Abstract
Objective. Male patients with systemic lupus erythematosus (SLE) are thought to be similar to female patients with SLE, but key clinical characteristics may differ. Comparisons were made between male and female patients with SLE in the Hopkins Lupus Cohort.
Methods. A total of 1979 patients in the Hopkins Lupus Cohort were included in the analysis.
Results. The cohort consisted of 157 men (66.2% white, 33.8% African American) and 1822 women (59.8% white, 40.2% African American). The mean followup was 6.02 years (range 0–23.73). Men were more likely than women to have disability, hypertension, thrombosis, and renal, hematological, and serological manifestations. Men were more likely to be diagnosed at an older age and to have a lower education level. Women were more likely to have malar rash, photosensitivity, oral ulcers, alopecia, Raynaud’s phenomenon, or arthralgia. Men were more likely than women to have experienced end organ damage including neuropsychiatric, renal, cardiovascular, peripheral vascular disease, and myocardial infarction, and to have died. In general, differences between males and females were more numerous and striking in whites, especially with respect to lupus nephritis, abnormal serologies, and thrombosis.
Conclusion. Our study suggests that there are major clinical differences between male and female patients with SLE. Differences between male and female patients also depend on ethnicity. Future SLE studies will need to consider both ethnicity and gender to understand these differences.
Male lupus is rare, comprising 4%–22% of patients with systemic lupus erythematosus (SLE)1,2,3,4,5,6,7,8 in different series. Despite numerous studies comparing male and female patients, no consistent differences or characteristics have emerged9,10. Male patients had more renal involvement in some, but not all, series7,11,12,13,14,15,16. An increased risk of renal failure in males was seen in 2 studies7,14. Male patients had more neurological involvement3,7,9,17, thrombotic events9,14,15,17, cardiovascular damage14,16,17, serositis6,8,11,18, arthritis19, hepatomegaly19, low C312, thrombocytopenia13, later disease onset3,20, fever12, infection17,21, weight loss12, and hypertension12 in some, but not all, series. In terms of serology, anticardiolipin antibodies9,12,14, anti-dsDNA15, and lupus anticoagulant (LAC)10 were more prevalent in men in a few studies (summarized in Table 1).
Studies of male versus female SLE.
There have also been reports of manifestations that occur less often in men, such as skin involvement6,17,19, hematological involvement1,11,21,22, serological involvement11,16,21, Raynaud’s phenomenon (RP)13,15,16,17,19, and arthritis6,10,18,21 in some, but not all, series.
The Hopkins Lupus Cohort offered a unique opportunity to compare male versus female SLE, in the largest cohort with systematic followup every 3 months to ensure complete identification of clinical and serologic manifestations. This cohort also offers an opportunity to compare male versus female SLE separately in white and African American patients.
MATERIALS AND METHODS
Study population
The Hopkins Lupus Cohort, established in 1987, comprises patients with SLE receiving ongoing care at the Hopkins Lupus Center. This study has been approved on an annual basis by the Johns Hopkins Hospital Institutional Review Board. Informed written consent is obtained from all subjects. Subjects enrolled in the cohort have clinic visits at 3-month intervals, or more frequently if medically necessary. Ninety-five percent of the patients met the revised American College of Rheumatology (ACR) classification criteria for SLE23. The proportions of males to females in the 5% who did not fulfill these criteria were slightly higher than those who did (0.15 vs 0.08). Information recorded at cohort entry (and updated at each visit) consists of basic demographic characteristics (date of birth, age at SLE onset, ethnicity, sex, socioeconomic status, years of education, combined annual household income) and presenting and cumulative clinical manifestations. At each patient visit, disease activity was assessed by the physician’s global assessment (0 to 3 on visual analog scale) and the Safety of Estrogens in Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index24. Laboratory tests included the complete blood cell count, erythrocyte sedimentation rate, serum creatinine, cholesterol, urinalysis, urine protein to creatinine ratio, C3, C4, and anti-dsDNA. The Systemic Lupus International Collaborating Clinics/ACR Damage Index25 was performed at cohort entry and updated at each visit.
Patients
There were 2121 patients in the entire Hopkins Lupus Cohort. We excluded 142 patients who were not white or African American for simplicity. A total of 1979 patients with SLE in the Hopkins Lupus Cohort were included in our analysis. There were 157 men (66.2% whites, 33.8% African Americans, mean age 49.8 ± 13.8 yrs) and 1822 women (59.8% whites, 40.2% African Americans, mean age at entry 37.6 ± 12.9 yrs). Cumulative ACR criteria included 51.4% malar rash, 20.2% discoid rash, 54.3% photosensitivity, 51.4% oral ulcers, 74.1% arthritis, 44.4% pleuritis, 22.5% pericarditis, 41.2% proteinuria, 9.9% seizures, 3.8% psychosis, 10.3% hemolytic anemia, 43.6% leukopenia, 39.6% lymphopenia, 20.2% thrombocytopenia, 62.2% anti-dsDNA, 18.0% anti-Sm, 26.6% LAC, 48.5% anticardiolipin, and 96.5% positive antinuclear antibody. The mean duration of followup in the cohort was 6.02 years (range 0–23.73 yrs). The mean age at last assessment for men was 47.3 ± 13.7 years and for women 43.7 ± 13.5 years. The mean duration of SLE at last assessment for men was 10.2 ± 7.6 years and for women 11.1 ± 8.5 years.
Statistical analysis
Male and female patients with SLE were compared with respect to demographic characteristics, clinical manifestations, serologic results, and therapy, using chi-square tests (SAS Institute, Cary, NC, USA). P values were then adjusted for ethnicity, history of smoking, age at last assessment, and duration of SLE at last assessment unless specified. Subsequent analyses focused on African Americans or whites separately and the comparison between African American and white males. A p value ≤ 0.05 was considered statistically significant, but OR are presented to allow the reader to assess clinical importance.
RESULTS
Clinical and laboratory manifestations in male and female patients
Demographic, clinical, and laboratory variables are summarized in Table 2. Men were more likely than women to have disability, lymphopenia, thrombocytopenia, positive anti-Sm, direct Coombs test, LAC, low C3, and anti-dsDNA. Men were also more likely to have had renal involvement, thrombotic events, and hypertension, compared to women. Men were more likely to be diagnosed at an older age and to have a lower education level than women. Men were less likely to have had malar rash, photosensitivity, oral ulcer, alopecia, RP, and arthralgias than women.
Comparison of cumulative clinical and laboratory features between male and female SLE (n = 1979).
Damage in male and female patients
Organ damage is summarized in Table 3 using the variables of the SLICC/ACR Damage Index. Men were more likely than women to have had neuropsychiatric, renal or cardiovascular manifestations, peripheral vascular disease, and myocardial infarction (MI), and to have died.
SLICC/ACR Damage Index comparison between male and female SLE (n = 1979).
Gender differences by ethnicity
Table 4 summarizes comparisons in the African American subset (n = 785). African American men were more likely to have had disability, history of smoking, proteinuria, and renal insufficiency than African American women. African American men were more likely to be diagnosed at an older age. They were also more likely than African American women to have neuropsychiatric, renal, and cardiovascular damage or to have died. However, they were less likely to have had alopecia.
Comparison of male and female African American SLE (n = 785).
Comparisons of white patients are shown in Table 5. White males were more likely than white women to have had obesity, disability, thrombocytopenia, a positive Coombs test, LAC, anti-Sm, anti-dsDNA, low C3, hypertension, and deep vein thrombosis. White men were also more likely to be diagnosed at an older age. In addition, they also had more renal manifestations such as proteinuria, nephrotic syndrome, hematuria, renal insufficiency, renal failure, and abnormal renal biopsy. They were more likely to experience neuropsychiatric, renal, cardiovascular, and musculoskeletal damage than white women. Endstage renal disease occurred in 6.7% of white men compared to 2.6% of white women (adjusted p value = 0.0141). White men were less likely than white women to have had malar rash, photosensitivity, oral ulcers, alopecia, or RP.
Comparison of male and female white SLE (n = 1194).
To further investigate the differences related to ethnicity, a comparison between white and African American males was performed (Table 6). African American men were more likely to have had discoid rash, alopecia, renal involvement such as proteinuria and renal insufficiency, and anti-Sm than white men. They were more likely to have later onset of lupus and to have a lower education level. However, they were less likely to have LAC. In addition, African American men were more likely than white men to have renal, pulmonary, and cardiovascular damage, and to have died.
Comparison of African American (AA) and white male SLE (n =157).
DISCUSSION
Male lupus has been thought to be clinically similar to female lupus7. Studies have reached conflicting results (Table 1), although several found arthritis to be less common in men with SLE. Several studies have found more organ damage in men, in particular renal insufficiency/failure. Our study has the largest number of men (except for the Veterans Administration study20, which did not systematically examine disease manifestations) and the largest prospective followup. In addition, the ethnic makeup of the Hopkins Lupus Cohort allowed us to look separately at white and African American male SLE.
We observed differences between men and women with respect to a large number of disease manifestations and outcomes. Among the differences found in our study, some dermatologic features such as oral ulcer and alopecia, some serologic tests such as LAC, and the renal manifestations such as renal insufficiency and renal failure, had OR > 2.0 or < 0.5, suggesting differences of substantial clinical importance.
In the all-patient analyses (Table 2), men were more likely than women to have had lymphopenia, thrombocytopenia, direct Coombs, LAC, anti-Sm, low C3, and anti-dsDNA. The striking increase in manifestations of hematologic and serologic lupus was suggested in one previous study that found an increase in thrombocytopenia13, one that found an increase in hemolytic anemia and low C312, and one that found an increase in anti-dsDNA15. The increase in LAC was reported in only one previous study10, but 3 studies found an increase in anticardiolipin9,12,14.
Men were more likely to have had an MI. This may be partially explained by the increase in several risk factors, including hypertension and LAC. In contrast, men were less likely to have dermatologic manifestations, including malar rash, photosensitive rash, oral ulcers, alopecia, and RP. A decreased frequency of RP has been found in 3 previous studies13,16,17. A decrease in alopecia was reported in 3 previous studies13,16,17. Our study differs strikingly from several others10,18,21 that found less arthritis in male SLE: there was no difference at all in our analysis. But our results agreed with 2 recent studies13,17 that found less arthralgia in male SLE.
We next analyzed white and African American lupus separately and did a direct comparison between African American and white men. African American men (compared to African American women) were more likely to have a history of smoking and less likely to have alopecia. African American men had a major increase in renal impairment and in death, compared to African American women. White men had less malar rash, photosensitivity, oral ulcers, alopecia, and RP than white women. They had more direct Coombs, thrombocytopenia, and LAC, and more obesity and hypertension than white women. African American men had more dermatologic lupus and more organ damage, including renal, pulmonary, and cardiovascular damage, than white men.
Strikingly, all damage differences except hypertension between male and female patients, and proteinuria between African American male and female patients, achieved an OR > 2.0, which strongly indicated that male patients with SLE had much more severe organ damage than female patients with SLE.
The substantial gender difference in disease manifestations is likely not just due to differences in estrogen or testosterone levels. Lu, et al26 reviewed a number of hypotheses to explain the underlying mechanism of gender differences, including the sex hormone hypothesis, the sex chromosome hypothesis, and the intrauterine selection hypothesis. In mice, Y chromosome polymorphism, X chromosome inactivation, X chromosome gene dosage and parental imprint can all affect autoimmunity27,28,29,30,31,32. Although SLE was found to be of greater severity in female than in male mice33, many studies, including our own, suggest the opposite is true for many organ manifestations in humans. Another possible explanation for some gender differences is that male patients are less likely to seek medical assistance, which might lead to later presentation, with more clinical manifestations, and lead to more organ damage and mortality. This might be part of the reason why, in our study, men tended to have later onset of SLE and diagnosis. Nevertheless, it remains unknown why male SLE differs substantially from female SLE and has a more severe expression in some organs.
There are major clinical differences between male and female lupus: more renal and hematologic lupus in males and less dermatologic lupus in males. Some of these differences, such as more proteinuria and hematuria, are found only in white patients. Men, regardless of ethnicity, had more renal insufficiency. Ethnicity greatly affected the results. White men had more MI than white women, but African American men did not have more MI than African American women. Studies of SLE are needed to analyze not just ethnicity but also gender, to further understand these differences and their underlying mechanisms.
Footnotes
-
The Hopkins Lupus Cohort is supported by NIH R01AR043727.
- Accepted for publication November 29, 2011.
REFERENCES
In this issue
