Summary
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.
Background. Common variable immunodeficiency (CVID) is a primary immune deficiency defined by defective antibody production. In most series, a small proportion of patients present with opportunistic ...infections (OIs). Methods.The French DEFI study has enrolled patients with primary hypogammaglobulinemia and allows a detailed clinical and immunologic description of patients with previous OIs and/or at risk for OIs. Results.Among 313 patients with CVID, 28 patients (8.9%) presented with late-onset combined immune deficiency (LOCID), defined by the occurrence of an OI and/or a CD4+T cell count < 200×106cells/L, and were compared with the remaining 285 patients with CVID. The patients with LOCID more frequently belonged to consanguineous families (29% vs 8%; P=.004). They differed from patients with CVID with a higher prevalence of splenomegaly (64% vs 31%), granuloma (43% vs 10%), gastrointestinal disease (75% vs 42%), and lymphoma (29% vs 4%). Even on immunoglobulin substitution, they required more frequent antibiotics administration and hospitalization. Lymphocyte counts were lower, with a marked decrease in CD4+T cell counts (158×106vs 604×106cells/L; P<.001) and a severe defect in naive CD45RA+CCR7+CD4+T cell counts (<20% of total CD4+T cells in 71% of patients with LOCID vs 37% of patients with CVID; P=.001). The CD19+B cell compartment was also significantly decreased (20×106vs 102×106cells/L; P<.001). Conclusions.LOCID differs from classic CVID in its clinical and immunologic characteristics. Systematic T cell phenotype may help to discriminate such patients from those with CVID. Identification of this phenotype should result in a more fitted diagnostic and therapeutic approach of infections and could provide insights for genetic diagnosis.
To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years.
One hundred ninety patients ...between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m(2) intravenous IV or melphalan 140 mg/m(2) IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction).
Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03).
With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM.
Pulmonary arterial hypertension (PAH) is a rare complication of systemic lupus erythematosus (SLE).
We identified all patients with SLE and PAH (SLE-PAH) who were enrolled in the French Pulmonary ...Hypertension Registry with a diagnosis confirmed by right heart catheterization (RHC). A control group of 101 patients with SLE without known PAH was selected from SLE expert centers participating in the Pulmonary Hypertension Registry. Survival was estimated by the Kaplan-Meier method. Hazard ratios associated with potential predictors of death were estimated using Cox proportional hazard models.
Of the 69 patients with SLE-PAH identified in the French Pulmonary Hypertension Registry, 51 were included in the study. They did not differ from the control group regarding age, sex, or duration of SLE at the time of the analysis but had a higher frequency of anti-SSA and anti-SSB antibodies. The delay between SLE diagnosis and PAH diagnosis was 4.9 years (range, 2.8-12.9) years. The 3- and 5-year overall survival rates were 89.4% (95% CI, 76.2%-96.5%) and 83.9% (95% CI, 68.8%-92.1%), respectively. The survival rate was significantly better in patients with anti-U1-RNP antibodies (P = .04).
Patients with SLE-PAH have an overall 5-year survival rate of 83.9% after the PAH diagnosis. Anti-SSA/SSB antibodies may be a risk factor for PAH, and the presence of anti-U1-RNP antibodies appears to be a protective factor regarding survival.
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.
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.
Schnitzler syndrome is a rare plasma cell disorder the pathogenesis of which is still not fully understood. We evaluated the circulating levels of four major angiogenic cytokines (VEGF, angiogenin, ...angiopoietin-1 and angiopoietin-2) and six bone remodeling markers (sRANKL, osteoprotegerin, dickkopf-1, CTX, osteocalcin and bone-specific alkaline phosphatase-bALP) in 13 patients with Schnitzler syndrome. At diagnosis, patients had elevated angiogenic cytokines. The mean VEGF levels were almost 3.5-fold higher in Schnitzler syndrome compared to controls, while 10 of 13 patients had higher VEGF than the upper control value. Successful treatment led to a significant reduction in VEGF. Patients with Schnitzler syndrome had increased bone formation (high bALP, osteocalcin and osteoprotegerin) which was not balanced by an increase in bone resorption (normal CTX and sRANKL). These data support a role for VEGF as a new minor criterion in the diagnosis and follow up of Schnitzler syndrome, while the uncoupling of bone remodeling in favor of bone formation justifies the presence of bone densification.
High dose chemotherapy in light chain or light and heavy chain deposition disease.
Conventional chemotherapy for myeloma yield unsatisfactory results in light and/or heavy chain deposition disease ...(H)CDD Because of the well-established dose-response effect of high dose melphalan in multiple myeloma, aiming to dramatically reduce the pathogenic monoclonal immunoglobulin (MIg) level, high dose therapy is a tempting alternative approach.
We treated 11 young patients with L(H)CDD by high dose therapy with the support of autologous blood stem cell transplantation. All had renal symptoms, including four who required dialysis and seven who had various, mainly cardiac, extrarenal manifestations.
No toxic deaths occurred. A decrease in the MIg level was observed in eight patients, with complete disappearance from serum and urine in six cases. Improvement in manifestations related to MIg deposits were observed in six patients, including renal, cardiac, and hepatic responses in 4/11, 4/4, and 2/2 cases, respectively. Histologic regression of MIg deposits was documented in cardiac, hepatic, and skin biopsies. In contrast, examination of the kidney still showed light chain deposits in one patient who had renal transplantation 3years after high dose therapy, at a time when he was in persisting remission.
Within a median follow-up of 51months, three patients were retreated because of multiple myeloma relapse, of whom one died and one required hemodialysis, and renal function secondarily deteriorated in a patient who had resistant multiple myeloma. Otherwise, no manifestations related to MIg deposits occurred or recurred in any patient.
Present results of this retrospective study argue in favor of a benefit of high dose therapy with stem cell support in young patients with L(H)CDD.
We evaluated the B cell memory pool among blood B cells from 20 patients with common variable immunodeficiency (CVID). CD27+ B cell number was normal or increased in 6 patients (with 95 % CD27+ B ...cells in 1 patient) and decreased in 14 patients. In 13 or 15 patients studied, the CD27 molecule was detectable on less than 50 % IgG or IgA B cells, indicating a defect in the maturation of these memory cells. Within the group of patients with a low number of CD27+ B cells, no up‐regulation of this molecule was observed after in vitro stimulation of purified B cells from 3 of 5 patients studied, suggesting an intrinsic B cell defect. In addition, ligation of the CD27 molecule was unable to trigger terminal differentiation of purified B cells in 1 of 2 cases with a large number of CD27+ B cells. Finally, the CD27 ligand was normally expressed on activated T cells in only 5 of 14 patients studied. These data confirm the heterogeneity of immunological defects in patients with CVID. Abnormal expression and / or function of the CD27‐CD70 members of the TNF / TNF receptor family contribute to the immunological defect.
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