RESUMO
Approaching patients with paraproteinemic neuropathies can be challenging for the practicing neurologist, and a well-defined strategy considering specific etiologies is necessary to arrive at the correct diagnosis. In this case, a 49-year-old man presented with a 2-year history of progressive upper then lower extremity numbness, weakness, gait instability, and tremors. His examination was marked by proximal and distal symmetric upper and lower extremity weakness, large more than small-fiber sensory loss, prominent sensory ataxia, action and postural tremors, and globally absent deep tendon reflexes. His workup was notable for a chronic demyelinating sensorimotor polyradiculoneuropathy and a monoclonal immunoglobulin (Ig) M kappa gammopathy. This case highlights the approach to a patient with a rare subtype of IgM paraproteinemic neuropathy with a review of the differential diagnoses, red flag features of co-occurring hematologic disorders, and guided workup. We further discuss typical features of this rare diagnosis and therapeutic options.
Assuntos
Raciocínio Clínico , Transtornos Neurológicos da Marcha , Hipestesia , Paraproteinemias , Tremor , Humanos , Masculino , Pessoa de Meia-Idade , Tremor/diagnóstico , Tremor/etiologia , Hipestesia/etiologia , Hipestesia/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/diagnóstico , Paraproteinemias/complicações , Paraproteinemias/diagnóstico , Diagnóstico DiferencialAssuntos
Coinfecção , Comorbidade , Paraproteinemias , Humanos , Estudos Retrospectivos , Prevalência , Masculino , Idoso , Feminino , Paraproteinemias/complicações , Paraproteinemias/epidemiologia , Coinfecção/epidemiologia , Coinfecção/virologia , Pessoa de Meia-Idade , Viroses/epidemiologia , Viroses/complicações , Idoso de 80 Anos ou mais , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/complicaçõesRESUMO
OBJECTIVES: Rheumatic diseases were previously associated with increased incidence of monoclonal gammopathy (MG) and its malignant transformation. The present study aimed to investigate the prevalence, malignant transformation risk, clinical correlates and prognostic impact of MG in SLE. METHODS: A retrospective cohort study based on the medical records of n=1039 patients with SLE fulfilling the 1997 American College of Rheumatology (ACR), the 2019 European Alliance of Associations for Rheumatology (EULAR)/ACR and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria managed at two tertiary care departments of the University Hospital (Krakow, Poland) from January 2012 until November 2019. RESULTS: SLE+MG cases were older at SLE diagnosis compared with non-MG SLE controls (53±15 years vs 37±15 years, respectively, p<0.01), had higher rates of lymphopenia, anaemia, haemolysis, serous effusions and interstitial lung disease (all p<0.05), and were more frequently treated with cyclophosphamide (57% vs 28%, p<0.01) or rituximab (13% vs 3%, p<0.01). Most MG cases were detected within a year after SLE diagnosis (Q25, Q75: 0, 12 years). With the median follow-up of 11 years (Q25, Q75: 6, 19 years), 34.8% (8 cases) of the SLE+MG cohort were diagnosed with malignancy, compared with 8.1% (82 cases) among the SLE controls (p<0.001). MG was associated with the relative hazard of death of HR 2.99 (95% CI 1.26 to 7.06, p<0.05) and a median survival time from SLE diagnosis to death of 5 years (Q25, Q75: 1, 14; range 0-41) for SLE+MG cases, as compared with 12 years (Q25, Q75: 6, 19; range 0-62) for the controls. The effect was non-independent on antimalarial medication use. CONCLUSIONS: Our study emphasises heightened malignancy and mortality rates in SLE+MG cases. The association between immunosuppression, MG incidence and progression warrants further research.
Assuntos
Lúpus Eritematoso Sistêmico , Neoplasias , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/mortalidade , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Masculino , Adulto , Idoso , Neoplasias/mortalidade , Neoplasias/complicações , Neoplasias/epidemiologia , Paraproteinemias/complicações , Paraproteinemias/mortalidade , Paraproteinemias/epidemiologia , Polônia/epidemiologia , Ciclofosfamida/uso terapêutico , Prognóstico , PrevalênciaRESUMO
Current guidelines recommend screening with serum M-protein and serum-free light chain analysis (S-FLC) when an M-protein-related disorder is suspected. Many patients with multiple myeloma will be overlooked if only serum M-protein is measured. Despite this, the general practitioners in some areas of Denmark cannot order S-FLC. This review aims to disseminate knowledge of the S-FLC analysis, its applicability, and limitations in the diagnostic workup for suspected monoclonal gammopathies.
Assuntos
Cadeias Leves de Imunoglobulina , Mieloma Múltiplo , Humanos , Cadeias Leves de Imunoglobulina/sangue , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/sangue , Paraproteinemias/diagnóstico , Paraproteinemias/sangue , Proteínas do Mieloma/análiseRESUMO
The clinical significance of an abnormal free light chain (FLC) test, performed due to unspecific complains in the absence of a known plasma cell dyscrasia (PCD) or lymphoproliferative disease (LPD), is not fully elucidated. We investigated the importance of an abnormal FLC ratio (FLC-R) in this setting. Patients registered in the Maccabi Healthcare Services database, tested for FLC during 2007-2023 without previously documented PCD/LPD or increased total protein (TP) level, were reviewed. Demographics, co-morbidities, and laboratory tests were recorded. FLC-R was defined as normal (0.26-1.65) or slightly (slAb 0.1-0.26/1.65-4), moderately (mAbn 0.1-0.05/4-8) and significantly abnormal (sigAb- < 0.05 or > 8). Factors associated with PCD/LPD and overall survival were identified. In total, 8,661 patients, 2,215 (25.6%) with abnormal FLC-R [2,090 (24.1%)-slAb, 65 (0.75%)-mAbn and 60 (0.7%)-sigAb], were analyzed. Almost none had anemia nor acute renal failure. 14% had concomitant increased immunoglobulins. Within a median follow-up of 52 months, 943 were diagnosed with PCD (816-MGUS, 127-MM/Amyloidosis/plasmacytoma) and 48 with LPD. Median time to PCD and LPD were 19 and 28 months. Multivariate analysis found slAb (HR = 1.8, CI95%:1.53-2.12, p < 0.001), mAbn (HR = 6.3, CI95%:4.16-9.53, p < 0.001), and sigAb FLC (HR = 10.4, CI95%:7.0-15.35, p < 0.001), to be associated with PCD/LPD diagnosis. Decreased IgG, increased IgA, and concomitant comorbidities predicted PCD, whereas increased IgM predicted LPD. Older age, male gender, anemia, decreased albumin, increased IgG and concomitant comorbidities, predicted shorter survival. Our large study emphasizes the independent clinical significance of abnormal FLC-R as a predictor of PCD/LPD diagnosis even in patients with normal TP level, promoting early detection of PCD/LPD.
Assuntos
Cadeias Leves de Imunoglobulina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Cadeias Leves de Imunoglobulina/sangue , Adulto , Paraproteinemias/sangue , Paraproteinemias/diagnóstico , Estudos Retrospectivos , Análise de Sobrevida , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/mortalidade , Doenças Hematológicas/sangue , Relevância ClínicaRESUMO
TEMPI syndrome is a rare, acquired disorder with multisystemic manifestations. It is classified as a plasma cell disorder and is characterized by telangiectasias, erythrocytosis, monoclonal gammopathy, perinephric fluid collections and intrapulmonary shunt. Even though TEMPI's pathophysiology remains elusive, it responds to anti-myeloma therapy indicating that the monoclonal protein or clone plays a key role. We present a challenging case of a 73-year-old man with erythrocytosis and deteriorating renal function with nephrotic-range proteinuria in whom after extensive work up, the diagnosis of TEMPI syndrome was made. He was received treatment with daratumumab-bortezomib-cyclophosphamide and dexamethasone (Dara-VCD) and achieved a hematological and clinical response. We also report preliminary data on a multiplex assay for cytokines and growth factors for two patients with TEMPI syndrome and note lower levels for non-specific innate immunity related cytokines. A direct link between renal impairment and TEMPI syndrome is not currently established; cytokine deregulation could potentially be involved in the ischemic changes observed in the renal biopsy of our patient.
Assuntos
Policitemia , Humanos , Idoso , Masculino , Policitemia/diagnóstico , Policitemia/terapia , Paraproteinemias/diagnóstico , Paraproteinemias/complicações , Síndrome , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Bortezomib/uso terapêutico , Bortezomib/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
IgG4-related diseases (IgG-RDs) are a group of fibroinflammatory diseases that affect a variety of tissues, resulting in tumour-like effects and/or organ dysfunction. Monoclonal gammopathies (MGPs) are a group of disorders characterized by clonal proliferation of plasma cells or lymphoid cells resulting in the secretion of a monoclonal immunoglobulin. Cases of MGPs in IgG4-RDs coexisting with plasma cell dyscrasias and lymphoid neoplasms have been reported over the past few years. Therefore, the results of examinations of M protein in IgG4-RD patients should be interpreted with caution. Herein, we report the case of a 58-year-old male with a history of type 2 diabetes who presented with submandibular masses, anosmia, swollen lymph nodes, proteinuria, and renal impairment. Laboratory tests revealed hyperglobulinemia and elevated levels of IgG4 (124 g/L) and serum-free light chains (sFLCs). Serum protein electrophoresis (SPEP) revealed an M spike of 5.6 g/dL, and immunofixation electrophoresis (IPE) revealed biclonal IgG-κ and IgG-λ. The patient underwent bone marrow, lymph node, and kidney biopsy, which ruled out plasma cell disorders and lymphoma. He was finally diagnosed with an IgG4-RD comorbid with diabetic nephropathy. The findings in this case highlight that significant activation of B cells in IgG4-RD patients, especially those with multiorgan involvement can lead to significant hyperglobulinemia and high sFLC and IgG4 levels, which are more pronounced in the setting of renal impairment. Relatively high concentrations of polyclonal IgG4 can give rise to a focal band bridging the ß and γ fractions, which may mimic the appearance of a monoclonal band on SPEP and monoclonal gammaglobulinemia in IFE. The patient experienced considerable improvement in his symptoms after rituximab combined with glucocorticoid therapy, and a monoclonal immunoglobulin was not detected.
Assuntos
Doença Relacionada a Imunoglobulina G4 , Imunoglobulina G , Paraproteinemias , Humanos , Masculino , Pessoa de Meia-Idade , Imunoglobulina G/sangue , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/complicações , Paraproteinemias/diagnóstico , Paraproteinemias/imunologia , Paraproteinemias/complicações , Diagnóstico Diferencial , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/diagnósticoRESUMO
ABSTRACT: Currently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.
Assuntos
Metilação de DNA , Epigênese Genética , Imunoglobulina M , Gamopatia Monoclonal de Significância Indeterminada , Macroglobulinemia de Waldenstrom , Humanos , Imunoglobulina M/genética , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/imunologia , Masculino , Gamopatia Monoclonal de Significância Indeterminada/genética , Gamopatia Monoclonal de Significância Indeterminada/patologia , Gamopatia Monoclonal de Significância Indeterminada/metabolismo , Feminino , Idoso , Pessoa de Meia-Idade , Carcinogênese/genética , Paraproteinemias/genética , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Estudos Prospectivos , Transdução de Sinais/genética , MultiômicaRESUMO
INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8â g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.
Assuntos
Mieloma Múltiplo , Osteosclerose , Humanos , Pessoa de Meia-Idade , Feminino , Osteosclerose/diagnóstico por imagem , Osteosclerose/etiologia , Osteosclerose/patologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/patologia , Mieloma Múltiplo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Paraproteinemias/complicações , Paraproteinemias/patologiaRESUMO
Flow cytometry plays an important role in the diagnosis and treatment of plasma cell diseases, particularly in the detection of circulating plasma cells (CPCs) in the peripheral blood. A consensus about the normalized use of flow cytometry in detection of CPCs in peripheral blood in clinical practice has been achieved. This consensus is founded on evidence-based principles, which elucidates the timing and value of flow cytometry for the detection of CPCs in the monoclonal gammopathy of undetermined significance, smoldering myeloma, multiple myeloma, and plasma cell leukemia and standardizes flow cytometry in the detection of CPCs in plasma cell diseases.
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Citometria de Fluxo , Mieloma Múltiplo , Plasmócitos , Citometria de Fluxo/métodos , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/sangue , China , Paraproteinemias/diagnóstico , Paraproteinemias/sangue , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Gamopatia Monoclonal de Significância Indeterminada/sangue , Consenso , População do Leste AsiáticoRESUMO
The incidence of monoclonal gammopathy (MG) increases with age. In individuals over 80 years of age, we can diagnose the presence of monoclonal immunoglobulin (MIg) in up to 10 % of cases. Not only malignant diseases such as multiple myeloma (MM), but also benign forms such as MGUS (monoclonal gammopathy of undetermined significance) can lead to renal involvement. The light chains of immunoglobulins (LC) are the most damaging to the kidneys, as they are freely filtered into the urine due to their molecular weight. Detection of MIg relies mainly on a combination of immunofixation electrophoresis of serum (IELFO) and urine and determination of free light chains (FLC) of kappa and lambda and their ratio (κ/λ) in serum. The combination of these tests will detect the presence of MIg with 99 % sensitivity. Renal damage in MG may be caused by direct deposition of MIg in the glomeruli (e.g. AL amyloidosis, LC deposition disease) or tubules (in the distal tubule as a myeloma kidney or in the proximal tubule as Fanconi syndrome or proximal tubulopathy). Typical urinary findings in these diseases are moderate or severe proteinuria or nephrotic syndrome. Acute kidney injury (AKI) can be expected especially when serum FLC is >500 mg/l. Renal biopsy is crucial to establish an accurate diagnosis and thus initiate the correct treatment. Treatment of these types of renal damage involves the same treatment regimens used in the treatment of MM, including proteasome inhibitors or daratumumab.
Assuntos
Mieloma Múltiplo , Paraproteinemias , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Paraproteinemias/complicações , Paraproteinemias/diagnóstico , Nefropatias/etiologia , Nefropatias/diagnósticoRESUMO
Paraproteinemias are a group of complex diseases associated with an overproduction of a monoclonal immunoglobulin that can cause a diversity of kidney disorders and end-organ damage. In this review, we focus on paraprotein-mediated glomerular diseases. Kidney biopsy plays a crucial role in diagnosing these disorders, enabling the identification of specific histological patterns. These lesions are categorized into organized (such as amyloidosis, immunotactoid glomerulopathy, fibrillary glomerulonephritis, cryoglobulinemic glomerulonephritis, and monoclonal crystalline glomerulopathies) and nonorganized deposits (such as monoclonal Ig deposition disease and proliferative glomerulonephritis with monoclonal Ig deposits) based on the characteristics of immunofluorescence findings and the ultrastructural appearance of deposits on electron microscopy. This review aims to provide an update, highlight, and discuss clinicopathological aspects such as definition, epidemiology, clinical manifestations, mechanisms of kidney injury, histological features, and diagnostic procedures.