Management of systemic lupus erythematosus: a systematic literature review informing the 2023 update of the EULAR recommendations.

OBJECTIVES: To analyse the new evidence (2018-2022) for the management of systemic lupus erythematosus (SLE) to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations. METHODS: Systematic literature reviews were performed in the Medline and the Cochrane Library databases capturing publications from 1 January 2018 through 31 December 2022, according to the EULAR standardised operating procedures. The research questions focused on five different domains, namely the benefit/harm of SLE treatments, the benefits from the attainment of remission/low disease activity, the risk/benefit from treatment tapering/withdrawal, the management of SLE with antiphospholipid syndrome and the safety of immunisations against varicella zoster virus and SARS-CoV2 infection. A Population, Intervention, Comparison and Outcome framework was used to develop search strings for each research topic. RESULTS: We identified 439 relevant articles, the majority being observational studies of low or moderate quality. High-quality randomised controlled trials (RCTs) documented the efficacy of the type 1 interferon receptor inhibitor, anifrolumab, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN), when compared with standard of care. For the treatment of specific organ manifestations outside LN, a lack of high-quality data was documented. Multiple observational studies confirmed the beneficial effects of attaining clinical remission or low disease activity, reducing the risk for multiple adverse outcomes. Two randomised trials with some concerns regarding risk of bias found higher rates of relapse in patients who discontinued glucocorticoids (GC) or immunosuppressants in SLE and LN, respectively, yet observational cohort studies suggest that treatment withdrawal might be feasible in a subset of patients. CONCLUSION: Anifrolumab and belimumab achieve better disease control than standard of care in extrarenal SLE, while combination therapies with belimumab and voclosporin attained higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favourable long-term outcomes. In patients achieving these targets, GC and immunosuppressive therapy may gradually be tapered. Cite Now.

EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.

OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.

Annals of the Rheumatic Diseases collection on lupus nephritis (2019-2022): novel insights and advances in therapy.

No single organ has received as much attention in systemic lupus erythematosus (SLE) as the kidneys. During the period 2019-2022, the Annals of the Rheumatic Diseases published several original papers, brief reports and letters that further elucidate the pathogenesis and advance the management of LN. A selection of representative original papers is highlighted in this review.

Preventing infections in immunocompromised patients with kidney diseases: vaccines and antimicrobial prophylaxis.

The coronavirus disease 2019 (COVID-19) pandemic revealed that our understanding of infectious complications and strategies to mitigate severe infections in patients with glomerular diseases is limited. Beyond COVID-19, there are several infections that specifically impact care of patients receiving immunosuppressive measures. This review will provide an overview of six different infectious complications frequently encountered in patients with glomerular diseases, and will focus on recent achievements in terms of vaccine developments and understanding of the use of specific antimicrobial prophylaxis. These include influenza virus, Streptococcus pneumoniae, reactivation of a chronic or past infection with hepatitis B virus in cases receiving B-cell depletion, reactivation of cytomegalovirus, and cases of Pneumocystis jirovecii pneumonia in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Varicella zoster virus infections are particularly frequent in patients with systemic lupus erythematosus and an inactivated vaccine is available to use as an alternative to the attenuated vaccine in patients receiving immunosuppressants. As with COVID-19 vaccines, vaccine responses are generally impaired in older patients, and after recent administration of B-cell depleting agents, and high doses of mycophenolate mofetil and other immunosuppressants. Strategies to curb infectious complications are manifold and will be outlined in this review.

The association between lupus serology and disease outcomes: A systematic literature review to inform the treat-to-target approach in systemic lupus erythematosus.

INTRODUCTION: Serological markers such as anti-double stranded (ds)DNA antibodies and complement fractions C3/C4, are integral components of disease activity assessment in patients with systemic lupus erythematosus (SLE). However, it remains uncertain whether treatment should aim at restoration of serological abnormalities. OBJECTIVES: To analyze and critically appraise the literature on the prognostic impact of active lupus serology despite clinical disease quiescence. METHODS: A systematic literature review was performed in PubMed and EMBASE using the PICOT(S) (population, index, comparator, outcome(s), timing, setting) system to identify studies evaluating the association of serum anti-dsDNA, C3 and C4 levels assessed at the time of clinical remission or during the disease course, against the risk for impending flares and organ damage. Risk of bias was determined by the Quality in Prognosis Studies and ROB2 tools for observational and randomized controlled studies, respectively. RESULTS: Fifty-three studies were eligible, the majority having moderate (70.6%) or high (11.8%) risk of bias and not adequately controlling for possible confounders. C3 hypocomplementemia during stable/inactive disease was associated with increased risk (2.0 to 3.8-fold) for subsequent flare in three out of seven relevant studies. Three out of four studies reported a significant effect of C4 hypocomplementemia on flare risk, including one study in lupus nephritis (likelihood ratio-positive 12.0). An increased incidence of flares (2.0 to 2.8-fold) was reported in 11 out of 16 studies assessing the prognostic effect of high anti-dsDNA, and similarly, the majority of studies yielded significant relationships with renal flares. Six studies examined the effect of combined (rather than individual) serological activity, confirming the increased risk (2.0 to 2.7-fold) for relapses. No consistent association was found with organ damage. CONCLUSION: Notwithstanding the heterogeneity and risk of bias, existing evidence indicates a modest association between abnormal serology and risk for flare in patients with stable/inactive SLE. These findings provide limited support for inclusion of serology in the treat-to-target approach but rationalize to further investigate their prognostic implications especially in lupus nephritis.

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

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.

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.

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.

An Update on the Diagnosis and Management of Lupus Nephritis.

PURPOSE OF REVIEW: Update on the diagnosis, treatment, and monitoring of lupus nephritis. RECENT FINDINGS: The recent criteria enable the earlier classification of lupus nephritis based on kidney biopsy and compatible serology. Treatment of active nephritis includes low-dose intravenous cyclophosphamide or mycophenolate, followed by maintenance immunosuppression. Recent trials have suggested superiority of regimens combining mycophenolate with either calcineurin inhibitor or belimumab, although their long-term benefit/risk ratio has not been determined. Encouraging results with novel anti-CD20 antibodies confirm the effectiveness of B cell depletion. Achievement of low-grade proteinuria (< 700-800 mg/24 h) at 12-month post-induction is linked to favorable long-term outcomes and could be considered in a treat-to-target strategy. Also, repeat kidney biopsy can guide the duration of maintenance immunosuppression. Lupus nephritis has increased cardiovascular disease burden necessitating risk-reduction strategies. An expanding spectrum of therapies coupled with ongoing basic/translational research can lead to individualized medical care and improved outcomes in lupus nephritis.

2019 update of the EULAR recommendations for the management of systemic lupus erythematosus.

Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.

Access to kidney transplantation in European adults aged 75-84 years and related outcomes: an analysis of the European Renal Association-European Dialysis and Transplant Association Registry.

To what extent access to, and allocation of kidney transplants and survival outcomes in patients aged ≥75 years have changed over time in Europe is unclear. We included patients aged ≥75-84 years (termed older adults) receiving renal replacement therapy in thirteen European countries between 2005 and 2014. Country differences and time trends in access to, and allocation of kidney transplants were examined. Survival outcomes were determined by Cox regression analyses. Between 2005 and 2014, 1392 older adult patients received 1406 transplants. Access to kidney transplantation varied from ~0% (Slovenia, Greece and Denmark) to ~4% (Norway and various Spanish regions) of all older adult dialysis patients, and overall increased from 0.3% (2005) to 0.9% (2014). Allocation of kidney transplants to older adults overall increased from 0.8% (2005) to 3.2% (2014). Seven-year unadjusted patient and graft survival probabilities were 49.1% (95% confidence interval, 95% CI: 43.6; 54.4) and 41.7% (95% CI: 36.5; 46.8), respectively, with a temporal trend towards improved survival outcomes. In conclusion, in the European dialysis population aged ≥75-84 years access to kidney transplantation is low, and allocation of kidney transplants remains a rare event. Though both are increasing with time and vary considerably between countries. The trend towards improved survival outcomes is encouraging. This information can aid informed decision-making regarding treatment options.

Lupus Nephritis: Improving Treatment Options.

Despite improvements in patient and renal death rates following the introduction of potent immunosuppressive drugs in earlier decades, a sizeable fraction of patients with lupus nephritis is burdened with suboptimal or delayed responses, relapses, chronic use of glucocorticoids and accrual of renal (chronic renal insufficiency) and extra-renal organ damage. The recently approved combinatory treatments comprising belimumab or voclosporin added to conventional agents, especially mycophenolate, hold promise for further improving disease outcomes and enabling a faster steroid tapering, thus being relevant to the treat-to-target context. However, it remains uncertain whether these dual regimens should become the first-line choice for all patients or instead be prioritized to certain subgroups. In the present article, we summarize the existing lupus nephritis management recommendations, followed by a critical appraisal of the randomized trials of belimumab and voclosporin, as well as the available data on obinutuzumab and other novel compounds under development. We conclude that pending the identification of accurate clinical, histological, or translational predictors for guiding personalized decisions, it is of utmost importance that lupus nephritis patients are monitored closely with appropriate treatment adjustments aiming at a prompt, deep response to ensure long-term preservation of kidney function.

Trends in Mortality Due to Myocardial Infarction, Stroke, and Pulmonary Embolism in Patients Receiving Dialysis.

Importance: During the past decades, improvements in the prevention and management of myocardial infarction, stroke, and pulmonary embolism have led to a decline in cardiovascular mortality in the general population. However, it is unknown whether patients receiving dialysis have also benefited from these improvements. Objective: To assess the mortality rates for myocardial infarction, stroke, and pulmonary embolism in a large cohort of European patients receiving dialysis compared with the general population. Design, Setting, and Participants: In this cohort study, adult patients who started dialysis between 1998 and 2015 from 11 European countries providing data to the European Renal Association Registry were and followed up for 3 years. Data were analyzed from September 2020 to February 2022. Exposures: Start of dialysis. Main Outcomes and Measures: The age- and sex-standardized mortality rate ratios (SMRs) with 95% CIs were calculated by dividing the mortality rates in patients receiving dialysis by the mortality rates in the general population for 3 equal periods (1998-2003, 2004-2009, and 2010-2015). Results: In total, 220 467 patients receiving dialysis were included in the study. Their median (IQR) age was 68.2 (56.5-76.4) years, and 82 068 patients (37.2%) were female. During follow-up, 83 912 patients died, of whom 7662 (9.1%) died because of myocardial infarction, 5030 (6.0%) died because of stroke, and 435 (0.5%) died because of pulmonary embolism. Between the periods 1998 to 2003 and 2010 to 2015, the SMR of myocardial infarction decreased from 8.1 (95% CI, 7.8-8.3) to 6.8 (95% CI, 6.5-7.1), the SMR of stroke decreased from 7.3 (95% CI, 7.0-7.6) to 5.8 (95% CI, 5.5-6.2), and the SMR of pulmonary embolism decreased from 8.7 (95% CI, 7.6-10.1) to 5.5 (95% CI, 4.5-6.6). Conclusions and Relevance: In this cohort study of patients receiving dialysis, mortality rates for myocardial infarction, stroke, and pulmonary embolism decreased more over time than in the general population.

Cardiovascular Disease in Systemic Lupus Erythematosus: Recent Data on Epidemiology, Risk Factors and Prevention.

Systemic Lupus Erythematosus (SLE) is associated with increased risk for accelerated atherosclerosis and cardiovascular (CV) events including coronary heart disease, cerebrovascular and peripheral artery disease. CV events occur both early and late during the disease course, with younger patients being at much higher risk than age-matched counterparts. The risk cannot be fully accounted for by the increased prevalence of traditional atherosclerotic factors and may be due to pathophysiologic intermediates such as type I interferons and other inflammatory cytokines, oxidative stress, activated granulocytes and production of extracellular chromatin traps, antiphospholipid and other autoantibodies causing dysfunction of lipoproteins, altogether resulting in endothelial injury and pro-atherogenic dyslipidaemia. These mechanisms may be further aggravated by chronic intake of prednisone (even at doses <7.5 mg/day), whereas immunomodulatory drugs, especially hydroxychloroquine, may exert antiatherogenic properties. To date, there is a paucity of randomized studies regarding the effectiveness of preventative strategies and pharmacological interventions specifically in patients with SLE. Nevertheless, both the European League Against Rheumatism recommendations and extrapolated evidence from the general population emphasize that SLE patients should undergo regular monitoring for atherosclerotic risk factors and calculation of the 10-year CV risk. Risk stratification should include diseaserelated factors and accordingly, general (lifestyle modifications/smoking cessation, antihypertensive and statin treatment, low-dose aspirin in selected cases) and SLE-specific (control of disease activity, minimization of glucocorticoids, use of hydroxychloroquine) preventive measures be applied as appropriate. Further studies will be required regarding the use of non-invasive tools and biomarkers for CV assessment and of risk-lowering strategies tailored to SLE.

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations.

OBJECTIVES: To analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations. METHODS: According to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012. RESULTS: We identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500-700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b). CONCLUSIONS: There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.

Transition to severe phenotype in systemic lupus erythematosus initially presenting with non-severe disease: implications for the management of early disease.

OBJECTIVE: Changes in the care of patients with SLE dictate a re-evaluation of its natural history and risk factors for disease deterioration and damage accrual. We sought to decipher factors predictive of a deterioration in phenotype ('transition') in patients initially presenting with non-severe disease. METHODS: Patients from the 'Attikon' cohort with disease duration ≥1 year were included. Disease at diagnosis was categorised as mild, moderate or severe, based on the British Isles Lupus Assessment Group manifestations and physician judgement. 'Transition' in severity was defined as an increase in category of severity at any time from diagnosis to last follow-up. Multivariable logistic regression was performed to identify baseline factors associated with this transition. RESULTS: 462 patients were followed for a median (IQR) of 36 (120) months. At diagnosis, more than half (56.5%) had a mild phenotype. During disease course, transition to more severe forms was seen in 44.2%, resulting in comparable distribution among severity patterns at last follow-up (mild 28.4%, moderate 33.1%, severe 38.5%). Neuropsychiatric involvement at onset (OR 6.33, 95% CI 1.22 to 32.67), male sex (OR 4.53, 95% CI 1.23 to 16.60) and longer disease duration (OR 1.09 per 1 year, 95% CI 1.04 to 1.14) were independently associated with transition from mild or moderate to severe disease. Patients with disease duration ≥3 years who progressed to more severe disease had more than 20-fold increased risk to accrue irreversible damage. CONCLUSION: Almost half of patients with initially non-severe disease progress to more severe forms of SLE, especially men and patients with positive anti-double-stranded DNA or neuropsychiatric involvement at onset. These data may have implications for the management of milder forms of lupus.

Prevention and treatment of childhood and adolescent obesity: a systematic review of meta-analyses.

BACKGROUND: The goal of this systematic review is to synthesize the published meta-analyses assessing the role of nutritional, behavioral and physical activity factors/interventions on the prevention or treatment of pediatric and adolescent obesity. METHODS: An online search was conducted in PubMed (end-of-search: September 30, 2015); English-language meta-analyses pooling observational and/or interventional studies examining weight-related indices on children and adolescents were included. RESULTS: Sixty-six meta-analyses corresponding to more than 900,000 children and adolescents were retrieved. The majority of meta-analyses included interventional studies most of which referred to mixed or combined interventions, including components such as diet, physical activity and sedentary behavior reduction. Discrepancies between meta-analyses on observational and interventional studies were noted. Combined interventions including physical activity and nutritional modifications seemed to represent the most effective means for tackling childhood obesity. CONCLUSIONS: Synthesis of interventional or observational evidence may yield discrepant results. The combination of enhanced physical activity and improved nutrition emerged as a promising intervention in the fight against childhood/adolescent obesity. However, further research is needed about the most effective multidimensional prevention strategy.