Central and peripheral neurological involvement in monoclonal gammopathies of undetermined significance

Several studies have suggested a pathogenetic role of paraproteinaemias in PNS damage. Over the few last years, the presence of symptomatic or subclinical PNS lesions in CNS diseases like multiple sclerosis has been described. On the other hand, CNS demyelinating lesions and cervical atrophy have been re- ported in patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Very few cases of MGUS associated with CNS disease alone or with both CNS and PNS disease have been re- ported. Since 1999, we have been studying 16 patients (8 M, 8 F), with a mean age 60.2 ± 13.4, affected by MGUS associated with symptomatic neurological central and/or peripheral diseases. Patients affected with lymphomas, lupus erithematosus and other immunological diseases were excluded. Involvement of both PNS and CNS was not associated to a particular type of paraproteinemia: monoclonal IgM were found in 8 patients;monoclonal IgG in 6 patients and mono- clonal IgA in 1 patient and Igl in 1 patient. High anti- nervous system autoantibodies were found in 10/16 patients and antiMAG antibodies were detected in patients with paraproteinemic demyelinating neuropathy (PDN). High reactivity anti-nervous system might support the hypothesis of a pathogenetic role of MGUS in these neurological diseases. Nevertheless, at present, we cannot exclude that there is only a circumstantial association between MGUS and neurological damages, particularly concerning CNS.

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

Monoclonal gammopathies are characterized by the presence of monoclonal immunoglobulin in patients with or without evidence of multiple myeloma （MM）, macroglobulinemia, amyloidosis （AL）, or a related plasma cell proliferative disorder. This study aims to evaluate laboratory diagnostic characters of monoclonal gammopathies and investigates the correlation between monoclonal gammopathies and transforming growth factor β1 （TGFβ1）. Immunofixation electrophoresis （IFE）, serum protein electrophoresis （SPE）, nephelometry and urine light chain ELISA were used for laboratory identification of monoclonal immunoglobulins. Plasma TGFβ1 was detected with double-antibodies ELISA. Lightcycler was used for single nucleotide polymorphism （SNP） analysis. Totally 2,007 cases of monoclonal immunoglobulin （M protein） were identified in 10,682 samples. The isotypes of M protein were IgG type 47.1%, IgA 23.0%, IgM 8.7%, IgD 5.3%, free light chain κ 6.1%, λ 9.8%. In reference to IFE, the coherency of diagnosis was serum light chain ratio （κ/λ） 94.4%, quantitation of Igs 83%, light chain quantitation 80.9%, and urine light chain ratio （κ/λ） 58.0%. Plasma TGFβ1 was elevated significantly compared to normal control. The allelic frequency of codon 10 （C 〉 T） was neither associated with the existence of the M protein nor with the M protein isotype. Monoclonal gammopathies can be identified with the combination of IFE, SPE, Igs quantitaion and urine light chain determination. Although TGFβ1, an important cytokine in immune regulation, was elevated in monoclonal gammopathies, the SNPs in coding region of TGFβ1 gene did not confer susceptibility to the development of monoclonal gammopathies in this study. Cellular ＆ Molecular Immunology. 2008;5（4）： 293-298.

Extensive Bi-Atrial Remodeling on Hypertensive Patient with Permanent Atrial Fibrillation Delayed Diagnosis of Fatal Cardiac Lambda Amyloidosis

Background: Amyloidosis is a disease characterized by the deposition of fibrillar proteins in tissues. The nature of the protein defines the type of amyloidosis. Cardiac involvement is most often secondary to deposits of transthyretin and immunoglobulin light chains. Treatment depends on the type of amyloidosis. Cardiac light chain amyloidosis is a medical emergency. Aim: To highlight the importance of an early diagnosis of cardiac light chain amyloidosis. Case Presentation: We report the case of an 88-year-old hypertensive female patient with sustained atrial fibrillation and recurrent heart failure, in whom echocardiography showed concentric left ventricle hypertrophy with mildly reduced left ventricle ejection fraction (LVEF) to 45%. Bone scintigraphy was normal. Serum analysis showed increased lambda free light chains. Accessory salivary gland biopsy revealed weak Kappa light chain staining and clear overexpression of lambda light chain deposits. The diagnosis of stage 3B cardiac amyloidosis secondary to lambda light chain myeloma was made. After a multidisciplinary meeting, it was decided to start treatment with DARATUMUMAB + LENALIDOMIDE. Patient’s general condition deteriorated with the occurrence of febrile pancytopenia. Chemotherapy was stopped and management was limited to comfort care until the patient’s death. Conclusion: Cardiac light-chain amyloidosis must be diagnosed early as it can be rapidly fatal.

Multiple myeloma presenting with amyloid arthropathy as the first manifestation:Two case reports

BACKGROUND Multiple myeloma(MM)can be accompanied by amyloidosis,which occurs in a small number of patients and is characterized by deposition of light chains in the joints,leading to multiple myeloma-associated amyloid arthropathy(MAA).As a rare complication of MM,clinical manifestations of MAA are often similar to those of rheumatoid arthritis,and the two are easily confused.CASE SUMMARY In recent years,our center treated two patients of MM with amyloid arthropathy as the first manifestation,both of whom presented with polyarthritis.After treatment for MM,both patients achieved complete remission.However,subsequently,the two patients underwent hip arthroplasty for femoral neck fractures.Congo red staining and immunofluorescence of the joint tissues confirmed MAA after surgery.Eventually,one of the patients died of MM recurrence,while the other survived.CONCLUSION MAA should be regarded as an initial symptom of MM and should be taken seriously.

Two cases of chronic myelomonocytic leukemia combined with monoclonal gammopathy of undetermined significance and a literature review

To describe myelodysplastic syndrome(MDS)/myeloproliferative neoplasm(MPN) combined with monoclonal gammopathy of undetermined significance(MGUS) in order to investigate the potential association between these 2 diseases. Two cases of confirmed chronic myelomonocytic leukemia(CMML) combined with MGUS were reported. In addition, prior publications of cases with combined MDS or MPN with MGUS were reviewed. The first case was of a 77-year-old man whose routine blood tests showed abnormal hemogram results. The diagnosis was CMML combined with Ig M monoclonal gammopathy, and the disease course was 4 years. The CMML gradually progressed and the patient presented with anemia, thrombocytopenia, autoimmune hemolysis, and an increase in the number of immature cells in the bone marrow. Although the MGUS caused fluctuations in the concentrations of Ig M, no Ig M-associated organ damage was observed. Eventually, this patient died from a lung infection. The second case was of a 78-year-old man who sought treatment because of fever and a cough. An increase in the number of monocytes was discovered in the peripheral blood. Bone marrow smear results suggested obvious active granulocytes and an increase in the percentages of promyelocytes, myelocytes, and metamyelocytes. Unhealthy granulocytes and immature monocytes could also be observed, and the percentage of monocytes was increased. In addition, serum Ig G levels were increased, and immunofixation electrophoresis results showed Ig G-κ type M proteins. The diagnosis was CMML combined with Ig G monoclonal gammopathy. These diseases were stable and follow-up was conducted for 1 year after diagnosis. The cases in this study combined with those that were reviewed in the relevant literature indicate that the presence of these 2 diseases in the same patient might not be a coincidence. The development of the 2 diseases in case 1 was different, and we speculate that they might have had different clonal origins. Whether CMML is a risk factor for MGUS and the role of clonal plasma cells in the occurrence and development of MDS and MDS/MPN requires further studies on a larger number of cases.

Underlying IgM heavy chain amyloidosis in treatment-refractory IgA nephropathy: A case report

BACKGROUND Monoclonal immunoglobulin can cause renal damage,with a wide spectrum of pathological changes and clinical manifestations without hematological evidence of malignancy.These disorders can be missed,especially when combined with other kidney diseases.CASE SUMMARY A 61-year-old woman presented with moderate proteinuria with normal renal function.She was diagnosed with IgA nephropathy combined with monoclonal gammopathy of undetermined significance after the first renal biopsy.Although having received immunosuppressive treatment for 3 years,the patient developed nephrotic syndrome.Repeated renal biopsy and laser microdissection/mass spectrometry analysis confirmed heavy chain amyloidosis.After nine cycles of bortezomib,cyclophosphamide and dexamethasone,she achieved very good partial hematological and kidney responses.CONCLUSION Renal injury should be monitored closely in monoclonal gammopathy patients without obvious hematological malignancy,especially in patients with other preexisting renal diseases.

Volumetric modulated arc radiotherapy for limited osteosclerotic myeloma

AIM:To assess the feasibility of volumetric intensity-modulated arc radiotherapy (VMAT) in patients with limited polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. METHODS:A 70-year-old male with histologically confirmed osteosclerotic myeloma was treated in our department in July 2010 with VMAT. Fourty-six Gray in 23 fractions were given on three bone lesions. Doses delivered to target volume and critical organs were compared with a tridimensional conformal radiotherapy (3D-RT) plan. Treatment was well tolerated without any side effects.RESULTS:VMAT improved dose homogeneity within the target volume, as compared to 3D-RT (standard deviations:2.9 Gy and 1.6 Gy for 3D and VMAT, respectively). VMAT resulted in a better sparing of critical organs. Dose delivered to 20% of organ volume (D20) was reduced from 22 Gy (3D-RT) to 15 Gy (VMAT) for small bowel, from 24 Gy (3D-RT) to 17 Gy (VMAT) for bladder and from 47 Gy (3D-RT) to 3 Gy (VMAT) for spinal cord. Volumes of critical organs that received at least 20 Gy (V20) were decreased by the use of VMAT, as compared to 3D-RT (V20 bladder:10% vs 99%; V20 small bowel:6% vs 21%). One year after treatment completion, no tumor progression has been reported. CONCLUSION:VMAT improved dose distribution as compared to 3D-RT for limited osteosclerotic myeloma, with better saving of critical organs.

Infiltrating ductal breast carcinoma with monoclonal gammopathy of undetermined significance:A case report

BACKGROUND Infiltrating ductal breast carcinoma with monoclonal gammopathy of undetermined significance(MGUS)is rare and easily misdiagnosed.Most patients are first diagnosed with MGUS.We report a rare case of MGUS secondary to infiltrating ductal breast carcinoma.We also review the literature to analyze the clinical characteristics and diagnostic methods.CASE SUMMARY A 51-year-old woman underwent modified radical mastectomy for infiltrating ductal carcinoma of the right breast and was then treated with radiation and chemotherapy.A decreased platelet count was found on routine blood examination,and MGUS was subsequently diagnosed.This is the first report of the occurrence of MGUS after breast cancer surgery.CONCLUSION Vigilance is required to distinguish this rare comorbidity from breast plasmacytoma.

Typing of Four Cases of Monoclonal Gammopathy: A Revival of Immunosubstraction Role

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by increased production of an immunoglobuling (Ig) from a clone of plasma cells and is a pre-malignant disorders in subjects older than 50 years. The prevalence of MGUS in Caucasian population is still not determined. MGUS is characterized by the presence of a monoclonal-protein(M-protein) (IgG and IgA) lower than 30 g/L, bone marrow plasma cell percentage lower than 10%, and absence of clinical signs related to multiple myeloma (MM). MGUS can be responsible for damage to organs through the production of toxic M proteins that may have autoantibody activity or deposit pathologically in the organ tissues. Many techniques are available for the characterization of M-proteins. These techniques can involve different expenses, skills, labor time, and sensitivity in detecting monoclonal proteins also at low-level. Detection of M-proteins needs of assays based on high-resolution electrophoresis and im-munofixation (or immunosubtraction). We show suggestive clinical cases where the subjects involved had not an apparent disease but they showed an interesting pattern in electrophoresis. All cases were investigated by capillary’s electrophoresis and immunofixation to confirm or not the clinical suspect, and then if the immunofixation is not exhaustive, additionally immunosubstraction is done. However in some cases, the interpretation of the peaks is not so easy. Clinical and scientific data provided evidences that immunofixaction technique can fail the identification of monoclonal components. In that cases, we opted for the immunosubtraction method as a third level test, in that cases when immunofixation failed the identification of a monoclonal protein.

MGUS:Proposal for outpatient management

The term monoclonal gammopathy of undetermined significance(MGUS) indicates the presence of a monoclonal protein(M-protein) without features of multiple myeloma, Waldenstrom's macroglobulinemia, primary amyloidosis or malignant lymphoproliferative disorders(LPD). While several guidelines on the treatment of LPD exist, many doubts and perplexities still exist on who should treat a MGUS, when and how. Even where MGUS does not require any therapy, the risk of progression to a LPD is 1% per year. This risk does not diminish over time and persists even in patients(pts) whose condition has remained stable for decades, and a prolonged follow up is, therefore, recommended. We met primary care doctors to share and agree on criteria for the management of outpatients with MGUS. Our aim is to draw up guidelines or, at least, suggestions that may help to determine which MGUS pts could be cared for by the primary care doctor and which should be followed by the hematologist. We suggest that once a MGUS is diagnosed, the primary care physician will attend patients with M-protein < 15 g/L if Ig G and pts with M-protein< 10 g/L if Ig A or Ig M, without end-organ damage and without signs and symptoms of LPD. However, a hematological evaluation is recommended for patients with M-protein Ig G > 15 g/L, or M-protein Ig A > 10 g/L, or Ig M > 10 g/L, or any M-protein with end-organ damage(not attributable to any others causes) or with signs and symptoms of LPD, or rapidly increasing M-protein(> 5 g/L per year).

Monoclonal Gammopathy of Undetermined Significance Occurred after Golimumab Therapy in a Patient with Ankylosing Spondylitis

Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease which is characterized by the involvement of the sacroiliac joint and the spine, the main therapy includes biological agents, which may increase the risk of tumor and infection in long term application. Case Presentation: A fifty-year- old man was diagnosed of AS. He received the therapy of golimumab 50 mg once every one month subcutaneously. After receiving this treatment for two years and eight months, the patient had an elevated level of IgA. The monoclonal protein was finally identified as the type of IgA-kappa from the immunofixation study. Bone marrow aspirate smear revealed infiltration by plasma cells (5%) and immunophenotyping was positive for CD27, CD28, CD38, CD45, CD138 and cKappa, which was finally diagnosed of MGUS. Conclusion: This case demonstrates that golimumab may increase the risk of premalignant disease in patients with AS. With our case report, we also like to highlight that patients with AS may have increased risk of plasma cell malignancies.

Monoclonal Gammopathy of Renal Significance(MGRS): Prospects for Treatment in Integrated Chinese and Western Medicine

Monoclonal gammopathy of renal significance(MGRS)is a pathological state which presents with a spectrum of renal lesions.MGRS is characterized by pathogenic monoclonal immunoglobulins or light chains produced by a premalignant plasma cell or B cell clone.In view of inadequate understanding in the past,the low detection rate of MGRS often results in poor outcomes and reduces quality of life of patients.Thus,MGRS stands for a group of clinical refractory renal diseases.To date,no standard treatment strategy for MGRS is available.Current consensus suggests a clone-directed approach that aims to eradicate the offending clone,but its long-term prognosis is not clear.In this article,we discuss the diagnostic methods,highlight treatment advances,and introduce integrated Chinese and Western medicine in the management of MGRS.

Impact of health care insurance on overall survival of patients with multiple myeloma and monoclonal gammopathy of undetermined significance

Aim:Health care insurance improves access to care and thus outcome in patients with solid tumors.Little information on the impact of health care insurance on hematological malignancies including multiple myeloma exists.The authors aimed to analyze the effect of health care insurance on the survival of patients with multiple myeloma(MM)and monoclonal gammopathy of undetermined significance(MGUS)at Louisiana State University Health Sciences Center in Shreveport,LA.Methods:Two hundred fifty seven patients were reviewed,of which 208 had MM and 49 had MGUS.Results:One hundred and seventy seven patients(69%)were funded and 80(31%)were non-funded.Funded patients with MM had an overall survival(OS)of 6.2 years compared to 3.8 years for non-funded patients(P<0.001).Survivals were not significantly affected by race or gender.The analysis demonstrates that funded patients with MM and MGUS patients have statistically significant increased OS compared to patients with no insurance.Conclusion:This study showed that patients with multiple myeloma and MGUS with health care insurance have longer overall survival when compared to non-funded patients.

Subepidermal Autoimmune Bullous Disease Associated With Monoclonal Gammopathy of Unknown Significance and Unexpected Positive Direct Nikolsky Phenomenon:A Case Report

Introduction:Numerous dermatoses associated with monoclonal gammopathy have been reported in the literature.Subepidermal autoimmune bullous diseases(SABD)are one of them which were not common.Case presentation:A 68-year-old male patient was admitted to our clinic with erosions on the oral mucosa,tense blisters,erosions,and ulcers on the trunk and extremities.Subepidermal vesicle formation was detected in the skin biopsy.Clinical examination revealed positivity for the Nikolsky phenomenon.The disease was unresponsive to conventional treatments and dysphagia and hoarseness occurred.The patient was screened for malignancy due to his unresponsiveness to the treatments and his severe oral mucosal involvement.Ig-G MGUS was detected in the patient.Discussion:The Nikolsky sign is an indicator of acantholysis and is known as a specific finding for pemphigus.However,when we look at gammopathy-associated autoimmune bullous dermatoses,skin fragility has been reported in cases.However,the meaning of fragility is not explained.The diagnosis of all these patients was Ig-M MGUS.Our patient was presented because of non-IgM MGUS,direct Nikolsky positivity,and severe mucosal involvement.Conclusion:Nikolsky positivity may be a clue for gammopathy-related subepidermal autoimmune bullous diseases.