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(LUP)
[1–7] [PREPRINTER stage]
Lupus (2014) 0,
1–7
http://lup.sagepub.com
PAPER
Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry MJ Gonc¸alves1,2,*, S Sousa3,*, LS Ineˆs4, C Duarte4, J Borges5, C Silva5, VC Roma˜o1,3, G Terroso6, M Bernardes6, M Cerqueira7, A Raposo7, G Sequeira8, A Barcelos9, C Macieira1, J Canas da Silva2, L Costa6, JA Pereira da Silva1, L Cunha-Miranda5, JAP Da Silva4, H Canha˜o1,2 and MJ Santos2,3 1 Hospital de Santa Maria, Lisboa, Portugal; 2Rheumatology Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal; 3Hospital Garcia de Orta, Almada, Portugal; 4Hospitais da Universidade de Coimbra, Coimbra, Portugal; 5Instituto Portugueˆs de Reumatologia, Lisboa, Portugal; 6 Hospital de Sa˜o Joa˜o, Porto, Portugal; 7Hospital Conde de Bertiandos, Ponte de Lima, Portugal; 8Hospital de Faro, Faro, Portugal; and 9 Hospital de Aveiro, Aveiro, Portugal
Background: Although the survival rate has considerably improved, many patients with systemic lupus erythematosus (SLE) develop irreversible organ damage. Objectives: The objectives of this paper are to characterize cumulative damage in SLE patients and identify variables associated with its presence and severity. Methods: A cross-sectional analysis of SLE patients from the Portuguese Lupus register Reuma.pt/SLE in whom damage assessment using the SLICC/ACR-Disability Index (SDI) was available was performed. Predictor factors for damage, defined as SDI 1, were determined by logistic regression analyses. A sub-analysis of patients with severe damage (SDI 3) was also performed. Results: In total, 976 patients were included. SDI was 1 in 365 patients, of whom 89 had severe damage. Musculoskeletal (24.4%), neuropsychiatric (24.1%) and ocular (17.2%) domains were the most commonly affected. Older age, longer disease duration, renal involvement, presence of antiphospholipid antibodies and current therapy with steroids were independently associated with SDI 1. The subpopulation with severe damage had, in addition, a greater interval between the first manifestation attributable to SLE and the clinical diagnosis as well as and more frequently early retirement due to SLE. Conclusions: This large lupus cohort confirmed that demographic and clinical characteristics as well as medication are independently associated with damage. Additionally, premature retirement occurs more often in patients with SDI 3. Diagnosis delay might contribute to damage accrual. Lupus (2014) 0, 1–7. Key words: Systemic lupus erythematosus; Reuma.pt; Portugal
Introduction Systemic lupus erythematosus (SLE) may present very different clinical manifestations, sometimes debilitating and life threatening.1,2 Over the last decades there has been a substantial increase in survival of these patients, yet life expectancy in SLE is still low compared to that expected for people of the same age and gender.1,3,4 Moreover, in the course of the disease, many patients develop Correspondence to: Sandra Sousa, Hospital Garcia de Orta, Department of Rheumatology, Avenida Torrado da Silva Almada, 2801-951 Portugal. Email: [email protected] *M.J.G. and S.S. are joint first authors of this work. Received 31 May 2014; revised: 8 August 2014 accepted 10 September 2014
irreversible organ damage. In 1992 the Systemic Lupus International Collaborative Clinics (SLICC) in collaboration with the American College of Rheumatology (ACR) developed and validated an index for the evaluation of irreversible damage.3,5,6 Damage measured by the SLICC/ACR Damage Index (SDI) is associated with higher mortality rate, especially when damage occurs early in the course of the disease or reflects renal involvement or cardiovascular (CDV) disease.7 Several studies have sought to identify risk factors for the occurrence and progression of irreversible damage in SLE. In addition to demographic and clinical characteristics such as age, disease duration, frequency of flares, presence of antiphospholipid antibodies, hypertension or steroid use,
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
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10.1177/0961203314555172
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(LUP)
[1–7] [PREPRINTER stage]
Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry MJ Gonc¸alves et al.
2
ethnic and socioeconomic differences may also affect the damage accrual.2–6,8–12 SLE in South European populations presents some distinct genetic and clinical characteristics.13 Damage is still poorly characterized in these populations. The Rheumatic diseases register from the Portuguese Society of Rheumatology (Reuma.pt) launched in September 2012 a longitudinal registry for SLE patients—the Reuma.pt/SLE. This registry captures more than 90% of the public rheumatology departments across Portugal (mainland, Azores and Madeira islands), as well as private practices.14 After providing signed informed consent, 1510 patients with SLE were retrospectively included between September 2012 and December 2012, and prospectively followed afterwards. All patients have a baseline assessment at which demographics, education, lifestyle habits, ACR and SLICC criteria for SLE, disease activity, pregnancy morbidity and thrombosis, accumulated damage, comorbidity and medication were recorded. Follow-up visits were conducted every three to four months, according to clinical practice. With this study we aim to characterize damage among SLE patients followed in different rheumatology centers and registered in Reuma.pt/SLE. Secondly, we intend to examine the association between demographic and clinical characteristics, presence of comorbidities, laboratory variables, including positivity for different antibodies and medication and damage measured by the SDI. Additionally we aim to analyze patients with severe damage (SDI within the upper quartile).
of SLE was established by the treating physician. Disease duration was defined as the interval between date of diagnosis and date of last visit. The presence of damage was defined as SDI 1. Variables We analyzed the following variables: age, gender, ethnicity, educational level, age at diagnosis, disease duration, cumulative clinical manifestations, disease activity assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K)15 at last visit, damage assessed by the SDI16 at the last visit and medications (current use). Comorbidities analyzed included hypertension, diabetes, thyroid diseases, and secondary SS and APS, according to the accepted definitions. Diagnosis delay was defined as the time between first symptom/manifestation attributable to SLE and the date of clinical diagnosis established by the treating physician. Definitions of clinical features included in ACR revised criteria were used to characterize organ involvement. All laboratory tests were performed locally. Anti-DNA, anti-Sm, anti-RNP, anti-SSA and anti-SSB were considered positive if the value was above the cutoffs for the laboratory at least in one determination during the follow-up period. Antiphospholipid antibodies were considered positive if immunoglobulin (Ig)G or IgM anticardiolipin or anti-beta2-glycoprotein titers were above the 99th percentile or a positive test for lupus anticoagulant using a standard method was detected. Statistical analysis
Material and methods Patients All patients registered in Reuma.pt/SLE fulfilling at least four of the 1997 ACR revised criteria for SLE and available SDI assessment were selected for analysis. Patients with incomplete lupus or with other rheumatic disease, except secondary Sjo¨gren’s syndrome (SS) or secondary antiphospholipid syndrome (APS), were excluded. A cross-sectional analysis of this cohort at the last recorded visit was made on the demographic, clinical and laboratory characterization of SLE, comorbidities, lupus activity, irreversible damage, as well as the medication used. Missing data were obtained, whenever possible, by review of all available medical records. The date of diagnosis was defined when the clinical diagnosis
Continuous variables are expressed as mean standard deviation, if they have a normal distribution or median with interquartile range if distribution is highly skewed. Categorical variables are presented as absolute values and frequencies. Student’s t-test and the chi-square tests were carried out to compare continuous and categorical variables, respectively. We compared demographic and clinical characteristics in groups of patients according to the presence of damage. Predictor factors for damage were determined by uni- and multivariate logistical regression analyses. Candidate covariates were entered in the multivariate model by backward selection if p < 0.05 in univariate analysis or if they were considered clinically relevant (gender and corticosteroid therapy). Diabetes was not tested as a predictor of damage to avoid circularity, since in the majority of patients diabetes was
Lupus Downloaded from lup.sagepub.com at TULANE UNIV on January 20, 2015
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(LUP)
[1–7] [PREPRINTER stage]
Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry MJ Gonc¸alves et al.
3
diagnosed after the onset of SLE and as such classified as damage. A significant level of 5% was used in all analyses. All statistical analyses were performed using the program Stata, version 12.0.
Results From the 1510 SLE patients registered in Reuma.pt/SLE were excluded those who did not fulfill ACR classification criteria (n ¼ 214) and those without available SDI score assessment (n ¼ 320). A total of 976 patients were included in our analysis. This sample is representative of the whole SLE population registered in Reuma.pt/SLE, with no significant differences in demographic and clinical characteristics. The majority were women, predominantly Caucasian with a mean age of 47 14 years and mean disease duration of 14.1 8.9 years. Of the 976 patients, 365 (37.4%) presented with irreversible damage with an average SDI score of
0.71 1.22. No difference in gender distribution was found between those with and without damage. Patients with SDI 1 were older (mean age of 52.8 years vs 45.0 years), had longer disease duration and later disease onset (Table 1). Oral ulcers, serositis, renal and neurologic involvement were more prevalent in those with damage, as was hypertension, secondary SS and APS. Disease activity assessed by SLEDAI-2K (at last visit) was not significantly different between groups (2.70 3.4 vs 2.56 3.1; p ¼ 0.289). The most frequently prescribed therapy for SLE is described in Table 2. The use of antimalarials was less frequent in those with damage. Characterization of damage in this group was considered in different systems, as shown in Table 3. Higher proportions of patients had musculoskeletal (24.4%), neuropsychiatric (24.1%) and ocular (17.2%) damage. In most cases only one SDI domain was affected; absolute frequencies of SDI scores are displayed in Figure 1. In multivariate analysis, age, disease duration, renal involvement, antiphospholipid antibodies
Table 1 Demographic and clinical characteristics of SLE patients included in analysis Feature Women Age at diagnosis (years) Disease duration (years) Ethnicity n ¼ 911 – Caucasian – African – Others Education (years), n ¼ 205 Malar rash, n ¼ 972 Photosensitivity, n ¼ 968 Oral ulcers, n ¼ 965 Arthritis, n ¼ 976 Serositis, n ¼ 974 Renal involvement, n ¼ 959 Neurologic disorder, n ¼ 970 Hematologic disorder, n ¼ 967 Anti-DNA, n ¼ 971 Anti-Sm, n ¼ 939 Anticardiolipin, n ¼ 742 Anti-SSA positivity, n ¼ 606 Anti-SSB positivity, n ¼ 606 Anti-RNP positivity, n ¼ 606 Low complement, n ¼ 890 Hypertension, n ¼ 526 Thyroid disease, n ¼ 526 Antiphospholipid syndrome, n ¼ 526 Sjo¨gren’s syndrome n ¼ 526
Patients without damage SDI ¼ 0 (n ¼ 611)
Patients with damage SDI 1 (n ¼ 365)
559 (91.5%) 34.4 14.7 12.6 8.1
335 (91.8%) 37 15.0 17.0 9.4
498 (95.6%) 18 (3.5%) 5 (1%) 9.8 4.4 258 (42.4%) 303 (50.0%) 179 (29.8%) 456 (74.6%) 114 (18.7%) 175 (29.2%) 9 (1.5%) 387 (64.0%) 508 (83.7%) 74 (12.5%) 185 (39.7%) 136 (35.8%) 65 (17.3%) 90 (24.3%) 413 (72.7%) 84 (28.9%) 37 (12.7%) 15 (5.2%) 26 (8.9%)
287 (92.3%) 24 (6.8%) 3 (1%) 9.0 4.2 165 (45.3%) 186 (51.4%) 133 (36.5%) 276 (75.6%) 103 (28.2%) 130 (36.2%) 41 (11.2%) 229 (63.3%) 364 (80.7%) 45 (12.9%) 138 (50.0%) 95 (42.0%) 45 (20.4%) 58 (26.5%) 240 (74.5%) 94 (40.0%) 22 (9.3%) 31 (12.3%) 38 (14.9%)
p 0.874 0.004
(LUP)
[1–7] [PREPRINTER stage]
Lupus (2014) 0,
1–7
http://lup.sagepub.com
PAPER
Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry MJ Gonc¸alves1,2,*, S Sousa3,*, LS Ineˆs4, C Duarte4, J Borges5, C Silva5, VC Roma˜o1,3, G Terroso6, M Bernardes6, M Cerqueira7, A Raposo7, G Sequeira8, A Barcelos9, C Macieira1, J Canas da Silva2, L Costa6, JA Pereira da Silva1, L Cunha-Miranda5, JAP Da Silva4, H Canha˜o1,2 and MJ Santos2,3 1 Hospital de Santa Maria, Lisboa, Portugal; 2Rheumatology Research Unit, Instituto de Medicina Molecular, Lisboa, Portugal; 3Hospital Garcia de Orta, Almada, Portugal; 4Hospitais da Universidade de Coimbra, Coimbra, Portugal; 5Instituto Portugueˆs de Reumatologia, Lisboa, Portugal; 6 Hospital de Sa˜o Joa˜o, Porto, Portugal; 7Hospital Conde de Bertiandos, Ponte de Lima, Portugal; 8Hospital de Faro, Faro, Portugal; and 9 Hospital de Aveiro, Aveiro, Portugal
Background: Although the survival rate has considerably improved, many patients with systemic lupus erythematosus (SLE) develop irreversible organ damage. Objectives: The objectives of this paper are to characterize cumulative damage in SLE patients and identify variables associated with its presence and severity. Methods: A cross-sectional analysis of SLE patients from the Portuguese Lupus register Reuma.pt/SLE in whom damage assessment using the SLICC/ACR-Disability Index (SDI) was available was performed. Predictor factors for damage, defined as SDI 1, were determined by logistic regression analyses. A sub-analysis of patients with severe damage (SDI 3) was also performed. Results: In total, 976 patients were included. SDI was 1 in 365 patients, of whom 89 had severe damage. Musculoskeletal (24.4%), neuropsychiatric (24.1%) and ocular (17.2%) domains were the most commonly affected. Older age, longer disease duration, renal involvement, presence of antiphospholipid antibodies and current therapy with steroids were independently associated with SDI 1. The subpopulation with severe damage had, in addition, a greater interval between the first manifestation attributable to SLE and the clinical diagnosis as well as and more frequently early retirement due to SLE. Conclusions: This large lupus cohort confirmed that demographic and clinical characteristics as well as medication are independently associated with damage. Additionally, premature retirement occurs more often in patients with SDI 3. Diagnosis delay might contribute to damage accrual. Lupus (2014) 0, 1–7. Key words: Systemic lupus erythematosus; Reuma.pt; Portugal
Introduction Systemic lupus erythematosus (SLE) may present very different clinical manifestations, sometimes debilitating and life threatening.1,2 Over the last decades there has been a substantial increase in survival of these patients, yet life expectancy in SLE is still low compared to that expected for people of the same age and gender.1,3,4 Moreover, in the course of the disease, many patients develop Correspondence to: Sandra Sousa, Hospital Garcia de Orta, Department of Rheumatology, Avenida Torrado da Silva Almada, 2801-951 Portugal. Email: [email protected] *M.J.G. and S.S. are joint first authors of this work. Received 31 May 2014; revised: 8 August 2014 accepted 10 September 2014
irreversible organ damage. In 1992 the Systemic Lupus International Collaborative Clinics (SLICC) in collaboration with the American College of Rheumatology (ACR) developed and validated an index for the evaluation of irreversible damage.3,5,6 Damage measured by the SLICC/ACR Damage Index (SDI) is associated with higher mortality rate, especially when damage occurs early in the course of the disease or reflects renal involvement or cardiovascular (CDV) disease.7 Several studies have sought to identify risk factors for the occurrence and progression of irreversible damage in SLE. In addition to demographic and clinical characteristics such as age, disease duration, frequency of flares, presence of antiphospholipid antibodies, hypertension or steroid use,
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at TULANE UNIV on January 20, 2015
10.1177/0961203314555172
XML Template (2014) [14.10.2014–11:25am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/140209/APPFile/SG-LUPJ140209.3d
(LUP)
[1–7] [PREPRINTER stage]
Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry MJ Gonc¸alves et al.
2
ethnic and socioeconomic differences may also affect the damage accrual.2–6,8–12 SLE in South European populations presents some distinct genetic and clinical characteristics.13 Damage is still poorly characterized in these populations. The Rheumatic diseases register from the Portuguese Society of Rheumatology (Reuma.pt) launched in September 2012 a longitudinal registry for SLE patients—the Reuma.pt/SLE. This registry captures more than 90% of the public rheumatology departments across Portugal (mainland, Azores and Madeira islands), as well as private practices.14 After providing signed informed consent, 1510 patients with SLE were retrospectively included between September 2012 and December 2012, and prospectively followed afterwards. All patients have a baseline assessment at which demographics, education, lifestyle habits, ACR and SLICC criteria for SLE, disease activity, pregnancy morbidity and thrombosis, accumulated damage, comorbidity and medication were recorded. Follow-up visits were conducted every three to four months, according to clinical practice. With this study we aim to characterize damage among SLE patients followed in different rheumatology centers and registered in Reuma.pt/SLE. Secondly, we intend to examine the association between demographic and clinical characteristics, presence of comorbidities, laboratory variables, including positivity for different antibodies and medication and damage measured by the SDI. Additionally we aim to analyze patients with severe damage (SDI within the upper quartile).
of SLE was established by the treating physician. Disease duration was defined as the interval between date of diagnosis and date of last visit. The presence of damage was defined as SDI 1. Variables We analyzed the following variables: age, gender, ethnicity, educational level, age at diagnosis, disease duration, cumulative clinical manifestations, disease activity assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K)15 at last visit, damage assessed by the SDI16 at the last visit and medications (current use). Comorbidities analyzed included hypertension, diabetes, thyroid diseases, and secondary SS and APS, according to the accepted definitions. Diagnosis delay was defined as the time between first symptom/manifestation attributable to SLE and the date of clinical diagnosis established by the treating physician. Definitions of clinical features included in ACR revised criteria were used to characterize organ involvement. All laboratory tests were performed locally. Anti-DNA, anti-Sm, anti-RNP, anti-SSA and anti-SSB were considered positive if the value was above the cutoffs for the laboratory at least in one determination during the follow-up period. Antiphospholipid antibodies were considered positive if immunoglobulin (Ig)G or IgM anticardiolipin or anti-beta2-glycoprotein titers were above the 99th percentile or a positive test for lupus anticoagulant using a standard method was detected. Statistical analysis
Material and methods Patients All patients registered in Reuma.pt/SLE fulfilling at least four of the 1997 ACR revised criteria for SLE and available SDI assessment were selected for analysis. Patients with incomplete lupus or with other rheumatic disease, except secondary Sjo¨gren’s syndrome (SS) or secondary antiphospholipid syndrome (APS), were excluded. A cross-sectional analysis of this cohort at the last recorded visit was made on the demographic, clinical and laboratory characterization of SLE, comorbidities, lupus activity, irreversible damage, as well as the medication used. Missing data were obtained, whenever possible, by review of all available medical records. The date of diagnosis was defined when the clinical diagnosis
Continuous variables are expressed as mean standard deviation, if they have a normal distribution or median with interquartile range if distribution is highly skewed. Categorical variables are presented as absolute values and frequencies. Student’s t-test and the chi-square tests were carried out to compare continuous and categorical variables, respectively. We compared demographic and clinical characteristics in groups of patients according to the presence of damage. Predictor factors for damage were determined by uni- and multivariate logistical regression analyses. Candidate covariates were entered in the multivariate model by backward selection if p < 0.05 in univariate analysis or if they were considered clinically relevant (gender and corticosteroid therapy). Diabetes was not tested as a predictor of damage to avoid circularity, since in the majority of patients diabetes was
Lupus Downloaded from lup.sagepub.com at TULANE UNIV on January 20, 2015
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(LUP)
[1–7] [PREPRINTER stage]
Characterization of damage in Portuguese lupus patients: analysis of a national lupus registry MJ Gonc¸alves et al.
3
diagnosed after the onset of SLE and as such classified as damage. A significant level of 5% was used in all analyses. All statistical analyses were performed using the program Stata, version 12.0.
Results From the 1510 SLE patients registered in Reuma.pt/SLE were excluded those who did not fulfill ACR classification criteria (n ¼ 214) and those without available SDI score assessment (n ¼ 320). A total of 976 patients were included in our analysis. This sample is representative of the whole SLE population registered in Reuma.pt/SLE, with no significant differences in demographic and clinical characteristics. The majority were women, predominantly Caucasian with a mean age of 47 14 years and mean disease duration of 14.1 8.9 years. Of the 976 patients, 365 (37.4%) presented with irreversible damage with an average SDI score of
0.71 1.22. No difference in gender distribution was found between those with and without damage. Patients with SDI 1 were older (mean age of 52.8 years vs 45.0 years), had longer disease duration and later disease onset (Table 1). Oral ulcers, serositis, renal and neurologic involvement were more prevalent in those with damage, as was hypertension, secondary SS and APS. Disease activity assessed by SLEDAI-2K (at last visit) was not significantly different between groups (2.70 3.4 vs 2.56 3.1; p ¼ 0.289). The most frequently prescribed therapy for SLE is described in Table 2. The use of antimalarials was less frequent in those with damage. Characterization of damage in this group was considered in different systems, as shown in Table 3. Higher proportions of patients had musculoskeletal (24.4%), neuropsychiatric (24.1%) and ocular (17.2%) damage. In most cases only one SDI domain was affected; absolute frequencies of SDI scores are displayed in Figure 1. In multivariate analysis, age, disease duration, renal involvement, antiphospholipid antibodies
Table 1 Demographic and clinical characteristics of SLE patients included in analysis Feature Women Age at diagnosis (years) Disease duration (years) Ethnicity n ¼ 911 – Caucasian – African – Others Education (years), n ¼ 205 Malar rash, n ¼ 972 Photosensitivity, n ¼ 968 Oral ulcers, n ¼ 965 Arthritis, n ¼ 976 Serositis, n ¼ 974 Renal involvement, n ¼ 959 Neurologic disorder, n ¼ 970 Hematologic disorder, n ¼ 967 Anti-DNA, n ¼ 971 Anti-Sm, n ¼ 939 Anticardiolipin, n ¼ 742 Anti-SSA positivity, n ¼ 606 Anti-SSB positivity, n ¼ 606 Anti-RNP positivity, n ¼ 606 Low complement, n ¼ 890 Hypertension, n ¼ 526 Thyroid disease, n ¼ 526 Antiphospholipid syndrome, n ¼ 526 Sjo¨gren’s syndrome n ¼ 526
Patients without damage SDI ¼ 0 (n ¼ 611)
Patients with damage SDI 1 (n ¼ 365)
559 (91.5%) 34.4 14.7 12.6 8.1
335 (91.8%) 37 15.0 17.0 9.4
498 (95.6%) 18 (3.5%) 5 (1%) 9.8 4.4 258 (42.4%) 303 (50.0%) 179 (29.8%) 456 (74.6%) 114 (18.7%) 175 (29.2%) 9 (1.5%) 387 (64.0%) 508 (83.7%) 74 (12.5%) 185 (39.7%) 136 (35.8%) 65 (17.3%) 90 (24.3%) 413 (72.7%) 84 (28.9%) 37 (12.7%) 15 (5.2%) 26 (8.9%)
287 (92.3%) 24 (6.8%) 3 (1%) 9.0 4.2 165 (45.3%) 186 (51.4%) 133 (36.5%) 276 (75.6%) 103 (28.2%) 130 (36.2%) 41 (11.2%) 229 (63.3%) 364 (80.7%) 45 (12.9%) 138 (50.0%) 95 (42.0%) 45 (20.4%) 58 (26.5%) 240 (74.5%) 94 (40.0%) 22 (9.3%) 31 (12.3%) 38 (14.9%)
p 0.874 0.004
