Patologías cutáneas asociadas a gammapatías monoclonales: ¿qué sabemos hasta ahora? / Dermatological manifestations of monoclonal gammopathies

Monoclonal gammopathies of uncertain significance (MGUS) correspond to pre-malignant hematological disorders characterized by the production of a monoclonal protein and infiltration of less than 10% of the bone marrow by plasma cells. Its importance lies in the risk of progression to malignant disorders and in the association with different renal, neurological and skin manifestations. There are pathophysiological mechanisms that support a causal relationship between monoclonal gammopathies (MGs) and different skin diseases, such as type I cryoglobulinemia (CG), primary systemic amyloidosis (PSA) or necrobiotic xanthogranuloma (NXG). However, there is a group of skin diseases associated with MGs whose pathogenesis has not been elucidated. In this context, the role of the dermatologist is crucial in the suspicion of different haematological disorders based on skin manifestations and in the multidisciplinary treatment of these patients. In this article, we carry out an exhaustive review of the literature published in this area and propose a screening algorithm for MGs in patients with specific skin diseases.

Nefropatías secundarias a paraproteína: perfil clínico a partir de hallazgos histológicos

Background: One of the devastating consequences of monoclonal gammopathies is the development of end-stage kidney disease, which can be prevented with an early diagnosis. Renal involvement can be secondary to saturation of paraproteins with intratubular precipitation or the glomerular deposition of paraproteins with secondary inflammation and destruction. These conditions can also be associated with monoclonal gammopathies that do not meet hematological treatment criteria, called monoclonal gammopathies of renal significance (MGRS). Aim: To report a retrospective analysis of patients who underwent a renal biopsy and whose final diagnosis was a form of monoclonal gammopathy. Material and Methods: We reviewed the clinical and laboratory features and response to treatment of 22 patients aged 63 ± 12 years (55% women) with a pathological diagnosis of a nephropathy associated with paraproteinemia. Results: The most common hematological diagnosis was amyloidosis in 50% of patients, followed by cast nephropathy. The predominant clinical presentations were proteinuria (without nephrotic syndrome) and nephritic syndrome. Classic criteria such as erythrocyte sedimentation rate > 100 mm/h and protein-albumin gap were unusual. Serum light chain quantification was the test with the best yield to detect paraproteins. Conclusions: In this group of patients, light chains tend to affect the kidney more commonly than heavy chains. The prognosis of multiple myeloma is much worse than MGRS.

A Case of Schnitzler's Syndrome without Monoclonal Gammopathy-Associated Chronic Urticaria Treated with Anakinra

Chronic urticaria may often be associated with interleukin (IL)-1-mediated autoinflammatory disease, which should be suspected if systemic inflammation signs are present. Here, we report a case of Schnitzler's syndrome without monoclonal gammopathy treated successfully with the IL-1 receptor antagonist anakinra. A 69-year-old man suffered from a pruritic urticarial rash for 12 years. It became aggravated episodically and was accompanied by high fever, arthralgia, leukocytosis, and an elevated C-reactive protein and erythrocyte sedimentation rate. The episodes each lasted for over one week. Neutrophilic and eosinophilic inflammation was found on skin biopsy. However, serum and urine electrophoresis showed no evidence of monoclonal gammopathy. The cutaneous lesions were unresponsive to various kinds of anti-histamines, systemic glucocorticoids, colchicine, cyclosporine, dapsone, and methotrexate, which were administered over a span of 3 years immediately preceding successful treatment. A dramatic response, however, was observed after a daily administration of anakinra. This observation suggests that the correct diagnosis of this case is Schnitzler's syndrome without monoclonal gammopathy. For an adult patient with refractory chronic urticaria and systemic inflammation, Schnitzler's syndrome could be considered as a possible differential diagnosis. Although the typical form of Schnitzler's syndrome exhibits the presence of monoclonal gammopathy as a diagnostic criterion, monoclonal gammopathy may be absent in an atypical form. In such a situation, an IL-1 antagonist should be effective for the management of chronic urticaria.

Acute tubulointerstitial nephritis with severe renal impairment associated with multisystem IgG4-related disease / Nefrite túbulo-intersticial aguda com insuficiência renal grave associada à doença multissistêmica por IgG4

Abstract The IgG4-related disease has a wide clinical spectrum where multiple organs can be affected, and the diagnosis depends on typical histopathological findings and an elevated IgG4 expression in plasma cells in the affected tissue. We describe the clinical presentation and evolution of a patient with acute tubulointerstitial nephritis, severe kidney failure and systemic manifestations such as lymphadenomegaly and chronic pancreatitis. The diagnosis was confirmed by the clinical picture and kidney and lymph node histopathology, in which immunohistochemistry of the lymphoid tissue showed policlonality and increased expression of IgG4, with a IgG4/total IgG ratio > 80%. The patient was treated with prednisone at a dose of 60 mg/day, followed by mycophenolate mofetil, and showed clinical and renal function improvement at 6 months of follow-up. The high index of suspicion of IgG4-related disease with multisystem involvement and the early treatment of this condition are essential to improve the prognosis of affected patients.

Resumo A doença relacionada à IgG4 tem um espectro clínico amplo em que múltiplos órgãos podem ser afetados, e o diagnóstico depende de achados histopatológicos típicos e elevada expressão de IgG4 em plasmócitos no tecido afetado. Descrevemos o quadro clínico e a evolução de um paciente com nefrite túbulo-intersticial aguda, insuficiência renal grave e manifestações sistêmicas como linfoadenomegalias e pancreatite crônica. O diagnóstico foi confirmado pelas características clínicas e pela histopatologia renal e de linfonodo, na qual a imunohistoquímica mostrou tecido linfoide com policlonalidade e expressão aumentada de IgG4, com uma relação IgG4/IgG total > 80%. O paciente foi tratado com prednisona na dose de 60 mg/dia, seguido de micofenolato mofetil, e apresentou melhora clínica e da função renal depois de 6 meses de tratamento. O alto índice de suspeição da doença relacionada ao IgG4 com comprometimento multissistêmico e o tratamento precoce desta condição são primordiais para a melhora do prognóstico destes pacientes.

Simultaneous Occurrence of Angioimmunoblastic T-cell Lymphoma and Plasma Cell Leukemia

No abstract available.

Small Bowel Obstruction Caused by Peritoneal Immunoglobulin G4-Related Disease Mimicking Carcinomatosis: Case Report

We hereby report a case of diffuse pelvic peritoneal involvement by immunoglobulin G4-related disease (IgG4-RD). Numerous pelvic masses and nodules showing delayed enhancement on enhanced abdominal CT were found to congregate in the pelvic organs of a 57-year-old female presenting with intestinal subocclusion. The differentiation between peritoneal IgG4-RD and pelvic peritoneal carcinomatosis was only made by histopathology and immunohistochemistry performed after surgical resection. Autoimmune pancreatitis represents the historical prototype of IgG4-RD, but the spectrum of manifestations involving various organs has expanded during the last decade. In this report, we shortly review this clinical entity.

Respuesta a la talidomida en escleromixedema / Response to thalidomide in scleromyxedema

El escleromixedema es una enfermedad poco frecuente caracterizada por una hiperproliferación de fibroblastos con depósito dérmico incrementado de mucina, que en la mayoría de los casos se asocia con una gammapatía monoclonal de significado incierto. Han sido comunicados diversos tratamientos, con resultados inconsistentes. Esto, sumado a la rareza de la enfermedad y a la falta de ensayos clínicos controlados aleatorios, da lugar a opciones terapéuticas derivadas de informes anecdóticos. Se describe el caso de una paciente de 52 años con diagnóstico de escleromixedema que desarrolló una gammapatía monoclonal, tratada con talidomida con buena respuesta clínica y de laboratorio. Es importante remarcar la necesidad de realizar un seguimiento clínico a largo plazo en estos pacientes, por el riesgo de evolución hacia mieloma múltiple y aparición de complicaciones relacionadas con los tratamientos sistémicos.

The scleromyxedema is a rare condition characterized by hyperproliferation of fibroblasts with increased dermal deposition of mucin and frequently associated with monoclonal gammopathy of undetermined significance. Various treatments have been reported, with inconsistent results. In addition, the rarity of the disease and the lack of randomized controlled trials results in treatment options derived from anecdotal reports. We describe the case of a 52 year-old female patient diagnosed with scleromyxedema who developed a monoclonal gammopathy, with adequate response to thalidomide. The follow up of these patients is important due to the risk of progression to multiple myeloma and complications related to systemic treatments.

Enfermedad renal por depósito idiopático de cadenas livianas: Caso clínico / Kidney involvement in idiopathic light chain disease: Report of one case

Idiopathic Light Chain disease (ILCD) is a systemic disease characterized by a deposit in different organs of light chain monoclonal immunoglobulins, produced by an abnormal clone ofB cells. It is usually found in the course ofa plasma cell dyscrasia and in other lymphoproliferative alterations; however it may occur in absence of any hematologic disease and is denominated as idiopathic. We report a 51-year-old mole admitted to the hospital due to anasarca. Laboratory evaluation showed a serum creatinine of 1.4 mg/dl, a serum albumin of1.6 g/dl, a serum cholesterol of 687 mg/dl and a proteinuria of 5.3 g/day Light chains with a predominance of a monoclonal component were identified in urinary proteins by electrophoresis and kappa chains were identified by immunofixation. A renal biopsy showed a diffuse nodular glomerulopathy with a 35% tubular atrophy and interstitial sclerosis. Electrón microscopy confirmed light chain deposition. The bone marrow biopsy showed a myeloid hyperplasia. Thepatient was initially treated with methylprednisolone and plasmapheresis with a reduction in serum creatinine and disappearance of urinary kappa component. Albuminuriapersisted and a malnutrition-inflammatory complex syndrome was diagnosed. Hemodialysis with ultrafiltration was started along with cyclophosphamide. Thepatient receivedhemodialysisforsixmonths and continued with methylprednisolone.

Aspergillus fumigatus Scleritis Associated with Monoclonal Gammopathy of Undetermined Significance

A 68-year-old woman presented with pain in her left eye. Necrosis with calcium plaques was observed on the medial part of the sclera. Aspergillus fumigatus was isolated from the culture of the necrotic area. On systemic work-up including serum and urine electrophoresis studies, the serum monoclonal protein of immunoglobulin G was detected. The patient was diagnosed with monoclonal gammopathy of undetermined significance and fungal scleritis. Despite intensive treatment with topical and oral antifungal agents, scleral inflammation and ulceration progressed, and scleral perforation and endophthalmitis developed. Debridement, antifungal irrigation, and tectonic scleral grafting were performed. The patient underwent a combined pars plana vitrectomy with an intravitreal injection of an antifungal agent. However, scleral and intraocular inflammation progressed, and the eye was enucleated. Aspergillus fumigatus was isolated from the cultures of the eviscerated materials. Giemsa staining of the excised sclera showed numerous fungal hyphae.

Linfoma renal primario en paciente con gammapatía monoclonal IgM / Primary renal lymphoma in a patient with IgM monoclonal gammapathy

Son infrecuentes los casos de linfoma renal primario, ya que la afectación renal por un proceso linfoproliferativo es, por lo general, secundaria a una enfermedad sistémica. Presentamos el caso de una paciente mujer de 48 años que acude por dolor lumbar y masa abdominal. Después de realizar estudios (TC), se práctica nefrectomía cuyo resultado anatomopatológico fue de linfoma no-hodking B primario renal. Asimismo el paciente presentaba una gammapatía monoclonal IgM asociada, por lo que precisó tratamiento quimioterápico sistémico. Realizamos una revisión bibliográfica centrándonos en los criterios diagnósticos y terapéuticos actuales.

Reports on primary renal lymphoma are scarce in the urological literature, the most part f them are secondary on a lymphomatous infiltration of the kidneys. We report the case of a 48 year old women with lumbar pain and adominal mass. After radiological studies (CT), we practise nephrectomy with a pathological result of a non-hodking B primary lymphoma. The patient present a IgM monoclonal gammapathy who need complementary treatment with chemotherapy. A literature review on currently recommended diagnostic and treatment practices in presented.

A Case of Light Chain Deposition Disease Involving Kidney and Bone Marrow with Microangiopathic Hemolytic Anemia / 대한진단검사의학회지

We report a case of light chain deposition disease in a 59-yr-old female showing deposition of monoclonal light chain in the kidney and bone marrow accompanied with a schistocytosis, the morphologic finding of microangiopathic hemolytic anemia. The immunofluorescence examination of the kidney revealed strongly stained kappa-light chain deposits on the glomerular mesangium and capillary wall, tubules, and vessel wall. The electron microscopy demonstrated electron-dense deposits on the glomerular basement membrane and mesangium. Anemia was observed with schistocytosis and Howell-Jolly body in the peripheral blood smears. The immunohistochemical examination of the bone marrow showed the presence of kappa-light chain deposits in scattered plasma cells and thickened vessel wall in the absence of a prominent plasma cell proliferation. Although an immunofixation electrophoresis failed to detect a monoclonal gammopathy, the presence of monoclonal protein could be identified by an abnormal kappa/lambda ratio on the serum free light chain analysis.

Incidence and Type of Monoclonal or Biclonal Gammopathies in Scrub Typhus / 대한진단검사의학회지

BACKGROUND: Korea is an endemic area of scrub typhus and it is a common seasonal febrile illness. Although, various humoral immune responses to scrub typhus have been documented, no association between gammopathy and scrub typhus has ever been reported. We analyzed the incidences and types of monoclonal and biclonal gammopathies in scrub typhus for better coping with those gammopathies in scrub typhus. METHODS: Anti-Orientia tsutsugamushi antibody-positive sera identified by indirect immunofluorescence assay were acquired from 40 patients with confirmed scrub typhus. Monoclonal and biclonal gammopathies were screened by protein electrophoresis and were confirmed using immunofixation electrophoresis (IFE). Laboratory findings on admission of the patients with monoclonal or biclonal gammopathy were investigated retrospectively to characterize the gammopathies. RESULTS: Monoclonal or biclonal gammopathies were detected in 30% (12/40) of patients with scrub typhus (IgG-lambda, 40%; IgG-kappa, 30%; IgM-kappa, 10%; IgM-lambda, 10%; IgA-kappa, 5%; IgA-lambda, 5%). Concentrations of clonal immunoglobulin were less than 3 g/dL in all gammopathies, and hypercalcemia was not detected in any of the patients. CONCLUSIONS: Our results suggest possible association between gammopathies and scrub typhus. Further studies in larger series will be needed for exact incidence and clinical course of gammopathies in scrub typhus.

A Case of Cardiac Dysfunction Associated with Monoclonal Gammopathy of Undetermined Significance

The monoclonal gammopathies (MG) are monoclonal neoplasms related to each other by virtue of their development from common progenitors in the B lymphocyte lineage. Cardiac dysfunction in patients with MG is not well established. We experienced a case of cardiac dysfunction associated with MG identified by echocardiography and biopsy. Fifty nine year-old man was admitted because of dyspnea for several months. Echocardiography revealed diastolic dysfunction showing restrictive physiology with elevated left ventricular filling pressure. Bone marrow (BM) studies and immunoelectrophoresis were compatible with monoclonal gammopathy of undetermined significance. Endomyocardial, BM, and enteral biopsies for ruling out for amyloidosis (Congo-red stain) were negative. This is the case of non-amyloidotic light chain deposition cardiomyopathy.

The combination of thrombotic microangiopathy and nodular sclerosis in light chain deposition disease.

The authors reported the first case of nodular glomerulosclerosis, mesangiolysis, and thrombotic microangiopathy in a 69-year-old Thai man with chronic glomerulopathy from light chain deposition disease associated with multiple myeloma and kappa monoclonal gammopathy. He presented with subacute onset of generalized edema, hypertension, and renal insufficiency. Blood examinations revealed kappa monoclonal gammopathy. The diagnosis of multiple myeloma was confirmed by bone marrow aspiration and biopsy. The renal pathologies demonstrated specific findings for light chain deposition disease which were type II nodular glomerulosclerosis, strongly PAS-stained tubular basement membrane, monotypic-kappa light chain deposition along tubular and glomerular basement membranes, and granular electron dense deposits in electron microscopy. However the authors also found the concomitant findings of mesangial and endothelial injuries which were mesangiolysis and thrombotic microangiopathy. Of interest, type II nodular sclerosis and thrombotic microangiopathy were caused by the same cell injury. These might shed new light on the pathogenesis of glomerular injury in monoclonal immunoglobulin deposition disease (MIDD).

Lymphoplasmacytic lymphoma with IgA paraproteinemia mimicking Waldenstrom's Macroglobulinemia.

Central to the diagnosis of Waldenstrom's Macroglobulinemia is the demonstration of bone marrow infiltration by lymphoplasmacytic lymphoma with Ig M monoclonal gammopathy. We describe a patient who presented with a clinical and haematological picture, highly suggestive of Waldenstrom's Macroglobulinemia, but whose serum monoclonal immunoglobulin belonged to Ig A class. Ig A secreting lymphoplasmacytic lymphoma undoubtedly exist but are exceedingly uncommon and their relationship to Waldenstrom's Macroglobulinemia needs to be clarified.

Widespread Scleredema Accompanied with a Monoclonal Gammopathy in a Patient with Advanced Ankylosing Spondylitis

Scleredema is a rare cutaneous mucinosis characterized by chronic diffuse induration of the skin, and it is occasionally associated with a monoclonal gammopathy (MG). Ankylosing spondylitis (AS) is noted to be another, chronic systemic inflammatory disorder of the axial skeleton that may accompany the MG. However, patients with scleredema and AS accompanied with a MG have not been reported in the literature. We here report a 40-yr-old man with scleredema and advanced AS accompanied with a MG of IgA-kappa protein. Widespread, long-standing scleredema has been developed over 10 yrs after the initial manifestation of AS. It is uncertain whether the coexistence of scleredema and AS is more than coincidental.

Insuficiencia hepática aguda en amiloidosis hepática asociada a mieloma múltiple. Caso clínico / Acute liver failure in a patient with liver amyloidosis associated to multiple myeloma

We report a 67 years old woman admitted to the hospital for the study of a cholestatic jaundice and massive hepatomegaly. On admission, the patient did not have liver failure. During hospital stay, the patient experienced a progressive deterioration of liver function and a monoclonal gammopathy was detected. An IgG Kappa myeloma was diagnosed. A fine needle liver biopsy disclosed the presence of amyloid. The patient developed acute liver failure and died three weeks after admission (Rev Méd Chile 2003; 131: 1301-04).