Diagnostic delay and characterization of the clinical prodrome in AL amyloidosis among 1523 US adults diagnosed between 2001 and 2019.

Light-chain (AL) amyloidosis is a multisystem disorder with a high early mortality and diagnostic delays of >1 year from symptom onset. This retrospective observational study sought to characterize the clinical prodrome and diagnostic delay to inform early detection. We identified 1523 adults with newly diagnosed AL amyloidosis in the Optum de-identified Clinformatics® Datamart US healthcare claims database as those with ≥2 new diagnosis codes for AL or other amyloidosis in 90 days with ≥1 multiple myeloma treatment within 730 days, excluding patients with prior hereditary or secondary amyloidosis and Familial Mediterranean Fever. We considered 34 signs/symptoms using diagnosis codes in all observable time on or before AL amyloidosis diagnosis. Sign/symptom prevalence was compared to that of 1:4 matched population controls. The overlap and sequence of signs/symptoms and the median time from first sign/symptom to AL amyloidosis diagnosis were explored. Healthcare utilization was summarized. The most common individual AL amyloidosis signs/symptoms were malaise/fatigue (61%) and dyspnea (59%). Cardiac signs/symptoms were observed in 77% of patients, followed by renal (62%) and neurologic (59%) signs/symptoms. Multisystem involvement (≥3 systems) was present in 54%. Monoclonal gammopathy was detected in 29% before diagnosis. Median time from symptom onset to AL amyloidosis diagnosis was 2.7 years. Healthcare utilization was high between first AL amyloidosis signs/symptoms and diagnosis, with 50% visiting ≥5 physician types. AL amyloidosis patients have a lengthy and complex clinical prodrome. Novel approaches to early diagnosis are needed to improve outcomes.

The Wide Spectrum of Pathophysiologic Mechanisms of Paraproteinemic Neuropathy.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation.

Crystalglobulinemia manifested as acute renal failure and thrombotic vasculopathy.

Crystalglobulinemia is an extremely rare pathology that is associated in most cases with plasma cell dyscrasia, mainly multiple myeloma. In most cases, it may be the manifestation of incipient gammopathy or it manifests shortly after diagnosis. We report a patient with ischemic lesions of thrombotic origin in lower limbs. Subsequently, renal involvement occurs, in view of this involvement, it is suspected that the patient may have an associated vasculitis. After performing the biopsy and with the subsequent diagnosis of monoclonal gammopathy of uncertain significance, the diagnosis is made. We review the most recent bibliography of patients who have been diagnosed with crystalglobulinemia associated with plasma dyscrasia focusing in those with thrombotic vasculopathy or acute renal failure. In our case, in addition to being associated with monoclonal gammopathy of undetermined significance that is less frequent, the debut of the symptoms is years before the detection of the monoclonal peak. This could speak of patients with a low peak of monoclonal component (not detected by immunoelectrophoresis) who could have kidney and vascular damage.

Serum Free Light Chain Assay: Shift Toward a Higher κ/λ Ratio.

BACKGROUND: The analysis of serum free light chains (FLCs) is clinically relevant for the diagnosis and therapeutic management of clonal plasma cell disorders. This study compares the performance of monoclonal and polyclonal FLC κ and λ assays in clinical samples determined in a single academic center. METHODS: Serum FLCs were analyzed from 102 patients using the Freelite (Binding Site) and N Latex (Siemens) assays on the BN ProSpec System (Siemens). When available, data for protein electrophoresis, immunofixation, C-reactive protein, and estimated glomerular filtration rate (eGFR) were combined with FLC results to evaluate performance. RESULTS: Method evaluation showed acceptable imprecision and inaccuracy measures of <4.4% and 12.9%, respectively. Poor agreement between the methods was observed, including constant and proportional bias and poor correlation (Kendall τ, 0.671-0.901). The N Latex assay was not affected by the renal impairment estimated by eGFR, unlike the FLC κ/λ ratio results by the Freelite assay. With the Freelite assay, 98% of putative controls without monoclonal gammopathy (n = 42) showed a κ/λ ratio that was above the median of the standard diagnostic range or renal diagnostic range. A shift toward higher κ/λ ratios was also observed when retrospective data between 2011 and 2017 were compared. CONCLUSIONS: Unlike the Freelite assay, κ/λ ratios analyzed with the N Latex assay were not affected by renal failure. Both methods showed acceptable performances using nephelometry, but they were poorly correlated. A shift toward κ/λ ratios might impair the specificity of borderline increased κ/λ results. This should be considered when interpreting FLC κ and λ results.

Monoclonal gammopathy of renal significance: clinical manifestation, pathogenic characteristic and treatment.

Monoclonal gammopathy of renal significance (MGRS) is a group of renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a dangerous plasmatic/B-cell clone hyperplasia through MIg deposition or dysfunction of complement pathway, with increasing risk of progress to end stage renal disease (ESRD) and the underlying hematologic malignancy. The combination of renal biopsy, complete laboratory examination and bone marrow biopsy is an indispensable diagnostic tool for MGRS to identify accurately and unequivocally the pathogenic monoclonal MIg and provide guidance to treatment. Treatment of MGRS is composed of conventional therapy, chemotherapy, and stem cell transplantation to target the underlying clone and eliminate the noxious MIg on the basis of clinical data of some retrospective studies and a small amount of prospective trial. In addition, it is worthwhile point out assessment of therapeutic effect is significantly relevant for renal and overall prognosis. Thus, by comprehensively analyzing the clinical manifestations and pathogenic characteristic of MGRS, early recognition and prompt treatment can improve the prognosis and prevent post-translation recurrence with multidisciplinary cooperation.

Antigen-mediated regulation in monoclonal gammopathies and myeloma.

A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies. Here, we show that recombinant Ig (rIg) cloned from sort-purified single tumor cells from lipid-reactive sporadic and GD-associated gammopathy specifically bound lysolipids. Liposome sedimentation and binding assays confirmed specific interaction of lipid-reactive monoclonal Ig with lysolipids. The clonal nature of lysolipid-binding Ig was validated by protein sequencing. Gene expression profiling and cytogenetic analyses from 2 patient cohorts showed enrichment of nonhyperdiploid tumors in lipid-reactive patients. In vivo antigen-mediated stimulation led to an increase in clonal Ig and plasma cells (PCs) in GD gammopathy and also reactivated previously suppressed antigenically related nonclonal PCs. These data support a model wherein antigenic stimulation mediates an initial polyclonal phase, followed by evolution of monoclonal tumors enriched in nonhyperdiploid genomes, responsive to underlying antigen. Targeting underlying antigens may therefore prevent clinical MM.

Dysproteinemias and Glomerular Disease.

Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage. The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomerulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Ig deposition include the activation of the complement system, which causes complement deposition in C3 glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be produced by clones from any of the B cell lineages and that a malignant state is not required for the development of kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal significance, preservation of renal function requires substantial reduction of the monoclonal protein. With better understanding of the pathogenesis, clone-directed strategies, such as rituximab against CD20 expressing B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These clone-directed therapies been found to be more effective than immunosuppressive regimens used in nonmonoclonal protein-related kidney diseases.

Vitamin D and plasma cell dyscrasias: reviewing the significance.

Monoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell disorder and precursor disease to multiple myeloma and other related cancers. While MGUS is considered a benign disorder, with a low risk of disease progression, patients have altered bone microarchitecture and an increased risk of bone fracture. In addition, alterations in immune function are regularly found to correlate with disease activity. Vitamin D, an important hormone for bone and immune health, is commonly deficient in multiple myeloma patients. However, vitamin D deficiency is also prevalent in the general population. The purpose of this review is to highlight the current understanding of vitamin D in health and disease and to parallel this with a review of the abnormalities found in plasma cell dyscrasias. While some consensus statements have advocated for vitamin D testing and routine supplementation in MGUS, there is no clear standard of care approach and clinical practice patterns vary. Further research is needed to better understand how vitamin D influences outcomes in MGUS patients.

Corneal Densitometry for Quantification of Corneal Deposits in Monoclonal Gammopathies.

PURPOSE: To assess the capability of Scheimpflug-based densitometry of the cornea to quantify light chain deposits in patients with active monoclonal gammopathies. METHODS: 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). RESULTS: 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 (P < 0.001), the CL (P < 0.001), and the TL (P < 0.001) 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. CONCLUSIONS: 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.

Monoclonal gammopathy of cutaneous significance: review of a relevant concept.

Some dermatologic entities are strongly associated with the presence of a monoclonal gammopathy. They should be referred to as monoclonal gammopathy of cutaneous significance (MGCS). A short review of the main entities that fit into the spectrum of MGCS is provided. Amyloidosis, macroglobulinoderma and follicular hyperkeratotic spicules result from extravascular immunoglobulin or immunoglobulin-related protein deposition. Skin findings include papules and plaques, follicular spicules, purpura, haemorrhagic bullae, macroglossia and nail changes. The skin findings in cryoglobulinemia (CG) result from vascular immunoglobulin deposition, either as immune complexes within the vessel walls in mixed CG or within the lumina of small vessels in monoclonal CG. Mixed CG manifests as palpable purpura of leukocytoclastic vasculitis, and monoclonal CG as stellar and/or retiform purpura that can evolve into extensive skin necrosis. In some rare instances, immunoglobulins have a specific biological activity. This is, for example, the case when they bind lipoproteins that precipitate and induce hypocomplementemic xanthomas. Xanthoderma related to antiflavin activity of the monoclonal component or acquired angioedema related to anti-C1INH activity is other example. Abnormal cytokine secretion is the hallmark of some entities. High vascular endothelial growth factor levels correlate with some of the skin manifestations of the Polyneuropathy organomegaly endocrinopathy monoclonal component skin changes syndrome, such as hypertrichosis or the adenopathy and extensive skin patch overlying plasmacytoma syndrome. All the clinical manifestations of the Schnitzler syndrome are IL-1 mediated. In other MGCS, such as scleromyxedema, Clarkson syndrome, TEMPI syndrome, cutis laxa and the neutrophilic dermatoses, the link between the monoclocal component and the entity is clearly established, but not understood so far.

[Expression of microRNA-221/222 in patients with monoclonal gammopathy of undetermined significance and multiple myeloma].

Objective: To detect the expression of miR-221/222 in serum and plasma cells in patients with monoclonal gammopathy of undetermined significance(MGUS) and multiple myeloma(MM), and to explore the possibility of miR-221/222 as biomarkers in the diagnosis and prognosis predicting of MGUS and MM. Methods: Bone marrow and serum samples from 14 patients with newly diagnosed MGUS, 81 patients with newly diagnosed or relapsed MM and 10 controls were collected from Sir Run Run Shaw Hospital of Zhejiang University and Tongde Hospital of Zhejiang Province during January 2013 and December 2015. The expressions of miR-221/222 in serum and in sorted CD138 positive plasma cells were detected by qRT-PCR, and the relative expression of miR-221/222 (Δct) was compared between the groups. Serum levels of miR-221 before and after treatment were compared in both remission group (n=22) and refractory group (n=13) in MM patients, and its correlation with serum level of ß2-MG was assessed using Pearson's correlation analysis. Results: Serum levels of miR-221/222 in MGUS and MM groups were significantly higher than those in control group (all P<0.01), while miR-221/222 levels in plasma cells were significantly lower in MGUS and MM groups than those in the control group (P<0.05 or<0.01). No significant difference in miR-221/222 levels in serum and plasma cells was observed between MGUS group and MM group (all P>0.05). There was no correlation between miR-221/222 levels in serum and plasma cells (r=0.024 and -0.127, all P>0.05), but miR-221 levels were correlated with miR-222 levels in both serum and plasma cells (r=0.534 and 0.552, all P<0.01). Receiver operating characteristic (ROC) curves showed that the areas under the curve (AUCs) of serum miR-221/222, plasma cell miR-221/222 in diagnosis of MGUS/MM were 0.968, 0.976, 0.801 and 0.727, respectively. There was no significant difference in serum level of miR-221 among MM patients with different paraprotein isotypes (P>0.05), but serum level of miR-221 in patients with relapsed MM was higher than that in patients with newly diagnosed MM (P<0.01). Compared with the patients with MGUS or MM stageⅠ and Ⅱ, patients with MM stage Ⅲ were of higher serum levels of miR-221 (P<0.01). Serum level of miR-221 decreased after chemotherapy in the remission group (U=51.5, P<0.01), but such decrease was not observed in the refractory group (U=67.5, P>0.05). Serum level of ß2-MG was positively correlated with serum level of miR-221 (r=0.524, P<0.01). Conclusion: miR-221/222 in serum and plasma cells may be biomarkers for early diagnosis of MGUS, and are helpful for diagnosis and efficacy evaluation of MM.

Enfermedades relacionadas con IgG4, diagnóstico histopatológico retrospectivo. Prevalencia en un hospital universitario / IgG4-related disease, retrospective histopathological diagnosis. Prevalence in a University Hospital

Introducción. Las enfermedades relacionadas con IgG4 (ER-IgG4) se caracterizan por inflamación y disfunción orgánica asociadas a células plasmáticas productoras de IgG4. Métodos. Analizamos pacientes con ER-IgG4 de acuerdo con: a)búsqueda de resultados en la base de datos de Patología con: reacción inflamatoria inespecífica con infiltrado linfoplasmocítico, pseudotumores inflamatorios y fibrosis estoriforme; b)análisis microscópico de biopsias con criterios de inclusión de la primer fase, y c)inmunohistoquímica de biopsias seleccionadas en la segunda fase. Resultados. Evaluamos en la primera fase 23.720 biopsias, y a 41/71 que reunieron los criterios de inclusión les realizamos inmunohistoquímica para IgG4. El 41,4% de estas tuvieron IgG4+, y el diagnóstico histológico más frecuente asociado fue mastitis granulomatosa (12,1% de muestras catalogadas inicialmente como probables). El resto incluyeron reportes de aortitis, dacrioadenitis o sialoadenitis, pseudotumor inflamatorio pulmonar y pancreatitis crónica. Conclusiones. La sospecha de enfermedades relacionadas con IgG4 no debe basarse únicamente en manifestaciones clínicas distintivas o solo en serología. Nuestro estudio incluye pacientes con ER-IgG4 sin sospecha clínica inicial (AU)

Introduction. IgG4 related diseases (IgG4-RD) are characterized mainly by organic dysfunction and inflammation with lymphoplasmacytic cells infiltration. Methods. We conducted a retrospective study. We analyzed patients with a diagnosis of IgG4-RD through histopathologic registries. We divided the study into three phases: (i)extraction of data from the registries of the Pathology Department, including specimens reported with: non-specific inflammation with plasmatic cell infiltration, inflammatory pseudo-tumors and storiform fibrosis, and excluding any report of cancer or infection; (ii)from the selected specimens, three pathologists microscopically re-analyzed these biopsies and included only those who had at least two of the inclusion criteria cited above; (iii)finally, immunostaining was performed in the specimens selected in the second phase. The selected biopsies were catalogued as compatible for IgG4-RD if they had at least 3 inclusion criteria and as probable if they had 2 inclusion criteria. Results. On the first phase of the study we analyzed 23,720 biopsies, from which we included 71 and excluded 29 specimens; the rest of the specimens (n=41) underwent immunostaining. From the biopsies included, 41.4% (n=17/71) were positive to IgG4, with the most common histological diagnosis for the positive specimens being granulomatous mastitis, which represented 12.1% of the specimens catalogued initially as probable. The rest of the positive biopsies were from aortitis, dacrioadenitis and/or sialoadenitis, lung pseudo-inflammatory tumor, pericarditis and chronic pancreatitis. Conclusions. The suspicion of IgG4 related disease should not be based solely on clinical manifestations or serology. In the present study we confirm the characteristic changes of IgG4-RD in patients without initial clinical suspicion (AU)

Hemodialysis Using High Cut Off Filters in Light Chain Cast Nephropathy.

BACKGROUND/AIM: Hemodialysis using high cutoff (HCO) filters possibly improves renal function in diseases with light chain (LC) overproduction and acute kidney injury. We established the effect of HCO dialysis on renal outcome in consecutive patients with malignant monoclonal gammopathies and LC cast nephropathy. METHODS: LC concentration was measured before and after each dialysis session in 10 patients receiving HCO dialysis and bortezomib-based chemotherapy, and their renal function was monitored by plasma creatinine. RESULTS: The number of HCO sessions ranged from 4 to 34 (mean 13). Six patients recovered kidney function, 3 regained partial function while 1 patient continued chronic dialysis. Patients with the largest reductions in LC during HCO treatments had the lowest creatinine at 6 and 9 months of follow-up. For comparison, only 2 out of 10 patients in a historic control group recovered kidney function. CONCLUSION: HCO dialysis combined with bortezomib results in good renal recovery with kidney function being dependent on the degree of LC lowering.

IgG4-related disease and the kidney.

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most frequent manifestations in the kidney­IgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4(+) T cells. Glucocorticoids are the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches.