Clinical Manifestations of Systemic Lupus Erythematosus in a Tertiary Center in Saudi Arabia

Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystemic involvement. The clinical presentation and immunological findings of SLE patients from different regions in Saudi Arabia have been studied. There have been no studies on the clinical manifestations of SLE in patients in Saudi Arabia's southern region. This article aims to explore the clinical manifestations of SLE in a tertiary center in the southern region of Saudi Arabia. Methods A retrospective study was carried out on 108 SLE patients who were seen in the rheumatology clinic at Aseer Central Hospital over six months from January 2022 to June 2022. Patients’ demographics, clinical and serological characteristics, and therapeutic data were reviewed. Results The male-to-female ratio was 1:12.5, with a mean age at presentation of 28.6 ± 10 years. The mean disease duration was 9.06 ± 5.96 years. Mucocutaneous and musculoskeletal manifestations were the most common, accounting for 76% and 57% of all cases, respectively. Neuropsychiatric involvement and lupus nephritis were present in 29% and 31% of patients, respectively. The hematological abnormalities that were present included anemia (60%), leukopenia (37%), and thrombocytopenia (15%). Antinuclear antibody (ANA) was detected in 100%, anti-double-stranded DNA (anti-dsDNA) antibody in 55%, anti-Smith antibody in 13%, and hypocomplementemia in 52% of patients. Hydroxychloroquine was received by 98% and oral steroids by 41% of the patients. Other drugs include azathioprine (23%), mycophenolate mofetil (15%), methotrexate (23%), belimumab (9%), cyclophosphamide (10%), and rituximab (6%). Conclusion The main clinical features of our patients were in parallel with previous studies in Saudi Arabia as well as in Arab countries. We found a lower prevalence of lupus nephritis, serositis, and anti-dsDNA antibody. Further multicenter studies are required to investigate the long-term outcome and survival of SLE patients.


Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystemic involvement. It is known to have a worldwide distribution, female predominance, and poorly known etiology. The clinical presentation of SLE is highly variable, ranging from mild skin and joint manifestations to severe major organ involvement [1]. The disease course is characterized by chronic and acute attacks and periods of remission [2]. Although it is a multisystemic disease, renal and neurological manifestations are the most serious complications [3]. Fatigue, fever, and weight loss are constitutional symptoms that are typically present in all SLE patients [4].
There are significant disparities in the incidence and prevalence of SLE around the world. In a systematic review of epidemiological studies that reported SLE incidence rates, the highest incidence was reported in North America (23.2/100,000 person-years), and the lowest incidences were reported in Africa and Ukraine (0.3/100,000 person-years for each) [5]. The prevalence of SLE in Saudi Arabia was estimated to be 19.28 per 100,000 population [6].
Genetic contributions have been found to be associated with SLE, where patients of Hispanic, African American, and Asian descent had an early onset of the disease and a severe presentation [7]. Studies on SLE patients from Arabic countries have revealed a similar age of onset, female predominance, and many similarities in clinical presentation and immunological findings [8].
To date, no studies have investigated the clinical presentation of SLE among patients in the southern region of Saudi Arabia. For that reason, the aim of this study was to determine the clinical manifestations of SLE in a tertiary center in Saudi Arabia.

Materials And Methods
A retrospective study was conducted on SLE patients who were seen in the rheumatology outpatient clinic at Aseer Central Hospital over six months from January 2022 to June 2022. All patients were aged 18 years or older and satisfied at least four of the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for the classification of SLE [9]. Patients who were lost to follow-up or had incomplete clinical data were excluded.
Medical records of the patients were reviewed for patient demographics (sex, current age, age at diagnosis, comorbidities, and duration of SLE). The main SLE manifestations evaluated in this study were constitutional symptoms, musculoskeletal, mucocutaneous involvement, cardiopulmonary involvement, Raynaud phenomenon, thromboembolic disease, gastrointestinal involvement, neuropsychiatric involvement, and lupus nephritis. Laboratory data include complete blood count (CBC), creatinine, inflammatory markers, urine analysis, proteinuria, and the immunological profile, including antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) antibody, anti-Smith antibody, rheumatoid factor (RF), complement (C3 and C4), anti-Sjogren's syndrome-related antigen A (anti-SS-A) and anti-Sjogren's syndrome-related antigen B (anti-SS-B) antibodies, and antiphospholipid antibodies. In the case of lupus nephritis, the results of the renal biopsy were documented. Renal biopsies were evaluated according to the International Society of Nephrology/Renal Pathology Society classification [10]. Treatment modalities such as steroids and immunosuppressive drugs were reviewed.
Ethical approval was obtained from the Ministry of Health, Asser Regional Committee for Research Ethics. As there was no direct influence on the participants, informed patient consent was not required.

Data analysis
The data were analyzed using the Statistical Package for the Social Sciences (SPSS) database program (IBM Corp., Armonk, NY). For continuous variables, descriptive statistics were performed, including the number of observations, mean, minimum, and maximum. For categorical variables, counts and percentages were used. The mean with standard deviation and median with range were used to describe scale data according to the shape of the distribution.

Results
During the period from January 2022 to June 2022, 108 patients fulfilling at least four of the SLICC criteria for SLE were enrolled in this study. Table 1 illustrates the demographic data of the patients.

TABLE 1: Demographic characteristics of our patients
The study comprised 100 females (92.6%) and eight males (7.4%), for a male-to-female ratio of 1:12.5. The patients' mean age at disease onset was 28.6 ± 10 years, while the duration of disease was 9.06 ± 5.96 years. Comorbid illnesses were found in 45.4% of SLE patients. Thyroid gland disorders, hypertension, and diabetes mellitus were prevalent in 20%, 18%, and 9% of patients, respectively. A total of 22 patients (20%) had secondary antiphospholipid syndrome.    The majority of patients (96.2%) had a positive ANA titer. The titer was as low as 1:40 in four patients with cutaneous symptoms but no involvement of internal organs. Of 101 patients who underwent anti-dsDNA antibody, 59 (55%) tested positive. Anti-Smith antibody was tested in half of the studied patients, and onethird of them had a positive result. Low complements levels were seen in 56% of patients.
At the time of the last follow-up, 106 (98%) and 45 (41%) of patients were taking hydroxychloroquine and steroids, respectively. Intravenous cyclophosphamide was received by 11 (10%) and rituximab by seven (6%) of the patients. Vitamin D and calcium were given to 99 (90%) of the patients. The other prescribed immunosuppressive medications are detailed in Table 4.

Discussion
This is the first review of the clinical manifestations of SLE in the southern region of Saudi Arabia. SLE predominantly affects women of reproductive age, and the female-to-male ratios vary significantly across regions of the world. Our finding reveals a female-to-male ratio of 12.5:1, in line with that reported in Arab countries. Our reported female-to-male ratio was higher than in Europe, Africa, and China, but lower than in Hispanics [11][12][13]. The pediatric-onset SLE frequency was 10%, which is consistent with that reported in non-Caucasian patients [14]. Thyroid gland disorders were the most prevalent comorbidities in our patients, which is consistent with numerous studies that have shown a significant association between SLE and thyroid gland disorders [15,16]. In a Saudi study, thyroid gland dysfunction was found in 17% of SLE patients [17].  Acute cutaneous lupus, particularly malar rash and photosensitivity, was present in 39% of our patients. In comparison, photosensitivity affected up to 91.5% of Egyptians and 16% of Lebanese [8]. Discoid rash was documented in 18.5% of our patients. It was uncommon in Sudan and Kuwait affecting 2.4% and 7%, respectively [8]. Photosensitivity and malar rash are seen more frequently in European patients, whereas discoid is more common in Blacks [12].
Lupus nephritis was found in 31.4% of our patients, which is lower than the previous studies in Saudi Arabia and Arab countries. Positive anti-dsDNA antibodies are well known to be strongly associated with lupus nephritis [22], which could explain the lower prevalence of anti-dsDNA antibodies in our patients.
When compared to Europeans, Africans and Hispanic descents are associated with more prevalent renal involvement [23]. In the series of Lee et al., up to 69.3% of Chinese patients had renal disease [24].
Neuropsychiatric manifestations affected a third of our patients. In two studies conducted at Aseer Central Hospital, 23.5% and 52% of patients had at least one neurological or psychiatric disorder, respectively [25,26]. In an analysis of 3,273 Arab patients, there was no significant difference in the frequency of neuropsychiatric manifestations when compared to the Euro-lupus cohort [8].
When compared to Arab countries, the frequency of serositis was similar in our study; one was from Yemen (9.4%), with Egypt and Tunisia having the highest rates (44 and 47%, respectively) [8]. In terms of hematological abnormalities, our results were comparable to other studies in Arab patients. In the California Lupus Surveillance Project, hematological manifestations were found to be more common among Blacks, Asians, and Hispanics [27].
The patients who had negative ANA had cutaneous lupus without other organ involvement. Anti-dsDNA antibody was positive in half of the patients in parallel to the Iraq, Lebanon, Kuwait, and Sudan populations. Anti-dsDNA antibody was found to be lower in Arabs than in Europeans [8]. When compared to previously published studies in Saudi Arabia, we have the lowest prevalence of anti-Smith and anti-dsDNA antibodies. It can be explained by the fact that in Saudi and Arabic studies, we have the lowest prevalence of lupus nephritis. Concerning the anti-Smith antibody, it was done in half of our patients, and it could be higher than documented.
Although serological tests were not done in all patients and it could be higher than documented, the results of anti-SS-A, anti-SS-B, anti-Smith antibodies, and anti-cardiolipin IgG and IgM were similar to Arabs from Oman, United Arab Emirates, and Tunisia [8]. In one study, the Afro-Caribbean population had the highest prevalence of anti-Smith, anti-SS-A, and anti-SS-B antibodies compared to Europeans and Asians [28]. The prevalence of antiphospholipid antibodies varies greatly among different populations [29].
Due to the variety of SLE clinical manifestations based on race and geographical area, our goal is to provide information about SLE in our population and compare it to Arabs and other ethnicities. We presented the first study reviewing clinical and serological manifestations of lupus in the southern region of Saudi Arabia, but it has some limitations. Firstly, it was conducted in a single center. Given that this was a retrospective study, it is not an appropriate study design to assess disease activity and outcomes. The results of serological tests may be higher than documented, which is explained by the fact that some patients were diagnosed elsewhere and the serological tests were not repeated in all of them.

Conclusions
Our findings revealed that the main clinical disease spectrum was comparable to previous studies in Saudi Arabia as well as in Arab countries. We found lower frequencies in lupus nephritis, serositis, and anti-dsDNA antibody. More multicenter studies in Saudi Arabia are needed to investigate SLE complications and outcomes.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. The Ministry of Health, Asser Regional Committee for Research Ethics issued approval H-06-B-091. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial