Objective To evaluate disease activity statuses’ (DAS’) impact on systemic lupus erythematosus (SLE) outcomes.
Materials and methods Four DAS were defined: remission off-therapy: SLE Disease Activity Index (SLEDAI)=0, no prednisone or immunosuppressive drugs (IS); remission on-therapy: SLEDAI=0, prednisone ≤5 mg/day and/or IS (maintenance); low (L) DAS: SLEDAI ≤4, prednisone ≤7.5 mg/day and/or IS (maintenance); non-optimally controlled: SLEDAI >4 and/or prednisone >7.5 mg/day and/or IS (induction). Antimalarials were allowed in all. Predefined outcomes were mortality, new damage (increase of at least one Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI) point) and severe new damage (increase of at least 3 SDI points). Univariable and multivariable Cox regression models were performed to define the impact of DAS, as time-dependent variable, on these outcomes.
Results 1350 patients were included, 79 died during follow-up, 606 presented new and 177 severe new damage. In multivariable analyses, remission (on/off-therapy) was associated with a lower risk of new (HR 0.60; 95% CI 0.43 to 0.85), and of severe new damage (HR 0.32; 95% CI 0.15 to 0.68); low disease activity status (LDAS) was associated with a lower risk of new damage (HR 0.66; 95% CI 0.48 to 0.93) compared with non-optimally controlled. No significant effect on mortality was observed.
Conclusions Remission was associated with a lower risk of new and severe new damage; LDAS with a lower risk of new damage after adjusting for other damage confounders.
- systemic lupus erythematosus
- low disease activity status
- disease damage
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Treat to target strategy (T2T) has been proposed for several chronic diseases as means of improving patients’ outcomes. For example, in rheumatoid arthritis, early combination therapy plus either prednisone or infliximab strategy resulted in patients achieving the target earlier than those on sequential monotherapy or step-up strategy.1
Recently, T2T strategy has been proposed for patients with systemic lupus erythematosus (SLE). However, there is no consensus about the definition of these possible outcomes.2 The Definitions Of Remission In SLE international task force proposed that remission should require the use of a validated index which could be supplemented with a physician’s global assessment (PGA). Additionally, two categories of remission should be considered: off-therapy (only antimalarials) and on-therapy (including prednisone ≤5 mg/day, immunosuppressives (IS) or biologics on maintenance dose).3 Given that remission is achieved infrequently, low disease activity status (LDAS) was considered an alternative outcome; there have been three definitions of LDAS: (1) Asian Pacific Lupus Consortium (APLC): SLE Disease Activity Index (SLEDAI)−2K≤4, no activity in any major organ, no new disease activity features, PGA ≤1, prednisone ≤7.5 mg/day and IS (maintenance dose)4; (2) Lupus Clinical Trials Consortium (LCTC): SLEDAI ≤4, PGA <1, prednisone ≤7.5 mg/day and IS (maintenance)5; and (3) Toronto Cohort: SLEDAI <3 with only one of these manifestations present: rash, alopecia, mucosal ulcers, pleurisy, pericarditis, fever, thrombocytopenia or leucopenia.6
The impact of these targets on SLE outcome, however, has not been fully evaluated. We aimed at determining the impact of remission and LDAS in two defined lupus outcomes, damage and mortality.
Grupo Latino Americano De Estudio de Lupus (GLADEL) is an observational inception cohort study started in 1997 in 34 centres from nine Latin American countries. A common protocol, consensus definitions and outcome measures were established. The general characteristics and composition of the 1480 GLADEL cohort patients have been described in detail elsewhere.7 The study was performed in accordance with the Declaration of Helsinki for the conduct of research in humans and following local institutional review board’s regulations.
For these analyses, we evaluated the intervals between visits which were defined as the period between two SLEDAIs or between one SLEDAI and the end of follow-up. Only patients with at least two intervals were included.
Disease activity was ascertained using the SLEDAI,8 and it was assessed, per protocol, twice a year. Each interval was classified as one of four disease activity statuses:
Remission off-therapy: SLEDAI=0 without prednisone or IS.
Remission on-therapy: SLEDAI=0 and a prednisone dose ≤5 mg/day and/or IS (maintenance dose).
LDAS: SLEDAI ≤4, a prednisone dose ≤7.5 mg/day and/or IS (maintenance dose).
Non-optimally controlled status: SLEDAI >4 and/or prednisone dose >7.5 mg/day and/or IS (induction dose).
Antimalarials were allowed in all groups.
Disease damage was ascertained using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI)9 and was measured, per protocol, once a year.
Predefined outcomes were mortality (any cause), new damage (an increase of at least one point in the SDI) and severe new damage (an increase of at least three points in the SDI).
Categorical variables were summarised as frequencies and percentages while continuous variables are presented as medians and IQR. Cox regression models were used to derive unadjusted and adjusted HRs and 95% CIs quantifying the association between disease activity status as a time-dependent variable and outcomes. Non-optimally controlled status was considered the reference level. Adjustment variables were age at baseline, gender, socioeconomic status, ethnicity, educational level, medical coverage and SDI at baseline. Due to the small number of intervals, both remission groups were combined. Additionally, exploratory analyses for glucocorticoids-related damage (cataracts, myocardial infarction, angina, ventricular dysfunction, osteoporosis with fracture, osteonecrosis and diabetes mellitus) were performed.
Statistical analyses were performed using SAS V.9.4.
There were 5672 intervals from 1350 patients. These patients’ baseline characteristics are depicted in table 1. The median number of intervals per patient was 4 (IQR 2–7), and the median length of the intervals was 7.1 months (5.1–11.7). The best and last status achieved by each patient is depicted in table 2.
New damage was present in 606 (44.7%) patients, severe new damage in 177 (13.1%); 79 (5.8%) patients died during the follow-up.
Of the intervals examined, the most frequent status was non-optimally controlled, with 4446 (78.4%) intervals, followed by LDAS 566 (10.0%), remission on-therapy 553 (9.7%) and remission off-therapy 107 (1.9%) intervals.
The impact of remission and LDAS on new damage, severe new damage and mortality is depicted in table 3. In multivariable analyses, remission was associated with a lower risk of new damage (HR 0.60; 95% CI 0.43 to 0.85; p=0.0042) and a lower risk of severe new damage (HR 0.32, 95% CI 0.15 to 0.68; p=0.0033); LDAS was associated with a lower risk of new damage (HR 0.66; 95% CI 0.48 to 0.93; p=0.0158). No association between disease activity status and mortality was observed. Furthermore, achieving remission and LDAS was associated with a lower risk of new and severe new damage accrual unrelated to glucocorticoids in both univariable and multivariable analyses. That was not the case for glucocorticoids-related damage.
Using GLADEL’s longitudinal data, a multiethnic, multinational inception cohort, we have evaluated if achieving LDAS or remission was associated with a lower risk of damage accrual and mortality. Remission was associated with a lower risk of new and severe new damage occurrence, whereas LDAS was only for new damage. Neither status impacted on mortality.
Remission off-therapy in the GLADEL cohort was rare with only 3.7% of the patients achieving it at least once, lower than reported in other cohorts; using the same definition 1.7% of Toronto Cohort’s patients achieved remission for at least 5 years, 10.2% for at least 1 year.10 In an Italian cohort, 7.1% of the patients achieved remission for at least 5 years11 whereas 12.8% did so in a Netherlands’ cohort12; 24% achieved remission for at least 1 year in a Spaniard cohort. Including PGA in the definition, 5.4% of LCTC patients were on remission for at least 1 year.5
Remission on-therapy was achieved in 16.8% of our patients, similar to other cohorts. In the Toronto Cohort remission, regardless of therapy, occurred for at least 5 years in 1.8% of the patients and in 18.9% for at least 1 year10 while 7.6% of patients achieved remission on-therapy for at least 1 year.5
LDAS was achieved in 14.4% of our patients, similar to LCTC patients (14.9%),5 but less frequently than in APLC where 88.5% of their patients achieved it at least once.4 Using the APLC definition 76.0% of the Netherland patients achieved LDAS at least once, and 64.5% were on it in at least 50% of the observations.12
Our data clearly show that remission on/off-therapy is protective of new and severe new damage, consistent with the Toronto Cohort’s data; patients who achieved remission off therapy accrued less damage than those with active disease (1.1 vs 1.6; p=0.03); furthermore, damage accrual among patients on remission, either off-therapy or on-therapy, was comparable.13 Likewise, in the Italian cohort, patients with unremitted disease had a two times higher risk of accruing damage compared with those on remission; the remission group included complete remission (remission off-therapy) and clinical remission (with or without serological activity, on/off-therapy). Furthermore, within the remission group, those patients on prednisone developed glucocorticoid-related damage more frequently than those not on it; glucocorticoid-unrelated damage was, however, similar in all patients in remission.11 In the same cohort, being 1 year in remission was not sufficient for preventing damage; and in those on remission for at least 5 years, being on prednisone was associated with a higher damage accrual than not being on it.14 In the Netherlands cohort, using the same definition than in the Italian cohort, prolonged remission (complete or clinical remission for at least 5 years) was associated with reduced damage accrual.12
LDAS was found to be protective of new damage accrual, similar to the report from APLC in which patients with at least 50% of the observation time on LDAS had a twofold reduction in the risk of new damage compared with those on LDAS for less of that time.4 In the Toronto Cohort, patients on LDAS had, after 2 years of follow-up, similar prognosis than those on remission in terms of flares, damage accrual, mortality or need for immunosuppressive drugs. Both groups together (LDAS and remission) had, after 2 years of follow-up, a better prognosis than those with high disease activity (SLEDAI >6) in terms of damage accrual, mortality, IS use, dose of prednisone and numbers of flares.6
Our study has some limitations. First, the relatively short follow-up (and consequently, few events) precluded us from finding an impact of remission or LDAS on mortality (resulting in wide CIs). Second, as there are no uniform remission and LDAS’ definitions, it is possible had we used different definitions, our results could have been different; however, similar definitions have been used in other studies, and they are considered reliable.5 10 11 15 Third, we used an alternative definition of LDAS given that the PGA had not been assessed in the GLADEL patients; however, in the SLE Response Index, which was developed for the belimumab’s trials,16 the SLEDAI was the variable with the highest impact on the definition of response. Thus the modified definition of LDAS we have used is entirely valid.
Despite these limitations, our data, from a very large multiethnic, multinational lupus cohort, emphasise the importance of achieving remission or LDAS in the prognosis of patients with SLE. In conclusion, remission diminished the risk of new and severe new damage, and LDAS diminished the risk of new damage after adjusting for other well-known risk factors of damage. These data support the use of these outcomes as targets in the treatment of patients with SLE.
The authors are grateful to Daniel Villalba and Leonardo Grasso for providing expert assistance with the ARTHROS (V.6.0) software. Preliminary results were presented at the 2016 American College of Rheumatology (ACR) Annual Meeting and at the 2016 Third Biannual Scientific Meeting of the North and South American Lupus Community.
Handling editor Tore K Kvien
Contributors All authors were involved in drafting or critically revising this manuscript for important intellectual content, and all authors approved the final version to be published. MFU-G, DW, GSA and BAP-E have full access to all the study’s data and take responsibility for their integrity and the accuracy of the analyses performed.
Competing interests None declared.
Ethics approval The study was performed according with the Declaration of Helsinki for the conduct of research in humans and following local institutional review board’s regulations.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators In addition to the authors, the following participants are members of the GLADEL Study Group and have incorporated at least 20 patients into the database with adequate follow-up. ARGENTINA: Enrique R Soriano, María Flavia Ceballos Recalde and Edson Velozo (Sección de Reumatología, Servicio de Clínica Médica; Hospital Italiano and Fundación Dr Pedro M Catoggio para el Progreso de la Reumatología, Buenos Aires,); Jorge A Manni, and Sebastián Grimaudo (Instituto de Investigaciones Médicas “Alfredo Lanari,” Buenos Aires); Emilce Schneeberger, María S Arriola and Graciela Gómez (Instituto de Rehabilitación Psicofísica, Buenos Aires); Mercedes A García, Ana Inés Marcos and Juan Carlos Marcos(Deceased) (Hospital Interzonal General de Agudos “General San Martín”, La Plata); Hugo R Scherbarth, Jorge A López and Estela L Motta (Hospital Interzonal General de Agudos “Dr Oscar Alende”, Mar del Plata); Susana Gamron, Laura Onetti and Sandra Buliubasich (Hospital Nacional de Clínicas, Córdoba); Verónica Saurit, Francisco Caeiro and Alejandro Alvarellos (Servicio de Reumatología, Hospital Privado, Centro Medico de Córdoba, Córdoba); Silvana Gentiletti(Deceased), Norberto Quagliatto, Alberto A Gentiletti and Daniel Machado(Deceased) (Hospital Provincial de Rosario, Rosario); Marcelo Abdala and Simón Palatnik(Deceased) (Hospital Provincial del Centenario, Universidad Nacional de Rosario, Rosario); Carlos A. Battagliotti(Deceased) (Hospital Escuela “Eva Perón”, Granadero Baigorria). BRASIL: Eloisa Bonfa (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo); Alexandre Wagner S Souza (Disciplina de Reumatología, Escola Paulista de Medicina, Universidade Federal da São Paulo -UNIFESP, São Paulo); Lilian T Lavras Costallat, Manoel Barros Bertolo and Ibsen Bellini Coimbra (Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas); Ricardo Xavier and Tamara Mucenic (Hospital das Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre); Fernando de Souza Cavalcanti, Ângela Luzia Branco Duarte and Claudia Diniz Lopes Marques (Centro de Ciências da Saúde, Universidade Federal de Pernambuco, Pernambuco); Nilzio Antonio da Silva, Ana Carolina de O e Silva and Tatiana Ferracine Pacheco (Faculdade de Medicina, Universidade Federal de Goiás, Goiânia). COLOMBIA: José Fernando Molina-Restrepo, Javier Molina-López and Gloria Vásquez (Universidad de Antioquia, Hospital Universitario “San Vicente de Paul,” Medellín); Antonio Iglesias-Rodríguez (Universidad del Bosque, Bogotá), Eduardo Egea-Bermejo (Universidad del Norte, Barranquilla); Antonio Iglesias-Gamarra, Renato A Guzmán-Moreno and José F Restrepo-Suárez (Clínica Saludcoop 104 Jorge Piñeros Corpas and Hospital San Juan de Dios, Universidad Nacional de Colombia, Bogotá). CUBA: Gil Reyes-Llerena and Alfredo Hernández-Martínez (Centro de Investigaciones Médico Quirúrgicas -CIMEQ, La Habana). CHILE: Sergio Jacobelli (Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago); Oscar Neira and Leonardo R Guzmán (Hospital del Salvador, Facultad de Medicina, Universidad de Chile, Santiago). GUATEMALA: Abraham García-Kutzbach, Claudia Castellanos and Erwin Cajas (Hospital Universitario Esperanza, Ciudad de Guatemala). MEXICO: Donato Alarcón-Segovia(Deceased), Virginia Pascual-Ramos and Antonio R Villa (Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán,” Ciudad de Mexico); Mary Carmen Amigo (Reumatología, Centro Medico ABC, Ciudad de Mexico); Leonor A Barile (Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico), Ignacio García De La Torre, Gerardo Orozco-Barocio and Magali L. Estrada-Contreras (Hospital General de Occidente de la Secretaría de Salud, Guadalajara,); María Josefina Sauza del Pozo, Laura E. Aranda Baca and Adelfia Urenda Quezada (Instituto Mexicano de Seguro Social, Hospital de Especialidades Nº 25, Monterrey,); Guillermo F Huerta-Yáñez (Hospital de Especialidades Miguel Hidalgo, Aguascalientes). PERÚ: Eduardo M Acevedo-Vasquez, José Luis Alfaro-Lozano and Jorge M Cucho-Venegas (Hospital Nacional “Guillermo Almenara Irigoyen,” Essalud, Lima); María Inés Segami, Cecilia P Chung and Magaly Alva-Linares (Hospital Nacional “Edgardo Rebagliatti Martins,” Essalud, Lima). VENEZUELA: Isaac Abadi and Neriza Rangel (Servicio de Reumatología, Centro Nacional de Enfermedades Reumáticas, Hospital Universitario de Caracas, Caracas); María H Esteva-Spinetti and Jorge Vivas (Hospital Central de San Cristóbal, San Cristóbal).