Elsevier

The Lancet

Volume 393, Issue 10188, 8–14 June 2019, Pages 2344-2358
The Lancet

Review
Novel paradigms in systemic lupus erythematosus

https://doi.org/10.1016/S0140-6736(19)30546-XGet rights and content

Summary

The heterogeneity of systemic lupus erythematosus (SLE), long recognised by clinicians, is now challenging the entire lupus community, from geneticists to clinical investigators. Although the outlook for patients with SLE has greatly improved, many unmet needs remain, chief of which is the development of safer and more efficacious therapies. To develop innovative therapies, a far better understanding of SLE pathogenesis as it relates to the array of clinical phenotypes is needed. Additionally, to efficiently achieve these goals, the lupus community needs to refine existing clinical research tools and better adapt them to overcome the obstacles created by the heterogeneity of manifestations. Here, we review progress towards the ultimate goal of safely reducing disease activity and preventing damage accrual and death. We discuss the new classification criteria from the European League Against Rheumatism and American College of Rheumatology, novel definitions of remission and low lupus disease activity, and new proposals for the histological classification of lupus nephritis. Recommendations for the treatment of SLE and novel approaches to drug development hold much promise to further enhance SLE outcomes.

Introduction

Systemic lupus erythematosus (SLE) is not only the prototypic systemic autoimmune disease, but also one of the most heterogeneous illnesses treated by physicians (panel 1). This heterogeneity presents immense challenges to diagnosis, treatment, and therapeutic advances. Despite these hurdles, SLE mortality has declined from 50% in the pre-corticosteroid era (circa 1948) to a 15-year survival of 85–95% in the modern era.1, 2 Although new therapies are largely responsible for improved outcomes, earlier diagnosis and better management of specific organ manifestations and complications, particularly those related to lupus nephritis, have also benefited patients. However, excessive damage accrual, morbidity, and mortality remain,3 indicating that a substantial medical need in SLE still exists. This Review highlights recent advances in the field and presents current treatment algorithms, the new European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification of SLE, new outcome measures, a proposal to modify the histological classification of lupus nephritis, and novel drug development strategies.

Section snippets

Epidemiology

The prevalence of SLE has been estimated to be 30–50 per 100 000, which equates to approximately 500 000 patients in Europe and 250 000 in the USA.4, 5 An analysis published in 2017 provided evidence that ancestry, race, and ethnicity have major impacts on SLE manifestations and severity.6 The incidence and prevalence of SLE are higher in black, Asian, and Hispanic patients, who tend to develop lupus earlier and have more severe and more active disease, with long-term disease damage and

Treatment goals

SLE treatment goals must be balanced by taking multiple disease-specific and patient-specific aspects into consideration, especially the individual profile of involved organ manifestations. Although the disease itself can cause severe and irreversible damage, therapeutics such as glucocorticoids or cyclophosphamide can contribute to damage or have substantial toxic effects.3 Thus, the development of an individual treatment strategy is rather complex with the ultimate challenge to reduce disease

Treatment goals

The preservation of quality of life through the achievement of clinical improvement during a 6–12 month induction phase followed by a maintenance phase that prevents further organ damage is the goal of lupus nephritis treatment. Joint recommendations for lupus nephritis treatment have been published by EULAR and the European Renal Association–European Dialysis and Transplant Association31 and the ACR32 (figure 3).

A return to pre-nephritic flare creatinine clearance is the goal. However, given

Treat to target, lupus low disease activity, and remission in SLE

Successful treat-to-target strategies have improved outcomes for patients with diabetes, hypertension, or rheumatoid arthritis. Adapting a similar approach, initiatives in SLE have defined treatment goals, which range from an operational definition of LLDAS22 (panel 2) to remission definitions (panel 3).23, 94 They serve multiple purposes, chief of which is the association with diminished damage accrual and mortality.

LLDAS in SLE22, 95 has been associated with reduced damage accrual. The

Conclusions

The future for patients with SLE is bright. The disease is being attacked from all sides to gain better insights so that remission is a possibility for more patients, and morbidity and mortality are greatly reduced. These goals will be achieved through the broad efforts of basic, translational, and clinical scientists, clinicians, patients and their families, allied professionals, and everyone engaged in the lupus community.

Search strategy and selection criteria

We searched for full-text English language articles in the PubMed database with the search terms “systemic lupus”, “lupus nephritis”, “DMARDs”, “biologics”, “remission”, “treat to target”, “antimalarials”, “calcineurin inhibitors”, “MMF/mycophenolate”, “rituximab”, “Jak inhibition”, “atacicept”, “belimumab”, “ustekinumab”, and “new therapies”, alone and in specific combinations. The date of our last search was Jan 31, 2019. We evaluated the retrieved papers and selected the most appropriate

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