Severe Severe Systemic Lupus Erythematosus Research Articles

Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease

ObjectiveTo evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE).MethodsA phase 1b double-blind, placebo-controlled, multicentre study...

Pharmacists' role in multidisciplinary diagnosis and treatment in adverse reactions: A case report of interferon alfa-2b induced severe lupus.

Various side effects of interferon alfa-2b (IFN-α2b) have been reported. However, no relevant research has been conducted on the identification and treatment scheme selection for IFN-α2b induced severe systemic lupus erythematosus (SLE). A 41-years-old man with a long history of hepatitis B who developed severe active SLE after IFN-α2b therapy for 24 months, with complete and persistent remission of clinical and laboratory abnormalities after IFN-α2b withdrawal, was not observed. The patient was diagnosed with interferon-associated lupus by a multidisciplinary team involving pharmacists, and lupus nephritis by renal biopsy. Methylprednisolone (40 mg/day) with intravenous cyclophosphamide (600 mg/body weight) was initiated and the symptoms were partially relieved. Cyclophosphamide was increased from 600 mg to 850 mg at the pharmacist's recommendation. The patient showed a favorable response to these therapies. Clinical pharmacists collaborated with other members of the health care team to diagnose and treat adverse reactions, resulting in improved patient management.

Anifrolumab in systemic lupus erythematosus: a profile of its use

Anifrolumab (Saphnelo™), an intravenously administered immunoglobulin G1 kappa monoclonal antibody targeting the type 1 interferon alpha receptor, is effective and generally well tolerated as an add-on to standard therapy in adults with moderate to severe systemic lupus erythematosus (SLE). Anifrolumab reduces overall disease activity in patients with moderate to severe SLE despite receiving stable standard-of-care treatment, based on the totality of evidence from randomized, double-blind, placebo-controlled, phase 2b and 3 clinical trials. Anifrolumab also has corticosteroid-sparing effects and reduces skin disease severity. Therapeutic benefits of anifrolumab appear to be sustained over longer-term treatment. With respect to tolerability, anifrolumab recipients are at increased risk of infections (including herpes zoster). Additional long-term data are being collected in an ongoing extension of the phase 3 trials.

MO257BELIMUMAB ADD-ON THERAPY MOBILIZES MEMORY B CELLS INTO CIRCULATION OF SLE PATIENTS

Abstract Background and Aims Belimumab (BLM), a recombinant human IgG-1λ monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients with active severe systemic lupus erythematosus (SLE) and lupus nephritis (LN). There is clinical evidence that combining belimumab with B cell depleting therapy can ameliorate disease activity in severe, refractory SLE patients. Although BLM is a B cell directed therapy and has been shown to significantly decrease total B cells, flow cytometry observations suggest a rapid increase of circulating memory B cells. The present study investigated the dynamics of B cell subsets in patients treated with or without BLM, with a special focus on the memory compartment in order to assess the characteristics of these memory B cells. Method We first performed extensive B cell subset phenotyping by high sensitivity flowcytometry according to the Euroflow protocol on whole blood from active lupus nephritis or SLE patients with other major organ involvement treated with standard of care (SOC) consisting of high dose steroids and mycophenolate mofetil combined with or without the addition of BLM. Next we characterized memory B cell gene expression profiles with single-cell RNA and V(D)J sequencing (ScRNA-SEQ). Results By employing high sensitivity flowcytometry, we established that the absolute increase in circulating memory B cells in SLE and LN patients was significant for patients who initiated BLM but not for patients treated with standard of care (Figure 1). The increase was observed in a broad range of memory B cell subsets (Unswitched, IgG1+, IgG2+, IgA1+, IgA2+) at 2 and 4 weeks following initiation of BLM treatment. This rise in memory B cells could hypothetically be attributed to either proliferation or homeostatic modulation of tissue-resident memory B cells causing a release into the circulation. ScRNA-SEQ cell cycle gene-expression was performed and established in both groups a non-proliferating phenotype [in approximately ∼94%] of memory B cells post-treatment, including absence of MKI67 as active proliferation marker. Additionally, BLM treatment did not result in an increased, and even in a severe reduction of the largest memory B cells clones after two weeks. In contrast, no change in clonality was seen after treatment with SOC. Together these data indicate that proliferation is not likely to be responsible for the observed increase in memory B cells by BLM. Furthermore, a clear difference was found in gene-expression levels between both treatment groups: BLM was responsible for the upregulation of 72 vs 10 genes in SOC, likewise 162 vs 32 genes were downregulated. Most importantly, a significant downregulation of the migration genes SELL (CD62L), CCR7, ITGB1, RAC2 and ICAM2, were specifically seen in BLM treated patients, possibly reflecting disrupted lymphocyte trafficking preventing memory B cells to either transmigrate into tissue or be retained at the tissue level. Conclusion The addition of BLM compared to standard of care in SLE patients leads to an increase of memory B cells in the circulation which appeared independent of proliferation. The process was accompanied with a strong modulation of gene-expression levels including a reduced expression of migration markers pointing towards disrupted lymphocyte trafficking. Altogether, these data could have important implications to further improve treatment strategies in severe SLE or lupus nephritis patients, for instance by establishing a deeper depletion of (autoreactive) memory B cells by the addition of rituximab after the initiation of belimumab.

POS0680 BELIMUMAB ADD-ON THERAPY MOBILISES MEMORY B CELLS INTO THE CIRCULATION OF PATIENTS WITH SLE

Background:Belimumab (BLM), a recombinant human monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients with active severe systemic lupus erythematosus (SLE) and lupus nephritis (LN). There is clinical evidence that combining BLM with B cell depleting therapy can ameliorate disease activity in severe, refractory SLE patients1. Although BLM is a B cell directed therapy and has been shown to significantly decrease total B cells, flow cytometry observations suggest a rapid increase of circulating memory B cells (MBC)2.Objectives:To investigate dynamics of B-cell subsets in SLE patients treated with or without BLM, with a focus on assessing MBC characteristics.Methods:Extensive B cell subset phenotyping was performed by high-sensitivity (HS) flow cytometry (acquisition of 107 leukocytes; per EuroFlow protocols3) on samples from active LN or SLE patients with major organ involvement treated with standard of care (SOC) consisting of high dose steroids and mycophenolate mofetil combined with or without the addition of BLM. MBC gene expression profiles were characterized with single-cell RNA and V(D)J sequencing (ScRNA-SEQ).Results:By employing HS flowcytometry, we established that the absolute increase in circulating MBC in SLE and LN patients was significant for patients who initiated BLM (Figure 1). The increase was observed in a broad range of MBC subsets (Unswitched, IgG1+, IgG2+, IgA1+, IgA2+) at 2 and 4 weeks following initiation of BLM treatment. This rise in MBC could hypothetically be attributed to either proliferation of blood MBC, BLM induced migration of tissue-resident MBCs or BLM related retention of tissue-destined MBC in the blood. ScRNA-SEQ analysis of cell cycle gene-expression was performed and established in both groups a non-proliferating phenotype [in approximately ~94%] of MBC post-treatment, including absence of MKI67 as active proliferation marker. Clonal diversity analysis comparing week 2 with baseline revealed an unexpected decrease of the largest MBC clones in BLM, whereas no change in clonality was observed with SOC alone. Together these data indicate that proliferation is unlikely to be responsible for the observed increase in MBC by BLM. Furthermore, a clear difference was found in gene-expression levels between both treatment groups: BLM was responsible for the upregulation of 72 vs 10 genes in SOC, likewise 162 vs 32 genes were downregulated. Most importantly, a significant downregulation of the migration genes SELL (CD62L), CCR7, ITGB1, RAC2 and ICAM2, were specifically seen in BLM treated patients. This may reflect disrupted lymphocyte trafficking, preventing MBCs from transmigrating from the blood into tissue owing to reduced migration molecules, or preventing MBCs from being retained at the tissue level owing to reduction in tissue adhesion proteins.Conclusion:The addition of BLM to SOC significantly increases MBCs in patients with SLE independently of proliferation, accompanied by a strong modulation of gene expression, including reduced expression of migration markers pointing towards disrupted lymphocyte trafficking. These data may have important implications for improving treatment strategies in patients with LN or severe SLE, as a deeper depletion of autoreactive MBCs could be established by adding B-cell-depleting therapy after the initiation of BLM.Figure 1.Change in pre-germinal center and memory B cell counts from baseline to week 4 of patients with SLE or LN treated with SOC (n=8) or SOC+BLM (n=11).

Treatment with intravenous immunoglobulins in systemic lupus erythematosus: a single-center experience with 63 patients.

Intravenous immunoglobulin (IVIG) is prepared using purified human plasma. IVIG therapy has immunomodulatory effects on autoimmune diseases, including severe systemic lupus erythematosus (SLE). However, reports of its effects on large cohorts are scarce. This single-center retrospective study included SLE patients treated with at least one IVIG cycle for SLE complications. Demographic data, indications, cycle numbers, and clinical improvement with IVIG were evaluated. SLE Disease Activity Index 2000 (SLEDAI-2K) scores were calculated at admission and after IVIG treatment in order to measure clinical improvement. Sixty-three SLE patients treated with IVIG (median age: 29 years; interquartile range 21-36 years; 84.13% female) were included, who received 2 g/kg IVIG for two to five days. Main indications were immune thrombocytopenia, hypogammaglobulinemia, infection during a SLE flare, bicytopenia, and immune hemolytic anemia. Seven patients received more than one IVIG cycle without severe adverse effects. Significant differences were found in SLEDAI-2K scores when the indications were immune thrombocytopenia and hypogammaglobulinemia, with a trend for hemolytic anemia. Patients with concomitant infection, myopathy, and gastrointestinal involvement showed a considerable reduction in their last SLEDAI-2K scores. Fourteen patients died during hospitalization, mainly due to septic shock and active SLE. IVIG showed adequate tolerance and effectiveness in selected severe SLE manifestations, mainly hematological involvement. It was useful for concomitant infection.

Rapid reduction of antibodies and improvement of disease activity by immunoadsorption in Chinese patients with severe systemic lupus erythematosus.

This was an exploratory analysis comparing the safety and efficacy of immunoadsorption (IAS) combination therapy in severe systemic lupus erythematosus (SLE) receiving corticosteroid pulse and immunosuppressant treatment. Patients enrolled all had predominant organ involvement including proteinuria, thrombocytopenia, pericardial effusion, and cerebral involvement requiring corticosteroid pulse treatment. Fifty-two patients in study group received IAS plus corticosteroid and cyclophosphamide treatment. Fifty-two patients in non-IAS group received corticosteroid and cyclophosphamide treatment. Outcome measurement included C3, dsDNA, AnuA, and SLE disease activity index (SLEDAI) 2k score and in particular cases, proteinuria quantification and platelet count. Disease activity dropped significantly in both groups. Improvement of disease activity markers was more significant in study group than that in non-IAS group. The lower dosage of steroid in study group suggested the steroid-sparing effect of IAS. No severe adverse effect occurred during IAS. Our study suggested IAS as an additional therapy to steroid pulse and immunosuppressant in treating severe SLE.

Comparison of the effects of virus inactivation of plasma and albumin in plasma exchange liquid gallinger therapy on the treatment of severe systemic lupus erythematosus

Objective To compare the clinical curative effect of virus inactivating activity of plasma and albumin compound sodium chloride injection in liquid plasma exchange(PE)for treatment of severe systemic lupus erythematosus(SLE). Methods A total of 75 cases of severe SLE patients were randomized according to the number table method patients for virus inactivation of plasma group A(37 cases)and liquid albumin plasma group B(38 cases). The changes of immunoglobulin protein(IgG,IgA,IgM),ESR, complement C3,C-reactive protein(CRP), blood urea nitrogen(BUN)and serum creatinine(CR)index in the two groups were observed before and after PE. Clinical SLE-DAI(systemic lupus erythematosus disease activity index)score changes, adverse reactions occurred rate and clinical efficacy of two groups were compared. Results After treatment of group A was treated with PE,laboratory indicators except IgM(t＝0.509,P＝0.612), other indexes were significantly decreased, differences were statistically significant (t＝29.447,186,56.447,41.867,12.841,92.675,92.980,all P＜0.01). In group B,the IgM,IgA,CRP,C3 and preoperative showed no statistical significance(t＝0.565,1.165,0.902,all P＞0.05), while IgG and ESR, bun, crea and replacement of the differences have statistical significance(t value were 28.999,194.9,40.634,40.634104.918,P value＜0.01). Ttotal efficiency of group A was 91.9%, the average clinical SLEDAI score was(9.4± 1.2)points, total efficiency of group B was 77.3%, clinical SLEDAI score was(13.8±1.1)points and the difference between the two groups were statistically significant(χ2＝8.831,t＝15.560,P＜0.01). In group A, the adverse reaction rate was 15.3%,that of group B was 16.2%, there was no significant difference between the two groups(χ2＝0.509,P＞0.05). Conclusion The clinical curative effect of virus inactivation of plasma replacement solution in treatment of severe SLE is better than that of albumin by Ringer's solution. Key words: Replacement fluid; Plasma exchange; Systemic, lupus erythematosus

Effect of the plasma exchange and immunoadsorption in children with severe systemic lupus erythematosus: a comparative study

Objective To compare the treatment response of plasma exchange and immunoadsorption for children suffering from severe systemic lupus erythematosus (SLE), and then find the more advan-tageous treatment method. Methods Between March 2007 and March 2013, 27 children with severe SLE were collected from the Department of Pediatric Nephrology and Rheumatology of Shengjing Hospital of China Medical University. Part of them about 11 children accepted plasma exchange treatment (plasma exchang group) and the others accepted immunoadsorption (immunoadsorption group). The clinical features, ANA, IgG, serum ions, the cost of treatment and the hospitalization time were reviewed, and the comparative analysis were performed in two groups. Results There were comparabilities between plasma exchange group and immunoadsorption group in age, gender, couse of disease and systemic lupus erythematosus disease activity index (SLEDAI) score before treatment. (1) In plasma exchang group, 11 children were conducted 26 times treatment. The SLEDAI score significantly decreased after plasma exchange (19.00±3.77 vs 5.34±4.35, P 0.05]. Conclusion The treatment both plasma exchange and immunoadsorption were effective methods for the children with severe SLE. However, the cost of plasma exchange was much higher and had a great influence on the concentration of antihypertensive drugs. Key words: Systemic lupus erythematosus; Plasma exchange; Immunoadsorption

Severe systemic lupus erythematosus in emergency department: a retrospective single-center study from China

This study describes the characteristics of severe systemic lupus erythematosus (SLE) patients who visited the emergency department of the Shanghai Renji Hospital, and the aim is to identify the causes, the outcome, and the prognostic factors. SLE patients who visited the emergency department between January 2007 and August 2010, and who were subsequently hospitalized or who died in emergency department, were included in this retrospective study. Of the total 131 SLE emergency events, overall mortality was 16.8%. Older age (≥45years), longer duration of disease, presence of pulmonary hypertension, renal insufficiency, and invasive infections are risk factors. Higher organ damage index (SLICC, 3.86 ± 2.14 vs. 0.93 ± 1.14, p < 0.001) but relatively lower disease activity (SLEDAI, 11.5 ± 7.7 vs. 16.5 ± 9.0, p = 0.015) were the characteristics of the deceased when compared with the survivors. Recent-onset (duration of disease ≤3months) SLE accounts for 32.1% of the patients in emergency, and this group showed a distinctive pattern of younger age with higher frequencies of neuropsychiatric and hematologic manifestations. A good short-term outcome with a 95.2% survival rate can be observed in such patients. Older age, longer disease duration and cumulative damage of vital organs determine the short-term outcome of severe SLE in the emergency department. Recognizing disease patterns and objective prognostic parameters may help physicians to provide better care, based on a risk-fitted approach, for the SLE patients in emergencies.

IL-21 Receptor signaling by B-cells is essential for BXSB-Yaa pathogenesis (99.39)

Abstract IL-21 is a member of the IL-2 cytokine family that exerts potent biological effects on multiple hemopoietic cell types. It is produced by activated CD4 T cells, while its receptor, IL-21R, is found on cells including NK cells, dendritic, T cells and B cells. To investigate the role of IL-21 signaling in autoimmune disease, we addressed whether this cytokine contributes to the severe systemic lupus erythematosus (SLE)-like syndrome developed by BXSB-Yaa mice. We show that BXSB-Yaa CD4 T cells produce IL-21 but lack discriminative T follicular helper cell markers. We also show that BXSB-Yaa mice completely lacking the IL-21R or Igh6 are remarkably resistant to multiple aspects of the prototypic BXSB-Yaa autoimmune disease. Finally, we show that mixed bone marrow chimeric BXSB-Yaa mice lacking IL-21R specifically in the B-cell compartment are similarly resistant. These results suggest that IL-21 produced by a novel population of BXSB-Yaa CD4 T-cells acts through B-cells to evoke multiple features characteristic of severe SLE. The results indicate that IL-21 signaling through B-cells is an essential step in the pathogenesis of this SLE-like autoimmune disease and potentially others. Funded by an Arthritis Foundation grant to JB.

Hematopoietic stem cell transplantation for severe and refractory lupus. Analysis after five years and fifteen patients.

To determine the safety and long-term efficacy of immune ablation and autologous hematopoietic stem cell transplantation (HSCT) in severe systemic lupus erythematosus (SLE). Fifteen patients with persistently active SLE after intravenous (IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells were mobilized with CYC (2.0 gm/m(2)) and granulocyte colony-stimulating factor (5 microg/kg/day). Lymphocytes were depleted from the graft by selection of CD34-positive cells. The conditioning regimen used was CYC (200 mg/kg), antithymocyte globulin (90 mg/kg), and methylprednisolone (3 mg/kg). Outcome was evaluated by the SLE Disease Activity Index (SLEDAI), serum complement levels, serologic features, function of diseased organs, and immunosuppressive medication requirements. Fifteen patients with persistent, severe SLE, 7 of whom were critically ill, were treated. No deaths occurred following treatment. The median followup after HSCT has been 36 months (range 12-66 months). All patients demonstrated a gradual, but marked, improvement. The SLEDAI score has declined to <or=5 in 12 patients. Complement and anti-double-stranded DNA levels have normalized and marked improvements in end organ function have occurred in all subjects. Of the 12 patients followed up for >1 year after HSCT, 10 have discontinued immunosuppressive medications, and the prednisone dosage has been tapered to 15 mg/day in 1. Only 2 patients have demonstrated clinical evidence of recurrence of active lupus. One of these patients currently requires no immunosuppressive medication and has a normal performance status. The other patient is currently receiving IV CYC. In patients experiencing the persistence of organ-threatening lupus following standard, aggressive therapy, HSCT may be performed safely, with marked improvement and sustained withdrawal of all immunosuppressive medication for most patients. A phase III randomized trial is warranted to determine the relative efficacy and durability of remission of HSCT compared with standard therapies.

Plasma exchange in systemic lupus erythematosus

Standard treatment for severe systemic lupus erythematosus (SLE) consists of corticosteroids and immunosuppressive drugs. A number of controlled studies purport to show that parallel application of plasmapheresis is no longer tenable since it imparts no additional benefit. Three indications for plasmapheresis in SLE appear to remain: (1) emergency intervention; (2) contraindication of cytotoxic drugs in severe SLE; and (3) so-called “synchronization”, which combines plasmapheresis with subsequent high-dose pulse cyclophosphamide and has achieved repeatedly long-term, treatment-free remission in severe SLE. Immunoadsorption, especially employing an anti-immunoglobulin adsorber, appears to represent a further useful technological advance. It is questionable whether photopheresis, lymphapheresis, and cascade filtration will have a role to play in the treatment of SLE. An additional indication for apheresis may be the new procedure of autologous transplantation of purged stem cells.

Treatment‐free remission in severe systemic lupus erythematosus following synchronization of plasmapheresis with subsequent pulse cyclophosphamide

To investigate the effect of an intensified treatment protocol synchronizing plasmapheresis with subsequent pulse cyclophosphamide for severe systemic lupus erythematosus (SLE). A protocol of plasmapheresis (3 x 60 ml/kg) and subsequent high-dose pulse cyclophosphamide (36 mg/kg) followed by 6 months of peroral immunosuppression was used to treat 14 patients with severe SLE. Rapid improvement was achieved in all patients. Immunosuppressants, including corticosteroids, were withdrawn at month 6 in 12 patients. Eight patients continued without treatment for a mean observation period of 5.6 years (46-91 months). The results demonstrate that treatment-free clinical remission can be achieved in some patients with severe SLE.

Antibody depletion and cytotoxic drug therapy in severe systemic lupus erythematosus

The established treatment of severe systemic lupus erythematosus (SLE) includes corticosteroids and cytotoxic drugs. Therapeutic plasmapheresis may provide additional rapid relief, but this is only temporary. Controlled trials have repeatedly demonstrated that long-term improvement cannot be achieved if plasmaphereses are performed in addition to long-term oral immunosuppression, as is the usual procedure. This might be an indication that the organism has a considerable ability to re-establish the status quo ante. By contrast, uncontrolled case reports indicate that both rapid and longterm benefits may be achieved by combining plasmapheresis with subsequent pulses of an alkylating agent. The approach used in these studies theorizes that antibody depletion induces increased proliferation of pathogenic clones and that it should be possible to exploit this increased proliferation for the enhanced deletion of pathogenic clones by the subsequent application of pulse cyclophosphamide. The present paper reviews the literature and summarizes the results achieved with the treatment of severe SLE using cytotoxic agents and antibody elimination. Additionally, the authors discuss how the organism's ability to achieve rapid counterregulation might be utilized to improve the therapeutic results, and they attempt to develop perspectives for the future.

Plasmapheresis and subsequent pulse cyclophosphamide versus pulse cyclophosphamide alone in severe lupus: Design of the LPSG trial

A group of clinics are collaborating in the Lupus Plasmapheresis Study Group (LPSG) to investigate whether repeated plasmapheresis prior to pulse cyclophosphamide improves the therapeutical results in severe systemic lupus erythematosus (SLE). The underlying rationale is the hypothesis that plasmapheresis 1) eliminates pathogenic autoantibodies and immune complexes and 2) induces compensatory lymphocyte activation via feedback mechanisms between circulating antibodies and their respective clones ("antibody rebound"). It should be possible to utilize this enhanced activity for increased clonal deletion if pulse cyclophosphamide is applied shortly after plasmapheresis. Accordingly, in a randomized study, the LPSG will be comparing the repeated application of pulse cyclophosphamide alone with a treatment involving repeated plasmapheresis prior to the cyclophosphamide pulses in severe SLE. A third arm of the study will be gathering experience with a more intensified procedure. This overview summarizes the most important details of the planned study.

Influence of thymic genotype on the systemic lupus erythematosus-like disease and T cell proliferation of MRL/Mp-lpr/lpr mice.

In young adulthood, MRL/Mp-lpr/lpr mice develop severe systemic lupus erythematosus (SLE)-like syndrome associated with massive T cell proliferation. The congenic MRL/Mp- mice lack the lpr gene and develop chronic SLE late in life. We have exchanged thymic transplants between these substrains so as to determine the role of the thymus in the development of early, severe SLE and of lymphoproliferation. The median survival times of unmanipulated lpr/lpr and mice were 160 and 510 d, respectively. The lpr/lpr and mice thymectomized when newborn and transplanted at 1 mo with the opposite type of thymus retained the diseases phenotype of their unmanipulated counterparts with 50% mortality at 186 and 498 d, respectively. In contrast, lpr/lpr mice thymectomized when newborn but not transplanted with thymus did not develop lymphoid hyperplasia and glomerulonephritis, and 100% of them were alive at 390 d. Serologically, the thymectomized but untransplanted lpr/lpr mice had significantly reduced levels of autoantibodies, whereas thymectomized and transplanted mice of either substrain were similar to unmanipulated controls. The results indicate that: (a) a thymus is essential for expression of lymphoproliferation and early SLE-like disease in the lpr/lpr phenotype; (b) the lpr/lpr disease is not a result of a unique hormonal or microenvironmental defect(s) of the thymus of this substrain because the genotype of the thymus is irrelevant for the development of T cell proliferation and early SLE; (c) differentiation of stem cells under the hormonal or microenvironmental influences of a thymus that possesses the lpr genotype does not lead to abnormal T cell differentiation or early autoimmunity; and (d) the lpr/lpr disease cannot be caused exclusively by an intrinsic B cell defect or environmental stimuli that cause B cell polyclonal activation.