Raphael Szalat

Pathogenesis and treatment of xanthomatosis associated with monoclonal gammopathy

Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.

Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease

Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m(2) and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.

Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma

Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma

Clinico-biological characteristics and treatment of type I monoclonal cryoglobulinaemia: a study of 64 cases

This retrospective analysis was conducted in 64 patients diagnosed with type I cryoglobulinaemia (CG) followed at two French centres. Median follow‐up was 6·75 years. CG was IgG in 60% and IgM in 40% of all cases and was asymptomatic in 16 patients (25%). Cold‐triggered ischaemic skin manifestations were observed in 33 patients (51%). Neurological manifestations were observed in 15 patients and renal manifestations in 13. Most of the patients with necrotic purpura (14/16, P = 0·009) and renal manifestations (11/13, P = 0·057) had IgG CG. IgG CG was associated with monoclonal gammopathy of undetermined significance (MGUS), myeloma, chronic lymphocytic leukaemia and lymphoplasmocytic lymphoma in 18, 13, 5 and 2 patients, respectively. IgM CG was associated with MGUS and Waldenström macroglobulinaemia in 8 and 18 cases, respectively. One third of patients did not receive any specific treatment. Various treatments, including rituximab, were administered to 25/31 patients with IgG CG and 6/25 patients with IgM CG due to CG‐related symptoms. Rituximab was ineffective in all cases associated with a predominantly plasmacytic proliferation. To conclude, type I CG has specific clinico‐biological characteristics compared to type II CG. Furthermore, there are differences in terms of related manifestations between type I IgG and type I IgM CG.

Genomic heterogeneity in multiple myeloma

Multiple myeloma (MM) is an incurable malignancy in majority of patients characterized by clonal proliferation of plasma cells. To date, treatment is established based on general conditions and age of patients. However, MM is a heterogeneous disease, featured by various subtypes and different outcomes. Thus, the understanding of MM biology is currently a major challenge to eventually cure the disease. During the last decade, karyotype studies and gene expression profiling have identified robust prognostic markers as well as a widespread genomic landscape. More recently, studies of epigenetic, transcriptional modifications and next generation sequencing have allowed characterization of critical genes and pathways, clonal heterogeneity and mutational profiles involved in myelomagenesis. Altogether, these findings constitute important tools to develop new targeted and personalized therapies in MM.

Aseptic meningitis and ischaemic stroke in Fabry disease

Background:  Fabry disease (OMIM 301 500) is an X‐linked lysosomal storage disease. Neurological symptoms in Fabry disease mainly include stroke, acroparesthesia, cranial nerve palsies and autonomic dysfunction. We report on aseptic meningitis in Fabry patients.

Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.

Xanthomatosis associated with monoclonal gammopathy includes hyperlipidaemic xanthoma (HX), normolipidaemic xanthoma (NX) and necrobiotic xanthogranuloma (NXG). All three pathologies are characterized by skin or visceral lesions related to cholesterol accumulation, monoclonal immunoglobulin (MIg) and hypocomplementemia. The pathophysiology underlying NXG remains unknown although the involvement of MIg is suspected.

Anti-NuMA1 and anti-NuMA2 (anti-HsEg5) antibodies: Clinical and immunological features: A propos of 40 new cases and review of the literature

OBJECTIVE Anti-NuMA1 and anti-NuMA2 antibodies are antinuclear antibodies (ANA) targeting the mitotic spindle apparatus. Our objective was to determine their clinical and immunological features and to review the literature available data. PATIENTS AND METHODS Between 2004 and 2008, 36,498 sera were analyzed for the presence of ANA, which included anti-NuMA1 and anti-NuMA2 antibodies. Clinical and immunological features of patients with positive anti-NuMA1 and anti-NuMA2 antibodies (titer> or =1/320) were retrospectively collected and analyzed. A review of the literature was secondly performed. RESULTS Out of the 36,498 sera analyzed, 10,585 sera were positive for ANA (29%). Out of ANA positive sera, 40 sera (0.38%) (40 different patients) were positive for anti-NuMA antibodies: 27 anti-NuMA1 (0.26%) and 13 anti-NuMA2 (0.12%). Compared to anti-NuMA2 positive patients, anti-NuMA1 positive patients were more often female (81.5% versus 46%; P=0.03), had more frequently a connective tissue disease (CTD) (40.7% versus 0%; P=0.016) and higher serum titers (877+/-466 versus 443+/-278; P=0.007). The anti-NuMA1 positive CTD were either Sjögrens syndrome (SS) (54.5%) or systemic lupus erythematosus (SLE) (45.5%). In the literature, 164 anti-NuMA positive patients (133 anti-NuMA1 and 31 anti-NuMA2) have been reported. Combining the reported cases to ours, up to 67.5% of anti-NuMA positive patients had an autoimmune disease, mostly pSS in 34% (31/90) and SLE in 31% (28/90). Anti-NuMA1 antibodies were the single positive ANA in 46% of anti-NuMA1 positive SS and 47% of anti-NuMA1 positive SLE, and anti-NuMA2 antibodies in 2/2 and 87.5%, respectively. CONCLUSION Detection of anti-NuMA1 and anti-NuMA2 antibodies is very uncommon. When present, they are mostly associated with connective tissue disease, mainly Sjögren syndrome and systemic lupus. Clinicians may be aware that in these latter conditions, anti-NuMA antibodies may be the single serological marker.

A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche: biologic and clinical applications.

Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM.

The spectrum of neutrophilic dermatoses associated with monoclonal gammopathy: Association with IgA isotype and inflammatory profile.

BACKGROUND Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome. OBJECTIVE We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg. METHODS We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules. RESULTS This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1. LIMITATIONS This is a retrospective study from a single institution with a limited number of participants. CONCLUSION Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules.