Epratuzumab is a monoclonal antibody targeting CD22. In EMBLEM™ (a dose-ranging phase IIb study), epratuzumab produced clinically relevant improvements in disease activity in patients with moderate-to-severe systemic lupus erythematosus (SLE).1 SL0008 (NCT00660881) was an open-label extension of EMBLEM™.
Objectives
To assess longer-term efficacy of epratuzumab in patients with moderate-to-severe SLE.
Methods
Patients from any EMBLEM™ arm completing 12 weeks’ blinded treatment and patients who discontinued due to lack of efficacy but completed ≥8 weeks were eligible. In SL0008, all patients received 1200mg epratuzumab at weeks 0 and 2 of repeating 12-week cycles. Evaluation visits were at weeks 4 and 8 of each cycle. Efficacy endpoints included BILAG improvement, SLEDAI assessment score, Physician Global Assessment (PGA) score and combined treatment response (defined as BILAG improvement without worsening, no SLEDAI worsening, no PGA worsening, relative to EMBLEM™ baseline).
Results
203 patients participated in SL0008: 95% female (n=192), 78% Caucasian (n=158), mean±SD age 39±11 years. 35 (17%) and 168 (83%) received placebo and epratuzumab (at various doses), respectively, for 12 weeks in EMBLEM™. The median (range) duration of epratuzumab exposure was 845 (75–1185) days. BILAG improvements were observed between EMBLEM™ baseline and week 108, the last timepoint when >50% of patients reported data for this endpoint. Median BILAG total score decreased by 64%. Median (range) BILAG total score was 25.0 (12–61) at EMBLEM™ baseline, 14.0 (0–57) at SL0008 screening, 9.0 (0–52) at week 48, 9.0 (0–52) at week 96 and 9.0 (0–52) at week 108. Epratuzumab treatment was associated with improvements in BILAG grade distribution across most body systems. At week 108, 60.3% of patients responded to treatment, according to combined treatment response criteria (Table). Median (range) SLEDAI total score was 12.0 (6–39) at EMBLEM™ baseline, 10.0 (0–34) at SL0008 screening, 6.0 (0–30) at week 48, 5.0 (0–22) at week 96 and 4.0 (0–24) at week 108. Median (range) PGA total score was 50.0 (9–90) at EMBLEM™ baseline, 31.0 (0–96) at SL0008 screening, 18.0 (0–81) at week 48, 19.0 (0–73) at week 96 and 17.5 (0–69) at week 108.
Conclusions
Epratuzumab was associated with sustained improvements in disease activity in patients with moderate-to-severe SLE. Responder rates were sustained beyond 2 years or increased during open-label treatment, particularly in patients previously treated with placebo.
References
Wallace DJ, et al. Ann Rheum Dis, Online First 12 January 2013. DOI: 10.1136/annrheumdis-2012-202760.
Disclosure of Interest
C. Gordon Grant/research support from: Aspreva, Consultant for: Aspreva, Bristol-Myers Squibb, Genentech, Biogen IDEC Inc, Merck Pharmaceuticals, Roche, UCB Pharma, M. Clowse Consultant for: UCB Pharma, F. Houssiau Grant/research support from: UCB Pharma, Consultant for: UCB Pharma, M. Petri Grant/research support from: UCB Pharma, Consultant for: UCB Pharma, B. Kilgallen Shareholder of: UCB Pharma, Employee of: UCB Pharma, K. Kalunian Grant/research support from: Genentech, Biogen IDEC Inc, Cephalon, Cypress, MedImmune, Novo Nordisk, UCB Pharma, Consultant for: Bristol-Myers Squibb, Genentech, Biogen IDEC Inc, Anthera, MedImmune, Novo Nordisk, Zymogenetics, Serono, UCB Pharma, V. Strand Consultant for: Abbott Immunology Pharmaceuticals, Amgen Inc, AstraZeneca, Biogen Idec, Canfite Pharma, Centocor Inc, Cypress Biosciences Inc, Euro-Diagnostica Inc, Fibrogen, Forest Laboratories, Genentech, Human Genome Sciences Inc, Incyte, Novartis Pharmaceuticals Corporation, Alder, CBio, Chelsea, Crescendo, Idera, Jazz Pharmaceuticals, Lexicon Genetics, Logical Therapeutics, Lux Biosciences, NovoNordisk, Nuon, Ono, SKK, Pfizer Inc, Rigel Pharma, Roche, Sanofi-Aventis, Savient Pharmaceuticals, Schering-Plough and UCB Pharma, S. Bongardt Employee of: UCB Pharma, D. Wallace Consultant for: Bristol-Myers Squibb, Genentech, Biogen IDEC Inc, GlaxoSmithKline, Human Genome Sciences Inc, MedImmune, Novo Nordisk and UCB Pharma
The very long-term consequences of absence of remission in lupus nephritis (LN) remain understudied.In this retrospective analysis, we studied a selected cohort of 128 patients with biopsy-proven class III, IV or V incident LN followed for a median period of 134 months (minimum 25). Remission was defined as a urine protein to creatinine (uP:C) ratio <0.5 g/g and a serum creatinine value <120% of baseline. Renal relapse was defined as the reappearance of a uP:C >1 g/g, leading to a repeat kidney biopsy and treatment change. Poor long-term renal outcome was defined as the presence of chronic kidney disease (CKD).Twenty per cent of patients never achieved renal remission. Their baseline characteristics did not differ from those who did. Absence of renal remission was associated with a threefold higher risk of CKD (48% vs 16%) and a 10-fold higher risk of end-stage renal disease (20% vs 2%). Patients achieving early remission had significantly higher estimated glomerular filtration rate (eGFR) at last follow-up compared with late remitters. Accordingly, patients with CKD at last follow-up had statistically longer time to remission. Among patients who achieved remission, 32% relapsed, with a negative impact on renal outcome, that is, lower eGFR values and higher proportion of CKD (33% vs 8%).Early remission should be achieved to better preserve long-term renal function.
Understanding the interaction of local anesthetics (LAs) with plasma proteins is essential to understanding their systemic pharmacology and toxicology. The molecular determinants of LA binding to the major variant (F1*S) of human α1-acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using whole AGP and a novel, F1*S variant-selective probe previously developed in our laboratory. Equilibrium- competitive displacement of this probe by LAs, observed by the recovery of AGP9s fluorescence as the quenching probe was displaced from its high-affinity site, was characterized by inhibitory dissociation constants for the various LAs. The importance of electrostatic factors was assessed by examining the pH dependent binding of an ionizable LA, lidocaine, using the quaternary lidocaine derivative QX-314 [N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium chloride] to control for pH dependent ionization of AGP. Uncharged lidocaine bound with at least 8 times the affinity of protonated lidocaine (KD = 4.0 ± 0.6 μM and >32 μM, respectively). This result is inconsistent with the current model of the AGP-binding site, which depicts a buried pocket having a negatively charged region that interacts with the amino termini of basic drugs. Consistent with the model, however, two sets of structurally homologous LAs (mepivacaine, ropivacaine, bupivacaine, and lidocaine, RAD-240, RAD-241, RAD-242, L-30, W-6603) demonstrated a strong positive correlation between hydrophobicity (measured as the octanol:buffer partition coefficient of the neutral species) and their free energies of dissociation. Given that the tertiary structure of AGP has proven refractory to resolution, these structure-activity studies should contribute to understanding the nature of the binding site on this important protein.
The discovery in the late 1940s of the very potent anti-inflammatory and immunosuppressive properties of glucocorticoids (GC)1 has dramatically improved the prognosis of severe systemic lupus erythematosus (SLE), with survival rates increasing markedly from 50% at 3 years in 19532 to 92% at 10 years in recent series.3 In particular, intravenous pulse methylprednisolone (MP) therapy, introduced as treatment for severe lupus manifestations in the 1970s,4 displays remarkable and prompt beneficial effects in acutely ill SLE patients suffering from renal impairment, central nervous system disease, arthritis, pleuropericarditis, fever or severe thrombocytopenia.5 ,6 Unfortunately, many patients, especially those taking >7.5 mg per day for long periods, experience the serious consequences of GC therapy, such as, increased risk of infection, avascular osteonecrosis, osteoporosis, myopathy, diabetes mellitus or Cushingoid features, as well as skin bruising and cataracts. Most of these side effects impact upon a patient's body image, being a huge source of emotional distress in young (sometimes teenaged) female patients, who are the principle victims of SLE.
Several longitudinal studies performed in SLE patients have revealed that GCs are the main cause of damage, as determined by the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) damage index (DI).7 Thus, the mean DI rose from 0.33 at baseline to 1.9 after 15 years of follow-up in an inception cohort, and damage was considered as …
Lupus nephritis (LN) is a severe manifestation of SLE, characterised by subendothelial and/or subepithelial immune complex depositions in the afflicted kidney, resulting in extensive injury and nephron loss during the acute phase and eventually chronic irreversible damage and renal function impairment if not treated effectively. The therapeutic management of LN has improved during the last decades, but the imperative need for consensual outcome measures remains. In order to design trials with success potentiality, it is important to define clinically important short-term and long-term targets of therapeutic and non-therapeutic intervention. While it is known that early response to treatment is coupled with favourable renal outcomes, early predictors of renal function impairment are lacking. The information gleaned from kidney biopsies may provide important insights in this direction. Alas, baseline clinical and histopathological information has not been shown to be informative. By contrast, accumulating evidence of pronounced discrepancies between clinical and histopathological outcomes after the initial phase of immunosuppression has prompted investigations of the potential usefulness of per-protocol repeat kidney biopsies as an integral part of treatment evaluation, including patients showing adequate clinical response. This approach appears to have merit. Hopefully, clinical, molecular or genetic markers that reliably reflect kidney histopathology and portend the long-term prognosis will be identified. Novel non-invasive imaging methods and employment of the evolving artificial intelligence in pattern recognition may also be helpful towards these goals. The molecular and cellular characterisation of SLE and LN will hopefully result in novel therapeutic modalities, maybe new taxonomy perspectives, and ultimately personalised management.
Objectives. The objectives of this study are to examine the efficacy and safety of low-dose aspirin (LDA) vs LDA plus low-intensity warfarin (LDA + W) in the primary thrombosis prevention of aPL-positive patients with SLE and/or obstetric morbidity and the role of clinical and serological markers in the development of thrombosis.
A woman with a history of polyarthralgias appeared to develop systemic lupus erythematosus and lymphoma simultaneously. The diagnosis of the concurrent lymphoma was made on biopsy of a left axillary lymph node. Generalized lymphadenopathy, splenomegaly and pruritus had given rise to suspicion of an underlying lymphoma. The lymphoma responded well to chemotherapy. Her condition was further complicated by an arterial occlusion involving the right 2nd toe which was eventually amputated, transient ischemic attacks (amaurosis fugax), livedo reticularis and thrombocytopenia which were accompanied by elevations of IgM anticardiolipin antibodies and a biological false test for syphilis. The lupus anticoagulant test was not performed as she was given anticoagulation therapy.
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