Our analysis, which compared the clinical features between males and females with lupus, showed that alopecia, photosensitivity, and oral ulcers were significantly higher in female patients (OR 0.36, 95% CI 0.29–0.46, P < 0.00001; OR 0.72, 95% CI 0.63–0.83, P < 0.00001; and OR 0.70, 95% CI 0.60–0.82, P < 0.00001, respectively). These results have been represented in Fig. 2.
Arthritis was also significantly lower in male patients (OR 0.72, 95% CI 1.25–1.84, P < 0.00001). However, serositis and pleurisies were significantly higher in male patients (OR 1.52, 95% CI 1.25–1.84, P < 0.0001; and OR 1.26, 95% CI 1.07–1.48, P = 0.006, respectively). Cardiovascular diseases favored females (OR 1.43, 95% CI 0.93–2.19, P = 0.10); however, the result was not statistically significant. These results have been represented in Fig. 3.
Our analysis showed renal involvement also to be significantly lower in female patients (OR 1.51, 95% CI 1.31–1.75, P < 0.00001). Pericarditis, seizure, and psychosis were almost similarly manifested between male and female patients with lupus (OR 1.19, 95% CI 0.97–1.45, P = 0.10; OR 1.18, 95% CI 0.92–1.50, P = 0.19; and OR 0.76, 95% CI 0.53–1.10, P = 0.14, respectively). These results have been represented in Fig. 4.
Hematological manifestations, as a whole, were similar between male and female patients with lupus (OR 0.92, 95% CI 0.71–1.19, P = 0.52). If analyzed individually, hemolytic anemia and lymphopenia were similar in males and females (OR 1.03, 95% CI 0.81–1.31, P = 0.80; and OR 1.13, 95% CI 0.96–1.33, P = 0.15, respectively). However, thrombocytopenia was significantly higher in male patients (OR 1.31, 95% CI 1.10–1.56, P = 0.002). These results have been represented in Fig. 5.
Since heterogeneity was higher while analyzing certain clinical features, a random-effect model has been used to analyze these features with high heterogeneity. Malar rash was significantly higher in female patients (OR 0.68, 95% CI 0.53–0.88, P = 0.003), whereas discoid rash was higher in male patients (OR 1.17, 95% CI 0.79–1.73, P = 0.43). However, the result for discoid rash was not statistically significant. Raynaud phenomenon and neurological manifestations were similar between males and females (OR 0.76, 95% CI 0.46–1.24, P = 0.27; and OR 1.16, 95% CI 0.80–1.69, P = 0.42, respectively). These results have been shown in Fig. 6.
Leukopenia was higher in female patients; however, the result was not statistically significant (OR 0.80, 95% CI 0.62–1.04, P = 0.09). Anti-Sm antibodies favored female patients (OR 1.56, 95% CI 0.94–2.59, P = 0.09. However, the result was not statistically significant in our study. Anticardiolipin antibodies were also similarly manifested between male and female patients (OR 1.26, 95% CI 0.79–2.00, P = 0.33). These results have been represented in Fig. 7.
Lupus anticoagulant was significantly higher in female patients (OR 1.98, 95% CI 1.53–2.57, P < 0.00001). Low level of C3 was also significantly apparent in females (OR 1.36, 95% CI 1.06–1.76, P = 0.02). Low C4 level was similarly observed in males and females (OR 0.98, 95% CI 0.74–1.31, P = 0.91). Anti-double stranded deoxyribonucleic acid (dsDNA) was significantly higher in male patients (OR 1.22, 95% CI 1.02–1.45, P = 0.03). Antinuclear antibodies (ANAs) favored male patients; however, the result was not statistically significant (OR 0.79, 95% CI 0.59–1.06, P = 0.12). These results have been represented in Fig. 8.
For all of the above analyses, sensitivity analyses yielded consistent results. Based on a visual inspection of the funnel plots, there has been no evidence of publication bias for the included studies that assessed all clinical endpoints in male and female patients with lupus. The funnel plot has been illustrated in Fig. 9.
This study aimed to show the impact of sex on the clinical manifestations in SLE patients from different population groups. The mean average female-to-male ratio of all the included studies was 9.3:1. This reflects the results of most previous studies, which suggest female predominance in SLE.[20,21] Several reasons have been brought forward to explain this. One of the main reasons is genetic susceptibility. At least 3 gene variants located on the X chromosome have been shown to be associated with increased risk of developing SLE (Interleukin-1 receptor-associated kinase 1, Methyl CpG binding protein 2, and toll-like receptor 7 [TLR7]). Another possible reason may be related to sex hormones. It is generally recognized that the male hormone, testosterone, is immunosuppressive, whereas the female hormone, estrogen, stimulates immune response.[23,24] Lower testosterone levels have been observed in male and female patients with SLE. Several studies indicate that testosterone also interacts with the immune system by suppressing both cellular and humoral responses. Exacerbations of the disease activities of SLE are commonly noted during the premenstrual period, early pregnancy, and in the puerperium. This is suggestive of a close relationship between increasing concentrations of plasma estrogen and flare-ups of SLE. Estrogen seems to play an important role in promoting autoimmune-related immune responses, including the production of cytokines such as Th2 cytokines (e.g., interleukin [IL]-4, IL-6, and IL-10), antibodies, and endogenous autoantigens such as Human endogenous retroviruses (HERV).[28–30] These HERV proteins seem to be related to autoantibody production, through molecular mimicry between HERV proteins and autoantigens such as ribonucleoprotein antigens, and are reported to be one of the pathogenic factors of SLE. Moreover, estrogens bind to and activate estrogen receptors which modulate the expression of many genes. The abnormal expression of estrogen or its receptors may lead to immunological diseases, including SLE. Possible mechanisms suggested for the high female predominance are fetal microchimerism, X chromosome inactivation, and X chromosome abnormalities. However, further research is warranted here. Specific mutations of X chromosome genes cause autoimmune syndromes characterized by different degrees of severity. Scofield et al suggested that the number of X chromosomes is another major cause of sex-specific difference because both the number of X chromosomes and genetic variants on the X chromosome are related to the risk of development of SLE. Hence, 2 functional X chromosomes, either by sex or by translocation or duplication, seem to confer a greater risk of SLE than 1 X chromosome. Male patients with Klinefelter syndrome (47,XXY) have similar risk to develop SLE compared with females (46,XX). It is also possible that women and men have different environmental exposures during their lifetimes, due to occupational or culturally-determined factors, which could be potentially linked to the increased incidence of SLE among women.
The mean age at disease onset and mean age at diagnosis of male and female patients in most of the included studies were comparable, as shown in Table 6. However, our data show a later age of disease onset and diagnosis in the studies from Spain.[35,36] Several other European studies have reported peak incidences to occur at a later age in both European males and females.[37–39] This has been attributed to genetic predisposition or the decreasing response of an aging immune system. Little research exists pertaining to the incidence or prevalence of SLE in many populations or their comprising ethnic groups. In the USA, the average incidence of SLE has been estimated to range between 1.8 and 7.6 cases per 100,000 person-years, and in Europe, the incidence rates range from 3.3 to 4.8 per 100,000 person-years. A study in Brazil detected an annual incidence of 8.4 per 100,000 habitants. The incidence of SLE is reported to be greater in Afro-Americans, Afro-Caribbeans, Native Americans, and Asians compared with Caucasians.[44–46] In Taiwan, the incidence was reported to be 8.1per 100,000 persons in 2007. Geographic and environmental factors play an important role in the prevalence and general manifestations of SLE. Vilar and Sato described a high prevalence of cutaneous manifestations leading to a high incidence of the disease in Brazil due to the great amount of sunlight exposure. Genetic susceptibility interacts with lifestyle and environmental factors, which include socioeconomic status, infectious agents (triggering or protective agents), and environmental hazards in determining the risk of developing autoimmunity.
Although the included studies were from countries of different geographical locations with distinct environmental, sociocultural, economic and behavioral backgrounds, and unalike accessibility to health service facilities, they showed some similar outcomes when clinical features of males and females were compared. Serositis, pleurisies, and renal involvement were noted to be significantly higher in male lupus patients, whereas in female patients, arthritis and cutaneous manifestations such as malar rash, oral ulcers, alopecia, and photosensitivity were predominant in almost all of them. This is reflected in several other previous studies. Impaired renal function, renal failure,[49,50] renal transplantation, chronic renal insufficiency, and renal end-stage disease were found to be more frequent in men than in women with SLE. Some series with biopsy results have shown a higher incidence of proliferative nephritis in males.[53,54] Renal involvement in men is indicator of poor prognosis. It has been suggested that the main female hormone, 17β estradiol, is capable of inhibiting inflammatory and proapoptotic processes, and protecting the renal tissue, as opposed to the male hormones, testosterone and dehydroepiandrosterone. With respect to hematological and autoantibody profiles, the incidence of leukopenia, presence of lupus anticoagulant, low levels of C3, and positive titers of ANA were higher in females, whereas in males, thrombocytopenia and positive titers of anti-dsDNA were more prevalent. Scofiel et al suggested that men are more likely to have thrombocytopenia, which is associated with serositis, neuropsychiatric disease, renal disease, and positive dsDNA titer, and which is an indicator of a more severe disease in SLE. Thrombocytopenia has been linked to genetic predisposition. Some of the antibodies have been associated with specific manifestations of the disease; for example, anti-dsDNA and anti-Sm antibodies are associated with nephritis.
Several limitations are present in this current study. Firstly, variability in cohort sizes and lengths of follow-up may not bring uniformity among the included studies. Secondly, we have not elaborated on the sex-specific differences in each ethnic group of each study due to lack of data. Moreover, the specific differences in pathogenesis and target organ damage amongst sexes, which have only been explained partly though genetic, hormonal, and immune responses, have been analyzed.
This is a quantitative analysis of multiple studies comparing various clinical manifestations, autoantibodies, and laboratory results of male and female lupus patients. The results of this meta-analysis suggest that alopecia, photosensitivity, oral ulcers, arthritis, malar rash, lupus anticoagulant level, and low level of C3 were significantly higher in female lupus patients, whereas renal involvement, serositis and pleurisies, thrombocytopenia and anti-dsDNA level were predominant in male patients. However, more clinical and population-based research is warranted to further elucidate these differences and permit the development of optimal sex-tailored treatment and better outcomes for patients.
1. Hopkinson N. Epidemiology of systemic lupus erythematosus
. Ann Rheum Dis
2. Manzi S. Epidemiology of systemic lupus erythematosus
. Am J Manag Care
2001; 7 (16 Suppl):S474–S479.
3. Lu LJ, Wallace DJ, Ishimori ML, et al Review: male systemic lupus erythematosus
: a review of sex disparities in this disease. Lupus
4. Stefanidou S, Benos A, Galanopoulou V, et al Clinical expression and morbidity of systemic lupus erythematosus
during a post-diagnostic 5-year follow-up: a male: female comparison. Lupus
5. Borba EF, Araujo DB, Bonfa E, et al Clinical and immunological features of 888 Brazilian systemic lupus patients from a monocentric cohort: comparison with other populations. Lupus
6. Faezi ST, Hosseini Almodaressi M, Akbarian M, et al Clinical and immunological pattern of systemic lupus erythematosus
in men in a cohort of 2355 patients. Int J Rheum Dis
7. Hwang J, Lee J, Ahn JK, et al Clinical characteristics of male and female Korean patients with systemic lupus erythematosus
: a comparative study. Korean J Intern Med
8. Andrade RM, Alarcon GS, Fernandez M, et al Accelerated damage accrual among men with systemic lupus erythematosus
: XLIV. Results from a multiethnic US cohort. Arthr Rheum
9. Pamuk ON, Akbay FG, Dönmez S, et al The clinical manifestations
and survival of systemic lupus erythematosus
patients in Turkey: report from two center. Lupus
10. Mongkoltanatus J, Wangkaew S, Kasitanon N, et al Clinical features of Thai male lupus: an age-matched controlled study. Rheumatol Int
11. Miller MH, XXX UM, Gladman DD, Killinger DW. Systemic lupus erythematosus
in males. Medicine (Baltimore)
12. Tan TC, Fang H, Magder LS, et al Differences between male and female systemic lupus erythematosus
in a multiethnic population. J Rheumatol
13. Feng JB, Ni JD, Yao X, et al Gender and age influence on clinical and laboratory features in Chinese patients with systemic lupus erythematosus
: 1,790 cases. Rheumatol Int
14. Ding Y, He J, Guo JP, et al Gender differences are associated with the clinical features of systemic lupus erythematosus
. Chinese Med J
15. Azizah MR, Ainol SS, Kong NC, et al Gender differences in the clinical and serological features of systemic lupus erythematosus
in Malaysian patients. Med J Malaysia
16. Font J, Cervera R, Navarro M, et al Systemic lupus erythematosus
in men: clinical and immunological characteristics. Ann Rheum Dis
17. Othmani S, Louzir B. Group d’etude du lupus. Systemic lupus erythematosus
in 24 Tunisian males: clinical, laboratory and evolution analysis. Rev Med Interne
18. Wiley, Higgins JPT, Altman DG. Higgins JPT, Green S. Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions
19. Liberati A, Altman DG, Tetzlaff J, et al The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ
20. Borchers AT, Naguwa SM, Shoenfeld Y, et al The geoepidemiology of systemic lupus erythematosus
. Autoimmun Rev
21. Pons-Estel GJ, Alarcon GS, Scofield L, et al Understanding the epidemiology and progression of systemic lupus erythematosus
. Semin Arthr Rheum
22. Lee TP, Chiang BL. Sex differences
in spontaneous versus induced animal models of autoimmunity. Autoimmun Rev
23. Sakiani S, Olsen NJ, Kovacs WJ. Gonadal steroids and humoral immunity. Nat Rev Endocrinol
24. Oertelt-Prigione S. The influence of sex and gender on the immune response. Autoimmun Rev
25. Cutolo M. Sex hormone adjuvant therapy in rheumatoid arthritis. Rheum Dis Clin N Am
26. Ostensen M. Sex hormones and pregnancy in rheumatoid arthritis and systemic lupus erythematosus
. Ann N Y Acad Sci
1999; 876:131–143.discussion 144.
27. Sekigawa I, Naito T, Hira K, et al Possible mechanisms of gender bias in SLE: a new hypothesis involving a comparison of SLE with atopy. Lupus
28. Portis JL. Perspectives on the role of endogenous human retroviruses in autoimmune diseases. Virology
29. Sekigawa IOH, Naito T, Kaneko H, et al Systemic lupus erythematosus
and human endogenous retroviruses. Mod Rheumatol
30. Perl A, Nagy G, Koncz A, et al Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE. Autoimmunity
31. Lleo A, Battezzati PM, Selmi C, et al Is autoimmunity a matter of sex? Autoimmun Rev
32. Valiaho J, Riikonen P, Vihinen M. Novel immunodeficiency data servers. Immunol Rev
33. Scofield RH, Bruner GR, Namjou B, et al Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus
patients: support for the notion of a gene-dose effect from the X chromosome. Arthr Rheum
34. Scofield RH, Bruner GR, Namjou B, et al Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus
patients: support for the notion of a gene-dose effect from the X chromosome. Arthr Rheum
35. Alonso MD, Martinez-Vazquez F, Riancho-Zarrabeitia L, et al Sex differences
in patients with systemic lupus erythematosus
from Northwest Spain. Rheumatol Int
36. Gomez J, Suarez A, Lopez P, et al Systemic lupus erythematosus
in Asturias, Spain: clinical and serologic features. Medicine
37. Alamanos Y, Voulgari PV, Siozos C, et al Epidemiology of systemic lupus erythematosus
in northwest Greece. J Rheumatol
38. Somers EC, Marder W, Cagnoli P, et al Population-based incidence and prevalence of systemic lupus erythematosus
: the Michigan Lupus Epidemiology and Surveillance program. Arthritis Rheum
39. Ståhl-Hallengren C, Jönsen A, Nived O, et al Incidence studies of systemic lupus erythematosus
in Southern Sweden: increasing age, decreasing frequency of renal manifestations and good prognosis. J Rheumatol
40. Alonso MD, Llorca J, Martinez-Vazquez F, et al Systemic lupus erythematosus
in northwestern Spain: a 20-year epidemiologic study. Medicine
41. Hochberg MC. Systemic lupus erythematosus
. Rheum Dis Clin North Am Aug
42. G M. Epidemiology of connective tissue disorders. Rheumatology
2006; 45 (Suppl. 3):iii3–4.
43. Vilar MJP, Sato EL. Estimating the incidence of systemic lupus erythematosus
in a tropical region (Natal, Brazil). Lupus
44. McCarty DJ, Manzi S, Medsger TA Jr, et al Incidence of systemic lupus erythematosus
. Race and gender differences. Arthritis Rheum
45. Hiraki LT, Benseler SM, Tyrrell PN, et al Ethnic differences in pediatric systemic lupus erythematosus
. J Rheumatol
46. Patel M, Clarke AM, Bruce IN, et al The prevalence and incidence of biopsy-proven lupus nephritis in the UK: evidence of an ethnic gradient. Arthritis Rheum
47. Chiu YM, Lai CH. Nationwide population-based epidemiologic study of systemic lupus erythematosus
in Taiwan. Lupus
48. Mok CC, Lau CS, Chan TM, et al Clinical characteristics and outcome of southern Chinese males with systemic lupus erythematosus
49. Ward MM, Polisson RP. A meta-analysis
of the clinical manifestations
of older-onset systemic lupus erythematosus
. Arthritis Rheum
50. Hsu CY, Chiu WC, Yang TS, et al Age- and gender-related long-term renal outcome in patients with lupus nephritis. Lupus
51. Molina JF, Drenkard C, Molina J, et al Systemic lupus erythematosus
in males. A study of 107 Latin American patients. Medicine (Baltimore)
52. Jacobsen S, Petersen J, Ullman S, et al A multicentre study of 513 Danish patients with systemic lupus erythematosus
. I. Disease manifestations and analyses of clinical subsets. Clin Rheumatol
53. Soto ME, Vallejo M, Guillen F, et al Gender impact in systemic lupus erythematosus
. Clin Exp Rheumatol
54. Schwartzman-Morris J, Putterman C. Gender differences in the pathogenesis and outcome of lupus and of lupus nephritis. Clin Dev Immunol 2012; 2012:604892.
55. Schwartzman-Morris J, Putterman C. Gender differences in the pathogenesis and outcome of lupus and of lupus nephritis. Clin Dev Immunol
56. Scofield RH, Bruner GR, Kelly JA, et al Thrombocytopenia identifies a severe familial phenotype of systemic lupus erythematosus
and reveals genetic linkages at 1q22 and 11p13. Blood
57. Rahman A, Hiepe F. Anti-DNA antibodies: overview of assays and clinical correlations. Lupus
Keywords:Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
clinical manifestations; meta-analysis; sex differences; systemic lupus erythematosus