Josefina Cortés-Hernández

Long-term outcomes—mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases

BACKGROUND Although mycophenolate mofetil (MMF) is being increasingly used to manage lupus nephritis (LN), long-term experience is limited. Despite treatment, a significant proportion of patients will be refractory to this regime. METHODS We report, in this observational study, our long-term experience treating 70 patients with biopsy-proven LN, with MMF as continuous induction-maintenance therapy, who were followed up prospectively over a 5-year period. As rescue therapy for MMF-resistant cases, tacrolimus (0.075 mg/kg/day) was added. The study primary end point was complete response (CR). Secondary end points included partial response (PR), treatment failure, relapse and side effects. Predictor factors associated to renal outcome were analysed by Cox regression analysis. RESULTS Thirty-six MMF-treated patients (51%) remained in CR, and 23 (33%) failed treatment at last follow-up. Time to treatment failure was associated with persistent hypoalbuminaemia (hazard ratio (HR) = 0.87; 95%CI, 0.81-0.95; P = 0.001), higher proteinuria (HR = 1.29; 95%CI, 1.03-1.62; P = 0.030) and fewer early responses (HR 0.28; 95%CI, 0.10-0.77; P = 0.014). Renal relapse occurred in 24 (34%) patients. Time to flare was associated with persistent anti-dsDNA titres (HR = 1.001; 95%CI, 1.001-1.003; P = 0.005) and younger age at inclusion (HR = 0.36; 95%CI, 0.14-0.90; P = 0.029). Tacrolimus was added to 17 (24%) patients. A significant reduction of proteinuria was already observed at 3 months (P = 0.002). After 2 years follow-up, 12 (70%) of them achieved clinical response (six CR and six PR). Conclusions. MMF is an effective treatment for LN. Combination therapy with tacrolimus is an effective and safe alternative for MMF-resistant patients.

Thalidomide in the treatment of refractory cutaneous lupus erythematosus: prognostic factors of clinical outcome.

Background  Although thalidomide has been shown to be effective in patients with refractory cutaneous lupus erythematosus (CLE), its use is still hampered by its potential severe side‐effects and the current restricted availability.

Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus

IntroductionCutaneous lupus erythematosus (CLE) is a chronic disease characterized by disfigurement and a relapsing course. Thalidomide has proven its efficacy in refractory cutaneous lupus disease, although it is not exempt from significant side effects and frequent relapses after withdrawal. New thalidomide analogues have been developed but lack clinical experience. The aim of this preliminary phase II study was to evaluate the efficacy and safety of lenalidomide in patients with refractory CLE.MethodsFifteen patients with refractory cutaneous lupus disease were enrolled in this single-center, open-label, non-comparative pilot trial between January 2009 and December 2010. Oral lenalidomide (5 to 10 mg/day) was administered and tapered according to clinical response. Patients were followed up for a mean of 15 months (range: 7 to 30). Primary efficacy endpoint was the proportion of patients achieving complete response, defined by a Cutaneous Lupus Erythematosus Disease Area and Severity index (CLASI) activity score of 0. Other secondary endpoints included development of side effects, evaluation of cutaneous and systemic flares, and impact on the immunological parameters.ResultsOne patient discontinued treatment due to side effects. All remaining patients saw clinical improvement and this was already noticeable after 2 weeks of treatment. Twelve of those patients (86%) achieved complete response but clinical relapse was frequent (75%), usually occurring 2 to 8 weeks after lenalidomides withdrawal. No influence on systemic disease, immunological parameters or CLASI damage score was observed. Side effects including insomnia, grade 2 neutropenia and gastrointestinal symptoms, were minor (13%). These resolved after withdrawing medication. Neither polyneuropathy nor thrombosis was observed.ConclusionLenalidomide appears to be efficacious and safe in patients with refractory CLE, but clinical relapse is frequent after its withdrawal.Trial registrationClinicalTrials.gov: NCT01408199.

Etanercept in refractory lupus arthritis: An observational study

OBJECTIVE To investigate the long-term safety and preliminary efficacy of etanercept in patients with refractory lupus arthritis. METHODS We evaluated 43 patients in this observational cohort study. All received etanercept (50mg/week) in addition to concomitant immunosuppressive agents. Patient and disease characteristics were collected. Incidence of adverse events and the effect on autoantibody levels were evaluated. Clinical efficacy was measured by the 28-joint count and the SLEDAI-2K scores. Remission of lupus arthritis was defined by a 28-joint score = 0. Clinically inactive systemic disease was defined by a SLEDAI-2K score <4. RESULTS The total follow-up time was 93 patient-years (median: 2.3 years per patient; range: 0.4-6.8 years). Most side effects were minor and related to local reactions. Only 2 significant adverse events occurred (8%), both were of infectious nature. The rate of autoantibody production was low (18%). A mild increase in titres of ANA (2), IgG anti-dsDNA (3) and IgM anticardiolipin (aCL) (2) antibodies was observed. All anti-dsDNA antibody increments were transient and coincided with systemic flares. No vascular events occurred. In general, disease activity declined during therapy. Most patients (83%) with lupus arthritis achieved clinical remission by week 12. All patients with simultaneous serositis experienced clinical and radiological resolution of this condition. Relapses were frequent (23%), mostly mild and related to etanercept reduction. A total of 24 patients discontinued treatment, 12 of them due to clinical remission. CONCLUSIONS Long-term therapy with etanercept was relatively safe and had remarkable long-term efficacy for refractory lupus arthritis. In view of these results, further controlled trials are warranted.

Neutrophil gelatinase-associated lipocalin as a biomarker for lupus nephritis

BACKGROUND One of the challenges of treating patients with lupus nephritis (LN) is to accurately assess disease activity and predict its outcome. Since renal-biopsy cannot be performed routinely, new surrogate biomarkers are needed. METHODS We evaluated neutrophil gelatinase-associated lipocalin (NGAL), to predict renal outcome in LN. Serum and urinary NGAL levels, measured by the enzyme-linked immunosorbent assay, and the fractional excretion (FE) of NGAL relative to the FE of proteins (FE NGAL/FE protein ratio) were determined in a cross-sectional (n = 199) and longitudinal (n = 45) cohort of systemic lupus erythematosus (SLE) patients. Global and renal disease activity was assessed by the SLE disease activity indices, SLEDAI and rSLEDAI, respectively. Correlations between traditional biomarkers were established. Sensitivity, specificity and predictive values of NGAL for renal flare, response to therapy and progression to chronic kidney disease were calculated. RESULTS The FE NGAL/FE protein ratio exhibited the best sensitivity and specificity to discriminate patients with active LN from those with non-renal flare and inactive SLE. In the prospective study, this biomarker was found to be the best candidate to predict proteinuric flares with an 87% sensitivity and 62% specificity for ratios >14.56 and complete response with a 61% sensitivity and 78% specificity for ratios >26.54 in the presence of a simultaneous worsening or improving rSLEDAIs, respectively. In both conditions, the FE NGAL/FE protein ratio outperformed the anti-dsDNA antibody titres and C3 predictive value. Progression to chronic kidney disease was best predicted by estimated glomerular filtration rate levels, but persistently high levels of serum NGAL (>444.4 ng/mL, P = 0.0001 by Kaplan-Meier) predicted a faster progression. CONCLUSIONS The FE NGAL/FE protein ratio is a reliable marker of disease activity in patients with SLE and could be used as an indicator of response to therapy, although further studies are required to confirm these results.

Systemic lupus erythematosus as a first presentation of common variable immunodeficiency associated with infrequent mannose-binding lectin gene polymorphisms

The association of common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE) is infrequent. Mannose-binding lectin (MBL) has been shown to play a role in CVID and SLE. The purpose of this study is to describe two cases of CVID who presented as SLE and also evaluate the presence of MBL polymorphisms and MBL serum levels in those patients. In both patients, SLE was the first manifestation of CVID. In these patients the SLE immunological markers and disease activity disappeared after the development of CVID. They carried the very infrequent MBL haplotype 4Q-57Glu. One of them had a homozygous genotype, whereas the other patient was heterozygous and also presented the haplotype 4P-57Glu that had never been previously detected. Interestingly, this last patient was presenting frequent respiratory tract infections, developed bronchiectasis and had low levels of circulating MBL. These results may support the role of MBL in the development of autoimmunity in CVID. Further genetic studies are needed to clarify the role of the MBL polymorphisms in the development of autoimmunity in CVID.

Enteric-coated mycophenolate sodium versus azathioprine in patients with active systemic lupus erythematosus: a randomised clinical trial

Objective To compare the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS) versus azathioprine (AZA) in patients with active systemic lupus erythematosus (SLE) disease. Methods A multicentre, 24-month, superiority, open-label, randomised controlled trial (NCT01112215) was conducted with 240 patients (120 per arm) receiving either EC-MPS (target dose: 1440 mg/day) or AZA (target dose: 2 mg/kg/day) in addition to prednisone and/or antimalarials. The primary endpoint was the proportion of patients achieving clinical remission, assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG), at 3 and 24 months. Secondary endpoints included time to clinical remission, BILAG A and B flare rates, time to flare, corticosteroid reduction and adverse events (AEs). Results Proportion of patients achieving clinical remission (clinical SLEDAI=0) was higher in the EC-MPS group at 3 (32.5% vs 19.2%; treatment difference, 13.3 (CI 2.3 to 24), p=0.034) and 24 months (71.2% vs 48.3%; treatment difference, 22.9 (CI 10.4 to 34.4), p<0.001). EC-MPS was superior with respect to time to clinical remission (HR 1.43; 95% CI 1.07 to 1.91; p=0.017). BILAG A/B and B flares occurred more frequently in the AZA group (71.7% vs 50%, p=0.001 and 21.67% vs 8.3%, p=0.004, respectively). EC-MPS was superior with respect to time to first BILAG A/B (HR 1.81; 95% CI 1.3 to 2.56; p=0.0004) and BILAG A flare (HR 2.84; 95% CI 1.37 to 5.89; p=0.003). AEs were similar in both groups except for leucopenia that occurred more frequently with AZA. Conclusions EC-MPS was superior to AZA in treating SLE and preventing further relapses. Trial registration number NCT01112215; Results.

Microarray study reveals a transforming growth factor-β-dependent mechanism of fibrosis in discoid lupus erythematosus†

Discoid lupus erythematosus (DLE) is characterized by scarring lesions that develop and perpetuate fibrotic lesions. These are not observed in subacute cutaneous lupus erythematosus (SCLE). The pathophysiological basis of this is currently unknown.

MicroRNA expression profiling identifies miR-31 and miR-485-3p as regulators in the pathogenesis of Discoid Cutaneous Lupus

Cutaneous lupus erythematosus is a common and disfiguring manifestation in systemic lupus erythematosus. Subacute cutaneous lupus erythematosus and discoid lupus erythematosus (DLE) are the most prevalent forms. Despite sharing histological similarities, clinically they differ in their course and prognosis, suggesting different pathogenesis. Here, we show that DLE-affected skin has a specific microRNA expression profile when compared with subacute cutaneous lupus erythematosus. Among the DLE-specific microRNAs, we identified one keratinocyte-derived microRNA, miR-31, and one leukocyte-derived microRNA, miR-485-3p. We show that UV and transforming growth factor-β1 stimulation up-regulates miR31 expression in DLE. Specific miR-31 overexpression induces keratinocyte apoptosis and NF-κB pathway activation with the production of related inflammatory cytokines and contributes to the recruitment of neutrophils and intermediate monocytes at the inflammation site. IL-1α and TGF-β1 stimulation increased the expression of miR-485-3p in peripheral mononuclear blood cells from DLE patients and induced T-cell activation, mainly of CD8 lymphocytes. In addition, miR-485-3p overexpression in dermal fibroblasts contributes to fibrosis by targeting peroxisome PGC-1α. Collectively, our findings suggest that overexpression of miR-31 and miR-485-p contribute to skin inflammation in DLE lesions by regulating the production of inflammatory mediators and attracting neutrophils and intermediate monocytes to the skin.

THU0377 MIR-29C in Urinary Exosomes as Predictor of Early Renal Fibrosis in Lupus Nephritis

Background Despite overall improvement in prognosis, 10-30% of patients with lupus nephritis (LN) will develop End-Stage Renal Disease [1]. To date, renal biopsy is still the gold standard test used to predict renal outcome. However, due to its invasive nature, new non-invasive biomarkers are required. The anti-fibrotic effects of microRNA-29c may be result of its ability to inhibit TGF-β/Smad3-mediated deposition of extracellular matrix (ECM) [2]. Urinary exosomes, microvesicles released by every epithelial cell facing the urinary space, represent an ideal source of markers for renal dysfunction and injury. Objectives Here we sought to evaluate miR-29c expression levels in urinary exosomes as a novel biomarker of renal fibrosis in LN and study the relation between the expression of miR-29c and genes related with TGF-B pathway to investigate more about the mechanism of renal fibrosis in lupus nephritis. Methods Urinary exosomes were isolated from 28 patients with biopsy-proven LN and 20 healthy controls. Electronic microscopy and western blot were used to characterize the exosomes. Expression levels of miR-29c were detected by RT-PCR quantitative and correlated with clinical and histological parameters along with the expression levels of Smad2/3, TGF-β and MMP2/9. For comparison, miRNA expression was also evaluated in the urinary pellet. Results MiR-29c levels in urinary exosomes showed a negatively strong correlation with the histological chronicity index (r=-0.898, p=0.001) and glomerular sclerosis (r=-0.555, p=0.007). No correlation with eGFR and creatinine levels was found. MiR-29c expression levels could predict the degree of chronicity in patients with LN with an area under the curve (AUC) of 0.946 (p<0.001) and with high sensitivity and specificity (94% and 82%). Smad3 and MMP2 expression in urinary exosomes correlated negatively with miR-29c expression (r=-0.737 and -0.856 respectively). In the urinary pellet, no miR-29c expression was detected; however, upregulation of Smad3 and MMP2 was observed (3.54 and 5.85 fold increase). Conclusions Overall, miR-29c correlated with the degree of renal chronicity but not with renal function, suggesting it could be used as a novel non-invasive marker of early progression to fibrosis in patients with LN. References Fiehn C. Early diagnosis and treatment in lupus nephritis: how we can influence the risk for terminal renal failure. J Rheumatol 2006; 33:1464–1466. Qin W. et al. TGF-/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J Am Soc Nephrol 2011; 22:1462-1474. Disclosure of Interest None declared