[Show abstract][Hide abstract] ABSTRACT: To assess the perspectives of women with lupus nephritis on barriers to medication decision making.
We used the nominal group technique (NGT), a structured process to elicit ideas from participants, for a formative assessment. Eight NGT meetings were conducted in English and moderated by an expert NGT researcher at 2 medical centers. Participants responded to the question: "What sorts of things make it hard for people to decide to take the medicines that doctors prescribe for treating their lupus kidney disease?" Patients nominated, discussed, and prioritized barriers to decisional processes involving medications for treating lupus nephritis.
Fifty-one women with lupus nephritis with a mean age of 40.6 ± 13.3 years and disease duration of 11.8 ± 8.3 years participated in 8 NGT meetings: 26 African Americans (4 panels), 13 Hispanics (2 panels), and 12 whites (2 panels). Of the participants, 36.5% had obtained at least a college degree and 55.8% needed some help in reading health materials. Of the 248 responses generated (range 19-37 responses/panel), 100 responses (40%) were perceived by patients as having relatively greater importance than other barriers in their own decision-making processes. The most salient perceived barriers, as indicated by percent-weighted votes assigned, were known/anticipated side effects (15.6%), medication expense/ability to afford medications (8.2%), and the fear that the medication could cause other diseases (7.8%).
Women with lupus nephritis identified specific barriers to decisions related to medications. Information relevant to known/anticipated medication side effects and medication cost will form the basis of a patient guide for women with systemic lupus erythematosus, currently under development.
The Journal of Rheumatology 07/2015; 42(9). DOI:10.3899/jrheum.150168 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vasculitis due to infection may occur as a consequence of the inflammation of vessel walls due to direct or contiguous infection, type II or immune complex-mediated reaction, cell-mediated hypersensitivity, or inflammation due to immune dysregulation triggered by bacterial toxin and/or superantigen production. As immunosuppressive therapy administered in the absence of antimicrobial therapy may increase morbidity and fail to effect the resolution of infection-associated vascular inflammation, it is important to consider infectious entities as potential inciting factors in vasculitis syndromes. The causality between infection and vasculitis has been established in hepatitis B-associated polyarteritis nodosa (HBV-PAN) and hepatitis C-associated (cryoglobulinemic) vasculitis (HCV-CV). The review summarizes the recent literature on the pathophysiological mechanisms and the approaches to the management of HBV-PAN and HCV-CV. Roles of other viral and microbial infections, which either manifest as vasculitic syndromes or are implicated in the pathogenesis of primary vasculitides, are also discussed.
Bailliè re s Best Practice and Research in Clinical Rheumatology 06/2015; 29(2). DOI:10.1016/j.berh.2015.05.007 · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective. To assess the efficacy and safety of a 24-week course of abatacept in the treatment of active lupus nephritis and to assess the potential of abatacept to induce "clinical tolerance," defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy. Methods. Patients with active lupus nephritis (n = 134) were enrolled in a randomized, double-blind phase II add-on trial in which they received either abatacept or placebo in conjunction with the Euro-Lupus Nephritis Trial regimen of low-dose cyclophosphamide (CYC) followed by azathioprine (AZA). The primary efficacy outcome was the frequency of complete response at week 24. Thereafter, patients who met either complete or partial response criteria continued blinded treatment through week 52. During this phase of the study, subjects in the abatacept treatment group in whom a complete response was achieved at week 24 discontinued immunosuppressive therapy other than prednisone (10 mg/day). Results. There were no statistically significant differences between groups with respect to the primary outcome or any of the secondary outcomes, including measures of safety. A complete response was achieved in 33% of the subjects in the treatment group and in 31% of the subjects in the control group at week 24. Fifty percent of the subjects in the treatment group who met complete response criteria and therefore discontinued immunosuppressive therapy at week 24 maintained their complete response status through week 52. Conclusion. The addition of abatacept to a regimen of CYC followed by AZA did not improve the outcome of lupus nephritis at either 24 or 52 weeks. No worrisome safety signals were encountered.
[Show abstract][Hide abstract] ABSTRACT: Objective
To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).
The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity.
AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03).
CBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing).
Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study.
Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%-9% during years 2-7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%-60% from baseline over 2-7 years with belimumab. Corticosteroid use decreased over time with ≥ 50-55% reduction in median dose during years 5-7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment.
Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. [ClinicalTrials.gov numbers: NCT00071487 and NCT00583362].
The Journal of Rheumatology 11/2013; 41(2). DOI:10.3899/jrheum.121368 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors. To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysis with Illumina Methylation450 microarrays. We identified 166 CpGs in B-cells, 97 CpGs in monocytes, and 1,033 CpGs in T-cells with highly significant changes in DNA methylation levels (p<1×10(-8)) among SLE patients. Common to all three cell-types were widespread and severe hypomethylation events near genes involved in interferon signaling (type I). These interferon-related changes were apparent in patients collected during active and quiescent stages of the disease, suggesting that epigenetically-mediated hypersensitivity to interferon persists beyond acute stages of the disease and is independent of circulating interferon levels. This interferon hypersensitivity was apparent in memory, naïve and regulatory T-cells, suggesting that this epigenetic state in lupus patients is established in progenitor cell populations. We also identified a widespread, but lower amplitude shift in methylation in CD4+ T-cells (>16,000 CpGs at FDR<1%) near genes involved in cell division and MAPK signaling. These cell type-specific effects are consistent with disease-specific changes in the composition of the CD4+ population and suggest that shifts in the proportion of CD4+ subtypes can be monitored at CpGs with subtype-specific DNA methylation patterns.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To determine the value of cell-bound complement activation products in combination with antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), and anti-mutated citrullinated vimentin antibody (anti-MCV) for the diagnosis of systemic lupus erythematosus (SLE).
This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescence-activated cell sorting. Serologic markers were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity.
Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Levels of EC4d, BC4d, and PC4d were several times higher, and levels of ECR1 lower, in SLE patients compared to patients with other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA-negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (≥20 units), anti-MCV negativity (≤70 units), and elevated levels of both EC4d and BC4d (AUC 0.918, P < 0.001). A positive index score corresponding to the weighted sum of these 4 markers correctly categorized 72% of SLE patients. Specificity in relation to patients with other rheumatic diseases and healthy controls was >90%. The combination of anti-dsDNA and index score positivity yielded 80% sensitivity for SLE and 87% specificity against other rheumatic diseases.
An assay panel combining anti-dsDNA, ANA, anti-MCV, EC4d, and BC4d is sensitive and specific for the diagnosis of SLE.
[Show abstract][Hide abstract] ABSTRACT: To reliably transport blood samples for cryoglobulin analysis, we have created a sample transport device containing a mixture of two waxes that solidifies at 38°C and maintains sample temperature at 38°C. Samples arriving at the laboratory at 37 to 38°C increased to 95% from 34% with the use of the device.
[Show abstract][Hide abstract] ABSTRACT: To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients.
Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels.
Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks.
Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.
[Show abstract][Hide abstract] ABSTRACT: In patients with systemic lupus erythematosus (SLE), evidence suggests that most vaccines (except live-virus vaccines) are safe, although antibody response may be reduced. This substudy from the phase III, randomized, double-blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE.
In BLISS-76, patients with autoantibody-positive, active SLE were treated with placebo or belimumab 1 or 10 mg/kg every 2 weeks for 28 days and every 28 days thereafter, plus standard SLE therapy, for 76 weeks. This analysis included a subset of patients who had received pneumococcal or tetanus vaccine within 5 years or influenza vaccine within 1 year of study participation. Antibodies to vaccine antigens were tested at baseline and Week 52, and percentage changes in antibody levels from baseline and proportions of patients maintaining levels at Week 52 were assessed. Antibody titers were also assessed in a small number of patients vaccinated during the study.
Consistent with preservation of the memory B cell compartment with belimumab treatment, the proportions of patients maintaining antibody responses to pneumococcal, tetanus, and influenza antigens were not reduced. In a small group receiving influenza vaccine on study, antibody responses were frequently lower with belimumab, although titer levels were > 1:10 in all patients treated with 10 mg/kg and in the majority treated with 1 mg/kg.
Treatment with belimumab did not affect the ability of patients with SLE to maintain antibody titers to previous pneumococcal, tetanus, and influenza immunizations. [ClinicalTrials.gov registration number NCT 00410384].
The Journal of Rheumatology 06/2012; 39(8):1632-40. DOI:10.3899/jrheum.111587 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Figure 2. 2012 American College of Rheumatology (ACR) recommendations update for the treatment of established rheumatoid arthritis (RA), defined as a disease duration ≥6 months or meeting the 1987 ACR classification criteria. Depending on a patient's current medication regimen, the management algorithm may begin at an appropriate rectangle in the figure, rather than only at the top of the figure. Disease-modifying antirheumatic drugs (DMARDs) include hydroxychloroquine (HCQ), leflunomide (LEF), methotrexate (MTX), minocycline, and sulfasalazine (therapies are listed alphabetically; azathioprine and cyclosporine were considered but not included). DMARD monotherapy refers to treatment in most instances with HCQ, LEF, MTX, or sulfasalazine; in few instances, where appropriate, minocycline may also be used. Anti–tumor necrosis factor (anti-TNF) biologics include adalimumab, certolizumab pegol, etanercept, infliximab, and golimumab. Non-TNF biologics include abatacept, rituximab, or tocilizumab (therapies are listed alphabetically). For the level of evidence supporting each recommendation, please see Supplementary Appendix 7 (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).* Definitions of disease activity are discussed in Tables 2 and 3 and Supplementary Appendix 4 (available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658) and were categorized as low, moderate, or high.† Features of poor prognosis included the presence of 1 or more of the following: functional limitation (e.g., Health Assessment Questionnaire score or similar valid tools), extraarticular disease (e.g., presence of rheumatoid nodules, RA vasculitis, Felty's syndrome), positive rheumatoid factor or anti–cyclic citrullinated peptide antibodies (33–37), and bony erosions by radiograph (38).‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based, with few exceptions (e.g., MTX + HCQ, MTX + LEF, MTX + sulfasalazine, sulfasalazine + HCQ), and triple therapy (MTX + HCQ + sulfasalazine).§ Reassess after 3 months and proceed with escalating therapy if moderate or high disease activity in all instances except after treatment with a non-TNF biologic (rectangle D), where reassessment is recommended at 6 months due to a longer anticipated time for peak effect.¶ LEF can be added in patients with low disease activity after 3–6 months of minocycline, HCQ, MTX, or sulfasalazine.# If after 3 months of intensified DMARD combination therapy or after a second DMARD has failed, the option is to add or switch to an anti-TNF biologic.** Serious adverse events were defined per the US Food and Drug Administration (FDA; see below); all other adverse events were considered nonserious adverse events.†† Reassessment after treatment with a non-TNF biologic is recommended at 6 months due to anticipation that a longer time to peak effect is needed for non-TNF compared to anti-TNF biologics.‡‡ Any adverse event was defined as per the US FDA as any undesirable experience associated with the use of a medical product in a patient. The FDA definition of serious adverse event includes death, life-threatening event, initial or prolonged hospitalization, disability, congenital anomaly, or an adverse event requiring intervention to prevent permanent impairment or damage.Download figure to PowerPoint
[Show abstract][Hide abstract] ABSTRACT: To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE).
In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody–positive or anti–double-stranded DNA–positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA–SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline).
Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA–SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups.
Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.
[Show abstract][Hide abstract] ABSTRACT: Death Receptor 5 (DR5) induces apoptosis in various types of cells and is a potential therapeutic target. We have investigated whether targeting DR5 could be used to eliminate pathogenic B lymphocytes from systemic lupus erythematosus (SLE) patients. We examined DR5 expression and function on B lymphocytes from healthy controls subjects, SLE patients, and human tonsil. DR5 was expressed similarly on all B cell subpopulations, including resting and activated B cells. Expression of DR5 was equivalent on B cells from SLE patients and healthy subjects. Additionally, DR5 expression was unchanged after B lymphocyte stimulation. However, B cells were resistant to DR5-induced apoptosis, including after in vitro activation. No changes in subsets of B cells were observed in subjects of a trial of CS-1008, an agonist anti-DR5. While DR5 shows promise as a way to selectively eliminate tumor cells and activated synoviocytes, these data suggest DR5 alone cannot be used as a target to remove pathogenic SLE B cells.
[Show abstract][Hide abstract] ABSTRACT: Sarcoidosis commonly involves the lungs but also not uncommonly presents as uveitis, arthritis, myositis or neurologic disease. Recognition of the presenting features, organ complications, and immunopathogenesis is important for timely diagnosis and appropriate management.
Current studies support the disorder developing as a consequence of a CD4+ T-cell-mediated response to variable environmental or microbial triggers in the context of one or more determined susceptibility genes including BTNL2, with other genes such as CARD15/NOD2, governing disease severity. Magnetic resonance imaging (MRI) is useful in defining the presence and extent of central nervous system (CNS), osseous, and both skeletal and cardiac muscle disease. Corticosteroids remain the mainstay of therapy; patients with refractory disease may respond to other immunomodulating drugs, including anti-TNF-alpha antibodies but the optimal roles of traditional immunomodulating as well as newer biologic therapies in management are continuing to be defined.
Insights into triggering immune events and susceptibility genes should provide potential new strategies and targets for therapy. The judicious use of MRI in suspected cases can enhance earlier recognition of disease in the CNS, bone, and both skeletal and cardiac muscle to guide diagnostic procedures as well as appropriate treatment.
Current opinion in rheumatology 10/2009; 22(1):85-90. DOI:10.1097/BOR.0b013e328333ba74 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials.
Data from a randomized, double-blind, placebo-controlled study in 449 patients of 3 doses of belimumab (1, 4, 10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56-week period were analyzed. The Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36 health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321 serologically active SLE patients (antinuclear antibodies >/=1:80 and/or anti-double-stranded DNA antibodies >/=30 IU/ml) at baseline was retrospectively evaluated using the SRI.
SRI response is defined as 1) a >/=4-point reduction in SELENA-SLEDAI score, 2) no new BILAG A or no more than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician's global assessment by >/=0.3 points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week 52 compared with 29% of the placebo patients (P = 0.006). SRI responses were independent of baseline autoantibody subtype.
This evidence-based evaluation of a large randomized, placebo-controlled trial in SLE resulted in the ability to define a robust responder index based on improvement in disease activity without worsening the overall condition or the development of significant disease activity in new organ systems.
[Show abstract][Hide abstract] ABSTRACT: To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).
Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score >/=4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study. Coprimary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare.
Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA-SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24-52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer >/=1:80 and/or anti-double-stranded DNA [anti-dsDNA] >/=30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (-28.8% versus -14.2%; P = 0.0435), physician's global assessment (-32.7% versus -10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti-dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.
Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) is associated with higher levels of autoantibodies and IL-17. Here, we investigated if ectopic lymphoid follicles and peripheral blood mononuclear cells (PBMCs) from RA patients exhibit increased activation-induced cytidine deaminase (AID), and if increased AID is correlated with serum levels of autoantibodies and IL-17. The results of immunohistochemical staining showed that organized AID(+) germinal centres were observed in six of the 12 RA synovial samples, and AID(+) cells were found almost exclusively in the B-cell areas of these follicles. Aggregated but not organized lymphoid follicles were found in only one OA synovial sample without AID(+) cells. Significantly higher levels of AID mRNA (Aicda) detected by RT-PCR were found in the PBMCs from RA patients than PBMCs from normal controls (P < 0.01). In the PBMCs from RA patients, AID was expressed predominately by the CD10(+)IgM(+)CD20(+) B-cell population and the percentage of these cells that expressed AID was significantly higher than in normal controls (P < 0.01). AID expression in the PBMCs correlated significantly and positively with the serum levels of rheumatoid factor (RF) (P </= 0.0001) and anti-cyclic citrullinated peptide (CCP) (P = 0.0005). Serum levels of IFN-gamma (P = 0.0005) and IL-17 (P = 0.007), but not IL-4, also exhibited positive correlation with the expression of AID. These results suggest that the higher levels of AID expression in B cells of RA patients correlate with, and may be associated with the higher levels of T helper cell cytokines IFN-gamma and IL-17, leading to the development of anti-CCP and RF.
[Show abstract][Hide abstract] ABSTRACT: IgA nephropathy (IgAN) is characterized by circulating immune complexes composed of galactose-deficient IgA1 and a glycan-specific IgG antibody. These immune complexes deposit in the glomerular mesangium and induce the mesangioproliferative glomerulonephritis characteristic of IgAN. To define the precise specificities and molecular properties of the IgG antibodies, we generated EBV-immortalized IgG-secreting lymphocytes from patients with IgAN and found that the secreted IgG formed complexes with galactose-deficient IgA1 in a glycan-dependent manner. We cloned and sequenced the heavy- and light-chain antigen-binding domains of IgG specific for galactose-deficient IgA1 and identified an A to S substitution in the complementarity-determining region 3 of the variable region of the gene encoding the IgG heavy chain in IgAN patients. Furthermore, site-directed mutagenesis that reverted the residue to alanine reduced the binding of recombinant IgG to galactose-deficient IgA1. Finally, we developed a dot-blot assay for the glycan-specific IgG antibody that differentiated patients with IgAN from healthy and disease controls with 88% specificity and 95% sensitivity and found that elevated levels of this antibody in the sera of patients with IgAN correlated with proteinuria. Collectively, these findings indicate that glycan-specific antibodies are associated with the development of IgAN and may represent a disease-specific marker and potential therapeutic target.
The Journal of clinical investigation 07/2009; 119(6):1668-77. DOI:10.1172/JCI38468 · 13.22 Impact Factor