Advertisement

Treat-to-target in systemic lupus erythematosus: Where are we?

Published:February 01, 2020DOI:https://doi.org/10.1016/j.ejim.2020.01.018

      Highlights

      • Treat-to-target (T2T) strategy led to improved care for patients with some diseases.
      • A multidisciplinary task force made in 2013 an initial proposal of the T2T in SLE.
      • Definition of remission and of lupus low disease activity received a broad consensus.
      • Unmet needs in the context of T2T in SLE are in an ongoing research agenda.

      Abstract

      Systemic lupus erythematosus (SLE) is the most paradigmatic disorder within systemic autoimmune diseases. The concept and principles of treat-to-target (T2T) in SLE were established half a decade ago and, since then, remarkable advances have been made. An international consensus was organized in order to define and unify the term remission, although plurality, with subtle nuances still exists and has not been overcome. Also, lupus low disease activity state (LLDAS) was coined as an alternative and, perhaps, more realistic target. Both of them have proven to be meaningful in terms of improving several outcomes, and have opened the path for future research in clinical trials. This review arises from the need to summarize the current state of some of the recommendations of the T2T task force.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kaul A.
        • Gordon C.
        • Crow M.K.
        • Touma Z.
        • Urowitz M.B.
        • van Vollenhoven R.
        • et al.
        Systemic lupus erythematosus.
        Nat Rev Dis Prim. 2016; 2: 16039https://doi.org/10.1038/nrdp.2016.39
        • Tsokos G.C.
        • Lo M.S.
        • Reis P.C.
        • Sullivan K.E
        New insights into the immunopathogenesis of systemic lupus erythematosus.
        Nat Rev Rheumatol. 2016; 12: 716-730https://doi.org/10.1038/nrrheum.2016.186
        • Steinberg A.D.
        • Decker J.L
        A double‐blind controlled trial comparing cyclophosphamide, azathioprine and placebo in the treatment of lupus glomerulonephritis.
        Arthritis Rheum. 1974; 17: 923-937https://doi.org/10.1002/art.1780170602
        • Steinberg A.D.
        • Steinberg S.C.
        Long‐term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only.
        Arthritis Rheum. 1991; 34: 945-950https://doi.org/10.1002/art.1780340803
        • Chan T.M.
        • Li F.K.
        • Tang C.S.O.
        • Wong R.W.S.
        • Fang G.X.
        • Ji Y.L.
        • et al.
        Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis.
        N Engl J Med. 2000; 343: 1156-1162https://doi.org/10.1056/NEJM200010193431604
        • Cervera R.
        • Khamashta M.A.
        • Font J.
        • Sebastiani G.D.
        • Gil A.
        • Lavilla P.
        • et al.
        Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients.
        Medicine (Baltimore). 2003; 82: 299-308https://doi.org/10.1097/01.md.0000091181.93122.55
        • Pons-Estel G.J.
        • Alarcón G.S.
        • Scofield L.
        • Reinlib L.
        • Cooper G.S
        Understanding the epidemiology and progression of systemic lupus erythematosus.
        Semin Arthritis Rheum. 2010; 39: 257-268https://doi.org/10.1016/j.semarthrit.2008.10.007
        • Yurkovich M.
        • Vostretsova K.
        • Chen W.
        • Aviña-Zubieta J.A
        Overall and cause-specific mortality in patients with systemic lupus erythematosus: a meta-analysis of observational studies.
        Arthritis Care Res. 2014; 66: 608-616https://doi.org/10.1002/acr.22173
        • Lee Y.H.
        • Choi S.J.
        • Ji J.D.
        • Song G.G
        Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis.
        Lupus. 2015; 25: 727-734https://doi.org/10.1177/0961203315627202
        • Jorge A.M.
        • Lu N.
        • Zhang Y.
        • Rai S.K.
        • Choi H.K
        Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999-2014).
        Rheumatol (U K). 2018; 57: 337-344https://doi.org/10.1093/rheumatology/kex412
        • Tektonidou M.G.
        • Lewandowski L.B.
        • Hu J.
        • Dasgupta A.
        • Ward M.M
        Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016.
        Ann Rheum Dis. 2017; 76: 2009-2016https://doi.org/10.1136/annrheumdis-2017-211663
        • Atar D.
        • Birkeland K.I.
        • Uhlig T
        “Treat to target”: moving targets from hypertension, hyperlipidaemia and diabetes to rheumatoid arthritis.
        Ann Rheum Dis. 2010; 69: 629-630https://doi.org/10.1136/ard.2010.128462
        • Van Vollenhoven R.F.
        • Mosca M.
        • Bertsias G.K.
        • Isenberg D.A.
        • Kuhn A.
        • Lerstrøm K.
        • et al.
        Treat-to-target in systemic lupus erythematosus: recommendations from an international task force.
        Ann Rheum Dis. 2014; 73: 958-967https://doi.org/10.1136/annrheumdis-2013-205139
        • Drenkard C.
        • Villa A.R.
        • García-Padilla C.
        • Pérez-Vázquez M.E.
        • Alarcón-Segovia D
        Remission of systemic lupus erythematosus.
        Medicine (Baltimore). 1996; 75: 88-98https://doi.org/10.1097/00005792-199603000-00005
        • Barr S.G.
        • Zonana-Nacach A.
        • Magder L.S.
        • Petri M
        Patterns of disease activity in systemic lupus erythematosus.
        Arthritis Rheum. 1999; 42: 2682-2688https://doi.org/10.1002/1529-0131(199912)42:12>2682::AID-ANR26<3.0.CO;2-6
        • Zen M.
        • Iaccarino L.
        • Gatto M.
        • Bettio S.
        • Nalotto L.
        • Ghirardello A.
        • et al.
        Prolonged remission in caucasian patients with SLE: prevalence and outcomes.
        Ann Rheum Dis. 2015; 74: 2117-2122https://doi.org/10.1136/annrheumdis-2015-207347
        • Urowitz M.B.
        • Feletar M.
        • Bruce I.N.
        • Ibañez D.
        • Gladman D.D
        Prolonged remission in systemic lupus erythematosus.
        J Rheumatol. 2005; 32: 1467-1472
        • Van Vollenhoven R.
        • Voskuyl A.
        • Bertsias G.
        • Aranow C.
        • Aringer M.
        • Arnaud L.
        • et al.
        A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS).
        Ann Rheum Dis. 2017; 76: 554-561https://doi.org/10.1136/annrheumdis-2016-209519
        • Franklyn K.
        • Lau C.S.
        • Navarra S V.
        • Louthrenoo W
        • Lateef A.
        • Hamijoyo L.
        • et al.
        Definition and initial validation of a Lupus Low Disease Activity State (LLDAS).
        Ann Rheum Dis. 2016; 75: 1615-1621https://doi.org/10.1136/annrheumdis-2015-207726
        • Petri M.
        • Magder L.S.
        Comparison of remission and lupus low disease activity state in damage prevention in a united states systemic lupus erythematosus cohort.
        Arthritis Rheumatol. 2018; 70: 1790-1795https://doi.org/10.1002/art.40571
        • Tani C.
        • Vagelli R.
        • Stagnaro C.
        • Carli L.
        • Mosca M
        Remission and low disease activity in systemic lupus erythematosus: an achievable goal even with fewer steroids? Real-life data from a monocentric cohort.
        Lupus Sci Med. 2018; 5: 1-7https://doi.org/10.1136/lupus-2017-000234
        • Zen M.
        • Iaccarino L.
        • Gatto M.
        • Saccon F.
        • Larosa M.
        • Ghirardello A.
        • et al.
        Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission.
        Ann Rheum Dis. 2018; 77: 104-110https://doi.org/10.1136/annrheumdis-2017-211613
        • Piga M.
        • Floris A.
        • Cappellazzo G.
        • Chessa E.
        • Congia M.
        • Mathieu A.
        • et al.
        Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus.
        Arthritis Res Ther. 2017; 19: 1-9https://doi.org/10.1186/s13075-017-1451-5
        • Tsang-A-Sjoe M.W.P.
        • Bultink I.E.M.
        • Heslinga M.
        • Voskuyl A.E
        Both prolonged remission and lupus low disease activity state are associated with reduced damage accrual in systemic lupus erythematosus.
        Rheumatology (Oxford). 2017; 56: 121-128https://doi.org/10.1093/rheumatology/kew377
        • Golder V.
        • Kandane-Rathnayake R.
        • Huq M.
        • et al.
        Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study.
        Lancet Rheumatol. 2019; 1: e95-e102https://doi.org/10.1016/S2665-9913(19)30037-2
        • Golder V.
        • Kandane-Rathnayake R.
        • Huq M.
        • et al.
        Evaluation of remission definitions for systemic lupus erythematosus: a prospective cohort study.
        Lancet Rheumatol. 2019; 1: e103-e110https://doi.org/10.1016/S2665-9913(19)30048-7
        • Parodis I.
        • Emamikia S.
        • Gomez A.
        • Gentline C.
        • Arkema E.V.
        • Chatzidionysiou K.
        • et al.
        Definitions of remission in systemic lupus erythematosus: a post-hoc analysis of two randomised clinical trials.
        Lancet Rheumatol. 2019; 1: e163-e173https://doi.org/10.1016/S2665-9913(19)30049-9
        • Oon S.
        • Huq M.
        • Golder V.
        • Ong P.X.
        • Morand E.F.
        • Nikpour M
        Lupus low disease activity state (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus.
        Ann Rheum Dis. 2019; 78: 629-633https://doi.org/10.1136/annrheumdis-2018-214427
        • Fanouriakis A.
        • Adamichou C.
        • Koutsoviti S.
        • Panopoulos S.
        • Staveri C.
        • Klagou A.
        • et al.
        Low disease activity—irrespective of serologic status at baseline—associated with reduction of corticosteroid dose and number of flares in patients with systemic lupus erythematosus treated with belimumab: a real-life observational study.
        Semin Arthritis Rheum. 2018; 48: 467-474https://doi.org/10.1016/j.semarthrit.2018.02.014
        • Tani C.
        • Elefante E.
        • Signorini V.
        • Di Zucchi
        • Lorenzoni V.
        • Carli L.
        • et al.
        Glucocorticoid withdrawal in systemic lupus erythematosus: are remission and low disease activity reliable starting points for stopping treatment? a real-life experience.
        RMD Open. 2019; 5: 1-7https://doi.org/10.1136/rmdopen-2019-000916
        • Ugarte-Gil M.F.
        • Pons-Estel G.J.
        • Vila L.M.
        • McGwin G.
        • Alarcón G.S
        Time in remission and low disease activity state (LDAS) are associated with a better quality of life in patients with systemic lupus erythematosus: results from Lumina (LXXIX), a multiethnic, multicentre US cohort.
        RMD Open. 2019; 5: 1-4https://doi.org/10.1136/rmdopen-2019-000955
        • Yeo A.L.
        • Koelmeyer R.
        • Kandane‐Rathnayake R.
        • Golder V.
        • Hoi A.
        • Huq M.
        • et al.
        Lupus low disease activity state is associated with reduced direct healthcare costs in patients with systemic lupus erythematosus.
        Arthritis Care Res (Hoboken). 2019; : 0-1https://doi.org/10.1002/acr.24023
        • Wilhelm T.R.
        • Magder L.S.
        • Petri M
        Remission in systemic lupus erythematosus: durable remission is rare.
        Ann Rheum Dis. 2017; 76: 547-553https://doi.org/10.1136/annrheumdis-2016-209489
        • Bruce I.N.
        • O'Keeffe A.G.
        • Farewell V.
        • Hanly J.G.
        • Manzi S.
        • Su L.
        • et al.
        Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.
        Ann Rheum Dis. 2015; 74: 1706-1713https://doi.org/10.1136/annrheumdis-2013-205171
        • Alarcón G.S.
        • Roseman J.M.
        • McGwin G.
        • Uribe A.
        • Bastian H.M.
        • Fessler B.J.
        • et al.
        Systemic lupus erythematosus in three ethnic groups. XX. Damage as a predictor of further damage..
        Rheumatology. 2004; 43: 202-205https://doi.org/10.1093/rheumatology/keg481
        • Mok C.C.
        • Ho C.T.K.
        • Wong R.W.S.
        • Lau C.S
        Damage accrual in southern Chinese patients with systemic lupus erythematosus.
        J Rheumatol. 2003; 30: 1513-1519
        • Gensous N.
        • Marti A.
        • Barnetche T.
        • Blanco P.
        • Lazaro E.
        • Seneschal J.
        • et al.
        Predictive biological markers of systemic lupus erythematosus flares: a systematic literature review.
        Arthritis Res Ther. 2017; 19: 238https://doi.org/10.1186/s13075-017-1442-6
      1. Jolly M., Annapureddy N., Arnaud L., Devilliers H. Changes in quality of life in relation to disease activity in systemic lupus erythematosus: post-hoc analysis of the BLISS-52 trial. Lupus2019:1–12. doi:10.1177/0961203319886065.

        • Legge A.
        • Doucette S.
        • Hanly J.G
        Predictors of organ damage progression and effect on health-related quality of life in systemic lupus erythematosus.
        J Rheumatol. 2016; 43: 1050-1056https://doi.org/10.3899/jrheum.150985
        • Poomsalood N.
        • Narongroeknawin P.
        • Chaiamnuay S.
        • Asavatanabodee P.
        • Pakchotanon R
        Prolonged clinical remission and low disease activity statuses are associated with better quality of life in systemic lupus erythematosus.
        Lupus. 2019; 28: 1189-1196https://doi.org/10.1177/0961203319862614
        • Gregersen J.W.
        • Jayne D.
        B-cell depletion in the treatment of lupus nephritis.
        Nat Rev Nephrol. 2012; 8: 505-514https://doi.org/10.1038/nrneph.2012.141
        • Tunnicliffe D.J.
        • Singh-Grewal D.
        • Kim S.
        • Craig J.C.
        • Tong A
        Diagnosis, monitoring, and treatment of systemic lupus erythematosus: a systematic review of clinical practice guidelines.
        Arthritis Care Res. 2015; 67: 1440-1452https://doi.org/10.1002/acr.22591
        • Ruiz-Irastorza G.
        • Danza A.
        • Khamashta M
        Glucocorticoid use and abuse in SLE.
        Rheumatol (U K). 2012; 51: 1145-1153https://doi.org/10.1093/rheumatology/ker410
        • Miloslavsky E.M.
        • Naden R.P.
        • Bijlsma J.W.J.
        • Brogan P.A.
        • Brown E.S.
        • Brunetta P.
        • et al.
        Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis.
        Ann Rheum Dis. 2017; 76: 543-546https://doi.org/10.1136/annrheumdis-2016-210002
        • Al Sawah S
        • X Zhang
        • Zhu B.
        • Magder L.S.
        • Foster S.A.
        • Iikuni N.
        • et al.
        Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus-the Hopkins lupus cohort.
        Lupus Sci Med. 2015; 2: 1-9https://doi.org/10.1136/lupus-2014-000066
        • Apostolopoulos D.
        • Kandane-Rathnayake R.
        • Raghunath S.
        • Hoi A.
        • Nikpour M.
        • Morand E.F
        Independent association of glucocorticoids with damage accrual in SLE.
        Lupus Sci Med. 2016; 3: 1-9https://doi.org/10.1136/lupus-2016-000157
        • Ruiz-Arruza I.
        • Barbosa C.
        • Ugarte A.
        • Ruiz-Irastorza G
        Comparison of high versus low-medium prednisone doses for the treatment of systemic lupus erythematosus patients with high activity at diagnosis.
        Autoimmun Rev. 2015; 14: 875-879https://doi.org/10.1016/j.autrev.2015.05.011
        • Ruiz-Irastorza G.
        • Ruiz-Estevez B.
        • Lazaro E.
        • Ruiz-Arruza I.
        • Duffau P.
        • Martin-Cascon M.
        • et al.
        Prolonged remission in SLE is possible by using reduced doses of prednisone: an observational study from the lupus-cruces and lupus-bordeaux inception cohorts.
        Autoimmun Rev. 2019; 18102359https://doi.org/10.1016/j.autrev.2019.102359
        • Pons-Estel G.J.
        • Andreoli L.
        • Scanzi F.
        • Cervera R.
        • Tincani A
        The antiphospholipid syndrome in patients with systemic lupus erythematosus.
        J Autoimmun. 2017; 76: 10-20https://doi.org/10.1016/j.jaut.2016.10.004
        • Sciascia S.
        • Sanna G.
        • Murru V.
        • Roccatello D.
        • Khamashta M.A.
        • Bertolaccini M.L
        GAPSS: the global anti-phospholipid syndrome score.
        Rheumatol (U K). 2013; 52: 1397-1403https://doi.org/10.1093/rheumatology/kes388
        • Sciascia S.
        • Sanna G.
        • Murru V.
        • Roccatello D.
        • Khamashta M.A.
        • Bertolaccini M.L
        The global anti-phospholipid syndrome score in primary APS.
        Rheumatol (U K). 2014; 54: 134-138https://doi.org/10.1093/rheumatology/keu307
        • Cohen H.
        • Hunt B.J.
        • Efthymiou M.
        • Arachchillage D.R.J.
        • Mackie I.J.
        • Clawson S.
        • et al.
        Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial.
        Lancet Haematol. 2016; 3: e426-e436https://doi.org/10.1016/S2352-3026(16)30079-5
        • Pengo V.
        • Denas G.
        • Zoppellaro G.
        • Jose S.P.
        • Hoxha A.
        • Ruffatti A.
        • et al.
        Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome.
        Blood. 2018; 132: 1365-1371https://doi.org/10.1182/blood-2018-04-848333
        • Ruiz-Irastorza G.
        • Ramos-Casals M.
        • Brito-Zeron P.
        • Khamashta M.A
        Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review.
        Ann Rheum Dis. 2010; 69: 20-28https://doi.org/10.1136/ard.2008.101766
        • Wallace D.J.
        • Gudsoorkar V.S.
        • Weisman M.H.
        • Venuturupalli S.R
        New insights into mechanisms of therapeutic effects of antimalarial agents in SLE.
        Nat Rev Rheumatol. 2012; 8: 522-533https://doi.org/10.1038/nrrheum.2012.106
        • Marmor M.F.
        • Kellner U.
        • Lai T.Y.Y.
        • Melles R.B.
        • Mieler W.F
        Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision).
        Ophthalmology. 2016; 123: 1386-1394https://doi.org/10.1016/j.ophtha.2016.01.058
        • Cervera R.
        • Khamashta M.A.
        • Hughes G.R.V
        The euro-lupus project: epidemiology of systemic lupus erythematosus in Europe.
        Lupus. 2009; 18: 869-874https://doi.org/10.1177/0961203309106831
        • Kawai V.K.
        • Solus J.
        • Oeser A.
        • et al.
        Novel cardiovascular risk predictionmodels in patients with systemic lupus erythematosus.
        Lupus. 2011; 20: 1526-1534https://doi.org/10.1177/0961203311420317
        • Fanouriakis A.
        • Kostopoulou M.
        • Alunno A.
        • et al.
        2019 update of the EULAR recommendations for the management of systemic lupus erythematosus.
        Ann Rheum Dis. 2019; : 78736-78745https://doi.org/10.1136/annrheumdis-2019-215089