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Serum protein electrophoresis (SPE) in combination with immunotyping (IMT) is the diagnostic standard for detecting monoclonal proteins (M-proteins). However, interpretation of SPE and IMT is weakly standardized, time consuming and investigator dependent. Here, we present five machine learning (ML) approaches for automated detection of M-proteins on SPE on an unprecedented large and well-curated data set and compare the performance with that of laboratory experts. SPE and IMT were performed in serum samples from 69,722 individuals from Norway. IMT results were used to label the samples as M-protein present (positive, n=4,273) or absent (negative n=65,449). Four feature-based ML algorithms and one convolutional neural network (CNN) were trained on 68,722 randomly selected SPE patterns to detect M-proteins. Algorithm performance was compared to that of an expert group of clinical pathologists and laboratory technicians (n=10) on a test set of 1,000 samples. The random forest classifier showed the best performance (F1-Score 93.2 %, accuracy 99.1 %, sensitivity 89.9 %, specificity 99.8 %, positive predictive value 96.9 %, negative predictive value 99.3 %) and outperformed the experts (F1-Score 61.2 ± 16.0 %, accuracy 89.2 ± 10.2 %, sensitivity 94.3 ± 2.8 %, specificity 88.9 ± 10.9 %, positive predictive value 47.3 ± 16.2 %, negative predictive value 99.5 ± 0.2 %) on the test set. Interestingly the performance of the RFC saturated, the CNN performance increased steadily within our training set (n=68,722). Feature-based ML systems are capable of automated detection of M-proteins on SPE beyond expert-level and show potential for use in the clinical laboratory. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Necrobiotic xanthogranuloma (NXG) is a rare non‐Langerhans cell histiocytosis associated with paraproteinemia. Skin lesions of NXG are difficult to treat and various therapies have been evaluated with inconsistent results. A therapeutic standard has not been established. We report on a patient severely affected by mutilating skin and ocular lesions as well as lung infiltrates of necrobiotic xanthogranuloma. After failure of several previous therapies including dapsone and adalimumab, lesions significantly improved during therapy with intravenous immunoglobulins (IVIg). IVIg are an effective treatment option to evaluate in NXG.

Background: Light-chain proximal tubulopathy (LCPT) is a rare disease characterized by the accumulation of monoclonal light chains within proximal tubular cells. This study aimed to investigate the clinical characteristics of LCPT from a single Chinese nephrology referral center.Methods: Patients with kidney biopsy-proven isolated LCPT between 2016 and 2022 at Peking University First Hospital were retrospectively included. Clinical data, kidney pathological type, treatment, and prognosis were analyzed.Results: Nineteen patients were enrolled, the mean age at diagnosis was 57 ± 11 and the sex ratio was 6/13 (female/male). Mean proteinuria was 2.44 ± 1.89 g/24 hr and the mean estimated glomerular filtration rate (eGFR) at the point of biopsy was 59.640 ± 27.449 ml/min/1.73 m2. κ-restriction (84%) was dominant among LCPTs. An abnormal free light chain ratio was observed in 86% of the patients. Proximal tubulopathy with cytoplasmic inclusions accounted for the majority (53%), followed by tubulopathy associated with interstitial inflammation reaction (26%), proximal tubulopathy without cytoplasmic inclusions (16%), and proximal tubulopathy with lysosomal indigestion/constipation (5%). One patient presented with acute kidney injury and 16 patients presented with chronic kidney disease. Regarding follow-up, patients received bortezomib-based or R-CHOP chemotherapy or supportive treatment only. The mean follow-up time was 22 ± 16 months, and the mean eGFR was 63.098 ± 27.439 ml/min/1.73 m2 at the end of follow-up. These patients showed improved or stable kidney function.Conclusions: This is the first case series report of LCPT in four different pathological types in northern China. Clone-targeted chemotherapy may help preserve the kidney function in these patients. [ABSTRACT FROM AUTHOR]

The objectives of the study were to present the experience of diagnosis, management, and therapy with IL-1 inhibitors in patients with Schnitzler's syndrome (SchS) according to a multicenter Russian cohort. An observational retrospective study for a 10-year period (2012–2022) involved 17 patients with SchS who were admitted to the hospital or were observed on an outpatient basis (eight women and nine men). The diagnosis of all of them corresponded to the Strasbourg diagnostic criteria. The age of patients ranged from 25 to 81 years (Me 53[46; 56]). The age at the time of the onset of the disease ranged from 20 to 72 years (Me 46[39; 54]), the duration of the disease before diagnosis ranged from 1 to 35 years (Me 6.5[3; 6]), in three patients it exceeded 10 years, in the rest it ranged from 1 to 8 years. Infectious and lymphoproliferative diseases, monogenic AIDs (CAPS, TRAPS, and HIDS) were excluded from all patients at the prehospital stage. The referral diagnosis for all of them was Still 's disease in adults. Clinical manifestations of the disease in all patients included fatigue, lethargy, fatigue, rash, and fever. In all patients, skin elements were urticular and were accompanied by itching in 6 (37.5%) patients. Bone pain was observed in 12 (70.6%) patients; arthralgias, in 16 (94.1%); arthritis, in 9 (52.9%); myalgia, in 7 (41.2%); and weight loss, in 4 (23.5%). Lymphadenopathy was detected in 6 (35.3%) patients; enlarged liver, in 6 (35.3%); pericarditis, in 4 (23.5%); angioedema, in 6 (35.3); redness and dryness in the eyes, in 3 (17.6%); sore throat, in 2 (11.8%); abdominal pain, in 1 (5.9%), distal polyneuropathy, in 2 (11.8%); paraesthesia, in 1 (5.9%); and chondritis of the auricles, in 1 (5.9%). Monoclonal gammopathy was detected in all patients with a secretion level of 2.9–15.1 g/L: IgMk (n = 10, 64.7%), less often IgMλ (n = 2), IgGk (n = 2), IgGλ (n = 1), and IgAλ (n = 1). Ben-Jones protein was not detected in any of them. All patients had an increased level of ESR and CRP. Before inclusion in the study, 16 patients received GCs (94.1%) with a temporary effect that disappeared with dose reduction or cancellation. Seven patients received cDMARDs, including methotrexate (5), hydroxychloroquine (2), and cyclophosphamide (1). All patients received NSAIDs and antihistamines, as well as biologics, including the anti-B-cell drug rituximab (1), monoclonal ABs to IgE omalizumab (2, 1 without effect and 1 with partial effect), IL-1i canakinumab (n = 10, 58.8%) subcutaneously once every 8 weeks, and anakinra (n = 4, 23.5%) subcutaneously daily. The duration of taking anakinra, which was prescribed in the test mode, ranged from 1 week to 2.5 months with a further switch to canakinumab in 3 patients. The duration of taking canakinumab at the time of analysis ranged from 7 months to 8 years. Against the background of treatment with IL-1i, 10 out of 11 (90.9%) patients received a complete response in terms of the clinical manifestations of the disease and a decrease in the level of ESR and CRP within a few days. In one patient, a partial response to the administration of anakinra was detected; however, after switching to canakinumab, the effect of treatment was finally lost. One patient received IL-6i for 8 months with an incomplete effect and a positive dynamics after switching to anakinra. Thus, anakinra was initially prescribed to four patients and changed to canakinumab in two of them; canakinumab was started as the first drug in seven patients. Treatment with anakinra was continued in two patients; with canakinumab, in nine patients. In one patient, due to the persistent absence of relapses, the interval between canakinumab injections was increased to 5 months without signs of reactivation; however, subsequently, against the background of stress and relapses of the disease, the intervals were reduced to 4 months. A healthy child was born by the same patient on the background of treatment. The tolerability of therapy was satisfactory in all patients, no SAEs were noted. SchS is a rare multifactorial/non-monogenic AID that should be differentiated from a number of rheumatic diseases and other AIDs. The onset in adulthood, the presence of recurrent urticarial rashes in combination with fever and other manifestations of a systemic inflammatory response are indications for examination for monoclonal secretion. The use of short- or long-acting IL-1i is a highly effective and safe option in the treatment of such patients. [ABSTRACT FROM AUTHOR]

Oligoclonal bands (OCB) analysis is the reference standard for detecting an intrathecal IgG synthesis. Alongside OCB, free light chains kappa (FLCκ) are considered an additional sensitive biomarker for determining patterns 2 or 3, indicating intrathecal Ig synthesis. However, kFLC IF is not suitable for detecting a monoclonal pattern 5. The primary aim of this study was to evaluate the impact of incorporating FLCκ analysis into routine cerebrospinal fluid (CSF) diagnostics instead of OCB testing on the rate of missed monoclonal IgG detection.A two-center retrospective biomarker study was conducted. OCB were identified using isoelectric focusing in polyacrylamide gels followed by silver staining or in agarose gels followed by immunofixation. FLCκ were quantified using nephelometry and FLCκ assay (Siemens).Out of a combined total of 17,755 OCB analyses conducted between 2011 and 2021, a subset of 269 cases (1.5 %) exhibited pattern 5. 98 samples (36 %), which included 18 samples with intrathecal inflammation as determined by additional OCB pattern 2 were included in the FLCκ analysis. Of those, 16 (89 %) had intrathecal FLCκ synthesis.While FLCκ offers a promising avenue for detecting an intrathecal inflammation, the pattern 5, though rare, remains a valuable additional finding of OCB analysis. A combined approach of FLCκ and OCB analysis is recommended for a comprehensive assessment of the humoral intrathecal immune response. [ABSTRACT FROM AUTHOR]

C3 glomerulopathy is a rare disease, characterized by an abnormal activation of the complement's alternative pathway that leads to the accumulation of the C3 component in the kidney. The disease recurs in more than half of kidney transplant recipients, with a significant impact on graft survival. Recurrence of the primary disease represents the second cause of graft loss after organ rejection. In C3 glomerulopathy, there are several risk factors which can promote a recurrence during transplantation, such as delayed graft function, infection and monoclonal gammopathy. All these events can trigger the alternative complement pathway. In this review, we summarize the impact of C3 glomerulopathy on kidney grafts and present the latest treatment options. The most widely used treatments for the disease include corticosteroids and mycophenolate mofetil, which are already used chronically by kidney transplant recipients; thus, additional treatments for C3 glomerulopathy are required. Currently, several studies using anti-complement drugs (i.e., eculizumab, Ravalizumab, avacopan) for C3 glomerulopathy in kidney transplant patients are ongoing with encouraging results. [ABSTRACT FROM AUTHOR]

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of interleukin-1 inhibitors demonstrates the key role of this cytokine in the pathogenesis of the disease. However, the physiopathology of Schnitzler syndrome remains elusive, and the main question regarding the relationship between autoinflammatory features and monoclonal gammopathy is still unanswered. The purpose of this narrative review is to describe what is currently known about the pathogenesis of this peculiar disease, as well as to address its diagnosis and management. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy‐related peripheral neuropathies encompass a spectrum of clinical presentations in which the monoclonal protein directly damages the tissues, including the peripheral nervous system. Given the prevalence of both peripheral neuropathy and monoclonal gammopathy in the general population, these conditions may overlap in clinical practice, posing a challenge for clinicians in determining causality. Therefore, a comprehensive understanding of primary clinical syndromes and their neurophysiological patterns is of great importance for accurate differential diagnoses and effective treatment strategies. In this article, we examine the main forms of monoclonal gammopathies that affect the peripheral nerve. We explore the clinical and electrophysiological aspects and their correlation with each syndrome's corresponding monoclonal protein type. This knowledge is essential for healthcare professionals to diagnose better and manage patients presenting with monoclonal gammopathy‐related peripheral nervous system involvement. [ABSTRACT FROM AUTHOR]

Purpose of Review: The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM. Recent Findings: Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4WHIM mutation or MYD88WT genotype. The development of BTKC481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi. Summary: Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM. [ABSTRACT FROM AUTHOR]

BackgroundWe found that a subset of patients with monoclonal gammopathy exhibited hypercalcemia without apparent causes or clinical manifestations In a cohort of 289 monoclonal gammopathy patients, 2.4% presented with such atypical hypercalcemia, with one notable case exhibiting normal ionized calcium levels, suggesting the presence of pseudohypercalcemia.ObjectiveThe aim of this study is to elucidate the factors contributing to pseudohypercalcemia in monoclonal gammopathy and to develop a novel globulin-corrected calcium formula for clinical application.MethodsThis observational study enrolled 110 monoclonal gammopathy patients from our center. An additional 33 patients were recruited to validate the newly proposed formula. Univariate analysis identified potential risk factors. And multivariate logistic regression identified definitive influential factors. The determined influential factors were utilized to develop a formula by multiple linear regression, which was validated by a paired t-test and the Youden index.ResultsThis study found that globulin was a risk factor for pseudohypercalcemia. It revealed that pseudohypercalcemia should be considered in patients with globulin levels ≥61 g/L (P=0.014). Both albumin and globulin were confirmed as independent factors associated with bound calcium. Given that, we developed a formula to correct ionized calcium levels, which was consistent with ionized calcium tested by blood gas analysis. The diagnostic accuracy of the new formula (Youden index is 0.906) is better than the traditional formula (Youden index is 0.906). Interestingly, all monoclonal immunoglobulin types, except for light chains, showed an equal propensity to develop pseudohypercalcemia (P=0.306). It also showed a linear correlation between IgA, IgG, and IgM and bound calcium.ConclusionThis study confirmed that elevated globulin affects serum total calcium and offered the threshold of globulin ≥ 61 g/L in the differential diagnosis of peudohypercalcemia from hypercalcemia. The new formula based on albumin and globulin was developed, which was verified to be better than the traditional formula for correctly diagnosing hypercalcemia. In addition, we found that neither light chains nor heavy chains of monoclonal immunoglobulin alone can result in pseudohypercalcemia.

Abstract Renal involvement is common in monoclonal gammopathy (MG); however, the same patient may have both MG and non-paraprotein-associated renal damage. Accordingly, distinguishing the cause of renal damage is necessary because of the different clinical characteristics and associated treatments. In this multicenter retrospective cohort study, we described the clinicopathological characteristics and prognosis of 703 patients with MG and renal damage in central China. Patients were classified as having MG of renal significance (MGRS), MG of undetermined significance (MGUS), or hematological malignancy. 260 (36.98%), 259 (36.84%), and 184 (26.17%) had MGRS, MGUS, and hematological malignancies, respectively. Amyloidosis was the leading pattern of MGRS (74.23%), followed by thrombotic microangiopathy (8.85%) and monoclonal immunoglobulin deposition disease (8.46%). Membranous nephropathy was the leading diagnosis of MGUS (39.38%). Renal pathological findings of patients with hematological malignancies included paraprotein-associated lesions (84.78%) and non-paraprotein-associated lesions (15.22%). The presence of nephrotic syndrome and an abnormal free light chain (FLC) ratio were independently associated with MGRS. The overall survival was better in patients with MGUS than in those with MGRS or hematological malignancies.

Background: Light-chain proximal tubulopathy (LCPT) is a rare disease characterized by the accumulation of monoclonal light chains within proximal tubular cells. This study aimed to investigate the clinical characteristics of LCPT from a single Chinese nephrology referral center.Methods: Patients with kidney biopsy-proven isolated LCPT between 2016 and 2022 at Peking University First Hospital were retrospectively included. Clinical data, kidney pathological type, treatment, and prognosis were analyzed.Results: Nineteen patients were enrolled, the mean age at diagnosis was 57 ± 11 and the sex ratio was 6/13 (female/male). Mean proteinuria was 2.44 ± 1.89 g/24 hr and the mean estimated glomerular filtration rate (eGFR) at the point of biopsy was 59.640 ± 27.449 ml/min/1.73 m2. κ-restriction (84%) was dominant among LCPTs. An abnormal free light chain ratio was observed in 86% of the patients. Proximal tubulopathy with cytoplasmic inclusions accounted for the majority (53%), followed by tubulopathy associated with interstitial inflammation reaction (26%), proximal tubulopathy without cytoplasmic inclusions (16%), and proximal tubulopathy with lysosomal indigestion/constipation (5%). One patient presented with acute kidney injury and 16 patients presented with chronic kidney disease. Regarding follow-up, patients received bortezomib-based or R-CHOP chemotherapy or supportive treatment only. The mean follow-up time was 22 ± 16 months, and the mean eGFR was 63.098 ± 27.439 ml/min/1.73 m2 at the end of follow-up. These patients showed improved or stable kidney function.Conclusions: This is the first case series report of LCPT in four different pathological types in northern China. Clone-targeted chemotherapy may help preserve the kidney function in these patients.

Less than 2% of all symptomatic multiple myeloma (MM) has immunoglobulin D (IgD) as monoclonal protein. Biclonal gammopathy is much rarer. At the time of diagnosis, disease is often in advanced stage, including renal failure, anemia, hypercalcemia and lytic bone lesions. Due to the rarity of myeloma itself, but also due to the fact that anti-IgD antisera is not used in routine practice, there are only a few reports of IgD MM described in the literature. This case report describes a patient with IgD lambda MM with anemia and renal failure. Anemia, renal failure, and > 80 percent plasma cells in bone biopsy in our patient with IgD lambda MM meets International Myeloma Working Group criteria for diagnosis of MM. The patient clinical course was similar to other patients with IgD MM. The final result of serum protein immunofixation (s-IFE) showed IgD lambda and free lambda monoclonal bands. To prevent misdiagnosis, it is necessary to use anti-IgD and anti-IgE antisera whenever the serum protein immunofixation with IgA, IgM, IgG, kappa and lambda antiserums shows a kappa or lambda monoclonal band without monoclonal band in heavy chain. [ABSTRACT FROM AUTHOR]

Renal involvement is common in monoclonal gammopathy (MG); however, the same patient may have both MG and non-paraprotein-associated renal damage. Accordingly, distinguishing the cause of renal damage is necessary because of the different clinical characteristics and associated treatments. In this multicenter retrospective cohort study, we described the clinicopathological characteristics and prognosis of 703 patients with MG and renal damage in central China. Patients were classified as having MG of renal significance (MGRS), MG of undetermined significance (MGUS), or hematological malignancy. 260 (36.98%), 259 (36.84%), and 184 (26.17%) had MGRS, MGUS, and hematological malignancies, respectively. Amyloidosis was the leading pattern of MGRS (74.23%), followed by thrombotic microangiopathy (8.85%) and monoclonal immunoglobulin deposition disease (8.46%). Membranous nephropathy was the leading diagnosis of MGUS (39.38%). Renal pathological findings of patients with hematological malignancies included paraprotein-associated lesions (84.78%) and non-paraprotein-associated lesions (15.22%). The presence of nephrotic syndrome and an abnormal free light chain (FLC) ratio were independently associated with MGRS. The overall survival was better in patients with MGUS than in those with MGRS or hematological malignancies. [ABSTRACT FROM AUTHOR]

Background and objectives: TEMPI (telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonaryshunting) syndrome is a rare multisystemic disease classified as a monoclonal gammopathy of cutaneous significance. The pathogenesis and etiology of TEMPIare not well known because of the rarity of this disorder. Although telangiectasias are the hallmark of this syndrome, skin biopsies are rarely performed. We aim to further characterize TEMPI syndrome through the evaluationof a skin biopsy. Methods: We reviewed the histopathology and immunophenotypic profile of a skin biopsy from a 53‐year‐oldwoman diagnosed with TEMPI syndrome. Other components of her syndromic complex included an IgA myeloma, elevated vascular endothelial growth factor (VEGF), and erythrocytosis. Results: A biopsy showed prominent vascular ectasia with some degree of microvascular basement membranezone thickening. Our patient had a reduction in neoplastic plasma cell burdenand clearing of her telangiectasias following myeloma directed treatment. Conclusions: TEMPI can beviewed as a reactive vascular paraneoplastic syndrome in the setting of a plasma cell dyscrasia. Elaboration of VEGF from neoplastic plasma cells is likely pathogenetically implicated and appears to be a common link that explains other vascular lesions associated with monoclonal gammopathy syndromes. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy (MG) is a spectrum of diseases ranging from the benign asymptomatic monoclonal gammopathy of undetermined significance to the malignant multiple myeloma. Clinical guidelines and laboratory recommendations have been developed to inform best practices in the diagnosis, monitoring, and management of MG. In this review, the pathophysiology, relevant laboratory testing recommended in clinical practice guidelines and laboratory recommendations related to MG testing and reporting are examined. The clinical guidelines recommend serum protein electrophoresis, serum immunofixation and serum free light chain measurement as initial screening. The laboratory recommendations omit serum immunofixation as it offers limited additional diagnostic value. The laboratory recommendations offer guidance on reporting findings beyond monoclonal protein, which was not required by the clinical guidelines. The clinical guidelines suggested monitoring total IgA concentration by turbidimetry or nephelometry method if the monoclonal protein migrates in the non-gamma region, whereas the laboratory recommendations make allowance for involved IgM and IgG. Additionally, several external quality assurance programs for MG protein electrophoresis and free light chain testing are also appraised. The external quality assurance programs show varied assessment criteria for protein electrophoresis reporting and unit of measurement. There is also significant disparity in reported monoclonal protein concentrations with wide inter-method analytical variation noted for both monoclonal protein quantification and serum free light chain measurement, however this variation appears smaller when the same method was used. Greater harmonization among laboratory recommendations and reporting format may improve clinical interpretation of MG testing. [ABSTRACT FROM AUTHOR]

Background: We used the University of Wisconsin cohort to determine the extent to which the EULAR Sjögren's syndrome disease activity index (ESSDAI) was associated with comorbidities that contribute to mortality. Methods: Our University of Wisconsin, Madison cohort had 111 patients with Sjögren's Disease (SjD) by 2016 ACR/EULAR criteria and 194 control patients with sicca. Our study was performed from March 1st, 2020 through April 1st, 2023. We collected data using a standardized collection tool, including components of the Charlson Comorbidity Index (CCI). Stratifying our SjD patients by ESSDAI < 5 and ESSDAI ≥ 5, we assessed differences in comorbidities associated with mortality. Results: At time of SjD diagnosis, the ESSDAI ≥ 5 group had increased odds of peripheral vascular disease compared to controls (OR 10.17; 95% CI 1.18–87.87). Patients with a current ESSDAI ≥ 5 were more likely to have a myocardial infarction compared to controls (OR 9.87; 95% CI 1.17–83.49). SjD patients had increased prevalence of monoclonal gammopathy compared to controls (9.3% vs 0.5%, p < 0.001). SjD patients with high ESSDAI at diagnosis had greater prevalence of monoclonal gammopathy compared to the SjD patients with a low ESSDAI (16% vs 5%, p =.04). As reported elsewhere, the ESSDAI ≥ 5 group had increased odds of chronic pulmonary disease (OR 4.37; 95% CI 1.59–11.97). Conclusion: We found high ESSDAI scores were associated with worse cardiovascular outcomes, specifically peripheral vascular disease and myocardial infarction. Furthermore, monoclonal gammopathy was more frequent in SjD patients compared to sicca controls, supporting screening for monoclonal gammopathy in the appropriate clinical scenario. Key Points • High ESSDAI scores are associated with worse cardiovascular outcomes, specifically peripheral vascular disease and myocardial infarction. • Monoclonal gammopathy is more frequent in SjD patients than sicca controls, supporting screening for monoclonal gammopathy in the appropriate clinical scenario. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the real-world performance and reference intervals of the Binding Site Freelite serum free light chain (SFLC) assay (Thermo Fisher Scientific), a global standard for diagnosis, prognostication, and response assessment for monoclonal gammopathies. Methods An informatics-based approach was used to retrospectively evaluate concordance between SFLC and the orthogonal Sebia HYDRASYS immunofixation assay results in a large clinical data set consecutively reported between 2010 and 2020. Results Among patients with monoclonal-negative results by both SFLC and Sebia HYDRASYS immunofixation assays, 25% (1226/5057) had κ/λ ratios (KLRs) outside the manufacturer-defined and International Myeloma Working Group–cited normal reference interval of 0.26 to 1.65. These results were consistent over the study period and were not affected by sex, age, impaired kidney function, or assay antisera lot variation. Assay drift, in addition to other potential factors, affected the KLR distribution. Using International Statistical Classification of Diseases (ICD) codes, kidney function data, and the central 95% of KLR values generated on the Optilite platform (Thermo Fisher Scientific), we derived a new reference interval of 0.67 to 2.13, reducing the KLR false-positive rate to 8%. However, normal KLR persisted among 16% (14/85) of samples with free λ chains by immunofixation, warranting caution during interpretation. Conclusions Our analysis indicated that revision of Freelite SFLC reference intervals improves assay interpretation and should prompt reconsideration of Freelite reference intervals worldwide. [ABSTRACT FROM AUTHOR]

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Background Serum protein electrophoresis (SPE) is widely used for diagnosis, management and monitoring of different immune disorders. Serum protein alterations provide valuable insights about these disorders. Electrophoresis separates proteins based on their physical properties, and the subsets of these proteins are used in interpreting the results. The purpose of this study was to analyze the results of pathological and non-pathological SPE of Ecuadorian patients. Methods A retrospective observational study was conducted using data of pathological (871 samples) and non-pathological (752 samples) serum protein electrophoresis data of 1623 patients who attended the Gamma Clinical Laboratory of Portoviejo, province of Manabi, Ecuador. Bivariate and exploratory factorial analysis were done using following parameters: age, sex, survival, laboratory diagnosis according to electrophoretogram. Results The highest frequency of deaths occurred in females (52.9%). The most frequent pathological outcomes were polyclonal hypergammaglobulinemia (49.5%), acute inflammation (21.1%), and monoclonal gammopathy (14.70%). Exploratory factorial analysis revealed that the results of pathological SPE were mainly influenced by albumin and ã-globulin fractions followed by á1-globulin, á2-globulin, and â1-globulin-â2-globulin behavior that differed from non-pathological SPE. The Kaiser-Meyer-Olkin measure was considered adequate for data analysis, and Bartlett’s test of sphericity was highly significant (p

Background: Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that usually mimics type 1 or 2A von Willebrand disease (VWD). Key Clinical Question: Can AVWS mimic the phenotype of type 2B VWD? Clinical Approach: A 64-year-old male patient presented with thrombocytopenia, normal routine hemostasis results, and normal VWF antigen and factor VIII levels but reduced von Willebrand factor (VWF) activity (31 IU/dL). The ristocetin-induced platelet aggregation test showed paradoxical aggregation at low doses of ristocetin, suggesting type 2B VWD, but no deleterious sequence variation was found in either the VWF or GP1BA genes, compatible with AVWS. Serum protein electrophoresis revealed a monoclonal immunoglobulin G antibody. Conclusion: This AVWS with a 2B phenotype VWD was probably related to a monoclonal immunoglobulin G antibody causing a VWF conformational change, resulting in increased affinity to platelet glycoprotein-Ib. In the event of surgery or bleeding, treatment with vonicog alfa seems to be the best option for this patient.

Objective: To report a case of bilateral reversible optic neuropathy as the first sign of Waldenström macroglobulinemia (WM).Methods: Observational case report.Results: A 52-year-old man had a sudden loss of vision in the left eye. Examinations revealed the presence of a serum monoclonal immunoglobulin (IgM kappa) in the serum. Even after a session of steroid pulse therapy, optic neuropathy became bilateral and then resolved almost completely after 4 months. The condition progressed to WM with multiorgan lesions years later. There was no evidence of optic neuropathy recurrence. The literature revealed two cases of monoclonal gammopathy (MG): a 64-year-old man with multiple myeloma (MM) with a and a 51-year-old man with MM with IgG kappa. These cases have similar conditions: 1) visual reduction as an initial symptom of MG, 2) bilateral involvement, 3) no sign of central nervous system (CNS) infiltration shown by normal brain magnetic resonance images, and ecovery to a visual acuity of ≥1.0 bilaterally with no reoccurrence. The excessive Igs or B-cell hyperactivity may activate an autoimmune mechanism that reversibly interferes with the bilateral optic nerves.Conclusion: Bilateral optic neuropathy was the initial symptom of WM. There was no evidence of CNS infiltration; it recovered and then did not reoccur. The pathogenesis remained unknown, but two cases of MG were reported in the literature with remarkably similar conditions.

Abstract Background Clarkson’s disease is a very rare entity characterised by acute episodes of systemic oedema and severe hypotension associated with paraproteinaemia. Its classical treatment relies on methylxanthine combined with terbutaline. Although this prophylactic therapy reduces the mortality rate, relapses are frequent. Eighty percent of patients with Clarkson’s disease present with monoclonal gammopathy of unknown significance (MGUS). The risk of progression to multiple myeloma is 1% per year. Case Description Here, we present a 49-year-old woman who suffered multiple such episodes requiring treatment in the intensive care unit. Treatment with terbutaline and theophylline was ineffective. She was diagnosed with multiple myeloma (MM) 8 years after the first of these acute episodes. Antimyeloma treatment with bortezomib and dexamethasone was started, followed by autologous haemopoietic transplantation, with no further acute episodes since then. Conclusion Our case is, to our knowledge, unique because eradication of MM was followed by complete disappearance of acute episodes of capillary leakage. Our case report is also the first to support the use of bortezomib and dexamethasone in this setting. Furthermore, autologous peripheral blood progenitor cell transplantation consolidated the MM stringent complete remission achieving a very long progression-free survival (> 11 years) of both MM and Clarkson’s disease.

The aim – to present the experience of diagnosis, management, and therapy with IL-1 inhibitors in patients with Schnitzler’s syndrome (SchS) according to a multicenter Russian cohort.Materials and methods. In an observational retrospective study for a 10-year period (2012–2022), 17 patients with SchS who were admitted to the hospital or were observed on an outpatient basis, among them 8 women, 9 men, were included in the study. The diagnosis of all corresponded to the Strasbourg diagnostic criteria.Results. The age of patients ranged from 25 to 81 years (Me 53 [46; 56] years). The age at the time of the onset of the disease ranged from 20 to 72 years (Me 46 [39; 54] years), the duration of the disease before diagnosis ranged from 1 to 35 years (Me 6.5 [3; 6] years), in 3 it exceeded 10 years, in the rest it ranged from 1 to 8 years. Infectious and lymphoproliferative diseases, monogenic AIDS (CAPS, TRAPS, HIDS) were excluded from all patients at the prehospital stage. The guiding diagnosis for all was Still’s disease in adults. Clinical manifestations of the disease included: fatigue, lethargy, fatigue, rash and fever in all, skin elements were urticular in all, accompanied by itching in 6 (37.5%). Bone pain had 12 (70.6%), arthralgia – 16 (94.1%), arthritis – 9 (52.9%), myalgia – 7 (41.2%), weight loss in 4 (23.5%). Lymphadenopathy (6), enlarged liver (6), pericarditis (4), angioedema (6), redness and dryness in the eyes (3), sore throat (2), abdominal pain (1), distal polyneuropathy (2), paraesthesia (1), chondritis of the auricles were less common (1). Monoclonal gammopathy was detected in all with a secretion level of 2.9–15.1 g/l: IgMk (n=10 (64.7%)), less often IgMλ (n=2), IgGk (n=2), IgGλ (n=1), IgAλ (n=1). Ben-Jones protein was not detected in any of them. All patients had an increase in the level of ESR, CRP. 16 patients before inclusion in the study received GC (94.1%) with a temporary effect and its escape with dose reduction or cancellation, DMARD – 7, among them methotrexate (5), hydroxychloroquine (2), cyclophosphamide (1), also NSAIDs and antihistamines in all, biological drugs: anti-B-cell the drug rituximab (1), monoclonal AT to IgE – omalizumab in 2 (1 – without effect, 1 – partial effect). 11 patients were prescribed IL-1: canakinumab – 9 (52.9%) subcutaneously once every 8 weeks, anakinra – 4 (23.5%) subcutaneously daily. The duration of taking anakinra, which was prescribed in the test mode, ranged from 1 week to 2.5 months with a further switch to canakinumab in 3. The duration of taking canakinumab at the time of analysis ranged from 7 months to 8 years. Against the background of treatment with IL-1, 10 out of 11 (90.9%) received a complete response from the clinical manifestations of the disease and a decrease in the level of ESR and CRP within a few days. In 1 patient, a partial response was received to the administration of anakinra, and when switching to canakinumab, the effect of treatment was finally lost. 1 patient received IL-6 for 8 months with incomplete effect and transition to IL-1 with positive dynamics. In 1 patient, due to the persistent absence of relapses, the interval between canakinumab injections was increased to 5 months without signs of reactivation, but subsequently, against the background of stress and relapses of the disease, the intervals were reduced to 4 months. A healthy child was born in the same patient on the background of treatment. The tolerability of therapy was satisfactory in all patients, no SAE was noted.Conclusion. SchS is a rare multifactorial/non–monogenic AID that needs to be differentiated from a number of rheumatic diseases and other AIDS. The onset in adulthood, the presence of recurrent urticarial rashes in combination with fever and other manifestations of a systemic inflammatory response are indications for examination for monoclonal secretion. The use of short- or long-acting IL-1 is a highly effective and safe option in the treatment of such patients.

Abstract Background It is crucial to identify patients with monoclonal gammopathy of renal significance (MGRS) from those without MGRS but with monoclonal gammopathy and concomitant kidney diseases. However, there have been few studies with large sample sizes, and their findings were inconsistent. This study aimed to conduct a meta-analysis of MGRS to describe the general characteristics of MGRS and its predictive factors. Methods Cohort or case-control studies published through December 2022 and related to clinicopathological features of MGRS were retrieved from the PubMed, Cochrane Library, Web of Science, Scopus, and Embase databases. Two researchers searched for studies that met the inclusion criteria. In the univariate analysis, fixed- or random- effects models were used to obtain pooled estimates of the weighted mean difference (WMD) and odds ratio (OR) for risk factors. In the multivariate analysis, the ORs of the independent risk factors from each study were pooled after transforming the original estimates. Results The meta-analysis included six studies. Univariate analysis showed that the following variables were statistically significant in MGRS: age (WMD = 1.78, 95%CI 0.21–3.35), hypertension (OR = 0.54, 95%CI 0.4–0.73), diabetes (OR = 0.42, 95%CI 0.29–0.59), albumin (WMD = − 0.26, 95%CI − 0.38–−0.14), urinary protein level (WMD = 0.76, 95%CI 0.31–1.2), urinary protein ≥ 1.5 g/d (OR = 1.98, 95%CI 1.46–2.68), lambda-chain value (WMD = 29.02, 95%CI 16.55–41.49), abnormal free light-chain ratio (OR = 4.16, 95%CI 1.65–10.47), bone marrow puncture rate (OR = 5.11, 95% CI 1.31–19.95), and abnormal bone marrow outcome rate (OR = 9.63, 95%CI 1.98–46.88). Multivariate analysis showed urinary protein ≥ 1.5 g/d (OR = 2.80, 95%CI 1.53–5.15) and an abnormal free light-chain ratio (OR = 6.98, 95%CI 4.10–11.91) were associated with predictors of MGRS. Conclusions Compared with non-MGRS patients with monoclonal gammopathy and concomitant kidney diseases, patients with MGRS were older, had fewer underlying diseases, more urinary protein, more abnormal free light-chain ratio, and more abnormal bone marrow results. Urinary protein ≥ 1.5 g/d and an abnormal free light-chain ratio were independent risk factors for MGRS.

This document discusses the use of the lipemia index (L-index) as a potential tool for identifying patients with monoclonal gammopathy. The study found that the L-index had good specificity but low sensitivity for detecting M-proteins in serum and plasma samples. The accuracy of the L-index varied depending on the type of M-protein, and there was a low concordance between plasma and serum L-index values. The article suggests that the L-index test could be useful for identifying IgM plasma cell disorders, but further research is needed to improve its diagnostic performance. [Extracted from the article]

This document presents a case study of a 69-year-old woman diagnosed with a rare form of multiple myeloma called IgE kappa with free kappa light chain multiple myeloma. The patient experienced symptoms such as bone pain, nausea, vomiting, and foamy urine. Through various tests, including genetic analysis, the diagnosis was confirmed, and the patient was treated with a specific regimen that showed positive results. The document emphasizes the significance of accurate diagnosis and the importance of collaboration between laboratories and clinicians in managing unique types of multiple myeloma. [Extracted from the article]

Background: Serum Protein Electrophoresis (SPE) is crucial for the diagnosis and follow-up of monoclonal gammopathy (MG), as it helps to separate and identify these paraproteins. Currently, Pakistan lacks standardized guidelines for SPE reporting and analytical performance. This survey aims to analyze reporting variations from Consultant Chemical Pathologists in Pakistani laboratories. Methods: This cross-sectional survey was conducted by the section of Chemical Pathology, Department of Pathology and Laboratory Medicine, at Aga Khan University Hospital, Karachi. A previously validated and published tool was used with some modifications to assess analytical techniques, reporting patterns, and interpretations provided with SPE by different laboratories. Frequency and percentages were calculated for each response and descriptive results were also evaluated. Differences between laboratories were also assessed qualitatively. Results: Out of the eight laboratories contacted, seven participated in the survey, yielding a response rate of 87.5%. Immunofixation Electrophoresis (IFE) was used by all labs for serum immunotyping. All labs reported a new small abnormal band in patients with no known monoclonal gammopathy or with a known M-protein. Variations were found in terminologies used to label paraprotein, terminologies used to report normal and pathological SPE patterns, electrophoretic technique, methods for quantifying paraprotein in the gamma region on SPE and for albumin quantification. Similarly, the number of decimal places reported, reporting of multiple monoclonal proteins and small paraprotein in the beta region or monoclonal proteins less than 1 g/L, approach for screening, number of fractions reported in gamma region and reporting of interferences were also not standardized and variations were noticed. Conclusions: Our survey highlighted variations in practices of SPE reporting. These differences in laboratory practices could result in inconsistent test results, which could adversely affect patient care. [ABSTRACT FROM AUTHOR]

Background: It is crucial to identify patients with monoclonal gammopathy of renal significance (MGRS) from those without MGRS but with monoclonal gammopathy and concomitant kidney diseases. However, there have been few studies with large sample sizes, and their findings were inconsistent. This study aimed to conduct a meta-analysis of MGRS to describe the general characteristics of MGRS and its predictive factors. Methods: Cohort or case-control studies published through December 2022 and related to clinicopathological features of MGRS were retrieved from the PubMed, Cochrane Library, Web of Science, Scopus, and Embase databases. Two researchers searched for studies that met the inclusion criteria. In the univariate analysis, fixed- or random- effects models were used to obtain pooled estimates of the weighted mean difference (WMD) and odds ratio (OR) for risk factors. In the multivariate analysis, the ORs of the independent risk factors from each study were pooled after transforming the original estimates. Results: The meta-analysis included six studies. Univariate analysis showed that the following variables were statistically significant in MGRS: age (WMD = 1.78, 95%CI 0.21–3.35), hypertension (OR = 0.54, 95%CI 0.4–0.73), diabetes (OR = 0.42, 95%CI 0.29–0.59), albumin (WMD = − 0.26, 95%CI − 0.38–−0.14), urinary protein level (WMD = 0.76, 95%CI 0.31–1.2), urinary protein ≥ 1.5 g/d (OR = 1.98, 95%CI 1.46–2.68), lambda-chain value (WMD = 29.02, 95%CI 16.55–41.49), abnormal free light-chain ratio (OR = 4.16, 95%CI 1.65–10.47), bone marrow puncture rate (OR = 5.11, 95% CI 1.31–19.95), and abnormal bone marrow outcome rate (OR = 9.63, 95%CI 1.98–46.88). Multivariate analysis showed urinary protein ≥ 1.5 g/d (OR = 2.80, 95%CI 1.53–5.15) and an abnormal free light-chain ratio (OR = 6.98, 95%CI 4.10–11.91) were associated with predictors of MGRS. Conclusions: Compared with non-MGRS patients with monoclonal gammopathy and concomitant kidney diseases, patients with MGRS were older, had fewer underlying diseases, more urinary protein, more abnormal free light-chain ratio, and more abnormal bone marrow results. Urinary protein ≥ 1.5 g/d and an abnormal free light-chain ratio were independent risk factors for MGRS. [ABSTRACT FROM AUTHOR]

Multiple myeloma or plasma cell myeloma has been described as a rare tumour in humans, cats, dogs, rats, mice, horses and a calf. Proliferation of plasma cells or plasmacytoid lymphocytes occurs. These large B lymphocytes originate primarily in the bone marrow with diffuse multifocal bone marrow involvement and bone destruction, but may also be of extramedullary origin. The result is an uncontrolled production of immunoglobulins (Igs) or Ig fragments, usually by a plasma cell clone. These Igs and their fragments are also referred to as paraproteins or M-components. Complete Ig, partial Ig, free light chains, light chain fragments or polymers can be detected. The heavy chains include, for example, the following Igs: IgG, IgA and IgM and the horse-specific IgG (T), while the light chains include kappa or lambda proteins. It is primarily a monoclonal gamma disease with Ig of the γ-region, but also IgA and IgM of the β-region and β-Ύ-globulin with an IgGA clone. Biclonal or atypical patterns may occur occasionally. Paraproteins in urine are called Bence Jones proteins. Depending on the detection of paraproteins in the serum or urine, a distinction is made between secretory and non-secretory multiple myeloma. In the case of the horse, no race or gender disposition is known. The clinical symptoms are non-specific. They correlate with the main location and spread of the neoplastic cells, the degree of plasma cell proliferation and the extent of paraproteinemia. Laboratory values vary according to the presence of secretory or non-secretory multiple myeloma. The case report of a 20-year-old polo mare presented here describes a rare disease course in non-secretory multiple myeloma with pathological fractures. The analysis and comparison with case reports already published should facilitate the diagnosis of the rare disease. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathies are a group of blood diseases characterized by presence of abnormal immunoglobulins in peripheral blood and/or urine of patients. Multiple myeloma and plasma cell leukemia are monoclonal gammopathies with unclear etiology, caused by malignant transformation of bone marrow plasma cells. Mass spectrometry with matrix-assisted laser desorption/ionization and time-of-flight detection is commonly used for investigation of the peptidome and small proteome of blood plasma with high accuracy, robustness, and cost-effectivity. In addition, mass spectrometry coupled with advanced statistics can be used for molecular profiling, classification, and diagnosis of liquid biopsies and tissue specimens in various malignancies. Despite the fact there have been fully optimized protocols for mass spectrometry of normal blood plasma available for decades, in monoclonal gammopathy patients, the massive alterations of biophysical and biochemical parameters of peripheral blood plasma often limit the mass spectrometry measurements. In this paper, we present a new two-step extraction protocol and demonstrated the enhanced resolution and intensity (>50×) of mass spectra obtained from extracts of peripheral blood plasma from monoclonal gammopathy patients. When coupled with advanced statistics and machine learning, the mass spectra profiles enabled the direct identification, classification, and discrimination of multiple myeloma and plasma cell leukemia patients with high accuracy and precision. A model based on PLS-DA achieved the best performance with 71.5% accuracy (95% confidence interval, CI = 57.1–83.3%) when the 10× repeated 5-fold CV was performed. In summary, the two-step extraction protocol improved the analysis of monoclonal gammopathy peripheral blood plasma samples by mass spectrometry and provided a tool for addressing the complex molecular etiology of monoclonal gammopathies. [ABSTRACT FROM AUTHOR]

The study of monoclonal serum proteins has led to the generation of two major theories: one proposing that individuals who had monoclonal proteins without any symptoms or evidence of end-organ damage have a benign condition; the other one suggesting that some individuals with asymptomatic monoclonal proteins may progress to multiple myeloma and thus are affected by a monoclonal gammopathy of undetermined significance (MGUS). Longitudinal studies of subjects with MGUS have supported the second theory. Subsequent studies have characterized and defined the existence of another precursor of multiple myeloma, smoldering multiple myeloma (SMM), intermediate between MGUS and multiple myeloma. Primary molecular events, chromosome translocations, and chromosome number alterations resulting in hyperploidy, required for multiple myeloma development, are already observed in myeloma precursors. MGUS and SMM are heterogeneous conditions with the presence of tumors with distinct pathogenic phenotypes and clinical outcomes. The identification of MGUS and SMM patients with a molecularly defined high risk of progression to MM offers the unique opportunity of early intervention with a therapeutic approach on a low tumor burden.

BackgroundParaproteins can interfere with several substances, producing erroneous laboratory measurements. The diagnosis of kidney disease in patients with hematological disorders has important prognosis implications. An elevated creatinine with no other signs of kidney disease should prompt the idea of a spurious creatinine. Communication between the clinical team and the laboratory is key.Case presentationIn this case, we present a 68-year-old woman with an elevated creatinine and an IgM lambda paraprotein. Interestingly, there were no other signs of chronic kidney disease besides the creatinine value, with no albuminuria or microhematuria. A kidney biopsy showed normal parenchyma and ruled out the possibility of paraprotein-related damage. The monoclonal component and creatinine levels raised parallelly during follow-up while maintaining normal urea levels. This prompted the hypothesis of a falsely elevated creatinine. It was confirmed with a normal glomerular filtration rate determined by a radioisotope, a cystatin C measurement and a reduction in creatinine when diluting the sample.ConclusionIt is important to consider the possibility of a falsely elevated creatinine in patients with paraproteinemia and no other signs of kidney disease to avoid unnecessary diagnostic tests and for the prognostic implications.

Abstract The presence of a serum immunoglobulin D (IgD) monoclonal protein (M‐protein) is seen in

Abstract Scleromyxedema is a rare clinical variant of primary cutaneous mucinosis. It is defined by a generalized papular and sclerodermoid eruption associated with monoclonal gammopathy. No specific definitive treatment is known and those tried have inconsistent results. The first‐line treatment is intravenous immunoglobulin infusions with variable response and frequent relapse. We describe, here, a patient with scleromyxedema with lambda monoclonal gammopathy treated effectively with low‐dose lenalidomide and dexamethasone. There was no clinical or biological relapse after 3 years of follow‐up. In our opinion, agents targeting the abnormal plasma cell clone like lenalidomide are the most promising in the treatment of scleromyxedema.

C3 glomerulopathy is a rare disease, characterized by an abnormal activation of the complement’s alternative pathway that leads to the accumulation of the C3 component in the kidney. The disease recurs in more than half of kidney transplant recipients, with a significant impact on graft survival. Recurrence of the primary disease represents the second cause of graft loss after organ rejection. In C3 glomerulopathy, there are several risk factors which can promote a recurrence during transplantation, such as delayed graft function, infection and monoclonal gammopathy. All these events can trigger the alternative complement pathway. In this review, we summarize the impact of C3 glomerulopathy on kidney grafts and present the latest treatment options. The most widely used treatments for the disease include corticosteroids and mycophenolate mofetil, which are already used chronically by kidney transplant recipients; thus, additional treatments for C3 glomerulopathy are required. Currently, several studies using anti-complement drugs (i.e., eculizumab, Ravalizumab, avacopan) for C3 glomerulopathy in kidney transplant patients are ongoing with encouraging results.

Introduction: Acquired angioedema (AAE), a rare cause of adult-onset non-urticarial mucocutaneous angioedema, can present as acute abdomen, a frequent complaint in the emergency room (ER), often leading to unnecessary and potentially harmful procedures. Case Presentation: We report a 47-year-old hypertense male, controlled with an angiotensin converting enzyme inhibitor (ACEI), who presented in the ER with progressively worsening abdominal pain, nausea, and vomiting, and a radiologic workup revealing small intestine thickening, initially diagnosed with ACEI-induced angioedema. However, further investigation revealed low serum levels of C4, C1q, and C1 inhibitors, with an abnormal function of the latter, favoring the diagnosis of AAE instead. The frequent association of this condition with lymphoproliferative disorders encouraged further studies, which unveiled a monoclonal gammopathy IgM/Kappa, representing an increased risk of Waldenström macroglobulinemia, non-Hodgkin lymphoma, and multiple myeloma. Discussion: AAE should be regarded as an important differential diagnosis in patients presenting with acute abdomen in the ER, especially when more common causes are excluded. A correct and early diagnosis may represent a chance for a better prognosis of underlying diseases.

Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells and the excretion of a monoclonal immunoglobulin (M-protein), or fragments thereof. This biomarker plays a key role in the diagnosis and monitoring of MM. Although there is currently no cure for MM, novel treatment modalities such as bispecific antibodies and CAR T-cell therapies have led to substantial improvement in survival. With the introduction of several classes of effective drugs, an increasing percentage of patients achieve a complete response. This poses new challenges to traditional electrophoretic and immunochemical M-protein diagnostics because these methods lack sensitivity to monitor minimal residual disease (MRD). In 2016, the International Myeloma Working Group (IMWG) expanded their disease response criteria with bone marrow-based MRD assessment using flow cytometry or next-generation sequencing in combination with imaging-based disease monitoring of extramedullary disease. MRD status is an important independent prognostic marker and its potential as a surrogate endpoint for progression-free survival is currently being studied. In addition, numerous clinical trials are investigating the added clinical value of MRD-guided therapy decisions in individual patients. Because of these novel clinical applications, repeated MRD evaluation is becoming common practice in clinical trials as well as in the management of patients outside clinical trials. In response to this, novel mass spectrometric methods that have been developed for blood-based MRD monitoring represent attractive minimally invasive alternatives to bone marrow-based MRD evaluation. This paves the way for dynamic MRD monitoring to allow the detection of early disease relapse, which may prove to be a crucial factor in facilitating future clinical implementation of MRD-guided therapy. This review provides an overview of state-of-the-art of MRD monitoring, describes new developments and applications of blood-based MRD monitoring, and suggests future directions for its successful integration into the clinical management of MM patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: Sporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset, acquired, muscle disease that can be associated with monoclonal gammopathy or HIV infection. The pathological hallmark of SLONM is the accumulation of nemaline rods in muscle fibers. We review here current knowledge about its presentation, pathophysiology, and management. Recent Findings: SLONM usually manifests with subacutely progressive proximal and axial weakness, but it can also present with chronic progressive weakness mimicking muscular dystrophy. The pathophysiology of the disease remains poorly understood, with evidence pointing to both autoimmune mechanisms and hematological neoplasia. Recent studies have identified histological, proteomic, and transcriptomic alterations that shed light on disease mechanisms and distinguish SLONM from inherited nemaline myopathies. A majority of SLONM patients respond to intravenous immunoglobulins, chemotherapy, or hematopoietic stem cell transplant. Summary: SLONM is a treatable myopathy, although its underlying etiology and pathomechanisms remain unclear. A high degree of suspicion should be maintained for this disease to reduce diagnostic delay and treatment in SLONM and facilitate its distinction from inherited nemaline myopathies. [ABSTRACT FROM AUTHOR]

The ratio of κ light chains to λ light chains (κ:λ) in serum is used as a biomarker of immunoglobulin secreting neoplasia in humans but has not been evaluated in dogs. A mass‐spectrometry based method for determining the canine serum κ:λ was developed and used to evaluate samples from control dogs, dogs with an infectious aetiology, dogs with secretory plasma cell tumours (sPCT) and dogs with non‐secretory B cell neoplasia. A human‐targeted immunoturbidometric κ:λ assay and immunofixation using antisera targeting human κ light chain or λ light chain was also performed on all samples. Using whole serum samples, the MS‐based κ:λ method identified 5 sPCT as κ‐predominant (mean κ:λ = 3.307) and 5 sPCT as λ‐predominant (mean κ:λ = 0.023) and documented differences between these groups and all other groups (p < 0.05 for all). The infectious aetiology group had a lower mean κ:λ ratio (mean κ:λ = 0.069) than control samples (mean κ:λ = 0.103, p = 0.035). Similar results were obtained when samples were enriched for proteins between 10 and 50 kDa using size exclusion chromatography, except for the statistical difference between the control and infectious aetiology group. All λ‐predominant cases had only anti‐human λ light chain labelling by immunofixation. Three κ‐predominant cases had only anti‐human κ‐light chain labelling and the remaining two cases did not label with either antisera by immunofixation. The immunoturbidometric method had high analytical CV% (λ light chain CV = 13%, κ light chain CV = 50%), was unable to measure light chains in 20.5% of samples and did not distinguish groups. The data suggests that the human‐targeted immunoturbidometric method would not be diagnostically useful and that the MS‐derived serum κ:λ may be a useful biomarker of canine immunoglobulin secretory neoplasia which may have the ability to distinguish neoplasia from infectious causes of immunoglobulin secretion. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Waldenström's macroglobulinemia may begin with constitutional symptoms that are common in primary care settings and it is crucial for physicians to be aware of the potential complications of hyperviscosity syndrome and to employ the appropriate diagnostic methods in order to achieve better outcomes. Waldenström's macroglobulinemia (WM) refers to a type of lymphoplasmacytic lymphoma distinguished by the hyperproliferation of plasma cells, lymphocytes, and plasmacytoid lymphocytes. The disease is primarily diagnosed by increased monoclonal immunoglobulin M (IgM) levels and lymphoplasmacytic cell infiltration into the bone marrow. Individuals exhibit a high risk for hyperviscosity syndrome (HVS) as immunoglobulin levels increase. In addition to constitutional symptoms (fever, night sweats, and unintentional weight loss), clinical findings such as cytopenia, hepatosplenomegaly, and lymphadenopathy, this condition may cause hyperviscosity‐related organ failures. Here we discuss a patient with WM who presented with neurological complaints and blurry vision and developed necrosis at distal portions of his body during the 6‐month course of the disease. [ABSTRACT FROM AUTHOR]

TEMPI syndrome is a new and poorly understood disease that is currently considered a type of plasma cell neoplasm with paraneoplastic manifestations. The TEMPI acronym defines the hallmarks of the syndrome: T for telangiectasia; E for erythrocytosis with elevated erythropoietin; M, monoclonal gammopathy; P, perinephric collections; and I, intrapulmonary shunting. Due to the marked erythrocytosis as the most common presenting feature, TEMPI is often misdiagnosed as polycythemia vera. However, unlike polycythemia vera, TEMPI is not associated with a JAK2 mutation. The pathogenesis of TEMPI syndrome is unknown, although a few hypothetical disease mechanisms have been previously discussed. Here we present a new case of TEMPI syndrome, discuss results of a next-generation sequencing (NGS) panel covering 1,425 known cancer-related genes, and review the current literature with focus on an update of the genetics of TEMPI syndrome. This is the first report of TEMPI that includes results of comprehensive NGS testing. [ABSTRACT FROM AUTHOR]

Background Immunoglobulin monoclonal light chains (MLCs) in serum and urine are markers for monoclonal gammopathy and could serve as markers of minimal residual disease (MRD) in multiple myeloma (MM). Excretion of MLCs in urine is known to result in renal damage and shorter survival in patients with LC-predominant MM. Methods Retrospective review of urine immunofixation in 1738 specimens at 3 medical centers was conducted to assess the utility of urinalysis for diagnosis and monitoring of monoclonal gammopathy. We tested 228 stored urine specimens via the modified urine immunofixation method, using antisera to assay free LCs (FLCs). Results Our review of urine immunofixation results and medical records validated the theory that the only meaningful value-added finding was detection of monoclonal free light chains. Examination of 228 urine specimens using our novel method revealed 18.4% additional positive results. The rate of incremental findings for lambda LCs was nearly 3-fold higher than for kappa LCs. Conclusions The new method of urine immunofixation is significantly more sensitive and more efficient than the conventional method for detecting MLCs in urine. The new assay appears to be sensitive enough to prove that MLCs serve as a marker of MRD in MM. [ABSTRACT FROM AUTHOR]