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Waldenstrom's macroglobulinemia (WM) is very distinct from other indolent lymphoma subtypes: by definition it is accompanied by a monoclonal IgM gammopathy; it presents always with bone marrow infiltration and often with clinical symptoms such as neuropathy or hyperviscosity. These disease characteristics and the frequently advanced age of the WM patient pose a major challenge to the treating clinician even today. Recently, there has been not only substantial progress in our understanding of the biology of WM, but we have also significantly improved our tools to prognostify and to treat patients with this disease. This review summarizes our current knowledge about WM and aims at offering a guideline for the clinical management of patients with this lymphoma subtype, covering questions on how to manage diagnosis, prognostification and treatment based on the most recent data.

No abstract available.

Neutrophilic urticarial dermatosis (NUD) is a useful diagnostic term for urticarial lesions that are less pruritic and more painful than conventional urticaria. The histopathologic features include neutrophilic infiltrates in the interstitial dermis with a higher density than idiopathic urticaria. NUD has been associated with several systemic conditions, which are predominantly autoimmune and autoinflammatory in nature. A woman with Crohn disease who developed NUD is described. Literature reports of other conditions in which neutrophilic urticarial dermatosis have been observed are also reviewed and summarized. NUD has not only been described in the setting of inflammatory bowel disease, but also in patients who have systemic lupus erythematosus, adult-onset Still disease, and IgA gammopathy. NUD is usually associated with an underlying disease. Therapeutic agents that target neutrophils (such as dapsone and colchicine) and antagonists to interleukin-1 receptor (such as anakinra) may be effective modalities for affected patients. NUD can be added to the list of dermatologic manifestations associated with systemic inflammation, particularly inflammatory bowel disease.

All cases of multiple myeloma (MM) are preceded by precursor states termed monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). Genetic analyses of MGUS cells have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes found in MM cells. Intraclonal heterogeneity is also established early during the MGUS phase. Although the genetic features of MGUS or SMM cells at baseline may predict disease risk, transition to MM involves altered growth of preexisting clones. Recent advances in mouse modeling of MGUS suggest that the clinical dormancy of the clone may be regulated in part by growth controls extrinsic to the tumor cells. Interactions of MGUS cells with immune cells, bone cells, and others in the bone marrow niche may be key regulators of malignant transformation. These interactions involve a bidirectional crosstalk leading to both growth-supporting and inhibitory signals. Because MGUS is already a genetically complex lesion, application of new tools for earlier detection should allow delineation of earlier stages, which we term as pre-MGUS. Analyses of populations at increased risk of MGUS also suggest the possible existence of a polyclonal phase preceding the development of MGUS. Monoclonal gammopathy in several patients may have potential clinical significance in spite of low risk of malignancy. Understanding the entire spectrum of these disorders may have broader implications beyond prevention of clinical malignancy.

To assess the capability of Scheimpflug-based densitometry of the cornea to quantify light chain deposits in patients with active monoclonal gammopathies.This is a case-control study in which data from a leading tertiary university center in myeloma care were analyzed. Ten eyes of 5 patients with monoclonal gammopathy and 26 eyes of 13 healthy controls undergoing clinical evaluation and Scheimpflug-based measurements were included in the study. The main outcome measures were densitometry data of the 4 corneal layers-anterior layer (AL), central layer (CL), posterior layer, and total layer (TL)-in 4 different annuli (central annular zone 0-2 mm, intermediate annular zone 2-6 mm, peripheral annular zone 6-10 mm, and total annular zone 0-12 mm).In 8 eyes of 4 patients with IgG-based gammopathy, corneal light backscatter was highest in the AL and decreased with increasing corneal depth. The peripheral annular zone showed a higher densitometry value compared with the corneal center. Compared with healthy controls, the AL (P0.001), the CL (P0.001), and the TL (P0.001) had significantly higher corneal light backscatter in patients with gammopathy in the total and the peripheral annular zones. In one patient with predominantly IgA-based disease, corneal light backscatter was not elevated.Scheimpflug-based densitometry of the cornea is able to quantify opacification by immunoglobulin G light chain deposits in monoclonal gammopathies. This noninvasive technique can complement presently used in vivo confocal microscopy and corneal photography to objectivize corneal changes. Densitometry might allow monitoring of corneal immunoglobulin deposits in follow-up examinations.

Immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) and Waldenstrom macroglobulinemia (WM) comprise a continuum, with IgM-MGUS recognized as a precursor condition for WM. Following early observations of clustering of WM (and IgM-MGUS) in families, several lines of evidence have developed that support the hypothesis of a genetic component of WM susceptibility. Family studies have provided seminal observations in delineating the phenotypic spectrum of WM susceptibility, in providing the rationale for large population-based epidemiologic studies of IgM-MGUS and WM, and in providing both the basis and substrate for ongoing genetic studies aimed at identifying WM predisposition genes. Together, these investigations may help elucidate the host genetic factors underlying WM development and more broadly may provide insights into the aging immune system.

Strait et al. described a novel mouse model of cryoglobulinaemia by challenging mice deficient in the immunoglobulin (Ig)G1 subclass (γ1(-) mice) with goat anti-mouse IgD [5]. The phenotype of wild-type mice was not remarkable, whereas γ1(-) mice developed IgG3 anti-goat IgG cryoglobulins as well as severe and lethal glomerulonephritis. Renal phenotype could not be rescued in γ1(-) mice by the deletion of C3, fragment crystalline γ receptor (FcγR) or J chain. On the other hand, early injection of IgG1, IgG2a or IgG2b inhibited the pathogenic effects of IgG3 in an antigen-dependent manner even in the absence of the FcγRIIb, an anti-inflammatory receptor. The authors concluded that the pathogenic role of IgG3 and the protective characteristic of IgG1 in this model were not explained by their abilities to bind to FcRs or effector molecules but are rather due to structural discrepancies enhancing the precipitation properties/solubility of IgG3/IgG1-containing immune complexes. The present article aims to discuss the current knowledge on IgG biology and the properties of IgGs explaining their differential propensity to acquire cryoglobulin activity.

The acronym CANOMAD encompasses chronic ataxic neuropathy combined with ophthalmoplegia, M protein, cold agglutinins, and anti-disialosyl antibodies. Herein we describe 2 patients presenting with progressive ataxic neuropathy who only developed ophthalmoplegia after a significant delay post-presentation, which in 1 case had features indicative of brainstem dysfunction. Both patients were found to have an IgM paraprotein and anti-disialosyl antibodies. They responded to treatment with intravenous immunoglobulin, thus illustrating the importance of diagnosing this condition. Muscle Nerve 44: 829-833, 2011

A 65-year-old patient with an IgM gammopathy, plasma cell infiltration of the bone marrow, lytic lesions of the skeleton, and symptoms of hyperviscosity was evaluated. A diagnosis of IgM myeloma was made. Treatment for multiple myeloma was initiated and resulted in a significant clinical response. There is ongoing debate whether IgM myeloma exists as a unique entity, oras a variant of Waldenstrom's macroglobulinemia. We reviewed the English literature and discovered only six cases documented as IgM multiple myeloma. Further investigation revealed 30 reported cases, which had characteristics typical of an IgM myeloma, but were documented as variations of B-cell neoplastic disease. We acknowledge IgM myeloma to be an entity distinct from Waldenstrom's macroglobulinemia. It is characterized by an IgM monoclonal gammopathy, a predominance of plasma cells infiltrating the bone marrow, and typically associated with osteolytic lesions and/or osteoporosis. Recognizing IgM myeloma is necessary for appropriate disease management.

Background: Schnitzler syndrome (SS) is a rare autoinflammatory disorder characterized by a recurrent urticarial rash and a monoclonal immunoglobulin M gammopathy, as well as 2 of the following minor criteria: recurrent fever (>38°C), objective signs of abnormal bone remodeling, elevated C-reactive protein level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. Alternatively, a monoclonal immunoglobulin G gammopathy may be present along with 3 minor criteria for diagnosis. Objective: To report a rare case of SS without monoclonal gammopathy and inform physicians of this possible clinical presentation so that treatment is not delayed. Methods: We report a case of a 62-year-old white man with a clinical diagnosis of SS without monoclonal gammopathy. He presented with chronic urticaria unresponsive to conventional therapy. Results and Conclusions: To our knowledge, there have only been 3 case reports of SS in the absence of monoclonal gammopathy documented in the literature. SS should be considered based on clinical presentation, even in the absence of monoclonal gammopathy, to facilitate appropriate management.

Multiple myeloma is a malignant plasma cell dyscrasia that is becoming more prevalent in an increasingly ageing population. It is a complex disease with clinical phases ranging from the premalignant monoclonal gammopathy of undetermined significance to asymptomatic (smouldering) myeloma and then symptomatic myeloma; the latter occasionally terminating in the clonal proliferation of plasma cells outside the bone marrow. We present a patient whose clonally evolved disease from monoclonal gammopathy of undetermined significance to multiple myeloma demonstrated the presence of an unusual combination of monoclonal immunoproteins. Capillary electrophoresis demonstrated the presence of three paraproteins in the gamma region (γ-region), two of which were additional to the IgGk paraprotein which migrated in the slow γ-region at initial diagnosis. Subsequent isotypic identification of the new paraproteins was not possible by immunotyping and initial immunofixation studies failed to definitively characterize the monoclonal proteins. After reduction with beta-mercaptoethanol, two paraproteins were detected by both capillary and gel electrophoresis. However, only immunofixation was able to resolve three distinct monoclonal bands, confirming the presence of free monoclonal kappa light chains in the mid-gamma region and free monoclonal heavy chains in the fast gamma region. Triple gammopathies in themselves are uncommon; this case presents a very unusual combination of paraproteins which required various electrophoretical and immunochemical techniques to identify and characterize them. The change of electrophoretic signature from the monoclonal gammopathy of undetermined significance phase to the diagnosis of multiple myeloma suggested that a number of genetically distinct subclones were present in the pretreatment clonal evolution of the disease.

A 59-year-old Caucasian male had a 28-year history of episodes of recurrent urticaria, fever, periorbital angio-oedema and conjunctival injection. The episodes would be preceded by prodromal symptoms of nightmares, general malaise/fatigue and anterior chest/upper abdominal pain similar to indigestion. This would then proceed to urticaria, which had been described as atypical, not always being raised or palpable but being intensely itchy (Figure 1), as well as fever, periorbital angio-oedema and sometimes gum or jaw pain. Four to 6 h after onset, symptoms would typically proceed to hypotension resulting in the loss of consciousness on several occasions. Attacks would last 3–4 days, and were followed by fatigue lasting 1–2 weeks. Figure 1 Photograph of rash during attacks. Investigations showed a monoclonal immunoglobulin G (IgG) kappa paraprotein that has fluctuated between 14 and 20 g/l throughout the course of his illness, although without increasing trend. He was also found to have low levels of kappa free light chains on urine electrophoresis. He had low C4 complement levels and C3 complement levels at the lower end of the normal range during remission, with raised C3d and elevated amounts of the terminal component complex, consistent with ongoing complement activation. Other investigations taken during remission, including C1 inhibitor levels; full blood count; renal and liver function; thyroid function; erythrocyte sedimentation rate (ESR); and C-reactive protein (CRP), did not show any significant abnormality. Anti-nuclear and anti-neutrophil cytoplasmic antibodies were not detected. Subsequently, he was admitted for observation during an attack. Investigations done at that time showed a markedly increased CRP of >250 mg/l, leucopenia and thrombocytopenia (with a nadir white cell count of 0.7 × 109/l, neutrophil count of 0.1 × 109/l and platelet count of 28 × 109/l) and decreased complement C3 and C4 levels. The ESR did not show a …

Cutaneous macroglobulinosis is a rare skin manifestation of Waldenstrom macroglobulinemia. It is characterized by the deposition of eosinophilic, immunoglobulin-derived material in the dermis. It typically presents as pink or skin-colored papules favoring the extensor surfaces of the extremities. There are 11 reported cases of cutaneous macroglobulinosis in the literature. In our consultative dermatopathology practice we encountered three additional cases. In Case 1, a 41-year-old female with a monoclonal immunoglobulin M (IgM)-kappa gammopathy developed skin-colored papules on her extensor extremities, forehead and back. Histopathologic and immunohistochemical analyses revealed periodic acid-Schiff (PAS)-positive pink material in the dermis that stained with IgM. In Case 2, an 83-year-old female with a monoclonal IgM-lambda paraproteinemia developed non-blanching papules and plaques on the lower extremities and cheeks. Skin biopsies showed a striking occlusion of the vessels with a PAS-positive eosinophilic precipitate, which was also found in the extravascular spaces and stained with IgM using direct immunofluorescence (DIF) and immunohistochemical stains. In Case 3, an 80-year-old male with Waldenstrom macroglobulinemia developed ulcerated papules and nodules on the lower extremities. The biopsy findings were similar to those of Case 2. We present a series of three patients with cutaneous macroglobulinosis and explore variations in the clinical and histopathological findings of this uncommon entity.

Multiple myeloma (MM) is a malignant hematological neoplasmand constitutes 10% of blood cancers. Recently, it has become evident that almost all cases of MM are preceded by gammopathy of undetermined significance (MGUS). MM is diagnosed by the presence of paraprotein in serum or urine, detected by serum electrophoresis and immunofixation, infiltration of malignant plasma cells in the bone marrow and related organ, or tissue damage. Cytogenetic status, International Staging System (ISS) and the quality of response to therapy are the most important prognostic factors. In the last decade the availability of new effective drugs, such as thalidomide, lenalidomide and bortezomib have provided a new therapeutic scenario expected to impact favorably on the outcome of MM patients. Today, for younger patients a triple-agent induction regimen incorporating novel agents followed by autologous stem cell transplantation (ASCT) is the best approach. In this setting ongoing clinical trials are evaluating the efficacy of consolidation and maintenance therapy based on the use of new drugs. For patients noteligible for ASCT the best initial regimens are combination therapy with melphalan and prednisone plus either thalidomide or bortezomibor the combination of lenalidomide and dexamethasone. Supportive therapy includes the use of erythropoietin and bisphosphonates according to the updated guidelines. In the future the identification of candidate therapeutic targets through gene expression profiling (GEP) and single-nucleotide polymorphism (SNP) analysis, as well as the availability of the targeted investigative agents will lead to a substantial progress in the development and implementation of personalized medicine in MM.

Small case series suggest tremor occurs frequently in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) neuropathy. Epidemiologic study to confirm this association is lacking. Whether the neuropathy or another remote IgM-effect is causal remains unsettled.An IgM-MGUS neuropathy case cohort (n = 207) was compared to age, gender, and neuropathy impairment score (NIS) matched, other-cause neuropathy controls (n = 414). Tremor details were extracted from structured neurologic evaluation. All patients underwent nerve conductions.Tremor occurrence was significantly higher in IgM-MGUS case cohort (29%) than in control cohort (9.2%) (p = 0.001). In IgM-MGUS cases, tremor was associated with worse NIS (p = 0.025) and demyelinating nerve conductions (p = 0.020), but 11 of 60 (18%) IgM-MGUS cases with tremor had axonal neuropathy. In other-cause neuropathy controls, tremor was associated with axonal nerve conductions (p = 0.03) but not with NIS severity (p = 0.57). Tremor occurrence associated with older age in controls, (p = 0.004) but not in IgM-MGUS cases (p = 0.272). Most IgM-MGUS tremor cases (49/60) had a postural-kinetic tremor, 8 had rest tremor, 3 had mixed rest-action. Alternative causes of tremor was identified in 42% of IgM-MGUS cases, the most common type is inherited essential tremor 6/60 (p = 0.04).This first epidemiologic case-control study validates association between IgM-MGUS neuropathy and tremor. Among IgM-MGUS neuropathy cases, severity as well as type of neuropathy (demyelinating over axonal) correlated with tremor occurrence. IgM-MGUS paraproteinemia may increase tremor expression in persons recognized with common other risk factors for tremor.

Some patients with immunoglobulin paraproteinemic neuropathy have intra-nerve deposits that morphologically mimick amyloid, but do no stain with Congo red. Patients with amyloid-like deposits were identified. The nerve amyloid-like aggregates were studied by laser microdissection and dual mass spectrometry. Three male patients, all with IgM gammopathy, and neuropathy were identified. Follow-up, disease duration was 5, 19, and 7 years, respectively. All had progressive asymmetric sensory-onset distal axonal polyneuropathy with late motor involvement. Autonomic symptoms occurred in only one after 13 years of symptoms. None had clinical cardio-renal involvement. One had skin papules with dermal amyloid-like deposits. Endoneurial amyloid-like deposits had granulo-fibrillar ultrastructure. Mass spectrometry of laser-dissected deposits identified IgM pentameric macroglobulin (heavy, light, and joining chains) without amyloid-associated proteins including absent apolipoprotein E and serum amyloid P-component. Amyloid-like neuropathy has distinct clinical, pathologic, and proteomic features which expand the spectrum of IgM neuropathies. Patients have favorable survival, relative absence of autonomic features, and distinct proteomic profiles of the infiltrative protein in nerve.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent useful models for studying multiple myeloma precursor disease, and for developing early intervention strategies. Administering a 4g dose of curcumin, we performed a randomised, double-blind placebo-controlled cross-over study, followed by an open-label extension study using an 8g dose to assess the effect of curcumin on FLC response and bone turnover in patients with MGUS and SMM. 36 patients (19 MGUS and 17 SMM) were randomised into two groups: one received 4g curcumin and the other 4g placebo, crossing over at 3 months. At completion of the 4g arm, all patients were given the option of entering an open-label, 8g dose extension study. Blood and urine samples were collected at specified intervals for specific marker analyses. Group values are expressed as mean ± 1 SD. Data from different time intervals within groups were compared using Student's paired t-test. 25 patients completed the 4g cross-over study and 18 the 8g extension study. Curcumin therapy decreased the free light-chain ratio (rFLC), reduced the difference between clonal and nonclonal light-chain (dFLC) and involved free light-chain (iFLC). uDPYD, a marker of bone resorption, decreased in the curcumin arm and increased on the placebo arm. Serum creatinine levels tended to diminish on curcumin therapy. These findings suggest that curcumin might have the potential to slow the disease process in patients with MGUS and SMM.

OBJECTIVE There is considerable recent interest in immunostimulation caused by opiates, but, although there is intense interest in this process within the central nervous system particularly in connection with the pathways underlying chronic pain, few studies set out to define the course of clinical markers of this process in the systemic circulation or over the temporal span of the life course. METHODS For this reason, we have compared clinical pathology results from 1747 opiate substance use disorder with 6450 non-substance use disorder patients taken from our clinical pathology database. All continuous data were transformed to their natural logarithm to improve normality assumptions. RESULTS Globulins, erythrocyte sedimentation rate, white cell count, lymphocytes, monocytes, and platelets were all high in substance use disorder (P ≤ 0.01). These variables, C-reactive protein, high-sensitivity C-reactive protein, and neutrophils were all high at multiple regression when corrected for age (P < 0.0001) in both sexes (P ≤ 0.01). There were significant interactions between age and addictive status for C-reactive protein, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, globulins, white cell count, and lymphocytes and monocytes (P < 0.01). CONCLUSIONS These results are consistent with immunostimulation affecting soluble and cellular elements of the blood both in relative terms and after correction for age. They are consistent with other data showing diffuse and generalized immunostimulation like the high-risk polyclonal immunosenescent gammopathy seen in the very elderly known as "inflamm-aging" that carries an uncommonly poor prognosis for longevity. As such, it merits further detailed investigation.

Monoclonal gammopathy reflects a serological disorder suggesting a plasma cell dyscrasia or a B-cell abnormality. However, it may occasionally be encountered as a transient manifestation in the course of several diseases including infections. This is the first reported case of a transient monoclonal gammopathy IgG lambda light chain associated with aStaphylococcus aureusinfection that was complicated with renal abscess and vertebral spondylodiscitis in a previously healthy 68-year-old male. We observed a complete resolution of the gammopathy within three months of medical treatment before the entire restoration of all clinical and laboratory findings. Many invasive and cost-intensive diagnostic procedures had preceded the exclusion of a malignancy. The clinical significance and the exact pathogenesis of transient monoclonality are poorly understood and remain a matter of speculation.

Free Light Chains of Immunoglobulin as a Prognostic Factor for Some Plasmaproliferative DiseasesQuantitation of monoclonal immunoglobulins and their fragments is used for monitoring the plasmaproliferative disease course and the effect of therapy. The aim of free light chains examination was to evaluate the significance of the FLC ratio as a prognostic factor for remission, progression and survival in different disease groups. The concentrations of immunoglobulins and free light chains were measured by an immunonephelometric method on a »SIEMENS« DADE BN II analyser with reagents (Freelite, The Binding Site, UK). In this examination 151 patients from 3 different disease groups: 1. Light chain disease or Bence Jones myeloma (37), 2. Biclonal gammopathy with FLC (23) and 3. Monoclonal gammopathy of undetermined significance (91), were investigated during a period of 7 years. The reference interval for FLC ratio is 0.26-1.65. According to the International Staging System for multiple myeloma, a serum FLC ratio of 32 was taken as abnormal. The patients with light chain disease and biclonal gammopathy with FLC with an abnormal FLC ratio and a combination of adverse risk factors (76.7%) had median survival times of 22-30 months, versus patients with a normal or slightly varied FLC ratio without adverse risk factors (23.3%) with median survival times of 39-51 months. About 38% of patients who had shown lowered free light chains values by more than 50% under therapy, achieved disease remission in the light chain disease and biclonal gammopathy with FLC groups. In the group of patients with monoclonal gammopathy of undetermined significance, 66.0% had a normal or slightly modified FLC ratio which corresponds to low and low-intermediate risk of disease progression, as opposed to 34.0% with an abnormal FLC ratio (4) which corresponds to high and high-intermediate risk. An abnormal FLC ratio in the examined groups could be an independent risk factor for progression and poorer disease prognosis.

Schnitzler's syndrome (SS) is a rare inflammatory disease of unknown origin characterized by chronic urticaria and monoclonal gammopathy (usually IgM) associated with at least two of the following components: fever, arthralgia or arthritis, bone pain, hepato- and/or splenomegaly, lymphadenopathy, elevated erythrocyte sedimentation rate, leukocytosis, and/or abnormal findings on bone morphological investigations. To date, about 100 cases have been described with only 4 being reported in the USA. The mean time to diagnosis from the onset of disease is 5.4 years, given the varied symptoms with which patients may present. The pathogenesis of SS remains unknown but likely involves dysregulation of the IL-1 pathway. We describe here a 48-year-old woman with a monoclonal IgM gammopathy and a 3-year history of chronic pruritic urticarial dermatosis, unexplained fevers, chronic polyarthritis, lymphadenopathy, leukocytosis, hepatomegaly, and weight loss. She also had a history of chronic pancreatitis as well as a family history of recurrent pancreatitis. The diagnosis of Schnitzler's syndrome was made, and she was successfully treated with the IL-1 receptor antagonist, anakinra.

Generalised pyogranulomatous disease and hyperviscosity syndrome associated with a presumed monoclonal gammopathy was diagnosed in a three-year-old intact female Pomeranian. The Bartonella henselae antibody titer was 1:64 and Bartonella species DNA was amplified from the splenic tissue. Monoclonal gammopathies in dogs are typically associated with plasma cell and lymphoid dyscrasias and other inflammatory or infectious diseases such as ehrlichiosis and leishmaniosis. Based on this case report, infection with Bartonella species should also be added to the differential diagnoses for gammopathy in dogs. To the authors' knowledge, this is the first report of molecular evidence of Bartonella species infection in a sick dog in Spain.

Gaucher disease (GD) is a lysosomal storage disease characterized by deficiency of glucocerebrosidase within lysosomes, altering degradation of glycosphingolipids, which causes accumulation of glycosylceramide. Patients with GD type 1 (GD1) have an increased incidence of gammopathy (i.e., hypergammaglobulinemia, monoclonal gammopathy of undetermined significance [MGUS]), and multiple myeloma (MM) when compared to the general population. No formal evaluation of gammopathy screening has been reported in the literature. We conducted an IRB approved retrospective analysis of clinical and laboratory data, including screening for MM, in adults with GD at Cincinnati Children’s Hospital Medical Center between 2010 and 2018. During the 8-year study period, 20 adults with GD (11 females/9 males) ages 19 to 71 (mean = 51.95 years) were screened for MM using serum protein electrophoresis (SPE) and immunofixation (IFE). Of those, 10 were treated with substrate reduction therapy (SRT) and 9 with enzyme therapy (ET). We identified no patients with MM, 2 with MGUS, and 1 with persistent polyclonal gammopathy. The 2 MGUS patients were 48 and 61 years-old, female and male respectively, with intact spleens. SPE and IFE follow-up has been stable without progression. The polyclonal gammopathy patient was a 54-year-old splenectomized male. All patients with abnormal SPE or IFE were on therapy (2 ET/ 1 SRT). Only one abnormal patient’s GBA genotype was known (p.Asn409Ser, p.Leu483Pro). Other SPE abnormalities included slight increases/decreases in albumin, protein, and beta globulin, or slight decreases in alpha 2 or gamma globulin without clinical significance. Family history of cancer was documented in 10 individuals, with no MM or blood-related malignancies reported. Our data show that as in the general population and previous GD studies, gammopathies are more common in patients greater than 50 years. These data support screening in GD1 for gammopathy greater than age 40 years.

Individuals with type I Gaucher disease (GD) have a 25-50-fold increased risk of developing monoclonal gammopathy of undetermined significance (MGUS), and its post-cursor, multiple myeloma, compared with the general population. Multiple myeloma is a major contributor to morbidity and mortality in patients with GD with up to 8.0% of patients progressing to a malignant gammopathy. Chronic immune activation and the pathogenic accumulation of lysolipids in GD are hypothesized to contribute to this increased risk. However, the response of MGUS to enzyme replacement therapy and/or an alteration in the risk of progression to multiple myeloma on treatment is not clear. Retrospective chart review of 85 patients with Type 1 GD revealed 12 patients with MGUS (incidence: 14%), including 4 who received enzyme replacement therapy (ERT). ERT resulted in an improvement in markers of disease activity (including chitotriosidase, ferritin, lysoGb1) and in reduction of the monoclonal protein. In the majority of patients, the response was sustained. One patient demonstrated a transient reduction in paraprotein with ERT but progressed to smoldering myeloma with an IgG-κ monoclonal component. These data suggest that MGUS may respond to ERT and provide further evidence that altering the levels of lysolipid accumulation in GD individuals with MGUS may attenuate the risk of progression to malignancy.

We report the case of a 71-year-old woman with typical signs of bulbar amyotrophic lateral sclerosis (ALS) associated with immunoglobulin M (IgM) monoclonal gammopathy and anti-MAG (myelin-associated glycoprotein) antibodies. This unusual association between ALS and anti-MAG antibodies has previously been reported in a single case. Our present case, at neuropathological examination, demonstrated no causative link between anti-MAG antibodies and ALS.

Introduction: Plasma cell disorders are a heterogeneous group of disease ranging from Monocloncal gammopathy of unknown significance to Multiple myeloma (MM) and the highly lethal plasma cell leukemia. The prognosis and therapy of MM has been revolutionized in the past two decades with the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs) and the monoclonal antibodies. The standard of care for induction has been become a triplet regimen lately. Here we describe our experience with the management of MM patients. Methods: This is a retrospective analysis of Thirty-five patients who were seen with diagnosis with plasma cell disorders from January 1, 2016 till June 30th 2018 at our center in the UAE. Patients with solitary plasmacytoma and plasma cell leukemia were excluded from further analysis (N=3). Thirty-two patients were included in the analysis. Results: The median age was 58 years (range 26 to 94 years). Male to female ratio was 3:1. Biochemical classification showed ten patients with light chain disease only. Twelve patients had IgG kappa disease, eight had IgG lambda while there was one with IgA lambda disease and one was non-secretory with diffuse plasmacytomas. ISS staging (based on albumin and Beta 2 microglobulin) showed ISS stage 1=7, ISS stage 2= 13, ISS stage 3=8 and data was not available for four patients (diagnosed elsewhere). Cytogenetic risk stratification was not possible due to lack of access to interphase FISH. Seven patients did not receive any therapy either due to refusal for further investigation and therapy or poor performance status and comorbidities. Four of these seven have expired while the other three have been lost to follow-up. Twenty-four patients were given induction therapy with a Bortezomib (V)-based regimen while one received IMIDs-based treatment. Regimens and patient numbers are as follows: RVd (Lenalidomide/V/dexamethasone) (N=16), PVd (pomalidomide instead of R due to renal insufficiency) (N=1), V/thalidomide (T) (N=1), VCd (N=2; one for secondary amyloidosis) and Vd (N=4) (poor performance status and/or comorbidities). All patients were given zoledronic acid as well as herpes zoster prophylaxis. Venous thromboembolism (VTE) prophylaxis was prescribed based on published guidelines. Response evaluation was performed in patients receiving at least four cycles of therapy: CR(N=7); Very Good Partial Remission (VGPR) (N=6); Partial Response (PR) (N=5) and not evaluable for response due to lack of data (N=7). Five patients were documented to have received autologous stem cell transplant (autoSCT). Seven patients, lost to follow up after induction presumably received an autoSCT. Conclusion: This is the first report on the management of MM patients in UAE. With a median follow-up of 216 days (range 3 to 839 days) the response rate to induction therapy was 72% (CR+ VGPR). We are unable to report progression free survival due to short follow-up. This response rate of 72% (VGPR or better) is less than the reported in the literature. This may partly be due to lack of patient data regarding induction therapy elsewhere, the use of double over triplet regimens and the absence of autoSCT facilities. Outcome measurement is a difficult task due to tendency of local citizens to travel outside UAE for treatment and the transient nature of the large expatriate population (88% of the total population of approximately 5.4 million) We are working on developing an infrastructure for consistent testing (CD138-selected FISH, consistent staging, use of PET-CT and bone marrow MRI as well as developing auto SCT facilities). We have formulated a uniform treatment plan based on weekly RVd based therapy for 16 weeks as induction followed by recommendation for Auto SCT. If auto SCT is not possible then patients will continue RVd therapy for a total of 12 cycles followed by maintenance lenalidomide till progression. The standardization of diagnosis, therapeutic approach and follow-up should optimize the care and outcomes of UAE MM patients. Disclosures McCarthy: Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

To characterize the morphological progression of neuropathy associated with immunoglobulin M-monoclonal gammopathy of undetermined significance with anti-myelin-associated glycoprotein antibody, we assessed histopathologic features of sural nerve specimens from 15 patients, emphasizing widely spaced myelin (WSM), demyelination, and tomaculous changes. The frequency of WSM correlated with that of demyelination and tomaculous appearance in teased-fiber preparations. In longitudinal sections at nodes of Ranvier and paranodal regions, the spaces between terminal myelin loops, particularly those adjacent to the node of Ranvier, were widened, indicating an early change before demyelination, and there was concomitant swelling of terminal myelin loops. Some conspicuously swollen terminal myelin loops were detached from the paranodal axolemma, thereby widening the nodes of Ranvier. Tomacula coexisted frequently with redundant myelin loops and WSM, particularly in the outermost layer of myelin sheaths, suggesting that loosening of the outer layers contributes to their formation. By immunofluorescence microscopy, immunoglobulin M and myelin-associated glycoprotein were colocalized in paranodal regions and Schmidt-Lanterman incisures. Confocal analysis revealed colocalization of immunoglobulin M and complement product C3d corresponding to the area of WSM. Thus, morphological changes in terminal myelin loops, formation of WSM at paranodes, and subsequent dissociation from paranodal axolemma (which may be associated with activation of the complement pathway) likely contribute to demyelination in this condition. Loosening of compact myelin seems to contribute to tomacula formation.

Schnitzler's syndrome is characterized by chronic urticarial rash, a monoclonal immunoglobulin (Ig)M gammopathy, and increased levels of markers of systemic inflammation. The response to immunosupp...

Monoclonal gammopathy (MG), a positive result of serum immunofixation electrophoresis (SIFE), has been reported in cases of diffuse large B-cell lymphoma (DLBCL). We performed this study to further investigate the prognostic value of MG in DLBCL.We retrospectively reviewed patients diagnosed

Waldenström macroglobulinemia (WM) is characterized by serum IgM monoclonal gammopathy, and only occasionally complicated by immune thrombocytopenia. Rarely, coexistence of non-IgM gammopathy in WM has been reported. Herein, we describe an 81-year-old case of WM with rapidly progressive immune thrombocytopenia accompanied by concurrent IgG gammopathy and elevation of platelet-associated IgG (PA-IgG). Immunostaining of the bone marrow specimen displayed not only IgM positive but also IgG positive plasmacytoid cells. Although dexamethasone therapy had no effect on thrombocytopenia, a modified RCD regimen (rituximab 375 mg/m(2) i.v. day 1, cyclophosphamide 375 mg/m(2) i.v. day 2 and dexamethasone 12 mg/body orally days 1-7) successfully normalized PA-IgG as well as IgG and IgM paraproteinemia and significantly increased platelet count. The current case suggests that the IgG gammopathy associated with WM is likely to be an etiology of immune thrombocytopenia and that tumor reduction, rather than immunosuppression, leads to an improvement of concurrent thrombocytopenia.

Background Monoclonal gammopathy has been noted with increased frequency in patients with HIV infection compared with the general population. The prevalence in patients on antiretroviral therapy (ART) has not been widely investigated. The present study aims to describe the prevalence and characteristics of monoclonal proteins in a population of HIV-infected patients in the Western Cape region of South Africa. Methods Clinical information and blood and urine samples were collected from patients with proven HIV infection attending two clinics in the Western Cape. Serum protein electrophoresis was performed on all patients using agarose gel. Those with visible mono- or oligoclonal bands or increased gamma fractions were subjected to immunofixation electrophoresis. Results Three hundred and sixty-eight patients were included in the study with a mean age of 37.7 y. Of these patients, 326 were on ART for a mean duration of 19.6 months. Monoclonal bands were found in 12 patients (3.2%) and oligoclonal bands in 14 (3.8%). These bands were associated with a shorter duration of ART, increased total protein, acute on chronic phase pattern on electrophoresis and an increased gamma fraction, but not associated with CD4 count and viral load. The majority were of low concentration and of the IgG isotype. Conclusion Our study confirms that the prevalence of monoclonal and oligoclonal bands is higher in this HIV-positive cohort on ART compared with that of the general population. However, the prevalence is lower than previously reported in other studies.

Monoclonal gammopathy-associated IgA pemphigus is a debilitating skin disorder with inconsistent response to treatment. A 61-year-old woman with IgA pemphigus and monoclonal gammopathy of unknown significance had been treated unsuccessfully with cyclophosphamide/dexamethasone and then with rituximab. When the monoclonal gammopathy progressed to multiple myeloma, the patient received treatment with cyclophosphamide/doxorubicin/dexamethasone but there was no clinical response. Second-line therapy with a thalidomide/cyclophosphamide/dexamethasone combination led to severe exacerbation of the skin disorder. However, therapy with a combination regimen that included bortezomib, cyclophosphamide and dexamethasone resulted in complete and durable remission of multiple myeloma and IgA pemphigus. This suggests that bortezomib-based therapy is useful for the treatment of the rare dermatologic disorder associated with IgA gammopathy.

The molecular basis of monoclonal gammopathy of undetermined significance (MGUS) progression to a malignant monoclonal gammopathy remains poorly understood. It was recently suggested that this process involves the suppression of innate and adaptive immunity. In this study, we examined immunogenic differences in bone marrow plasma cells among individuals without gammopathy (controls) and patients with MGUS, multiple myeloma (MM), and plasma cell leukemia. We detected differences in major histocompatibility complex (MHC) class I expression, MHC class I chain-related molecule A, and CD95 that were more evident between MGUS and MM samples; there appeared to be a critical imbalance between natural killer (NK)-cell activating and inhibitory signals during the transition from MGUS to MM. Our results indicate that the human leukocyte antigen (HLA) class I(bright), MICA(dim/-), and CD95(dim/-) immunophenotype reported in myeloma cells may result from an extensive interaction of malignant cells with cytotoxic T and NK cells and appears to be immunoedited for the evasion of immunosurveillance.

We relate three cases of IgM gammopathy with haemostatic dysfunction in the perioperative period. The acquired von Willebrand syndrome due to IgM gammopathy is rare and sometimes serious. Its different treatments and their efficiency are discussed: desmopressin, intravenous gammaglobulin, chemotherapy and plasmapheresis.

Objective: To determine the responses to treatment of patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies. Methods: Patients with chronic sensory ataxic neuropathy associated with anti-GD1b IgM antibodies followed in our department for at least 12 months between 2001 and 2008 were identified and studied retrospectively. Patients were tested at regular intervals using the INCAT disability score. Patients whose disability scores improved by at least one point were taken to have responded to the treatment. Intravenous immunoglobulin (IVIg; 2 g/kg) was administered for 3 to 5 days once every 6 weeks or corticosteroids at an initial daily dose of 1 mg/kg. Results: 13 patients treated during the 8-year period of interest were included in this study. Seven of 13 patients displayed IgM anti-GQ1b, GT1b and GD3 antibodies suggesting reactivity against disialosyl epitope. IgM gammopathy was detected in four of six of serum with anti-disialosyl antibodies and two of the seven other sera. Nine of the 13 patients improved in response to IVIg. Oral corticosteroid treatment was attempted on four patients prior to IVIg treatment, and partial recovery occurred in one, who became steroid-dependent and showed little benefit in the long term. Conclusions: Screening for anti-GD1b IgM antibodies should be carried out on all patients with chronic ataxic sensory neuropathies. In 69% of the cases studied, the patients’ condition improved in response to IVIg. This study shows the short-term efficiency of this treatment. Sustained responses were obtained in the long term by continuing the infusions.

Granulocyte function was studied in 22 patients with untreated myelomatosis or macroglobulinaemia. Granulocyte adhesiveness (GA) and migration in capillary tubes (Tm) were, except for light chain disease, significantly decreased in patients of all gammopathy classes especially IgG myelomatosis. A plasma factor inhibited GA. The impairment of Tm was due to an inhibiting factor as well as lack of a stimulating plasma factor. Migration of granulocytes to skin chambers was decreased in patients with IgG myelomatosis. Chemiluminescence production during phagocytosis of opsonized zymosan was decreased. Compared to control sera, the opsonic activity of patient sera was strongly decreased. The impaired granulocyte functions in patients with malignant monoclonal gammopathy may contribute to the enhanced susceptibility to infections in these patients.

The presence of 2 M-components in single patients (double gammopathy) was studied retrospectively by means of the electrophoresis files in Umeå (serving a population of approximately 150 000 inhabitants). During the 11-year period 1974-1984, 109 000 electrophoreses were performed, among which 1034 patients with gammopathy were found. Of these, 20 (2%) had double gammopathy; 3 were associated with lymphoma, 7 with myelomatosis, 9 with monoclonal gammopathy of undetermined significance (MGUS), and 1 with lupus erythematosus disseminatus. It is suggested that one subgroup of double gammopathy (6 patients) had a neoplastic cell clone combined with a normally regulated cell line, the latter marked by a transient M-component. Another subgroup (14 patients) seems to have 2 coexisting different neoplastic cell lines, with persistent double gammopathy.

Three cases of von Recklinghausen's disease have been observed in the same family comprising four members. Two of the patients, father and son, had aorta outflow obstruction and biclonal gammopathy (IgG(kappa/lambda) and IgA(kappa)/IgG(kappa)). In one of these patients, no concanavalin suppressor cell activity was demonstrated, indicating that the gammopathy may be related to suppressor T-cell deficiency. Further study of the other family lineages showed that aorta stenosis/mors subita occurred frequently, but genetic marker studies failed to reveal any linkage between these entities. The syndrome, which has not been reported previously, was probably restricted to the first kindred studied. Detailed biochemical and immunological studies of the monoclonal components involved are in progress.

This is the first case, hitherto described, of benign essential gammopathy, presenting symptoms and histological evidence of peripheral neuropathy. Furthermore, in no previous case, has a specific localization of immunoglobulin (type IgM) to the areas of nerves involved by the lymphocytes been demonstrated. After six months' treatment with chlorambucil the neurological symptoms disappeared and in a biopsy from the right n saphenus no endoneural lymphocytes or local IgM could be found.

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 (IgGλ , 40%; IgG-κ , 30%; IgM-κ , 10%; IgM-λ , 10%; IgA-κ , 5%; IgA-λ , 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. (Korean J Lab Med 2009;29:116-21)

In an amyotrophic lateral sclerosis (ALS) patient who also had an IgA gammopathy, autopsy studies identified the IgA in the surviving motor neurons. Further, the IgA bound the surface of isolated bovine motor neurons and inhibited neuronal proliferation in culture. To determine the pathologic basis of this IgA interaction with motor neurons, a neuroblastoma cDNA library was generated and screened with the IgA monoclonal antibody. Reactive clones were identified as flavin adenine dinucleotide (FAD) synthetase. To extend this finding to ALS in general, quantitative RT-PCRs were performed on blood samples from 26 ALS and 30 control blood samples to determine mRNA expression levels of FAD synthetase and other electron transport chain proteins, specifically riboflavin kinase (RFK), cytochrome C1 (CYC1), and succinate dehydrogenase complex subunit B (SDHB). All expression levels were measured against a control enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Expression levels for a non-respiratory chain protein (beta-actin) were also measured. We found that FAD synthetase expression levels were decreased in ALS samples compared to expression levels in controls (P = 0.0151). Expression levels for RFK, CYC1, and SDHB were also significantly decreased in the ALS group (P = 0.0025, P = 0.0002, and P < 0.0001, respectively). As control, expression levels for beta-actin did not show a significant difference between ALS and control groups (P = 0.2118). Our data show that a reduction in electron transport proteins, namely FAD synthetase, RFK, CYC1, and SDHB, is seen in patients with ALS. It is possible that this may have an effect on oxygen-dependent metabolic pathways. Human motor neurons may be particularly susceptible to injury if there is sub-optimal oxidative metabolism.

With higher age, monoclonal gammopathies are more frequently diagnosed as the underlying cause of polyneuropathies. Whereas in approximately one-third of the patients, the gammopathy is related to multiple myeloma, lymphoma, other lymphoproliferative diseases, or amyloidosis, the remaining patients are diagnosed with monoclonal gammopathy of undetermined significance (MGUS). As underlined by the two reported cases, in IgG/IgA-type gammopathies electrophysiological findings of axonal lesions in mildly impaired patients are more likely to be found in patients with MGUS, while demyelinating polyneuropathies with more severe clinical impairment are more commonly seen in myeloma patients.

BACKGROUND Elevated haemoglobin and erythrocytosis are frequent causes for investigation. MATERIAL AND METHODS A 50-year-old woman with elevated haemoglobin and erythrocytosis was referred to our hospital for investigation. RESULTS AND INTERPRETATION She had elevated serum erythropoietin and iron deficiency. Mutational status of the JAK2 gene was negative with respect to polycythemia vera, and no secondary reasons for polycythemia - including tumours - were revealed. A bone marrow biopsy and bone marrow smear showed a moderately increased number of lambda- positive monoclonal plasma cells, and small amounts of lambda light chains were detected in the urine. Serum electrophoreses showed no gammopathy. The reason for her elevated haemoglobin could be an erythropoietin-producing tumour or an idiopathic erythrocytosis based on a mutation in exon 12 of the JAK2 gene. Investigation of her plasma cells revealed a 10-fold increase in erythropoietin mRNA expression, indicating the reason for her elevated serum erythropoietin and haemoglobin values.

Schnitzler's syndrome is characterized by chronic urticaria and monoclonal immunoglobulin (Ig) M gammopathy, with other features including intermittent fever, joint and/or bone pain with radiologic evidence of osteosclerosis, lymphadenopathy, enlarged liver and/or spleen, leukocytosis, and elevated erythrocyte sedimentation rate. The etiology of the syndrome remains obscure, although involvement of various cytokines has been proposed. Bone metabolism and angiogenesis markers are deregulated in Waldenström macroglobulinemia and IgM monoclonal gammopathy of unknown significance, but these markers have not been assessed in Schnitzler's syndrome. Herein, we report a patient with Schnitzler's syndrome who was treated with oral pefloxacin. Serum levels of osteoclast regulators, markers of bone remodeling and angiogenesis cytokines, were measured before treatment and serially after the initiation of treatment. High bone turnover and strikingly elevated levels of angiogenic cytokines were observed at diagnosis. Treatment with pefloxacin resulted in a normalization of the bone remodeling process and a significant reduction of angiogenic cytokines, with rapid and sustained improvement of symptoms, suggesting that these factors might be implicated in the pathophysiology of this syndrome. Furthermore, pefloxacin was proven to be an effective treatment for patients with Schnitzler's syndrome.