Disappearance of bone marrow B cell clonal expansion in patients with type II hepatitis C virus-related cryoglobulinemic glomerulonephritis after clinical efficient rituximab therapy
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Abstract:
Preliminary data provided encouraging results on efficacy and safety of B cell depletion with rituximab in active glomerulonephritis in the course of mixed cryoglobulinemia (MC).1 2
B cell oligomonoclonal expansion in peripheral blood and in bone marrow (BM) seems to be a key pathological and molecular feature in MC.3 4 Recently, renal involvement in MC has been associated with B cell clonal expansion in the BM.5 We report new data on the possible relationship between clinical efficacy of rituximab in MC nephritis and the disappearance of BM B cell clonal expansion after (month +6) rituximab administration demonstrated by molecular studies (fig 1).4
Figure 1 Bone marrow (BM) B cell expansion before and after rituximab. Bone marrow B cell expansion was evaluated in BM needle aspiration samples by semi-nested PCR using an upstream primer directed to the third framework variable (V) region of the IgH genes and downstream primers directed to the joining (J) region, as described previously.5 Samples were tested in duplicate, and the results were confirmed in repeated experiments. PCR products were analysed on 10% polyacrylamide gels stained with ethidium bromide. A clonal B cell expansion was defined by the presence of discrete, reproducible narrow band(s) within the predicted size range, while a polyclonal pattern by a ladder of bands with similar intensities or by the presence of weakly dominant bands, not become reproducible in repeated amplification. A monoclonal pattern of B cell expansion is shown at baseline in patients 1 and 2, and an oligoclonal pattern in patient 3. At 6 months after rituximab therapy the molecular pattern of B cell expansion had changed in all the three cases from clonal to polyclonal.
Three patients, two females and one male, aged 58, 62 …Cite
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Rituximab, an anti-CD2O monoclonal antibody, is an emerging and effective option for the treatment of patients with refractory steroid-dependent nephrotic syndrome (SDNS), but few studies have assessed the long-term prognosis in these patients. We therefore evaluated the efficacy of rituximab in 35 patients, aged 4-21 years, who experienced SDNS while being treated with immunosuppressants. Patients were monitored for 24-63 months. After the first infusion of rituximab, the number of relapses and the dose of prednisolone were significantly reduced, and the steroid withdrawal period was significantly increased. However, 22 patients (63%) required retreatment with rituximab owing to relapses. At the last observation, only three patients (9%) could discontinue immunosuppressants completely and only three continued to show remission during the observation period. Although rituximab could not induce a complete cure of refractory SDNS, it resulted in longer remission times when immunosuppressants were continued after rituximab therapy, indicating the effectiveness of rituximab followed by immunosuppressants. We also found that patients who experienced more relapses before rituximab therapy were more likely to relapse earlier after rituximab therapy.
Prednisolone
Refractory (planetary science)
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Experience with rituximab in patients with new ANCA-associated vasculitis (AAV) is still very limited, especially in patients with severe (organ- or life-threatening) AAV. Rituximab may be more effective in anti-PR3 AAV, but potentially less effective in some granulomatous manifestations of AAV. We do not know what the response is to rituximab on the tissue level. Rituximab induction needs to be followed by maintenance treatment, and potentially very long rituximab maintenance may result in higher risk of rituximab-related complications (e.g. decrease in IgG levels). Long-term experience with rituximab in AAV is insufficient. Treatment with rituximab is more expensive than the standard treatment with cyclophosphamide and corticosteroids and seems to be cost-effective only in patients primarily treated with cyclophosphamide. Rituximab can be used in some newly diagnosed patients with AAV (e.g. women with child-bearing potential, or patients with active vasculitis and severe infection), but with the available information, it may be too early to use it as a first-line treatment in all new AAV patients.
ANCA-Associated Vasculitis
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Background: PP and rituximab are two major therapies commonly used in transplantation. They are often used in combination to prevent or treat AMR. Since PP can remove antibodies while rituximab is a B-cell depleting monoclonal antibody. The right sequence of using rituximab and PP is critical to achieve the best treatment efficacy. This meta-analysis analyzed the commonly used PP/rituximab protocols and pointed out a common error in current clinic practice. Methods: We did a PubMed title search for recent 5 years literature in major transplant journals and investigated treatment protocols with rituximab and PP. We tried to address the question whether rituximab treatment followed by multiple sessions of PP will compromise B-cell depleting effects of rituximab. Results: Among a total of 12 papers in which rituximab was used with concomitant PP, three papers did not describe detailed treatment sequence. Rituximab was given after multiple sessions of PP in three studies. In the rest 6 studies, one or two doses of rituximab were administered followed by multiple sessions of PP. The half-life of rituximab is approximately 2-4 weeks with a wide variability between subjects. The clearance rate of rituximab after one session of PP/PE is 47-54%. Multiple (4-5) sessions of PP/PE can clear it to undetectable level. Apparently, the B cell depletion effect of rituximab will be significantly compromised if PP treatment is performed right after the rituximab is given. Significantly, a single dose of rituximab without PP usually completely removed peripheral B cells within 1-2 days and sustained profound B cell suppression up to 2-3 years of observation period. However, when multiple cycles of PP were performed right after rituximab therapy, peripheral B cells were detectable within 1st week in 60-71% of patients. B cell counts started to increase from month 5-6, and recovered to baseline levels with 1-2 years. Conclusion: A combined treatment with rituximab therapy followed by multiple cycles of PP is a very common error in current clinic practice. These treatment protocols significantly diminished treatment efficacy of rituximab. People may argue that the maximum effect of rituximab in depleting circulating B cells was observed within 2 days with more than 90% depletion rate. However, this argument ignores the long-term effect of rituximab on CD20+ B cells in lymphoid tissues. Similar mistaken treatment sequence is commonly found in other protocols which also need to be paid attention to. Authors suggest that PP should be used either before or after 1-2 half-life of any given immune-suppressants, which will help maintain or maximize their effects. Certainly, it is a different issue if PP is used to remove rituximab or other drugs from peripheral blood in order to minimize their severe side effects.
Plasmapheresis
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Maintenance therapy
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Serum protein electrophoresis was performed in 63% of 1,069 consecutive patients with lymphoma. No monoclonal peaks of IgM specificity were found in sera from 345 patients with nodular lymphoma or Hodgkin's disease. Of the remaining 333 patients with diffuse lymphoma, 1.5% had an IgG peak, suggesting a coincidental relationship of IgG peaks to lymphoma. IgM peaks occurred in 3.6% of patients with diffuse lymphoma, a prevalence about 60 times more frequent than that in normal subjects. Such peaks were more frequent in older patients, suggesting an increased incidence of lymphomas producing monoclonal macroglobulins with advancing age. There was a close correlation between lymphoma mass and the level of the IgM peak in individual patients. Results supported the value of identifying monoclonal components in all patients with lymphoma, particularly those with diffuse lymphocytic infiltration.
Macroglobulinemia
Immunoglobulin M
Lymphoplasmacytic Lymphoma
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About 20% of TTP are resistant to plasma exchange. As reported in a few case reports and small case series, rituximab has been used in the treatment of TTP with some benefit. However, the optimal dosing, frequency, and timing of rituximab remain to be determined. We treated three cases of refractory TTP with rituximab. Case 1 exhibited brain sequelae probably due to the late administration of rituximab, case 2 died before the expected effect of rituximab could occur, and case 3 recovered completely because of the early administration of rituximab. These results suggest that rituximab should be given as early as possible in TTP, but large clinical studies are required to determine the optimal use of rituximab in TTP.
Refractory (planetary science)
Thrombocytopenic purpura
Plasmapheresis
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Monoclonal immunoglobulins have been implicated in the development of C3 glomerulonephritis (C3GN) and Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID). We report a 58-year-old female who showed a switch from C3GN to PGNMID. She presented with mild proteinuria and normal renal function for the first time. Her renal biopsy showed a severe mesangial proliferation with isolated C3 deposits, thus being diagnosed as C3GN. Two years later, her condition became serious. Repeat renal biopsy showed a membranoproliferative glomerulonephritis with deposition of the κ light chain of IgG3 in the glomeruli. She was diagnosed with proliferative glomerulonephritis with monoclonal IgG deposits (IgG3-κ). This case demonstrates that there are several types of monoclonal gammopathy (MGP)-associated glomerulonephritis, and they can switch among each other in some patients.
Membranoproliferative glomerulonephritis
Mesangial proliferative glomerulonephritis
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Several types of glomerulonephritis associated with dysproteinemia, such as AL-amyloidosis, light- and heavy-chain deposition disease, and type 1 cryoglobulinemic glomerulopathy, demonstrate monoclonal immunoglobulin deposition. Progressive glomerulonephritis with monoclonal IgG deposits (PGNMID) is also known to feature monoclonal glomerular deposits, but most of these cases occur without underlying disease. We here report a case of recurrent PGNMID that developed as diffuse cellular crescentic glomerulonephritis 8 years after an initial diagnosis of membranoproliferative glomerulonephritis (MPGN). Determination of the monoclonality of the deposited immunoglobulin is vital to make the correct diagnosis and enable an early administration of aggressive immunosuppressive therapy.
Membranoproliferative glomerulonephritis
Glomerulopathy
Rapidly progressive glomerulonephritis
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Among new treatments for ANCA-associated vasculitis, rituximab is the most promising. It has already been demonstrated that rituximab is not inferior to cyclophosphamide in inducing remission. This drug is therefore an alternative to cyclophosphamide for induction treatment. In the long term, it has been shown that patients who have received 4 infusions of rituximab to induce remission, not followed by a maintenance treatment, have the same relapse rate as patients who have been treated with azathioprine for maintenance. This high relapse rate supports a maintenance treatment which could also be rituximab. The results obtained with rituximab vs. azathioprine are encouraging and could favour rituximab use, but long-term results are still needed. Rituximab is safe and side effect frequency and severity are comparable to the side effects observed in patients treated with cyclophosphamide for induction, and azathioprine or methotrexate for maintenance. New studies are needed to evaluate the long-term side effects of this biotherapy.
Maintenance therapy
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