Nephrology – Proteinuria: By Manish Suneja M.D.
Nephrotisches Syndrom beginnend im Kindesalter: Rituximab ist eine wirksame und sichere OptionRituximab, an anti-CD20 monoclonal antibody, was originally used to treat B-cell malignancies. Its use has significantly increased in recent years, as it is now also used to steroide herz a variety of autoimmune diseases including rheumatoid arthritis and ANCA-associated vasculitis AAV. Initial studies suggested that the adverse effects of rituximab were minimal. Though the risk of malignancy with rituximab-based immunosuppressive regimens appears similar to that of the general population, there are now concerns regarding the risk of stsroid complications. The risk of infection rituximab for steroid dependent nephrotic syndrome to be the result of a variety of mechanisms, including prolonged B-cell depletion, B-cell—T-cell crosstalk, panhypogammaglobulinaemia, late-onset neutropenia and blunting of the immune response after vaccination. Importantly, the risk of infectious complications is also related to individual patient characteristics and the indication for rituximab. Individualization of treatment is, therefore, crucial.
Authors / Contributors
Rituximab, an anti-CD20 monoclonal antibody, was originally used to treat B-cell malignancies. Its use has significantly increased in recent years, as it is now also used to treat a variety of autoimmune diseases including rheumatoid arthritis and ANCA-associated vasculitis AAV. Initial studies suggested that the adverse effects of rituximab were minimal. Though the risk of malignancy with rituximab-based immunosuppressive regimens appears similar to that of the general population, there are now concerns regarding the risk of infectious complications.
The risk of infection appears to be the result of a variety of mechanisms, including prolonged B-cell depletion, B-cell—T-cell crosstalk, panhypogammaglobulinaemia, late-onset neutropenia and blunting of the immune response after vaccination. Importantly, the risk of infectious complications is also related to individual patient characteristics and the indication for rituximab.
Individualization of treatment is, therefore, crucial. Particular attention should be given to strategies to minimize the risk of infectious complications, including vaccinating against bacterial and viral pathogens, monitoring white cell count and immunoglobulin levels, prophylaxis against PJP and screening for HBV and TB.
As a precursor of antibody-secreting plasma cells, B-cells have an important role in the pathogenesis of antibody-mediated autoimmune disease [ 5 ]. They generate cytokines, activate T cells and can act as antigen-presenting cells [ 5 ]. The CD20 receptor is found on the cell surface of B-cells at their pre-B-cell stage [ 6 ]. It is not expressed on other tissues and does not appear on B-cells after their differentiation into plasma cells [ 5 ].
Rituximab targets the CD20 receptor leading to B-cell depletion through complement-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and B-cell apoptosis [ 6 ]. However, we now know that treatment with rituximab is not without risk [ 7 ]. Though the risk of malignancy with rituximab-based immunosuppressive regimens appears similar to that of the general population, there are concerns regarding the risk of serious infections [ 8—10 ].
In this issue, Trivin et al [ 11 ]. This risk appears to be the result of a variety of mechanisms, including prolonged B-cell depletion, B-cell—T-cell crosstalk, panhypogammaglobulinaemia, late-onset neutropenia and blunting of the immune response after vaccination. B-cell reconstitution is variable after administration of rituximab. Rarely, B-cell depletion can persist beyond this [ 12 , 13 ]. Despite mature plasma cells lacking the CD20 receptor, panhypogammaglobulinaemia occurs relatively frequently during this period, though severe panhypogammaglobulinaemia associated with infection is less common [ 5 ].
Patients that suffered severe infections were noted to have a more profound decline in total immunoglobulins during treatment [ 14 ]. Moreover, lower levels of immunoglobulins increased the risk of chronic infection [ 14 ]. In , Besada [ 15 ] demonstrated that low baseline levels of immunoglobulin G IgG were associated with hypogammaglobulinaemia during treatment. These studies highlight the importance of assessing immunoglobulin levels prior to and during treatment with rituximab.
Late-onset neutropenia was associated with more severe B-cell depletion and an increased risk of severe infections [ 16 ]. A later study published by Salmon et al.
Thus, late-onset neutropenia after rituximab administration may not be as significant a risk factor for infection as hypogammaglobulinaemia. The mechanism of this neutropenia remains unclear and it may be underdiagnosed, as most patients are asymptomatic. As mentioned earlier, there is a blunted immune response after vaccination in those that have received rituximab [ 18 , 19 ].
Furthermore, Heusele et al. Accordingly, current guidelines emphasize the importance of patients receiving vaccinations prior to rituximab therapy to minimize the infection risk during their treatment course [ 20 , 21 ]. Several other factors appear to contribute to the risk of developing severe infections with rituximab treatment.
In this issue, Trivin et al. It is important to note that there are patient- and disease-related factors that have an impact on infection risk, in addition to the risk caused by immunosuppression treatment alone. All the following influence the risk of infections associated with rituximab: These influences make it difficult to attribute the risk of infections entirely to rituximab.
Cyclophosphamide remains the first-line treatment for life-threatening organ involvement in AAV. Rituximab is indicated in relapsing AAV, in disease resistant to cyclophosphamide or when cyclophosphamide is contraindicated, as is the case with urothelial malignancy or in patients of childbearing age. Based on the Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis RAVE trial, it is reasonable to conclude that rituximab is at least as safe as cyclophosphamide in the treatment of AAV and possibly more effective than cyclophosphamide in patients with relapsing disease [ 4 ].
Rituximab has been used to treat a variety of other glomerulonephritides. Reports of the adverse event rate following rituximab administration in idiopathic membranous nephropathy, lupus nephritis, MCD and FSGS are all encouraging. Similarly, Cravedi et al. However, overall rates of serious adverse events, including infections, were similar in the rituximab and non-rituximab-treated groups. The infection rate appears to be higher in those with cryoglobulinaemia treated with rituximab.
Furthermore, ABO-incompatible kidney transplant recipients who had a poor HLA mismatch showed the highest rates of infection. The predictive factors for death due to infection included the combined use of rituximab and anti-thymocyte globulin ATG , age and bacterial and fungal infections [ 32 ].
However, Scemla et al. Further research is required to more clearly establish the infection risk of rituximab use in kidney transplantation. Most infections encountered during rituximab treatment are secondary to bacterial pathogens. Pneumonia was the most commonly reported infection. Heusele et al [ 8 ] reported that more than half the patients that suffered a serious bacterial infection in their study had a history of a h hospitalization in the last 90 days.
Hospital-acquired infection may thus be an important cause of bacterial infection in this patient population. Indeed, evidence suggests that B-cell—T-cell crosstalk is interrupted by rituximab and thus it can increase the risk of viral and fungal infections.
Literature is limited in this regard. The FDA issued a warning in that patients receiving treatment with rituximab have an increased risk of hepatitis B virus HBV reactivation [ 36 ].
They recommended that all patients should be screened for HBV prior to commencing treatment with rituximab [ 36 ]. The American Gastroenterological Association subsequently published a review of HBV reactivation with immunosuppressive therapy in [ 37 ]. They concluded that rituximab poses a high risk for HBV reactivation compared with other immunosuppressive agents [ 37 ]. However, this opinion was based primarily on reports of HBV reactivation in patients with haematological malignancies who received rituximab-based treatment regimens [ 37 ].
The risk of reactivation of HBV has been reported to be lower for patients receiving rituximab treatment for autoimmune conditions than those receiving rituximab for haematological conditions [ 38 ]. This may be a result of the differing adjunctive agents used in the management of these diseases. In a large group of SLE patients, rituximab use was associated with a significantly increased incidence of herpes virus infection compared with placebo [ 41 ].
The addition of rituximab to chemotherapy in lymphoma patients significantly increases the risk of Pneumocystis jiroveci pneumonia PJP infections [ 43 ]. In the RAVE trial, opportunistic infections were not reported in the rituximab arm but three fatal cases were seen in the cyclophosphamide arm [ 4 ]. We do not see this effect in the RA population, highlighting that patient and disease factors are important in determining the risk of infection with rituximab treatment.
Nonetheless, even in lymphoma patients, PJP prophylaxis is highly effective in preventing infection [ 43 ]. As the literature regarding the infection risk of individual rheumatic and renal conditions treated with rituximab is limited, one can postulate that the infection risk for AAV patients is intermediate between that of RA and lymphoma. Although reactivation of tuberculosis TB is common with tumour necrosis factor blockade, it is atypical mycobacterial infections that are reported with rituximab [ 45 , 46 ].
In fact, rituximab has been successfully administered to RA patients with latent TB [ 45 ]. Other opportunistic infections such as cryptococcal meningitis are limited to individual case reports [ 47 ]. The overall risk of opportunistic infections with rituximab appears to be as low as 0. Progressive multifocal leucoencephalopathy PML is a rare demyelinating disease of the human brain that results from lytic infection of oligodendrocytes caused by the reactivation of JC polyomavirus.
It presents as progressive motor symptoms, cortical blindness, quadriparesis, coma and death. Although the majority of these cases were seen in haematological malignancies with confounding effects of other immunosuppressive drugs, there were six cases of RA [ 48 ]. As these numbers were more frequent than expected, risk mitigation strategies have been proposed.
The majority of patients had lymphoproliferative disorders. The other conditions included SLE, RA, idiopathic autoimmune pancytopenia and immune thrombocytopenia. They concluded that rituximab administration may increase the risk of developing PML but absolute risks are probably low. Certainly patients need to be warned about this very rare but fatal complication. More information about adverse events is evolving. While it is certain that the use of rituximab will continue to increase, attention must be paid to reduce the risk of complications.
We have a better understanding of the use of rituximab and the accompanying infectious risks for malignancies than we do for autoimmune disorders. However, rituximab appears to be much safer than other biologics used in rheumatic disease [ 51 ].
It is undeniable that the risk of infections cannot be entirely attributed to rituximab, and disease and patient factors are crucial as can be seen in the RA and lymphoma populations. National registries need to be created to collect information on the infectious complications associated with the use of rituximab in rare conditions. Until this information is available, a pragmatic approach should be taken to minimize the infection risk. Ideally, patients should also have completed a course of HBV vaccination prior to receiving rituximab, though in practice this can be challenging given the time period required for HBV vaccination.
Although response to vaccination can be blunted after rituximab treatment, vaccination still offers partial protection [ 18 ]. Generally speaking, live vaccines such as the shingles vaccine are contraindicated in immunosuppressed patients; accidental administration has been described without adverse effects but cannot be recommended.
Panhypogammaglobulinaemia is a well-recognized effect of rituximab treatment, although the reduction in pathological autoantibodies seems to be far more marked than the decrease in overall antibody levels [ 52 ]. If possible, other treatment strategies should be adopted in patients with hypogammaglobulinaemia. Currently there is no evidence that panhypogammaglobulinaemia is related to cumulative rituximab dose or that it is sustained.
Prior exposure to cyclophosphamide may increase the risk of panhypogammaglobulinaemia. PJP prophylaxis has clearly been shown to be effective in the lymphoma population and is recommended [ 54 ]. Patients considered high risk for reactivation of TB can be considered for chemoprophylaxis. Patients should also be screened for HBV [ 37 ]. Prophylaxis with lamivudine or entacavir is effective in preventing reactivation [ 37 ].
Algorithm for minimizing the risk of hepatitis B virus reactivation in patients receiving ritumaxib. PCR, polymerase chain reaction.
Nephrotisches Syndrom beginnend im Kindesalter: Rituximab ist eine wirksame und sichere Option
In the past 10 years, many reports have suggested that rituximab, a chimeric with complicated, frequently relapsing or steroid-dependent nephrotic syndrome . At least 20 % of children with this syndrome show frequent relapses and/or steroid dependence during or after immunosuppressive therapies, a condition. 4. März Das steroidabhängige nephrotische Syndrom birgt ein hohes Risiko für die " Rituximab in Children with Steroid-Dependent Nephrotic.