Chinese Systemic Lupus Erythematosus Treatment and Research Group (CSTAR) Registry XI: gender impact on long-term outcomes

Abstract

Objective

The objective of this paper is to assess the role of gender on survival rate and causes of death and organ damage in systemic lupus erythematosus (SLE) patients in China from 2009 to 2015.

Methods

We conducted a multicenter cohort study to analyze the differences in outcome data between male and female SLE patients. A group of 1494 SLE patients who fulfilled the 1997 American College of Rheumatology SLE classification criteria were enrolled in the Chinese Systemic Lupus Erythematosus Treatment and Research Group (CSTAR) registry from April 2009 to February 2010. All enrolled patients were followed up at least once per year from 2009 to 2015. For patients who could not attend the outpatient clinic, follow-up was conducted by telephone interview. We collected demographic data, clinical manifestations and damage scores (System Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)). Survival rates were evaluated using the Kaplan-Meier method.

Results

This study included 1352 women and 142 men. The five-year survival rates were 92.0% for men and 97.6% for women. The survival rates of males were significant lower than for females (p = 0.019). Male patients received methylprednisolone pulse therapy and cyclophosphamide significantly more than female patients (p = 0.010). During follow-up, 12 male patients and 66 female patients died. The most common cause of death was infection (41.7%) for men and active SLE disease (27.3%) for women. At the end of the study, the major accumulated organ damages included renal (8.5%) and musculoskeletal (7.7%), and nervous system (5.6%) for men and renal (8.8%) and musculoskeletal (6.7%) for women. There were no significant differences in SDI scores between the two groups at baseline and at the end of the study.

Conclusions

Male SLE patients had lower survival rates than female patients. Male patients received more methylprednisolone pulse and cyclophosphamide therapy. The most common causes of death were infection for male patients and active SLE disease for female patients. The major accumulated organ damages were renal, musculoskeletal, and nervous system both for male and female SLE patients in China.

Keywords

gender survival rate systemic lupus erythematosus (SLE)System Lupus International Collaborating Clinics/ACR Damage Index

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical and immunological features.¹ During the last few decades, SLE prognosis has significantly improved, mostly because of earlier diagnosis, better immunosuppressive therapies, and improved management of associated complications, such as infection.^2–4 Studies report five-year survival rates of more than 95% in some patient cohorts.⁵ Previous studies have reported that male patients often exhibit a poorer prognosis, especially involving the renal, cardiovascular, and neurologic systems.⁶ Higher mortality rates in male SLE patients have also been reported.^4,5 There are no multicenter cohort studies evaluating outcomes between genders in Chinese SLE patients. Therefore, we investigated survival rate, causes of death, and damage in male and female SLE patients in China.

Methods

Patient recruitment and follow-up

We analyzed preliminary data from the Chinese Systemic Lupus Erythematosus Treatment and Research Group (CSTAR) online registry,⁷ which included patients from 104 high-ranking rheumatology centers, covering 30 provinces in China. The Medical Ethics Committee of the Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (Approval number, S-197), the lead study site, approved this study. Written informed consent was obtained from all patients. Baseline data were collected for 1494 Chinese patients with SLE who fulfilled four or more criteria for SLE diagnosis as defined by the 1997 revised American College of Rheumatology (ACR) criteria.^8,9 Patients were registered between April 2009 and February 2010. All enrolled patients were followed up at least once per year. For patients who could not attend the outpatient clinic, follow-up was conducted by telephone interview. Patients who ceased follow-up or who chose to leave the study after enrollment were defined as lost to follow-up.

Data collection

All CSTAR centers used the same protocol-directed methods to provide uniform evaluations and to record patient data. Investigators received training on diagnostic confirmation, disease activity evaluation, data input, and data quality control. The demographic data collected included gender, age at onset, age at diagnosis, age at enrollment, family history of rheumatic diseases, and reproductive history, as well as socioeconomic status, education and marital status. Systemic manifestations (e.g. neuropsychiatric SLE, vasculitis, arthritis, myositis, lupus nephritis, rash, oral ulceration, alopecia, pleuritis, pericarditis and fever) were assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). All occurrences were classified according to SLEDAI definitions. Survival time was defined as the time from the date of diagnosis until death or last contact. Follow-up visits were conducted every three to four months, according to clinical practice.¹⁰

Organ or system damage, defined as irreversible impairment, was recorded if the damage was persistent for at least six months.¹¹ Damage was assessed by the System Lupus International Collaborating Clinics/ACR Damage Index for Systemic Lupus Erythematosus (SDI)¹² at last visit and included medications (previous and current use).¹³ According to the SDI, damage was assessed in 12 organ systems as follows: ocular (range 0–2), neuropsychiatric (0–6), renal (0–3), pulmonary (0–5), cardiovascular (0–6), peripheral vascular (0–5), gastrointestinal (0–6), musculoskeletal (0–7), skin (0–3), gonadal (0–1), endocrine (0–1) and malignancy (0–2), with a possible maximum total score of 47.¹⁴ The follow-up period was identified as the time of disease onset to the time of death or last follow-up. Cause of death was determined by a review of case records and by discussion with the attending physicians.¹⁵

Statistical analysis

Continuous data are expressed as mean ± SD. An independent sample t test was used to compare variables between the two groups. For non-normally distributed data, the Mann-Whitney U test was used. Categorical data are expressed as numbers or percentages. The chi-squared test or Fisher exact test was used to analyze the relationship between categorical variables. P values less than 0.05 indicated statistically significant results; values less than 0.1 were also reported. The Kaplan-Meier method was used for survival analysis. The Cox proportional hazard model was adopted to analyze predicting factors for mortality. Statistical analysis was carried out using SPSS 17.0 for Windows.

Results

Demographic and clinical characteristics of SLE patients

Of the 2104 SLE patients registered in the CSTAR online registry from April 2009 to February 2010, a total of 1494 patients were successfully followed up for a median time of 6.18 ± 1.82 years. There were 142 male and 1352 female patients. The mean time of follow-up was 6.11 ± 2.21 years for men and 6.17 ± 1.77 years for women. The disease duration at entry was 2.49 ± 3.04 and 3.56 ± 4.84 years for men and women, respectively (p = 0.010). The antibodies-positive rates showed no significant differences between male and female patients. SLEDAI scores at entry for male patients were significantly higher than for females (10.94 ± 7.96 vs 9.47 ± 7.00, p = 0.019). The immunosuppressive therapy at entry showed male patients received methylprednisolone pulse therapy and cyclophosphamide significantly more than female patients (p = 0.010). (Table 1).

Table 1

Demographic and clinical characteristics of SLE patients.

	Male, n (%) n = 142	Female, n (%) n = 1352	p
Age at onset (years)	27.68 ± 14.92	29.04 ± 11.83	0.206
Age at diagnosis (years)	28.80 ± 15.25	29.89 ± 12.03	0.325
Disease duration (years)	2.49 ± 3.04	3.56 ± 4.84	0.010
SLEDAI	10.94 ± 7.96	9.47 ± 7.00	0.019
Antibodies
ANA positive	97.9	98.4	0.668
Anti-dsDNA positive at entry	59.9	53.4	0.142
Anti-Sm positive	23.9	17.3	0.050
Anti-RNP positive	8.5	10.9	0.360
Anti-SSA positive	23.9	24.8	0.826
Anti-SSB positive	9.2	11.5	0.407
Anti-ribosomal P protein positive	13.4	13.2	0.962
Anticardiolipin positive	26.8	27.6	0.833
Immunosuppressant drugs at entry
Corticosteroids	90.1	90.9	0.767
Pulsed methylprednisolone	26.4	17.6	0.010
Antimalarial drugs	44.4	50.9	0.139
Cyclophosphamide	46.5	35.6	0.010
Mycophenolate mofetil	9.2	11.6	0.380
Cyclosporine	1.4	2.2	0.526
Tacrolimus	0.7	1.0	0.762
Azathioprine	4.9	4.4	0.755
Methotrexate	8.5	10.9	0.373
Leflunomide	9.2	12.2	0.286

ANA: antinuclear antibody; dsDNA: double-stranded DNA; RNP: ribonucleoprotein; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. P values that were ≤0.05 are shown as italics and bold.

P values that were ≤0.05 are shown as italics and bold.

Survival rate

Figure 1 shows the Kaplan-Meier survival plot of the cohort. The one-year survival rate was 97.8% in male patients and 99.1% in female patients, the three-year survival rate was 95.4% in male patients and 98.4% in female patients, and the five-year survival rate was 92.0% in male patients and 97.6% in female patients; these were significantly different (p = 0.019).

Figure 1

The survival rates of two genders in systemic lupus erythematosus patients for one, three and five years (y).

Mortality and causes of death

Seventy-eight (5.2%) patients died during follow-up, including 12 male and 66 female patients. The mean age at death was 47.0 ± 14.7 years for men and 38.7 ± 15.4 years for women. The mean time from diagnosis to death was 3.8 ± 3.5 years for men and 5.7 ± 4.4 years for women; five (41.7%) male and 13 (19.7%) female patients died during the first two years after diagnosis (p = 0.097). A univariate analysis for mortality revealed a significant difference after controlling for age of onset and time from onset to diagnosis (hazard ratio (HR): 2.082; confidence interval (CI): 1.119–3.873; p = 0.021). In men, infection was the most common cause of death, followed by active lupus disease. In women, the most common cause of death was active lupus disease, followed by infection (Table 2).

Table 2

Underlying causes of death with gender distribution in patients with systemic lupus erythematosus (SLE) in China

	Male, n (%) n = 12	Female, n (%) n = 66	p
Age of death	47.0 ± 14.7	38.7 ± 15.4	0.090
Diagnosis to death (year)	3.8 ± 3.5	5.7 ± 4.4	0.159
Death earlier than two years from diagnosis	5 (41.7%)	13 (19.7%)	0.097
Underlying cause of death	Male (n = 12)	Female (n = 66)	Total
Infection	5	17	27
Pneumonia	2	13	15
Central nervous system	3	3	6
Urinary tract	0	1	1
Sepsis	0	2	2
Unknown	0	3	3
Active SLE	3	18	21
Pulmonary fibrosis	1	1	2
Pulmonary hypertension	0	3	3
Diffuse alveolar hemorrhage	0	1	1
Renal	1	7	8
Neuropsychiatric	1	3	4
Gastrointestinal	0	1	1
Hemolytic anemia	0	2	2
Malignancy	1	3	4
Lung cancer	1	0	1
Leukemia	0	2	2
Neuro origin	0	1	1
Cardiovascular	2	1	3
Cerebrovascular	1	1	2

Organ damage

At the time of study enrollment, 247 of 1494 (16.5%) SLE patients had chronic damage in at least one organ or system (SDI ≥ 1), including 20 male and 227 female patients, with a mean SD score of 1.19 ± 0.42 (range, 0–5). The score for female patients was 1.19 ± 0.474, and the score for male patients was 1.15 ± 0.366 (p = 0.718); 208 of 1494 patients (13.9%) had an SDI of 1, including 17 male patients (12.0%) and 191 female patients (14.1%); 31 of 1494 patients (2.1%) had an SDI of 2, including three male patients (2.1%) and 28 female patients (2.1%); eight of 1494 patients (0.5%) had an SDI of 3 (all were female patients) (Table 3).

Table 3

SLICC/ACR Damage Index comparison between male and female patients with SLE (n = 1494)

	Male, n (%) n = 142	Female, n (%) n = 1352	p
Organ damage at entry
Ophthalmology	0 (0)	18 (1.3)	0.167
Neuropsychiatric	4 (2.8)	33 (2.4)	0.784
Renal	10 (7.0)	89 (6.6)	0.834
Pulmonary	1 (0.7)	31 (2.3)	0.214
Cardiovascular	1 (0.7)	17 (1.3)	0.565
Peripheral vascular	2 (1.4)	10 (0.7)	0.396
Gastrointestinal	0 (0)	5 (0.4)	0.468
Musculoskeletal	3 (2.1)	36 (2.7)	0.696
Skin	1 (0.7)	14 (1.0)	0.706
Premature gonadal failure	0 (0)	5 (0.4)	0.468
Diabetes	1 (0.7)	5 (0.4)	0.549
Malignancy	0 (0)	1 (0.1)	0.746
SDI=1 at entry	17 (12.0)	191 (14.1)	0.480
SDI=2 at entry	3 (2.1)	28 (2.1)	0.974
SDI=3 at entry	0 (0)	8 (0.6)	0.358
Organ damage at the endpoint
Ophthalmology	2 (1.4)	37 (2.7)	0.345
Neuropsychiatric	8 (5.6)	51 (3.8)	0.279
Renal	12 (8.5)	119 (8.8)	0.888
Pulmonary	3 (2.1)	52 (3.8)	0.297
Cardiovascular	3 (2.1)	31 (2.3)	0.891
Peripheral vascular	3 (2.1)	17 (1.3)	0.399
Gastrointestinal	1 (0.7)	9 (0.7)	0.957
Musculoskeletal	11 (7.7)	91 (6.7)	0.648
Skin	3 (2.1)	17 (1.3)	0.399
Premature gonadal failure	0 (0)	15 (1.1)	0.207
Diabetes	3 (2.1)	11 (0.8)	0.126
Malignancy	0 (0)	6 (0.4)	0.426
SDI=1 at endpoint	28 (19.7)	275 (20.3)	0.861
SDI=2 at endpoint	6 (4.2)	61 (4.5)	0.875
SDI=3 at endpoint	3 (2.1)	21 (1.6)	0.614
SDI=4 at endpoint	1 (0.7)	3 (0.2)	0.290

SDI: System Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLE: systemic lupus erythematosus.

At the end of the study, 398 of 1494 (26.6%) SLE patients had chronic damage in at least one organ or system (SDI ≥ 1), including 38 male and 360 female patients, with a mean SD score of 1.32 ± 0.64 (range, 0–5). The score of female patients was 1.31 ± 0.62 and the score of male patients was 1.39 ± 0.76 (p = 0.438); 303 of 1494 patients (20.3%) had an SDI of 1, including 28 male patients (19.7%) and 275 female patients (20.3%); 67 of 1494 patients (4.6%) had an SDI of 2, including six male patients (4.2%) and 61 female patients (4.5%); 24/1494 patients (1.6%) had an SDI of 3, including three male patients (2.1%) and 21 female patients (1.6%); four of 1494 patients (0.3%) had an SDI of 4, including one male patient (0.7%) and three female patients (0.2%) (Table 3).

At the end of the study, the major accumulated organ damage included renal (8.5%), musculoskeletal (7.7%) and nervous system (5.6%) for men and renal (8.8%), musculoskeletal (6.7%), nervous system (3.8%) and pulmonary (3.8%) for women. Damage accrual was not significantly associated with gender. SDI item accrual during the follow-up period is summarized in Table 3. The total SDI increased from 1.19 ± 0.42 to 1.32 ± 0.64 across six years.

We also detected new damage during follow-up. Musculoskeletal damage was the most commonly involved organ or system (64/1494 patients; 4.3%) both for men (8/142; 5.6%) and women (56/1352; 4.1%) (Table 4). A univariate analysis revealed no significant difference after controlling for the influence of onset age and time from onset to diagnosis (HR: 1.316; CI: 0.842–2.056; p = 0.228).

Table 4

New damage comparison between male and female patients with SLE from entry to the endpoint

New damage	Male, n (%) n = 142	Female, n (%) n = 1352	p
Ophthalmology	2 (1.4)	19 (1.4)	0.998
Neuropsychiatric	4 (2.8)	19 (1.4)	0.194
Renal	2 (1.4)	32 (2.4)	0.466
Pulmonary	2 (1.4)	21 (1.6)	0.894
cardiovascular	3 (2.1)	14 (1.0)	0.250
Peripheral vascular	1 (0.7)	7 (0.5)	0.772
Gastrointestinal	1 (0.7)	4 (0.3)	0.423
Musculoskeletal	8 (5.6)	56 (4.1)	0.404
Skin	2 (1.4)	3 (0.2)	0.020
Premature gonadal failure	0 (0)	10 (0.7)	0.304
Diabetes	2 (1.4)	6 (0.4)	0.134
Malignancy	0 (0)	5 (0.4)	0.468
Total	27	196

Discussion

To the best of our knowledge, this is the first Chinese study focused on the gender impact of long term-outcomes in a large cohort of SLE patients. Previous studies have reported five-year survival rates of more than 95% in some SLE patient cohorts.^5,16–18 Our study showed that five-year survival rates for female patients were more than 95%; however, the rates for male patients did not reach that level, indicating that male patients have less-favorable outcomes than females. Many factors have been found to be related to the mortality of SLE, including gender, course of disease, onset of SLE after age 50 years, and the level of activity of disease.^6,19

Male gender has previously been associated with a poorer prognosis,^20–26 as in our study. Variables predicting early death (two years after diagnosis) include male gender, young age at diagnosis, and skin complications.²⁷ Our study also showed that male patients die sooner than female patients. The probable explanation for poorer prognosis and earlier death is that male patients often have more active disease with rapid progressive courses.²⁷ Previous studies have shown that renal disease, vasculitis, and neuropsychiatric lupus are more common in male SLE patients with higher SLEDAI scores compared with female SLE patients in China.²⁸ Higher mortality rates associated with worse renal outcomes are thought to occur in male patients since renal involvement in SLE is a major determinant of outcomes.^24,25

Smoking is a well-known risk factor for the development of proteinuria and the progression of renal disease in the general population, especially in males.^29,30 In SLE patients, studies have shown that smokers have significantly more nephropathy, microscopic hematuria, proteinuria, and higher SLEDAI scores than nonsmokers.³¹ Xu et al. showed that the number of male SLE patients who smoke is nearly three times higher than female patients.³¹ While the effect of gender on mortality in SLE is not entirely clear, a higher prevalence of male smokers with SLE may explain this poorer prognosis.

Our data showed that the main cause of death was infection in men and active SLE disease in women. Previous studies from China have shown that the presence of infection with disease flare was the main cause of death in lupus patients and an independent predictor for poor survival.^32,33 Lu and colleagues found that the causes of death in SLE are usually similar across genders.³² Another study found that, although the most common cause of death was cardiovascular disease in men and active SLE, infections and malignancies in female patients, there was no significant difference between groups.³³ Because our cohort had data for only six years, the cause of death can only indicate early death; thus, long-term damage from diseases, such as cardiovascular disease, requires longer-term data to evaluate. Because male patients have more organ involvements and higher SLEDAI scores than female patients,²⁸ rheumatologists would give them more aggressive immunosuppressive therapy. According to our study, the proportion of male patients treated with pulsed methylprednisolone and cyclophosphamide was significantly higher than that of female patients. Other research showed a similar result of more prevalent of cyclophosphamide use in men.³⁴ Strong immunosuppressive therapy would increase the risk of infections, so there would be a greater chance of acquiring infections; this could explain the high rates of infections in male patients.

According to SDI, our study found that renal damage was the most frequently involved system in both genders, followed by musculoskeletal and neuropsychiatric systems. The prevalence of renal damage in our result was similar to some other studies, which was approximately 8% to 14.5%. Meanwhile, one study showed the proportion of renal involvement was as high as 37.5%.³⁵ This difference may be due to different treatment protocols and various changes in renal histology.³⁶ Some investigators have reported musculoskeletal system and neuropsychiatric as the most involved systems.^10,36 Damage accrual varies among ethnic groups, and damage in different systems does not follow a common pattern in SLE patients.^37–40

The prevalence of eye damage was lower in our cohort of patients in contrast to other studies, which reported them to be more than 5%.^10,36 In our study, ophthalmology examinations were not routine items for follow-up. It is possible that patients without obvious eye symptoms might not visit an ophthalmologist, which could explain why the rate of eye involvement is low.

The five-year survival of SLE patients has significantly improved from the 50% reported in the 1950s to currently more than 90%.^4,41,42 Increased survival of SLE patients implies the accrual of cumulative organ damage, while adverse events of treatment, disease activity and comorbidities represent major risk factors.^43,44 Some previous studies have indicated that men are more likely than women to experience organ damage, including neuropsychiatric, renal, cardiovascular, peripheral vascular disease and myocardial infarction.⁴⁵ However, unlike some other studies,⁴⁶ we could not conclude that male patients had much more organ damage than female patients. Some researchers obtained the same results as we did, indicating that gender is not a definite predictor of damage.^47–49 One possible explanation is that certain characteristics included in damage scores appear more frequently in women.³⁶

This study has limitations. First, this study had a short follow-up. Longer-term studies are needed to investigate late mortality and organ damage in SLE patients. In addition, it remains to be determined whether disease relapses are risk factors for mortality.

In summary, male SLE patients had lower survival rates than female patients. Male patients received more methylprednisolone pulse and cyclophosphamide therapy. The most common causes of death were infection for male patients and active SLE disease for female patients. The major accumulated organ damages were renal, musculoskeletal, and nervous system both for male and female SLE patients in China.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Chinese National Key Technology R&D Program, Ministry of Science and Technology (2017YFC0907601, 2017YFC0907602, 2017YFC0907603), and the Chinese National High Technology Research and Development Program, Ministry of Science and Technology (2012AA02A513).

References

Manson

Rahman

. Systemic lupus erythematosus. Orphanet J Rare Dis 2006; 1: 6.

Bernatsky

Boivin

Joseph

et al.

Mortality in systemic lupus erythematosus. Arthritis Rheum 2006; 54: 2550–2557.

Abu-Shakra

Gladman

Urowitz

. Mortality studies in SLE: How far can we improve survival of patients with SLE? Autoimmun Rev 2004; 3: 418–420.

Doria

Iaccarino

Ghirardello

et al.

Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med 2006; 119: 700–706.

Cervera

Khamashta

Font

et al.

Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 1999; 78: 167–175.

Zhen

Ling-Yun

Yao-Hong

et al.

Death-related factors of systemic lupus erythematosus patients associated with the course of disease in Chinese populations: Multicenter and retrospective study of 1,958 inpatients. Rheumatol Int 2013; 33: 1541–1546.

Zhang

Leng

et al.

Chinese SLE Treatment and Research Group (CSTAR) registry: I. Major clinical characteristics of Chinese patients with systemic lupus erythematosus. Lupus 2013; 22: 1192–1199.

Tan

Cohen

Fries

et al.

The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277.

Hochberg

. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

10.

Gonçalves

Sousa

Inês

et al.

Characterization of damage in Portuguese lupus patients: Analysis of a national lupus registry. Lupus 2015; 24: 256–262.

11.

Gladman

Ginzler

Goldsmith

et al.

The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus. Arthritis Rheum 1996; 39: 363–369.

12.

Gladman

Ginzler

Goldsmith

et al.

Systemic Lupus International Collaborative Clinics: Development of a damage index in systemic lupus erythematosus. J Rheumatol 1992; 19: 1820–1821.

13.

Sousa

Gonçalves

Inês

et al.

Clinical features and long-term outcomes of systemic lupus erythematosus: Comparative data of childhood, adult and late-onset disease in a national register. Rheumatol Int 2016; 36: 955–960.

14.

Conti

Ceccarelli

Perricone

et al.

The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: Results from a monocentric cohort. Lupus 2016; 25: 719–726.

15.

Mok

. Epidemiology and survival of systemic lupus erythematosus in Hong Kong Chinese. Lupus 2011; 20: 767–771.

16.

Mahmoud

Shahin

Zayed

Moghazy

Eissa

. Clinical and immunological pattern and outcome of Egyptian systemic lupus erythematosus patients: A single center experience. Lupus 2018; 27: 1562–1569.

17.

das Chagas Medeiros

Bezerra

Braga

et al.

Clinical and immunological aspects and outcome of a Brazilian cohort of 414 patients with systemic lupus erythematosus (SLE): Comparison between childhood-onset, adult-onset, and late-onset SLE. Lupus 2016; 25: 355–363.

18.

Artim-Esen

Şahin

Çene

et al.

Comparison of disease characteristics, organ damage, and survival in patients with juvenile-onset and adult-onset systemic lupus erythematosus in a combined cohort from 2 tertiary centers in Turkey. J Rheumatol 2017; 44: 619–625.

19.

Kasitanon

Magder

Petri

. Predictors of survival in systemic lupus erythematosus. Medicine (Baltimore) 2006; 85: 147–156.

20.

Specker

Becker

Lakomek

Bach

Grabensee

. Systemic lupus erythematosus in men—a different prognosis? [article in German]. Z Rheumatol 1994; 53: 339–345.

21.

Alamanos

Voulgari

Papassava

Tsamandouraki

Drosos

. Survival and mortality rates of systemic lupus erythematosus patients in northwest Greece. Study of a 21-year incidence cohort. Rheumatology (Oxford) 2003; 42: 1122–1123.

22.

Mayor

Vilá

. Gender differences in a cohort of Puerto Ricans with systemic lupus erythematosus. Cell Mol Biol (Noisy-le-grand) 2003; 49: 1339–1344.

23.

Xie

Feng

. Long term follow-up of patients with systemic lupus erythematosus. J Dermatol 1998; 25: 367–373.

24.

Garcia

Marcos

et al.

Male systemic lupus erythematosus in a Latin-American inception cohort of 1214 patients. Lupus 2005; 14: 938–946.

25.

Chang

Kuo

Chu

Chang

. The clinical features and prognosis of male lupus in Taiwan. Lupus 1998; 7: 462–468.

26.

Pons-Estel

Alarcón

Scofield

Reinlib

Cooper

. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 2010; 39: 257–268.

27.

Heller

Ahmed

Siddiqqi

Wallrauch

Bahlas

. Systemic lupus erythematosus in Saudi Arabia: Morbidity and mortality in a multiethnic population. Lupus 2007; 16: 908–914.

28.

Zhang

et al.

Chinese SLE Treatment and Research Group (CSTAR) registry: V. Gender impact on Chinese patients with systemic lupus erythematosus. Lupus 2015; 24: 1267–1275.

29.

Halimi

Giraudeau

Vol

et al.

Effects of current smoking and smoking discontinuation on renal function and proteinuria in the general population. Kidney Int 2000; 58: 1285–1292.

30.

Orth

Stöckmann

Conradt

et al.

Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney Int 1998; 54: 926–931.

31.

You

Wang

et al.

Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry VI: Effect of cigarette smoking on the clinical phenotype of Chinese patients with systemic lupus erythematosus. PLoS One 2015; 10: e0134451.

32.

Wallace

Ishimori

Scofield

Weisman

. Review: Male systemic lupus erythematosus: A review of sex disparities in this disease. Lupus 2010; 19: 119–129.

33.

Riveros Frutos

Casas

Rúa-Figueroa

et al.

Systemic lupus erythematosus in Spanish males: A study of the Spanish Rheumatology Society Lupus Registry (RELESSER) cohort. Lupus 2017; 26: 698–706.

34.

Santamaría-Alza

Motta

JZN

Fajardo-Rivero

Pineda

CLF

. Systemic lupus erythematosus, gender differences in Colombian patients. Clin Rheumatol 2018; 37: 2423–2428.

35.

Petri

Orbai

Alarcón

et al.

Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677–2686.

36.

Ghazali

WSW

Daud

SMM

Mohammad

Wong

. SLICC Damage Index score in systemic lupus erythematosus patients and its associated factors. Medicine (Baltimore) 2018; 97: e12787.

37.

Stoll

Stucki

Malik

Pyke

Isenberg

. Association of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index with measures of disease activity and health status in patients with systemic lupus erythematosus. J Rheumatol 1997; 24: 309–313.

38.

Gladman

Urowitz

Rahman

Ibañez

Tam

. Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol 2003; 30: 1955–1959.

39.

Maddison

Farewell

Isenberg

et al.

The rate and pattern of organ damage in late onset systemic lupus erythematosus. J Rheumatol 2002; 29: 913–917.

40.

Cooper

Treadwell

St Clair

Gilkeson

Dooley

. Sociodemographic associations with early disease damage in patients with systemic lupus erythematosus. Arthritis Rheum 2007; 57: 993–999.

41.

Moss

Ioannou

Sultan

Haq

Isenberg

. Outcome of a cohort of 300 patients with systemic lupus erythematosus attending a dedicated clinic for over two decades. Ann Rheum Dis 2002; 61: 409–413.

42.

Urowitz

Gladman

Tom

Ibañez

Farewell

. Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus. J Rheumatol 2008; 35: 2152–2158.

43.

Rivest

Lew

Welsing

et al.

Association between clinical factors, socioeconomic status, and organ damage in recent onset systemic lupus erythematosus. J Rheumatol 2000; 27: 680–684.

44.

Rahman

Gladman

Urowitz

Hallett

Tam

. Early damage as measured by the SLICC/ACR Damage Index is a predictor of mortality in systemic lupus erythematosus. Lupus 2001; 10: 93–96.

45.

Tan

Fang

Magder

Petri

. Differences between male and female systemic lupus erythematosus in a multiethnic population. J Rheumatol 2012; 39: 759–769.

46.

Andrade

Alarcón

Fernández

et al.

Accelerated damage accrual among men with systemic lupus erythematosus: XLIV. Results from a multiethnic US cohort. Arthritis Rheum 2007; 56: 622–630.

47.

Petri

Purvey

Fang

Magder

. Predictors of organ damage in systemic lupus erythematosus: The Hopkins Lupus Cohort. Arthritis Rheum 2012; 64: 4021–4028.

48.

Renau

Isenberg

. Male versus female lupus: A comparison of ethnicity, clinical features, serology and outcome over a 30 year period. Lupus 2012; 21: 1041–1048.

49.

Voulgari

Katsimbri

Alamanos

Drosos

. Gender and age differences in systemic lupus erythematosus. A study of 489 Greek patients with a review of the literature. Lupus 2002; 11: 722–729.