Clinical and Laboratory Manifestations of Yemeni Patients with Systemic Lupus Erythematosus

OBJECTIVES
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by multi-systemic involvement. This is the first study undertaken to determine the relationships between serological marker positivity and age, gender, signs and symptoms, risk factors and the treatment of SLE in Yemen.


METHODS
We investigated the cases of 149 patients with SLE admitted to Al-Thawra Hospital in Sana'a city between November 2009 and November 2010. Of the 149 patients, females represented 75.2% and males, 24.8%.


RESULTS
The most frequent presenting signs and symptoms were fatigue (84.6%), fever (81.9%), arthropathy (81.2%), anaemia (64.4%), photosensitivity (54.4%), renal involvement (53%), malar rash (52.3%), and alopecia (49%). Antinuclear antibodies (ANA) were detected in 95.3% of the patients and were associated significantly with most clinical presentations, except weight loss, hypertension and serositis. Anti-ds deoxyribonucleic acid (anti-dsDNA) was detected in 59.7% of the patients, and was associated significantly with fever and fatigue. Anti-Smith (anti-Sm) antibodies were detected in 27.5% of the patients, but were not significantly associated with all clinical presentations. Social stress was the most important risk factor for inducing SLE, with an odds ratio (OR) of 6.0, followed by common exposure to sunlight (OR = 2.2).


CONCLUSION
In this study, SLE was more prevalent among females and young adults. The clinical presentation was characterised by a high incidence of fatigue and fever, and a low incidence of oral ulcers and serositis. ANA was associated with most clinical presentations except weight loss, hypertension, and serositis. Anti-dsDNA antibodies were most frequently associated with fever, fatigue and hypertension. There was no significant association of the anti-Sm antibodies with any clinical presentations.


S
ystemic lupus erythematosus (SLE) is an autoimmune disorder characterised by multisystem microvascular inflammation with the generation of numerous auto-antibodies, particularly antinuclear antibodies (ANA).SLE can affect persons of both sexes, all ages, and all ethnic groups.However, more than 90% of new patients presenting with SLE are women in their childbearing years. 1 SLE is a disease that affects multiple systems and its symptoms vary widely.The multiple organ damage in SLE is due to the production of auto-antibodies, which include auto-antibodies to antigens of the brain, renal and vascular tissues, ribosomes, nuclear antigens and phospholipids.Intracranial vascular lesions (vasculitis and thrombosis) and inflammation have been related to the local release of cytokines. 1In addition, recent data have suggested that both renal and neuropsychiatric involvement negatively affects the overall five-year survival rate.However, the neuropsychiatric involvement did not change for the 10-year survival rate, in spite of the fact that the involvement of the nervous system in SLE remains poorly understood. 2 SLE affects the immune system, thus reducing the body's ability to prevent and fight infection.In addition, many of the drugs used to treat SLE also impair the functioning of the immune system, thereby further reducing the patient's ability to fight infection.The most common infections involve the respiratory tract, urinary tract and skin; these infections do not require hospitalisation if they are treated promptly.4][5] Fatigue in SLE is probably multifactorial and has been related not only to disease activity, but also to complications such as anaemia or hypothyroidism.
SLE is known to differ among people with different racial, geographical and socioeconomic backgrounds.Asia encompasses people of many sociocultural backgrounds with diverse ethnic groups-broadly Orientals in East and Southeast Asia, Indians in South Asia and Arabs in the Middle East.It has been shown that race is a major predictor of the clinical manifestations of SLE, laboratory and serological tests, and disease-related morbidity.][5] Due to a lack of national epidemiological research, the incidence and prevalence of SLE in Middle Eastern and Arab countries, have only recently been studied.There have been no previous studies on SLE in Yemen; therefore, this study aims to determine the relationships between serological marker positivity and age, gender, signs and symptoms, risk factors and the treatment of SLE in Yemen.

Methods
This study was carried out over a period of one year from November 2009 to November 2010.The study was approved by the Department of Medical Microbiology & Clinical Immunology of the Faculty of Medicine & Health Sciences at Sana'a University, Yemen.A consent form was completed by each participant.
A total of 149 Yemeni patients, admitted to medical wards and/or attending medical clinics at Al-Thawra Hospital in Sana'a city, were enrolled in this study.All patients fulfilled four or more of the revised American College of Rheumatology (ACR) criteria for the diagnosis of SLE. 6 The specifically-designed questionnaires were analysed retrospectively for relevant data such as patients' age, sex, their clinical manifestation at presentation and during follow-up, and their exposure to possible risk factors of SLE.The treatments, either initially or during their follow-up appointments, currently no other studies of this disease in Yemen.
-Moreover, SLE is likely to be a growing problem in Yemen that could go unrecognised if new information about the disease is not promoted within the national medical community.
Application to Patient Care -The findings of this research could contribute to the formulation of a treatment and management policy for SLE, including, ultimately, the management of its complications and sequelae.However, further studies are required to form a more comprehensive understanding of the risk factors and characteristics of SLE in Yemen.

Results
The mean age of patients was 28.8 years (range 11-57 years).Females had a higher SLE prevalence  than males, with a female to male ratio of 3:1.The prevalence of SLE was greater in the 16-35 years age group [Table 1].The clinical presentation of SLE was characterised by a high incidence of fatigue and fever, while there was a low incidence of oral ulcers and serositis [Table 5].The blood picture of the patients showed a low prevalence of leukopaenia and lymphopaenia, and a high prevalence of thrombocytopaenia [Table 5].Tables 2, 3 and 4 show the relationship between the autoantibody positivity and the clinical symptoms.ANA was statistically significant (χ 2 >3.9 and P <0.05) and associated with most clinical presentations (OR 5.1-10.2) except weight loss, hypertension and serositis [Table 2].Anti-dsDNA antibodies, which are a specific marker for SLE, showed a statistically significant association with fever (OR = 3.12; CI: 1.2-8.12;X 2 = 5.9; P = 0.01); fatigue (OR = 2.7; CI: 1-7.4;X 2 = 3.84; P = 0.05), and hypertension (OR = 2.15; CI: 1.0-4.6;χ 2 = 3.84; P = 0.05) [Table 3].Anti-Sm antibodies, which are a highly specific marker for SLE, were not significantly associated with any clinical presentations [Table 4].Lupus nephritis was significantly associated with red blood cell (RBC) casts, proteinuria, hyaline casts, elevated creatinine levels and hypertension.The two main risk factors in Yemeni SLE patients were found to be frequent exposure to sunlight (OR = 6.0;CI: 2.6-13.9;P <0.0001) and to social and mental stress (OR = 2.8; CI: 0.4-9.6;P = 0.04), while the use of contraceptives by females was not a risk factor (OR = 0.5; CI: 0.1-1.5;P = 0.17).Similarly, chewing qat (plant containing an amphetaminelike stimulant native to the horn of Africa and the Arabian Peninsula) was not found to be a risk factor for SLE in this study (OR = 0.5; CI: 0.2-0.9;P = 0.01) [Table 6].Table 5 shows the frequencies of clinical and laboratory features of SLE among different ethnicities compared with the present study.The  mortality rate in our study was 4.7%; the causes of death were pulmonary embolism (2%), septicaemia (2%) and disseminated intravascular coagulopathy with refractory heart failure (0.7%).

Discussion
The ratio of male patients to female patients in the current study was 1:3.This result is in disagreement with the results of other studies which have reported an even higher prevalence of SLE among females; these include male to female ratios of 1:7.2, 1:9 and 1:9.9. 3,7,8e mean patient age in the present study of 28.8 years was similar to that reported from Dubai, United Arab Emirates (28.9 years) 9 and Spain (29 years). 10The majority of patients (88.6%) were adults, while 11.4% were children under 15 years.This is similar to the study by Alballa whose patients were predominately above 15 years. 11The high rate among adults may be related to adult sex hormones which play an important role in triggering the disease. 12atigue, the most common constitutional symptom associated with SLE, could be caused by active SLE, medications, lifestyle habits or concomitant fibromyalgia-or affective disorders.Fatigue due to active SLE generally occurs in concert with other clinical and laboratory markers. 3he most frequent clinical symptom among the SLE patients in this study was fatigue (84.6%).This finding is in contrast to other studies performed in Saudi Arabia and Iran, where the frequency of fatigue was reported as 9.2% 13 and 30.2%, 14 respectively.This could be explained by the fact that our questionnaire included fatigue as a potentially important symptom of SLE, while questionnaires used in previous studies did not consider fatigue to be important.Fever was also common in the patients int this study (81.9%), and their temperature usually showed diurnal variation-being high in the afternoon and evening.The frequency of fever was higher than that reported in other studies-in Spain 42% of patients studied experienced fever, while in Saudi Arabia it was 30%. 10,7rthropathy was a common sign (81.2%) in this study, and this result is similar to findings reported from Dubai (81.1%) 9 and Saudi Arabia (80.4%). 7owever, the rates of arthropathy in Yemen were far higher than those experienced in Pakistan (38%). 3hotosensitivity occurred in 54.5% of the current study's patients, which was similar to that reported in Tunisia (53%) 15 and Iran (54.5%). 14However, lower prevalence rates have been reported from Pakistan (6%), 3 Saudi Arabia (22%) 16 and Europe (22.9%). 8This difference can be explained by the patients' high exposure to sunlight in this study.
In this study group, renal involvement of SLE was variable in clinical presentation and prognosis, ranging from mild asymptomatic proteinuria to rapidly progressive glomerulonephritis (GN) leading to end-stage renal disease.Renal involvement affected 53.3% of the patients.Similar findings were reported by studies in Lebanon (50%) 17 and Dubai (51%), 8 but these are in contrast to the low frequencies reported in Pakistan (33%) 2 and European countries (27.9%). 9Yemen's findings of similar renal involvement to that of other Arabic countries (Lebanon and Dubai) may be due to the shared factors (genetic, environmental and dietary) that could trigger or control the presentation of the disease.
Malar rash was present in 52.3% of the current study's patients which is similar to findings in Lebanon (52%) 16 and Spain (54%) 9 but is in disagreement with the lower prevalence found in Pakistan (29%). 3Alopecia occurred in 49% of our patients, which is similar to the study in Kuwait (44.0%) by Al-Jarallah et al, 18 but lower than that of Spain (81%), reported by Font et al. 10 Oral ulcers were less frequent in our study (10.7%) and were of similar occurrence to findings from Latin America (10.5%) 19 but lower than those from Lebanon (40%) 17 and Saudi Arabia (39.1%). 7The present study had the lowest incidence of serositis (9.4%) compared to studies in Lebanon (45%) 17 and in Iran (38%). 14This finding could be related to a failure of physicians to record the symptoms.
The presence of ANA is a hallmark of SLE disease and one of the diagnostic criteria established by the ACR.In the present study, the prevalence of ANA was 95.3% [Table 5].Similar findings have been reported from Saudi Arabia (95%) 16 and European countries (96%), 8 but an even higher prevalence was noted in Tunisia (100%). 15owever, our figure was slightly higher than those of India (71.4%), 20 Lebanon (87%) 17 and Pakistan (86%). 3In spite of its apparent importance, some researchers have not agreed that ANA is a hallmark of SLE disease.Anti-dsDNA antibodies are quite specific and diagnostically important for SLE. 21The prevalence of circulating anti-dsDNA antibodies in Yemeni patients was 59.7% [Table 5].Very similar results have been obtained from Tunisia (56%) 15 and Kuwait (58%), 18 but are in contrast to the higher frequency found in Saudi Arabia (93%), 11 Spain (90%) 10 and Dubai (88%). 9These differences may reflect a variable prevalence of anti-dsDNA in the world.In the current study, the prevalence of anti-Sm antibodies was 27.5% [Table 5] which indicates that anti-Sm antibodies are highly specific and of considerable diagnostic value for SLE as they appear almost exclusively in SLE, as reported by Tan et al. 22 Our prevalence is higher than that in Spain (12%) 10 but lower than that in Tunisia (61.2%). 15he great diversity of clinical manifestations in SLE, ranging, for example, from arthritis and serositis to life-threatening neuropsychiatric manifestations, is accompanied by a high titre of auto-antibodies. 23The current study found a strong statistical correlation between ANA and most clinical manifestations except weight loss, serositis and hypertension [Table 2].There was also a significant correlation between anti-dsDNA and clinical manifestations such as fever, fatigue and hypertension, but no significant correlation with weight loss, arthropathy, renal involvement, alopecia, malar rash, serositis, oral ulcer and photosensitivity [Table 3].The absence of a statistically significant correlation between anti-dsDNA and renal involvement in our study, even though dsDNA is known to be one of the main markers of lupus nephritis as described by Raz et al., 24 may be related to unknown factors in Yemen that need to be clarified.There was no significant association between anti-Sm antibodies and most of the clinical manifestations in Table 4, except fever, as has been confirmed by Hitchon and Peschken. 25atients with SLE have a complex array of abnormalities involving their immune system.A history of multiple cytopaenias such as leukopaenia, lymphopaenia, anaemia or thrombocytopaenia may suggest SLE, among other aetiologies. 1,2In our series, anaemia was the most frequently occurring haematological abnormality in our patients [Table 5].It occurred in about 64.4% of our patients, similar to the rate reported in Saudi Arabia (63.1%), 7 but higher than that reported in Spain (19%). 10ymphopaenia was present in 36.2% of our patients, the same as (30%) in Saudi Arabia, 6 but lower than the 50% rate in Tunisia 15 and 82% rate in Spain. 10The low incidence can probably be explained by the fact that the immunological response of our patients was not typical of the disease, in which the auto-antibodies in SLE are directed against a wide variety of self-antigens.Leukopaenia occurred in 28.2% of our patients.This is quite similar to other studies reported by Agrawal et al. 26 and Al-Arfaj and Khalil, 7 but much lower than the 83% reported by Al-Jarallah et al. 18 and the 64.6% recorded by Nazarinia et al. 14 Our study found a high prevalence of thrombocytopaenia (44.3%); a similar result was reported in Iran by Nazarinia et al., 14 while lower prevalence was reported from Tunisia (12%), 15 Kuwait (26%) 18 and Saudi Arabia (10.9%). 9rythrocyte sedimentation rate (ESR) is one of the major monitoring tests for acute phase inflammation because it correlates with increased levels of acute phase reactants, in particular fibrinogen.In the present study, the frequency of ESR was 89.9%.A similar finding was reported in a study on Indian children (98.5%) by Agrawal et al., 26 which is in contrast to studies with low frequency in Iran(64.6%) 14 and Saudi Arabia (54%). 7This difference may be due to many factors that affected the ESR result, including the patient's age, sex, red blood count morphology, haemoglobin concentration and serum levels of immunoglobulin. 27he mortality rate in our patients was low (4.7%) and was somewhat similar to the rates in three different studies from Saudi Arabia; 3%, 13 4%, 11 and 5.4%. 7This could be attributed to early diagnosis and effective treatment in controlling the disease.
The second aim of this study was to examine the risk factors that could have influenced the occurrence of SLE among our study group, this being the first study designed to determine the risk factors of contracting SLE in Yemen.Frequent exposure to sunlight and stress (social and mental) were found to be risk factors in Yemeni SLE patients.This might be explained by the fact that psychological stress can activate an acute phase response, which is part of the innate immune inflammatory response; it is also evidence that the inflammatory response is contained within the stress response, and that stress can induce an inflammatory response. 28This study also indicates that sunlight, especially ultraviolet B light (290-320 nm), plays an important role in inducing this systemic disease. 29Oral contraceptive pills, especially those with high oestrogen doses, may provoke flares of SLE. 30 In the present study, however, no association was discovered between oral contraceptives and SLE.

Conclusion
SLE was more prevalent among females and young adults.The clinical presentation was characterised by a high incidence of fatigue and fever, and a low incidence of oral ulcers and serositis.ANA was significantly associated with most clinical presentations except weight loss, hypertension and serositis.Anti-dsDNA antibodies were a specific marker and significantly associated with fever, serositis, oral ulcer, fatigue, hypertension and arthropathy.Anti-Sm antibodies were highly specific markers for SLE and significantly associated with oral ulcers.

Table 1 :
Gender and age distribution among systemic lupus erythematosus patients attending Al-Thawra hospital in Sana'a city, Yemen

Table 3 :
The relationship between clinical manifestations and presence of ds deoxyribonucleic acid (dsDNA) autoantibodies among systemic lupus erythematosus patients *Fisher's exact test P value; Significant result χ 2 ≥ 3.84, P <0.05.

Table 4 :
The relationship between clinical manifestations and presence of anti-Smith antibodies (anti-Sm) autoantibodies among systemic lupus erythematosus patients *Fisher's exact test P value; Significant result χ 2 ≥ 3.84, P <0.05.

Table 5 :
Frequencies of clinical and laboratory features of systemic lupus erythematosus among studies of different ethnicities compared with the current study

Table 6 :
The potential risk factors of systemic lupus erythematosus among the patients of the current study