Publications by authors named "Frédéric A Houssiau"

71 Publications

From sequential to combination and personalised therapy in lupus nephritis: moving towards a paradigm shift?

Ann Rheum Dis 2021 Sep 14. Epub 2021 Sep 14.

Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium

The current treatment paradigm in lupus nephritis consists of an initial phase aimed at inducing remission and a subsequent remission maintenance phase. With this so-called sequential treatment approach, complete renal response is achieved in a disappointing proportion of 20-30% of the patients within 6-12 months, and 5-20% develop end-stage kidney disease within 10 years. Treat-to-target approaches are detained owing to uncertainty as to whether the target should be determined based on clinical, histopathological, or immunopathological features. Until reliable non-invasive biomarkers exist, tissue-based evaluation remains the gold standard, necessitating repeat kidney biopsies for treatment evaluation and therapeutic decision-making. In this viewpoint, we discuss the pros and cons of voclosporin and belimumab as add-on agents to standard therapy, the first drugs to be licenced for lupus nephritis after recent successful randomised phase III clinical trials. We also discuss the prospect of obinutuzumab and anifrolumab, also on top of standard immunosuppression, currently tested in phase III trials after initial auspicious signals. Undoubtably, the treatment landscape in lupus nephritis is changing, with combination treatment regimens challenging the sequential concept. Meanwhile, the enrichment of the treatment armamentarium shifts the need from lack of therapies to the challenge of how to select the right treatment for the right patient. This has to be addressed in biomarker surveys along with tissue-level mapping of inflammatory phenotypes, which will ultimately lead to person-centred therapeutic approaches. After many years of trial failures, we may now anticipate a heartening future for patients with lupus nephritis.
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http://dx.doi.org/10.1136/annrheumdis-2021-221270DOI Listing
September 2021

Absence of renal remission portends poor long-term kidney outcome in lupus nephritis.

Lupus Sci Med 2021 08;8(1)

Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Background: The very long-term consequences of absence of remission in lupus nephritis (LN) remain understudied.

Methods: 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).

Results: 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%).

Conclusion: Early remission should be achieved to better preserve long-term renal function.
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http://dx.doi.org/10.1136/lupus-2021-000533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395364PMC
August 2021

Quality indicators for systemic lupus erythematosus based on the 2019 EULAR recommendations: development and initial validation in a cohort of 220 patients.

Ann Rheum Dis 2021 09 23;80(9):1175-1182. Epub 2021 Jun 23.

Rheumatology and Clinical Immunology, Medical School, National and Kapodistrian University of Athens, "Attikon" University Hospital of Athens, Athens, Greece

Background: Quality of care is receiving increased attention in systemic lupus erythematosus (SLE). We developed quality indicators (QIs) for SLE based on the 2019 update of European League Against Rheumatism recommendations.

Methods: A total of 44 candidate QIs corresponding to diagnosis, monitoring and treatment, were independently rated for validity and feasibility by 12 experts and analysed by a modified Research and Development Corporation/University of California Los Angeles model. Adherence to the final set of QIs and correlation with disease outcomes (flares, hospitalisations and organ damage) was tested in a cohort of 220 SLE patients with a median monitoring of 2 years (IQR 2-4).

Results: The panel selected a total of 18 QIs as valid and feasible. On average, SLE patients received 54% (95% CI 52.3% to 56.2%) of recommended care, with adherence ranging from 44.7% (95% CI 40.8% to 48.6%) for diagnosis-related QIs to 84.3% (95% CI 80.6% to 87.5%) for treatment-related QIs. Sustained remission or low disease activity were achieved in 26.8% (95% CI 21.1% to 33.2%). Tapering of prednisone dose to less than 7.5 mg/day was achieved in 93.6% (95% CI 88.2% to 97.0%) while 73.5% (95% CI 66.6% to 79.6%) received the recommended hydroxychloroquine dose. Higher adherence to monitoring-related QIs was associated with reduced risk for a composite adverse outcome (flare, hospitalisation or damage accrual) during the last year of observation (OR 0.97 per 1% adherence rate, 95% CI 0.96 to 0.99).

Conclusion: We developed QIs for assessing and improving the care of SLE patients. Initial real-life data suggest face validity, but a variable degree of adherence and a need for further improvement.
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http://dx.doi.org/10.1136/annrheumdis-2021-220438DOI Listing
September 2021

What are the topics you care about making trials in lupus more effective? Results of an Open Space meeting of international lupus experts.

Lupus Sci Med 2021 05;8(1)

Policlinic and Hiller Research Unit, Heinrich Heine University Düsseldorf, Dusseldorf, Nordrhein-Westfalen, Germany.

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about 'What are the topics you care about for making trials in lupus more effective?'. The Open Space is a participant-driven technology, where the discussion topics and schedule are selected during the meeting by all participants and discussion rounds are led by the people attending encouraging active contributions. Eleven topics were selected for further discussion, of which 6 were voted to be more intensively discussed in two consecutive rounds. Major topics were the optimal handling of glucocorticoids in clinical trials, the improvement of outcome measures, reducing or controlling the placebo response and the identification of biomarkers and stratification parameters. Further, the importance of local and international networks was emphasised. By networking, collaborations are facilitated, patient recruitment is more efficient and treatment can be harmonised thus lead to more successful SLE trials. Further discussions are needed to substantiate the results and develop new trial designs.
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http://dx.doi.org/10.1136/lupus-2021-000506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141446PMC
May 2021

Management of Lupus Nephritis.

J Clin Med 2021 Feb 9;10(4). Epub 2021 Feb 9.

Department of Rheumatology, Cliniques Universitaires Saint-Luc and Institut de Recherche Expérimentale et Clinique, UCLouvain, 1200 Bruxelles, Belgium.

Lupus nephritis (LN) is a frequent and severe manifestation of systemic lupus erythematosus. The main goal of the management of LN is to avoid chronic kidney disease (CKD). Current treatment strategies remain unsatisfactory in terms of complete renal response, prevention of relapses, CKD, and progression to end-stage kidney disease. To improve the prognosis of LN, recent data suggest that we should modify our treat-to-target approach by including, in addition to a clinical target, a pathological target and switch from conventional sequential therapy to combination therapy. Here, we also review the results of recent controlled randomized trials.
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http://dx.doi.org/10.3390/jcm10040670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916202PMC
February 2021

Improving medication adherence in patients with lupus nephritis.

Kidney Int 2021 02;99(2):285-287

Service de Rhumatologie, Cliniques Universitaires Saint-Luc, 10 avenue Hippocrate, 1200 Bruxelles, Belgique; Pôle de pathologies rhumatismales inflammatoires et systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Louvain-la-Neuve, Belgium.

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http://dx.doi.org/10.1016/j.kint.2020.10.037DOI Listing
February 2021

Very Late-Onset Systemic Lupus Erythematosus as Unusual Cause of Reversible Functional and Cognitive Impairments in an Octogenarian Patient.

Eur J Case Rep Intern Med 2020 7;7(8):001570. Epub 2020 May 7.

Rheumatology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

While functional decline is a common syndrome in geriatric medicine, the diagnosis of the underlying disease can be complex. We present a case of very late-onset systemic lupus erythematosus with fever, arthritis, lymphadenopathy, sicca syndrome, pleurisy, renal impairment and reversible functional and cognitive impairments. Prompt improvement was observed on prednisolone and hydroxychloroquine.

Learning Points: Systemic lupus erythematosus (SLE) rarely occurs in octogenarian patients.In such oldest old patients, SLE may predominantly present with subacute cognitive and functional impairments.Low-dose treatment (prednisolone 7.5 mg/day and hydroxychloroquine 5 mg/kg/day) can reverse all SLE manifestations within 1 month.
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http://dx.doi.org/10.12890/2020_001570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417056PMC
May 2020

Comparison of the disease activity score and the revised EUSTAR activity index in diffuse cutaneous systemic sclerosis patients.

Clin Exp Rheumatol 2020 May-Jun;38 Suppl 125(3):53-58. Epub 2020 Jun 15.

Department of Rheumatology, Cliniques Universitaires Saint-Luc, Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Université Catholique de Louvain, Brussels, Belgium.

Objectives: To compare the ability of the Disease Activity Score (DAS) and the Revised EUSTAR Activity Index (RAI) to detect diffuse cutaneous systemic sclerosis (dcSSc) patients requiring treatment intensification in a Belgian cohort.

Methods: We retrospectively compared the widely used DAS and the recently developed RAI in a longitudinal cohort (median follow-up of 42 months) of 62 dcSSc patients, of whom 30 with a disease duration ≤3 years at inclusion. Active disease was defined by a DAS ≥3/10 or a RAI ≥2.5/10. We chose a pragmatic definition to assess disease progression, namely any start or increase of glucocorticoids, immunosuppressants, anti-endothelin receptors or prostanoids. Sensitivity, specificity, negative and positive predictive values (NPV and PPV) of DAS and RAI for prediction of actual treatment changes were compared by ROC curves.

Results: According to RAI, 48% (of all dcSSc patients) and 55% (of ≤3 years dcSSc patients) were categorised as effectively active during follow-up while 34% and 43% according to DAS, respectively. The PPV and the NPV to detect disease progression, in ≤3 years dcSSc patients, were 59% and 89% for RAI vs 73% and 87% for DAS, respectively. The area under ROC curves were high for both scores (0.85 for RAI and 0.87 for DAS).

Conclusions: Both scores are proven as predictive to detect disease activity, with a slightly better sensitivity for RAI. By contrast, RAI lacks specificity in predicting a real need for treatment intensification, thereby possibly leading to overtreatment.
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September 2020

Per-protocol repeat kidney biopsy portends relapse and long-term outcome in incident cases of proliferative lupus nephritis.

Rheumatology (Oxford) 2020 11;59(11):3424-3434

Rheumatology Department, Cliniques Universitaires Saint-Luc and Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain.

Objectives: In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment.

Methods: Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3-26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies.

Results: Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR < 1.0 g/g still had a high degree of histological activity (AI > 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8-178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies.

Conclusion: Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.
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http://dx.doi.org/10.1093/rheumatology/keaa129DOI Listing
November 2020

Tapering of biological antirheumatic drugs in rheumatoid arthritis patients is achievable and cost-effective in daily clinical practice: data from the Brussels UCLouvain RA Cohort.

Arthritis Res Ther 2020 04 28;22(1):96. Epub 2020 Apr 28.

Rheumatology, Cliniques universitaires Saint-Luc - Université catholique de Louvain - Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium.

Background/purpose: Studies have demonstrated that rheumatoid arthritis (RA) patients who achieve low disease activity or remission are able to taper biological disease-modifying antirheumatic drugs (bDMARDs). The aim of this study was to evaluate the proportion of patients in whom bDMARDs can be tapered in daily practice and to analyse the characteristics of these patients. Other objectives were to analyse which bDMARDs are more suitable for dose reduction and the cost savings.

Results: Data from 332 eligible RA patients from our Brussels UCLouvain cohort were retrospectively analysed; 140 patients (42.1%) received a tapered regimen, and 192 received stable doses of bDMARDs. The age at diagnosis (43.1 vs 38.7 years, p = 0.04), health assessment questionnaire (HAQ) score (1.3 vs 1.5, p = 0.048), RF positivity rate (83.3 vs 72.9%, p = 0.04) and disease duration at the time of bDMARD introduction (9.7 vs 12.1 years, p = 0.034) were significantly different between the reduced-dose and stable-dose groups. Interestingly, relatively more patients receiving a tapered dose were treated with a combination of bDMARDs and methotrexate (MTX) (86.7% vs 73.8%, p = 0.005). In our cohort, anti-TNF agents were the most commonly prescribed medications (68%). Only 15 patients experienced a flare during follow-up. Adalimumab, etanercept and rituximab were the most common bDMARDs in the reduced-dose group and were associated with the most important reductions in annual cost.

Conclusion: In daily practice, tapering bDMARDs in RA patients who have achieved low disease activity or remission is an achievable goal in a large proportion of patients, thereby reducing potential side effects and annual drug-associated costs. The combination of bDMARDs with MTX could improve the success of dose reduction attempts.

Trial Registration: This retrospective non-interventional study was retrospectively registered with local ethics approval.
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http://dx.doi.org/10.1186/s13075-020-02165-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189594PMC
April 2020

2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis.

Ann Rheum Dis 2020 06 27;79(6):713-723. Epub 2020 Mar 27.

Rheumatology and Clinical Immunology Unit, "Attikon" University Hospital, Athens, Greece

Objective: To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN).

Methods: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.

Results: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.

Conclusions: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.
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http://dx.doi.org/10.1136/annrheumdis-2020-216924DOI Listing
June 2020

Unusual cause of lymphadenopathy in a patient with systemic sclerosis.

Clin Exp Rheumatol 2020 May-Jun;38 Suppl 125(3):178-179. Epub 2020 Mar 19.

Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, Institut de Recherche Expérimentale et Clinique, UC Louvain, Bruxelles, and Service de Rhumatologie des Cliniques Universitaires Saint Luc, Bruxelles, Belgium.

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September 2020

Prediction of prognosis and renal outcome in lupus nephritis.

Lupus Sci Med 2020 18;7(1):e000389. Epub 2020 Feb 18.

Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

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.
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http://dx.doi.org/10.1136/lupus-2020-000389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046967PMC
May 2021

Toll-like receptor 3 increases antigen-presenting cell responses to a pro-apoptotic stimulus, yet does not contribute to systemic lupus erythematosus genetic susceptibility.

Clin Exp Rheumatol 2020 Sep-Oct;38(5):881-890. Epub 2020 Jan 20.

Pôle de Pathologies Rhumatismales Systémiques et Inflammatoires, Institut de Recherche Expérimentale et Clinique, Univ. Catholique de Louvain, and Dept.of Rheumatology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

Objectives: TLR3 mediates skin solar injury by binding nuclear material released from apoptotic keratinocytes, resulting in the production of pro-inflammatory cytokines. Because the TLR3 gene is located in 4q35, a known systemic lupus erythematosus (SLE) susceptibility locus, we wondered whether TLR3 single nucleotide polymorphisms (SNPs) were associated with inflammatory mechanisms relevant to the development of SLE, and disease susceptibility.

Methods: Functional assays were carried out in TLR3-transfected HEK293 cells and in monocyte-derived dendritic cells (moDCs). TLR3 and IFNβ immunofluorescence studies were performed in skin samples from 7 SLE patients and 3 controls. We performed a SNP association study in a discovery cohort of 153 patients and 105 controls, followed by a confirmation study in an independent cohort of 1,380 patients and 2,104 controls.

Results: TLR3 and IFNβ are overexpressed in SLE skin lesions. TLR3 overexpression in HEK293 cells amplifies their sensitivity to a pro-apoptotic stimulus. Taking advantage of a naturally occurring polymorphic TLR3 variant (rs3775291) that weakly versus strongly responds to poly I:C stimulation, we found that TLR3 is associated with amplified apoptotic responses, production of the Ro/SSA autoantigen and increased maturation of myeloid-derived dendritic cells (moDC) after exposure to UV irradiation. However, TLR3 SNPs are not associated with susceptibility to SLE in a large population of patients and controls.

Conclusions: TLR3 is overexpressed in SLE skin lesions and amplifies apoptotic and inflammatory responses to UV-irradiation in antigen-presenting cells in vitro. However, TLR3 SNPs do not impact susceptibility to the development of the disease.
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October 2020

IFN-α kinoid in systemic lupus erythematosus: results from a phase IIb, randomised, placebo-controlled study.

Ann Rheum Dis 2020 03 23;79(3):347-355. Epub 2019 Dec 23.

Department of Physiology, College of Medicine, University of the Philippines Manila and ManilaMed, Manila, Philippines.

Objective: To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care.

Methods: Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering.

Results: IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable.

Conclusions: IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering.

Trial Registration Number: NCT02665364.
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http://dx.doi.org/10.1136/annrheumdis-2019-216379DOI Listing
March 2020

STAT3 phosphorylation mediates the stimulatory effects of interferon alpha on B cell differentiation and activation in SLE.

Rheumatology (Oxford) 2020 03;59(3):668-677

Pôle de pathologies rhumatismales inflammatoires et systémiques, Institut de Recherche Expérimentale et Cliniques, Université catholique de Louvain, Brussels, Belgium.

Objective: Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation.

Methods: Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals.

Results: Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation.

Conclusion: IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.
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http://dx.doi.org/10.1093/rheumatology/kez354DOI Listing
March 2020

Response to Correspondence to 'Time to change the primary outcome of lupus trials' by Oon .

Ann Rheum Dis 2021 07 20;80(7):e110. Epub 2019 Aug 20.

Pôle de Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium

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http://dx.doi.org/10.1136/annrheumdis-2019-216160DOI Listing
July 2021

Overexpression of ubiquitin-specific peptidase 15 in systemic sclerosis fibroblasts increases response to transforming growth factor β.

Rheumatology (Oxford) 2019 04;58(4):708-718

Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Belgium.

Objective: Ubiquitination of proteins leads to their degradation by the proteasome, and is regulated by ubiquitin ligases and substrate-specific ubiquitin-specific peptidases (USPs). The ubiquitination process also plays important roles in the regulation of cell metabolism and cell cycle. Here, we found that the expression of several USPs is increased in SSc tenosynovial and skin biopsies, and we demonstrated that USP inhibition decreases TGF-β signalling in primary fibroblast cell lines.

Methods: High-density transcriptomic studies were performed using total RNA obtained from SSc tenosynovial samples. Confirmatory immunostaining experiments were performed on tenosynovial and skin samples. In vitro experiments were conducted in order to study the influence of USP modulation on responses to TGF-β stimulation.

Results: Tenosynovial biopsies from SSc patients overexpressed known disease-associated gene pathways: fibrosis, cytokines and chemokines, and Wnt/TGF-β signalling, but also several USPs. Immunohistochemistry experiments confirmed the detection of USPs in the same samples, and in SSc skin biopsies. Exposure of primary fibroblast cell lines to TGF-β induced USP gene expression. The use of a pan-USP inhibitor decreased SMAD3 phosphorylation, and expression of COL1A1, COL3A1 and fibronectin gene expression in TGF-β-stimulated fibroblasts. The effect of the USP inhibitor resulted in increased SMAD3 ubiquitination, and was blocked by a proteasome inhibitor, thereby confirming the specificity of its action.

Conclusion: Overexpression of several USPs, including USP15, amplifies fibrotic responses induced by TGF-β, and is a potential therapeutic target in SSc.
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http://dx.doi.org/10.1093/rheumatology/key401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434377PMC
April 2019

Ustekinumab: a promising new drug for SLE?

Lancet 2018 10 21;392(10155):1284-1286. Epub 2018 Sep 21.

Service de Rhumatologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Université Catholique de Louvain, Brussels, Belgium.

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http://dx.doi.org/10.1016/S0140-6736(18)32330-4DOI Listing
October 2018

Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes.

Arthritis Rheumatol 2019 03 1;71(3):411-419. Epub 2019 Feb 1.

Ohio State University Wexner Medical Center, Columbus.

Objective: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials.

Methods: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression.

Results: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.89-0.92).

Conclusion: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.
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http://dx.doi.org/10.1002/art.40724DOI Listing
March 2019

Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis.

Ann Rheum Dis 2018 12 31;77(12):1782-1789. Epub 2018 Jul 31.

Department of Rheumatology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

Objectives: Chronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.

Methods: We performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.

Results: A group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.

Conclusion: Interstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.
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http://dx.doi.org/10.1136/annrheumdis-2018-213485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241616PMC
December 2018

Time to change the primary outcome of lupus trials.

Ann Rheum Dis 2019 05 19;78(5):581-582. Epub 2018 Jun 19.

Pôle de Rhumatologie, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

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http://dx.doi.org/10.1136/annrheumdis-2018-213788DOI Listing
May 2019

International and multidisciplinary expert recommendations for the use of biologics in systemic lupus erythematosus.

Autoimmun Rev 2017 Jun 18;16(6):650-657. Epub 2017 Apr 18.

Internal Medicine Department, Lille University Hospital, University of Lille, Lille, France.

Background/purpose: Despite conventional immunosuppressants, active and steroid-dependent systemic lupus erythematosus (SLE) represents a therapeutic challenge. Only one biologic, belimumab, has been approved, but other biologics are sometimes used off-label. Given the lack of evidence-based data in some clinical situations encountered in real life, we developed expert recommendations for the use of biologics for SLE.

Methods: The recommendations were developed by a formal consensus method. This method aims to formalize the degree of agreement among experts by identifying, through iterative ratings with feedback, the points on which experts agree, disagree or are undecided. Hence, the recommendations are based on the agreed-upon points. We gathered the opinion of 59 French-speaking SLE experts from 3 clinical networks dedicated to systemic autoimmune diseases (FLEUR, IMIDIATE, FAI2R) from Algeria, Belgium, France, Italy, Morocco, Switzerland and Tunisia. Represented medical specialities were internal medicine (49%), rheumatology (34%), nephrology (7%), dermatology (5%), pediatrics (3%) and cardiology (2%). Two methodologists and 3 strictly independent SLE expert groups contributed to developing these recommendations: a steering group (SG) (n=9), an evaluation group (EG) (n=28) and a reading group (RG) (n=22). Preliminary recommendations were drafted by the SG, then proposed to the EG. Each EG member rated the degree of agreement from 1 to 9 (1: lowest; 9: strongest) for each recommendation. After 2 rating rounds, the SG submitted a new version of the recommendations to the RG. With comments from the RG, the SG finalised the recommendations.

Results: A total of 17 final recommendations were formulated by the SG, considering all agreement scores and comments by the EG and RG members and the two methodologists. These recommendations define the subset of patients who require a biologic; the type of biologics to use (belimumab, rituximab, etc.) depending on the organ involvement and associated co-treatments; what information should be given to patients; and how to evaluate treatment efficacy and when to consider discontinuation.

Conclusion: Overall, 17 recommendations for the good use of biologics in SLE were formulated by a large panel of SLE experts to provide guidance for clinicians in daily practice. These recommendations will be regularly updated according to the results of new randomized trials and increasing real life experience.
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http://dx.doi.org/10.1016/j.autrev.2017.04.011DOI Listing
June 2017

Brief Report: The Euro-Lupus Low-Dose Intravenous Cyclophosphamide Regimen Does Not Impact the Ovarian Reserve, as Measured by Serum Levels of Anti-Müllerian Hormone.

Arthritis Rheumatol 2017 06 3;69(6):1267-1271. Epub 2017 May 3.

Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.

Objective: The Euro-Lupus regimen of low-dose intravenous cyclophosphamide (IV CYC) (cumulative dose of 3 gm) was developed to reduce gonadal toxicity. To address the possibility of a marginal effect on the ovarian reserve, we measured serum titers of anti-Müllerian hormone (AMH) in patients with systemic lupus erythematosus (SLE) treated with the Euro-Lupus regimen and compared them with those measured in patients who were treated with higher doses of IV CYC or were never treated with IV CYC.

Methods: Serum AMH levels were measured by enzyme-linked immunosorbent assay in a cohort of 155 premenopausal SLE patients; 30 of these patients had been treated with the Euro-Lupus regimen, and 24 had received higher doses of IV CYC. None had received oral CYC. AMH levels were age-adjusted using a slope computed from levels measured across the group of SLE patients who had not been treated with IV CYC. Demographic and clinical data were collected.

Results: Serum titers of AMH measured in SLE patients treated with the Euro-Lupus IV CYC regimen (median dose 1.46 ng/ml) did not differ from those measured in patients never treated with the cytotoxic drug (median 1.85 ng/ml). As expected, patients given >6 gm of IV CYC had significantly lower serum titers of AMH (median 0.83 ng/ml) compared with those never treated with IV CYC (P = 0.047). Median serum AMH titers did not change before (1.24 ng/ml) and after (2.50 ng/ml) treatment with the Euro-Lupus IV CYC regimen in the subset of patients for whom paired samples could be tested (P = 0.43).

Conclusion: The Euro-Lupus regimen of low-dose IV CYC does not impact the ovarian reserve of SLE patients and can therefore be proposed as treatment in patients seeking to become pregnant.
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http://dx.doi.org/10.1002/art.40079DOI Listing
June 2017

Off-label use of rituximab for systemic lupus erythematosus in Europe.

Lupus Sci Med 2016 6;3(1):e000163. Epub 2016 Sep 6.

Department of Sperimental and Clinical Medicine , University of Florence , Firenze , Italy.

Objectives: Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy.

Methods: Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries.

Results: The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy.

Conclusions: RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.
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http://dx.doi.org/10.1136/lupus-2016-000163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013507PMC
September 2016

Effects of two different exercise programs on chronic fatigue in lupus patients.

Acta Clin Belg 2016 Dec 1;71(6):403-406. Epub 2016 Jul 1.

b Rheumatology Department, Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques , Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain , Bruxelles , Belgium.

Objectives: Fatigue is a major complaint of patients with systemic lupus erythemasosus (SLE). While several studies have demonstrated the benefits of exercise, the effects of supervised training were never compared to those of home training.

Methods: Forty-five SLE patients suffering from fatigue, as defined by Krupp's fatigue severity scale (FSS) ≥ 3.7, were randomized in 3 groups: supervised training group (STG), home training group (HTG), and control group (CG). Primary outcome was the change in FSS at month 3. In parallel, we measured the physical working capacity measured at 75% of the predicted maximal heart rate (PWC75%/kg) and the modified Borg's scale to assess perception of exertion.

Results: Both STG and HTG, but not the CG, statistically improved their FSS at month 3. By contrast, the PWC75%/kg and the Borg's scale did not improve in none of the groups. Surprinsingly, compliance was similar and low (±50%) in both exercise groups. Moreover, less compliant patients improved their fatigue as much as more compliant patients.

Conclusions: Patients included in the STG and the HTG similarly improved their fatigue, irrespectively of their level of compliance, raising the possibility that the beneficial effect on fatigue was not only exercise-related.
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http://dx.doi.org/10.1080/17843286.2016.1200824DOI Listing
December 2016

Interferon α kinoid induces neutralizing anti-interferon α antibodies that decrease the expression of interferon-induced and B cell activation associated transcripts: analysis of extended follow-up data from the interferon α kinoid phase I/II study.

Rheumatology (Oxford) 2016 Oct 28;55(10):1901-5. Epub 2016 Jun 28.

Institut de Recherche Expérimentale et Clinique, Pôle de pathologies rhumatismales inflammatoires et systémiques, Université catholique de Louvain Département de Rhumatologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

Objective: IFN α Kinoid (IFN-K) is a therapeutic vaccine composed of IFNα2b coupled to a carrier protein. In a phase I/II placebo-controlled trial, we observed that IFN-K significantly decreases the IFN gene signature in whole blood RNA samples from SLE patients. Here, we analysed extended follow-up data from IFN-K-treated patients, in order to evaluate persistence of neutralizing anti-IFNα Abs antibodies (Abs), and gene expression profiling.

Methods: Serum and whole blood RNA samples were obtained in IFN-K-treated patients included in the follow-up study, in order to determine binding and neutralizing anti-IFNα Ab titres, and perform high-throughput transcriptomic studies.

Results: Neutralization studies of 13 IFNα subtypes demonstrated the polyclonal nature of the Ab response induced by IFN-K. Follow-up analyses in six patients confirmed a significant correlation between neutralizing anti-IFNα Ab titres and decrease in IFN scores compared to baseline. These analyses also revealed an inhibitory effect of IFNα blockade on the expression of B cell associated transcripts.

Conclusions: IFN-K induces a polyclonal anti-IFNα response that decreases IFN- and B cell-associated transcripts.

Trial Registration: ClinicalTrials.gov, clinicaltrials.gov, NCT01058343.
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http://dx.doi.org/10.1093/rheumatology/kew262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034220PMC
October 2016

Why will lupus nephritis trials not fail anymore?

Rheumatology (Oxford) 2017 May;56(5):677-678

Service de Rhumatologie, Cliniques Universitaires Saint-Luc.

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http://dx.doi.org/10.1093/rheumatology/kew252DOI Listing
May 2017

Higher expression of TNFα-induced genes in the synovium of patients with early rheumatoid arthritis correlates with disease activity, and predicts absence of response to first line therapy.

Arthritis Res Ther 2016 Jan 20;18:19. Epub 2016 Jan 20.

Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, B2.5390, 1200, Brussels, Belgium.

Background: IL6-related T cell activation and TNFα-dependent cell proliferation are major targets of therapy in the RA synovium. We investigated whether expression of these pathways in RA synovial biopsies is associated with disease activity and response to therapy.

Method: Correlation and gene set enrichment studies were performed using gene expression profiles from RA synovial biopsies. Immunostaining experiments of GADD45B and PDE4D were performed on independent additional sets of early untreated RA samples, obtained in two different centers by needle-arthroscopy or US-guided biopsies.

Results: In 65 RA synovial biopsies, transcripts correlating with disease activity were strongly enriched in TNFα-induced genes. Out of the individual variables used in disease-activity scores, tender joint count, swollen joint count and physician's global assessment, but not CRP or patient's global assessment displayed a similar correlation with the expression of TNFα-dependent genes. In addition, TNFα-induced genes were also significantly enriched in transcripts over-expressed in synovial biopsy samples obtained from poor-responders to methotrexate or tocilizumab, prior to initiation of therapy. GADD45B (induced by TNFα in monocytes) and PDE4D (induced by TNFα in FLS) immunostaining was significantly higher in overall poor-responders to therapy in 46 independent baseline samples obtained from early untreated RA patients prior to initiation of therapy. GADD45B (but not PDE4D) immunostaining was significantly higher in the sub-group of patients with poor-response to methotrexate therapy, and this was confirmed in another population of methotrexate-treated patients.

Conclusion: Higher expression of TNFα-induced transcripts in early RA synovitis is associated with higher disease activity, and predicts poor response to first-line therapy. That over-expression of TNFα-induced genes predicts poor-response to therapy regardless of the drug administered, indicates that this molecular signature is associated with disease severity, rather than with specific pathways of escape to therapy.
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http://dx.doi.org/10.1186/s13075-016-0919-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719339PMC
January 2016

Moving East: the Euro-Lupus Nephritis regimen in Asia.

Kidney Int 2016 Jan;89(1):25-7

Rheumatology Department, Cliniques Universitaires Saint-Luc, Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium. Electronic address:

Treatment of lupus nephritis is more evidenced-based than ever. Yet many areas of uncertainty persist. The article by Rathi et al. brings a piece to the puzzle by comparing, in a group of Indian patients, the Euro-Lupus low-dose i.v. cyclophosphamide regimen with mycophenolate mofetil. Although some caveats must be raised, the results suggest that, after crossing the Atlantic, the Euro-Lupus regimen may well be moving East.
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http://dx.doi.org/10.1016/j.kint.2015.11.003DOI Listing
January 2016
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