Lupus Nephritis: Immunoadsorption (IAS) and Proteinuria
Lupus Nephritis: Immunoadsorption (IAS) and Proteinuria
Background. Systemic lupus erythematosus (SLE) is characterized by pathogenic autoantibodies, which can be removed by extracorporeal procedures. While previous studies have shown short-term efficacy of immunoadsorption (IAS) in SLE, no information on long-term benefit and safety is available.
Methods. IAS was offered to patients with highly active renal disease when conventional therapy had failed. Eleven patients entered the prolonged IAS programme and were followed for up to 10 years (mean 6.4 ± 3.5). Efficacy of IAS was determined by reduction in proteinuria (primary outcome), global disease activity [SLE Disease Activity Index (SLEDAI)] and anti-double-stranded DNA (anti-dsDNA) levels (secondary outcomes). Full/partial remission was defined as ≤0.5/≤1.0 g/day for proteinuria, ≤5/≤8 for SLEDAI and ≤25/≤50 IU/mL for anti-dsDNA levels. We further assessed flares, infections, malignancies and procedure-related adverse events.
Results. Short-term IAS (≤1 year) resulted in a significant reduction of proteinuria (9.2 ± 3.7 to 2.3 ± 2.4, P = 0.0001), disease activity (SLEDAI 19 ± 8 to 4 ± 2, P = 0.0004) and dsDNA levels (168 ± 205 to 45 ± 34, P = 0.001). In patients without remission after 1 year (n = 5), prolonged IAS decreased proteinuria from 4.3 ± 2.4 to 0.5 ± 0.4 g/day, P = 0.02. At the end of observation, complete remission in proteinuria was achieved in seven patients (64%) and partial remission in two (18%) additional patients. One patient flared and was discontinued; in all other patients, disease activity and anti-dsDNA stabilized at remission levels. Flares (0.28 ± 0.30) and infections (0.66 ± 0.70 per patient/year) were relatively uncommon; no malignancies, anaphylactic or orthostatic adverse events were observed.
Conclusion. IAS is effective in short-term use but prolonged IAS can provide additional therapeutic benefit while showing an acceptable safety profile. The vast majority of initially therapy-refractory patients met the remission criteria at the end of observation.
Pathogenic autoantibodies are a hallmark of Systemic lupus erythematosus (SLE). They bind directly or via formation of immune complexes (IC) to cells and tissues, inducing complement activation and severe inflammation in the affected organ, such as the kidneys. Among these IC-forming antibodies are anti-double-stranded DNA antibodies (anti-dsDNA), which are associated with lupus nephritis. Inhibiting the production of, or directly removing, such pathogenic autoantibodies should prevent their pathogenetic consequences. In fact, SLE therapy in general, and immunosuppression in particular, aims at interfering with autoantibody and IC formation.
In severe SLE with major organ involvement, therapy initially aims at halting disease progression and reducing disease activity (induction phase); ultimately, the goal is to stabilize disease activity at low levels (maintenance phase). Intravenous pulse cyclophosphamide (IVCP) therapy continues to be the standard treatment for induction therapy in severe SLE with major organ involvement according to the EULAR (European League Against Rheumatism) recommendations. It is effective in many, but not all, patients, encompasses a wide array of adverse events and is contraindicated in some situations, such as acute infection. Therefore, alternative approaches have been sought. Mycophenolate mofetil (MMF) is established as a maintenance therapy of lupus nephritis and increasing evidence suggests its efficacy also in the induction phase, but a prospective head-to-head trial could not demonstrate superiority over IVCP. Given the pathogenetic effects of auto-antibodies, B-cell depletion by monoclonal antibodies like rituximab came into the focus of interest. Meanwhile, a large body of evidence showed benefit, but, nevertheless, two controlled clinical trials could not reach their primary goals.
Extracorporeal treatment options like immunoadsorption (IAS) do not directly aim at B cells, but on their products: they remove (auto-) antibodies and IC and have been successfully applied in acute life-threatening situations of SLE. Their benefit lies in the fast mode of action, the flexibility to adjust the frequency of therapeutic sessions (and the processed plasma volume) and the option to suspend them for a time when optimal B-cell function is needed. IAS allows for the specific clearance of immunoglobulins (Ig) and IC while neither removing other plasma proteins nor necessitating substitution with blood products.
Previous reports have shown short-term efficacy and biocompatibility of IAS in SLE, but no information on long-term outcome beyond the first year of treatment is available. In addition, the issue of infections and malignancies has not been analysed under prolonged treatment: since immune system function is altered by removal of Ig under IAS, the defense against infections and malignancies of any kind might be impaired.
Prospective randomized controlled trials (RCT) on IAS in SLE are lacking and would be preferable. But given that most patients entering this procedure have failed multiple therapies including cyclophosphamide, have contraindications to certain treatment modalities or have no alternative in the light of negative clinical trials on such alternatives, it is difficult to study severe SLE in RCTs because of the unavailability of alternative therapies in the comparator arm and because of the heterogeneity of the disease. Therefore, observational studies involving patients with nephritis have often been a prelude to RCTs.
In the present study, we identified patients with lupus nephritis, who were treated with IAS at our centre and followed them for up to 10 years. Prolonged IAS (>1 year) added therapeutic benefit and led to sustained remission in a considerable percentage of formerly highly active refractory patients. In addition, IAS was safe with respect to infections, malignancies and adverse events.
Abstract and Introduction
Abstract
Background. Systemic lupus erythematosus (SLE) is characterized by pathogenic autoantibodies, which can be removed by extracorporeal procedures. While previous studies have shown short-term efficacy of immunoadsorption (IAS) in SLE, no information on long-term benefit and safety is available.
Methods. IAS was offered to patients with highly active renal disease when conventional therapy had failed. Eleven patients entered the prolonged IAS programme and were followed for up to 10 years (mean 6.4 ± 3.5). Efficacy of IAS was determined by reduction in proteinuria (primary outcome), global disease activity [SLE Disease Activity Index (SLEDAI)] and anti-double-stranded DNA (anti-dsDNA) levels (secondary outcomes). Full/partial remission was defined as ≤0.5/≤1.0 g/day for proteinuria, ≤5/≤8 for SLEDAI and ≤25/≤50 IU/mL for anti-dsDNA levels. We further assessed flares, infections, malignancies and procedure-related adverse events.
Results. Short-term IAS (≤1 year) resulted in a significant reduction of proteinuria (9.2 ± 3.7 to 2.3 ± 2.4, P = 0.0001), disease activity (SLEDAI 19 ± 8 to 4 ± 2, P = 0.0004) and dsDNA levels (168 ± 205 to 45 ± 34, P = 0.001). In patients without remission after 1 year (n = 5), prolonged IAS decreased proteinuria from 4.3 ± 2.4 to 0.5 ± 0.4 g/day, P = 0.02. At the end of observation, complete remission in proteinuria was achieved in seven patients (64%) and partial remission in two (18%) additional patients. One patient flared and was discontinued; in all other patients, disease activity and anti-dsDNA stabilized at remission levels. Flares (0.28 ± 0.30) and infections (0.66 ± 0.70 per patient/year) were relatively uncommon; no malignancies, anaphylactic or orthostatic adverse events were observed.
Conclusion. IAS is effective in short-term use but prolonged IAS can provide additional therapeutic benefit while showing an acceptable safety profile. The vast majority of initially therapy-refractory patients met the remission criteria at the end of observation.
Introduction
Pathogenic autoantibodies are a hallmark of Systemic lupus erythematosus (SLE). They bind directly or via formation of immune complexes (IC) to cells and tissues, inducing complement activation and severe inflammation in the affected organ, such as the kidneys. Among these IC-forming antibodies are anti-double-stranded DNA antibodies (anti-dsDNA), which are associated with lupus nephritis. Inhibiting the production of, or directly removing, such pathogenic autoantibodies should prevent their pathogenetic consequences. In fact, SLE therapy in general, and immunosuppression in particular, aims at interfering with autoantibody and IC formation.
In severe SLE with major organ involvement, therapy initially aims at halting disease progression and reducing disease activity (induction phase); ultimately, the goal is to stabilize disease activity at low levels (maintenance phase). Intravenous pulse cyclophosphamide (IVCP) therapy continues to be the standard treatment for induction therapy in severe SLE with major organ involvement according to the EULAR (European League Against Rheumatism) recommendations. It is effective in many, but not all, patients, encompasses a wide array of adverse events and is contraindicated in some situations, such as acute infection. Therefore, alternative approaches have been sought. Mycophenolate mofetil (MMF) is established as a maintenance therapy of lupus nephritis and increasing evidence suggests its efficacy also in the induction phase, but a prospective head-to-head trial could not demonstrate superiority over IVCP. Given the pathogenetic effects of auto-antibodies, B-cell depletion by monoclonal antibodies like rituximab came into the focus of interest. Meanwhile, a large body of evidence showed benefit, but, nevertheless, two controlled clinical trials could not reach their primary goals.
Extracorporeal treatment options like immunoadsorption (IAS) do not directly aim at B cells, but on their products: they remove (auto-) antibodies and IC and have been successfully applied in acute life-threatening situations of SLE. Their benefit lies in the fast mode of action, the flexibility to adjust the frequency of therapeutic sessions (and the processed plasma volume) and the option to suspend them for a time when optimal B-cell function is needed. IAS allows for the specific clearance of immunoglobulins (Ig) and IC while neither removing other plasma proteins nor necessitating substitution with blood products.
Previous reports have shown short-term efficacy and biocompatibility of IAS in SLE, but no information on long-term outcome beyond the first year of treatment is available. In addition, the issue of infections and malignancies has not been analysed under prolonged treatment: since immune system function is altered by removal of Ig under IAS, the defense against infections and malignancies of any kind might be impaired.
Prospective randomized controlled trials (RCT) on IAS in SLE are lacking and would be preferable. But given that most patients entering this procedure have failed multiple therapies including cyclophosphamide, have contraindications to certain treatment modalities or have no alternative in the light of negative clinical trials on such alternatives, it is difficult to study severe SLE in RCTs because of the unavailability of alternative therapies in the comparator arm and because of the heterogeneity of the disease. Therefore, observational studies involving patients with nephritis have often been a prelude to RCTs.
In the present study, we identified patients with lupus nephritis, who were treated with IAS at our centre and followed them for up to 10 years. Prolonged IAS (>1 year) added therapeutic benefit and led to sustained remission in a considerable percentage of formerly highly active refractory patients. In addition, IAS was safe with respect to infections, malignancies and adverse events.
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