nacido en Ambato-Ecuador, con ingreso en noviembre del 2017, en emergencias del Hospital de Especialidades Carlos Andrade Marín, con presencia de tos con hemoptisis leve, febrícula, astenia, pérdida de peso e hiporexia de dos semanas de evolución. Se realizó múltiples exámenes, tras observar infiltrados pulmonares intersticiales, con elevación de inmunoglobulina G en suero, negativas para malignidad; se sospechó de enfermedad relacionada a inmunoglobulina G4. Se ampliaron los estudios para descartar otras patologías más prevalentes y cuyo diferencial es primordial. Se inició tratamiento con prednisona y micofenolato con buena respuesta clínica; durante dos años. DISCUSIÓN. La evidencia científica registró que el hallazgo más importante en la enfermedad relacionada con inmunoglobulina G4 fue un aumento de sus niveles séricos. La recurrencia de la enfermedad en un órgano afectado o la aparición de un nuevo órgano involucrado pudo conducir al diagnóstico en el caso presentado. CONCLUSIÓN. La enfermedad relacionada con inmunoglobulina G4 al ser una patología heterogénea, inmunomediada, al simular otras afecciones puede retrasar el diagnóstico; se debe tener una alta sospecha clínica, si al excluir otros procesos infecciosos, autoinmunes y/o eoplásicos, hay evidencia de patología fibroesclerosante multiorgánica sin causa establecida.

INTRODUCTION. IgG4-related disease is a multiorgan fibroinflammatory pathology of unknown origin that mimics malignant, infectious, and inflammatory disorders. The criteria of the American College of Rheumatology and the European League against Rheumatism 2019 are useful for the differential diagnosis of this disease when there is no evidence of immunoglobulin G4 in blood. CLINICAL CASE. 45-year-old male patient, born in Ambato-Ecuador, with admission in November 2017, in the emergency room of the Hospital de Especialidades Carlos Andrade Marín, with the presence of cough with mild hemoptysis, fever, asthenia, weight loss and hyporexia of two weeks of evolution. Multiple tests were performed, after observing interstitial pulmonary infiltrates, with elevated serum immunoglobulin G, negative for malignancy; immunoglobulin G4-related disease was suspected. Studies were extended to rule out other more prevalent pathologies whose differential is paramount. Treatment with prednisone and mycophenolate was started with good clinical response; for two years. DISCUSSION. The scientific evidence recorded that the most important finding in immunoglobulin G4-related disease was an increase in its serum levels. Recurrence of the disease in an affected organ or the appearance of a new involved organ could have led to the diagnosis in the presented case. CONCLUSION. Immunoglobulin G4-related disease, being a heterogeneous, immune-mediated pathology, by simulating other conditions may delay diagnosis; a high clinical suspicion should be maintained if, when other infectious, autoimmune and/or neoplastic processes are excluded, there is evidence of multiorgan fibrosclerosing pathology without established cause.

Pseudotumor retroperitoneal como apresentação de doença relacionada à IgG 4: relato de caso / Retroperitoneal pseudotumor as a presentation of IgG4-related disease: a case report

Apresentamos um caso de doença relacionada à IgG4 devido às suas várias formas de apresentação clínica e dificuldades diagnósticas, objetivando acrescentar à literatura científica essa apresentação atípica. Trata-se de um homem de 65 anos com dor abdominal, febre e sintomas urinários. Exames laboratoriais inocentes para processo infeccioso agudo. Em tomografia computadorizada de abdome, evidenciou-se pseudotumor em região retroperitoneal, envolvendo ureter, veia e artéria ilíacas. Foi submetido à ressecção cirúrgica, tendo sido confirmado o diagnóstico de doença relacionada à IgG4 pela imuno-histoquímica. Iniciou tratamento com glicocorticoide com melhora clínica importante, seguindo em acompanhamento ambulatorial.

This is a case report of IgG4-related disease because of its wide variety of clinical presentations and difficulties in diagnosis, aiming at adding this atypical presentation to scientific literature. It is a case of a 65-year-old man with abdominal pain, fever and urinary symptoms. Laboratory tests were naive for acute infectious processes. In a computed tomography of the abdomen, retroperitoneal pseudotumor involving ureter, and iliac vein and artery was found. The patient underwent surgical resection, and the diagnosis of IgG4-related disease was confirmed by immunohistochemistry. The treatment was begun with glucocorticoids, with important clinical improvement. He was followed in outpatient settings.

Apresentação periorbitária de doença relacionada ao IgG4 / Periorbital presentation of IgG4 related disease

Resumo A doença relacionada ao IgG4 é uma condição imunomediada caracterizada pela presença de lesões com reação inflamatória associada à fibrose e à infiltração linfoplasmocitária rica em plasmócitos tissulares IgG4 positivos, compondo um espectro de doenças fibroproliferativas. A patogênese da DRIgG4 ainda é pouco compreendida e o tratamento é empírico. Relatamos o caso de um homem de 50 anos com lesões amareladas palpebrais associadas a edema local, diagnosticadas previamente como processo alérgico, até que biópsia com estudo imuno-histoquímico e dosagem de IgG4 sérico aventaram a hipótese de doença relacionada ao IgG4. Foi iniciado tratamento com corticoide e rituximabe, observando-se estabilização do quadro e sem apresentação de outras formas clínicas da doença.

Abstract IgG4-Related Disease is an immunomediated condition that is characterized by the presence of inflammatory lesions associated with fibrosis and lymphoplasmacytic infiltration rich in positive IgG4 tissue plasmocytes, forming a spectrum of fibroproliferative diseases. The pathogenesis of IgG4-RD is still poorly understood and the treatment is empirical. We report the case of a 50-year-old man with yellow eyelid lesions associated with local edema, previously diagnosed as an allergic process, until biopsy with immunohistochemical study and serum IgG4 dosage revealed the hypothesis of IgG4 related disease. Treatment with corticoid and rituximab was initiated, showing stabilization of the condition, without presenting other clinical forms of the disease.

Enfermedad relacionada con IgG4 a propósito de dos casos / Disease related to IgG4. Apropos of two cases

RESUMEN La enfermedad relacionada con IgG4 (ER-IgG4), es una enfermedad autoinmune multisistémica caracterizada por lesiones fibroesclerosantes inflamatorias formadoras de masas o pseudotumores, concentraciones elevadas de IgG4 séricas e infiltración tisular extensa por células plasmáticas IgG4 positivas. Incluye numerosas entidades que previamente se consideraban órgano-específicas. Puede afectar prácticamente a cualquier órgano, siendo los más afectados páncreas, glándulas salivales, glándulas lacrimales, ganglios linfáticos, retroperitoneo y riñones. El diagnóstico se realiza mediante una combinación de hallazgos clínicos, serológicos, imagenológicos e histopatológicos. Tiene pronóstico reservado pero con un diagnóstico precoz se logra el control y en ocasiones la regresión de la enfermedad, aunque tiende a presentar recaídas. Es una entidad infradiagnosticada debido en parte, a que fue caracterizada recientemente. Se presentan dos casos que forman parte del espectro que abarca esta entidad, la tiroiditis de Riedel y la fibrosis retroperitoneal, que una vez diagnosticados respondieron inicialmente a la terapéutica con altas dosis de corticoides (AU).

ABSTRACT The disease related to IgG4 (ER-IgG4 in Spanish) is a multi-systemic, autoimmune disease characterized by inflammatory fibro-sclerotizing lesions forming masses or pseudo tumors, high concentrations of serum IgG4 and extensive tissue infiltrations by IgG4-positive plasma cells. It includes several entities previously considered organ-specific ones. It can affect almost any organ, being pancreas, salivary glands, lacrimal glands, lymphatic ganglion, retroperineum and kidneys the most affected ones. The diagnosis is made through combining clinical, serologic, imaging and histopathological findings. It has a reserved prognosis but with an early diagnosis its control is reached, and occasionally also the disease’s remission, although it tends to have relapses. It is an underdiagnosed disease, partially due to its recent characterization. We present two cases entering the range covered by this disease, the Riedel’s thyroiditis and retroperitoneal fibrosis, both initially answering to therapy with high doses of corticoids after diagnosis (AU).

Panhipopituitarismo y escotoma perimacular como presentación de enfermedad relacionada a IgG4 / IgG4 related disease presenting as panhypopituitarism and perimacular scotoma

La enfermedad relacionada a IgG4 (IgG4-RD) constituye una entidad sistémica recientemente descrita, de causa desconocida. Afecta predominantemente a hombres mayores y presenta características histopatológicas distintivas, como fibrosis estoriforme, flebitis obliterante y denso infiltrado linfoplasmocitario con inmunomarcación para IgG4, pudiendo estar asociada a elevación sérica de dicha inmunoglobulina. Si bien cualquier órgano puede estar afectado, el compromiso de la hipófisis es infrecuente. Describimos el caso de un hombre de 36 años que se presentó con cefaleas, alteración del campo visual, panhipopituitarismo, diabetes insípida y una imagen que mostraba una lesión infiltrativa infundíbulo-panhipofisaria extendida. Arribamos al diagnóstico de IgG4-RD a través de biopsia hipofisaria. La respuesta al tratamiento con dosis inmunosupresoras de corticoides fue exitosa.

IgG4-related disease (IgG4-RD) is a recently described systemic entity of unknown origin. It predominantly affects older men and has distinctive histopathologic features as storiform fibrosis, obliterative phlebitis, dense lymphoplasmacytic infiltrate with immunostaining for IgG4, and it may be associated with elevated serum levels of IgG4. Although any organ can be affected, pituitary gland is rarely involved. We describe the case of a 36-year-old man who presented with headaches, impaired vision, panhypopituitarism with diabetes insipidus and an infiltrative lesion mainly of infundibulum and pituitary. We arrived at diagnosis of IgG4-RD by pituitary biopsy. A successful response to treatment with immunosuppressive doses of corticosteroids was achieved.

Doença sistêmica relacionada à IgG4 com linfopenia: relato de caso e breve revisão de literatura / IgG4-related systemic disease associated with lymphopenia: case report and brief literature review

A doença sistêmica relacionada à IgG4 é uma doença emergente, recentemente descrita, caracterizada clinicamente por aumento parcial ou total de um órgão, e, por isso, com amplo espectro de manifestações clínicas. Esta é uma doença sistêmica fibroinflamatória, patologicamente provocada pela infiltração de plasmoblastos IgG4 positivos que levam à inflamação eosinofílica do tecido e, consequentemente, fibrose estoriforme. Quando o diagnóstico é precoce, a melhora clínica e resposta sustentada com corticosteroides sistêmicos é impressionante. O diagnóstico é baseado em critérios patológicos, mas, recentemente, alguns trabalhos têm descrito que plasmoblastos no soro podem servir como um fator independente para auxiliar no diagnóstico da doença. Este artigo descreve uma apresentação atípica da doença relacionada à IgG4, em um paciente linfopênico com medição inconclusiva de plasmoblastos no soro.

IgG4-related systemic disease is a recently described, emerging condition, clinically characterized by partial or total enlargement of an organ, with a broad spectrum of clinical manifestations. It is a systemic fibroinflammatory condition caused by the infiltration of IgG4-positive plasmablasts that lead to eosinophilic inflammation of tissues and consequently storiform fibrosis. When diagnosis is early, clinical improvement and maintained response achieved with systemic corticosteroids is impressive. Diagnosis is based on pathological criteria, but recent papers have described that serum plasmablasts may serve as an independent factor to aid in diagnosis. This paper describes an atypical presentation of IgG4-related disease in a lymphopenic patient with inconclusive serum plasmablast measurement.