Prevalence of major adverse cardiovascular events among Saudi patients with systemic lupus erythematosus compared with the general population: updates from the national SLE and PURE cohorts.

OBJECTIVE: This study examined the prevalence of major adverse cardiovascular events (MACE) among Saudi patients with SLE and the general population and considered factors associated with such outcomes were taken into consideration. METHODS: This is a cohort study evaluating the period prevalence of MACE from 2020 to 2023. The study used two datasets, namely the Saudi national prospective cohort for SLE patients and the Prospective Urban-Rural Epidemiology Study Saudi subcohort (PURE-Saudi) for the general population. Participants in both studies were monitored using a standardised protocol. MACE was defined as myocardial infarction (MI), stroke or angina. The analysis was adjusted for demographics, traditional cardiovascular risk factors and SLE diagnosis through logistic regression models. RESULTS: The PURE and national SLE cohorts comprised 488 and 746 patients, respectively. Patients with SLE from the SLE cohort were younger (40.7±12.5 vs 49.5±8.6 years) and predominantly female (90.6% vs 41.6%). The prevalence of traditional risk factors was greater in the PURE cohort compared with the SLE cohort. These factors included dyslipidaemia (28.9% vs 49.4%), obesity (63% vs 85%) and diabetes (7.8% vs 27.2%), but not hypertension (19.3% vs 18.8%). MACE (defined as MI or stroke or venous thromboembolism or heart failure) occurred more frequently in patients with SLE (4.3% vs 1.6%, p=0.004). Older age and lupus diagnosis were independently associated with MACE after adjusting for conventional risk factors. The odds of MACE were significantly related to age and lupus diagnosis (p=0.00 and p=0.00, respectively), but not cardiovascular disease (CVD) risk factors (p=0.83). CONCLUSION: Patients with SLE have a significantly higher risk of developing MACE than the general population. This risk is not well explained by traditional risk factors, which may explain the failure of CVD risk scores to stratify patients with SLE adequately. Further studies are needed to understand CVD risk's pathogenesis in SLE and mitigate it.

Levels of Proteinuria and Renal Pathology in Systemic Lupus Erythematosus Patients.

According to the current guidelines, renal biopsies are performed in systemic lupus erythematosus (SLE) patients for proteinuria of 0.5 g/24 h or higher. Renal pathology may be present in patients with lower-level proteinuria (<0.5 g/24 h). We aimed to review the renal histopathology in SLE patients, with lower levels of proteinuria. In this retrospective study, we retrieved SLE patients' data, including 24-h urinary protein excretion and renal histopathology results. We compared various parameters in different lupus nephritis (LN) classes and in different levels of proteinuria (urinary protein <0.5 g, 0.5 to <1 g, and ≥1 g per 24 h). Out of 476 patients, 274 (57.6%) had proteinuria of <0.5 g, 44 (9.2%) had 0.5 to <1 g, and 158 (33.2%) had ≥1 g per 24 h. SLE patients with proteinuria of <0.5 g/24 h were found to have LN, including the proliferative classes. Of the 299 LN cases confirmed by a renal biopsy, low-level proteinuria (<0.5 g) was found in 39.8% of all LN patients, in 50% of patients with Class III LN, 33.3% of those with Class IV LN, 31.4% of those with Class V LN, and 41.4% of those with other LN classes (II/V, III/V, and IV/V). Overall, 35.9% (87/242) of patients with the proliferative LN classes (III, IV, V, II/V, III/V and IV/V) had low-level proteinuria of <0.5 g/24 h. SLE patients with low-level proteinuria had significant renal pathology. Our study suggests there is a need to perform renal biopsies at lower levels of proteinuria.

Impact of telemedicine on disease activity assessment: A case-crossover study nested within a cohort of patients with systemic lupus erythematosus.

INTRODUCTION: The utilisation of telemedicine has been rapidly growing among patients with rheumatic diseases, especially following the corona virus disease 2019 pandemic. Ease and convenience appear to dominate the reasons for this growth. However, the effects of this approach in patients with systemic lupus erythematosus (SLE) are yet to be revealed. In this study, we examined the effect of telemedicine on disease activity assessment and damage scores in patients with SLE. METHODS: This case-crossover study was nested within a national prospective cohort of patients with SLE in Saudi Arabia. Patients with SLE were included if they fulfilled the Systemic Lupus International Collaborating Clinics classification criteria between March 2020 and March 2021 and were assessed at three time points with 3 months between assessments, according to the standardised protocol of this cohort. Telemedicine was conducted for the first evaluation, while in-person assessments were used at the second and third visits. The primary outcome was the difference in the SLE disease activity index 2000 (SLEDAI-2K) score. The primary analysis was conducted using the repeated measure model and adjusted for potential confounders, including demographics, medications, and changes in steroid doses. Several sensitivity analyses were conducted to mitigate selection and time-varying confounders. RESULTS: A total of 92 participants were included in this study. Most patients were females (88%), with a mean (±standard deviation [SD]) age of 36 (±13) years. The mean (±SD) disease activity scores at baseline were as follows: SLEDAI-2K, 5 (±5); SLE responder index, 3.8 (±3.5); Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, 1 (±1). The mean difference in SLEDAI-2K score was -1.641 (95% confidence interval -2.773 to -0.510, p = 0.005*) between telemedicine and follow-up visits. The results were consistent in all sensitivity analyses. CONCLUSION: We found that telemedicine assessment was associated with a much higher disease activity score than subsequent assessments, which may suggest an overestimation of disease activity and later assessment accuracy. Cautious adoption has been suggested for SLE patients with active disease.

The administration of methotrexate in patients with Still's disease, "real-life" findings from AIDA Network Still Disease Registry.

OBJECTIVES: To describe clinical characteristics of patients with Still's disease treated with methotrexate (MTX) and to assess drug effectiveness evaluating change in disease activity, reduction of inflammatory markers, and glucocorticoid (GC)-sparing effect. METHODS: Patients with Still's disease treated with MTX were assessed among those included in AIDA Network Still Disease Registry. RESULTS: In this registry, 171 patients with Still's disease were treated with MTX (males 43.3%, age 37.1 ± 16.0 years). They were mainly characterised by joint features and fever without a prominent multiorgan involvement. MTX was administered with GCs in 68.4% of patients, with other conventional synthetic DMARDs in 6.4%, and with biologic DMARDs in 25.1%. A significant reduction of the modified systemic score was observed, and 38.6% patients were codified as being in clinical remission at the end of follow-up. The concomitant administration of a biologic DMARD resulted a predictor of the clinical remission. Furthermore, a reduction of inflammatory markers and ferritin levels was observed following the administration of MTX. Additionally, a marked reduction of the dosage of concomitant GCs was identified, while 36.7% discontinued such drugs. Male gender appeared as a predictor of GC discontinuation. MTX was discontinued in 12.3% of patients because of adverse effects, and in 12.3% for lack of efficacy. CONCLUSIONS: Clinical characteristics of patients with Still's disease treated with MTX were described, mainly joint features and fever without a prominent multiorgan involvement. The clinical usefulness of MTX was reported in reducing the disease activity, decreasing the inflammatory markers, and as GC-sparing agent.

Granuloma faciale in a patient with remitting seronegative symmetric synovitis with pitting edema.

Granuloma faciale (GF) is a rare benign chronic inflammatory dermatologic disease which is characterized by facial lesions. The diagnosis is mainly based on clinical and histopathology findings. It may be resistant to treatments and prone to relapse. Different treatment modalities include corticosteroid therapy, tacrolimus, cryotherapy and surgical methods. We report a case of GF in a patient with remitting seronegative symmetric synovitis with pitting edema (RS3PE). A male patient with RS3PE presented with reddish brown soft nodules on and over lateral aspects of his nose and adjacent areas on his face which were diagnosed histologically as GF. He was treated with prednisolone, methotrexate and clobetasol propionate cream successfully without recurrence. To the best of our knowledge this is the first case report of GF occurring in a patient with RS3PE.

Incidence of hemorrhagic cystitis after cyclophosphamide therapy with or without mesna: A cohort study and comprehensive literature review.

BACKGROUND: Cyclophosphamide is an alkylating agent associated with significant toxicities, most importantly hemorrhagic cystitis. Many approaches including mesna use were established to reduce this toxicity. However, data on mesna efficacy are conflicting. OBJECTIVE: To investigate the incidence of hemorrhagic cystitis in patients receiving cyclophosphamide therapy with or without mesna. METHODS: A retrospective chart review was done on all adult patients receiving cyclophosphamide therapy with or without mesna at the King Saud University Medical City. The incidence of hemorrhagic cystitis was recorded. Patients receiving mesna were compared with those not receiving mesna. Data were reported as numbers and percentages, and appropriate statistical tests of association were used. This step was followed by a comprehensive literature review using appropriate keywords in PubMed from the inception of the database until August 2019. All studies of interest were reported. RESULTS: A total of 718 patients' medical records were reviewed. The majority of the patients received mesna (n = 433, 60%). The mesna group had a greater incidence of hemorrhagic cystitis (3.5% vs. 0.4%, p < 0.004) and received a significantly larger cumulative dose (3103 ± 1696 vs. 2465 ± 1528, p < 0.001) mg of cyclophosphamide therapy. Our literature review revealed large differences in the conclusions of published trials with highly diverse study designs and populations, emphasizing on the need of large prospective trials to address this topic.Conclusion and relevance: Our study results do not support the use of mesna in preventing hemorrhagic cystitis. We found that the only influential factor in the development of hemorrhagic cystitis was the dose of cyclophosphamide therapy.

ANCA associated vasculitis in patients from Saudi Arabia.

OBJECTIVE: To explore clinical and laboratory features, therapy and outcome of antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) patients from our tertiary care center. METHODS: This study of AAV patients seen in Rheumatology clinics at King Khalid University hospital (KKUH), King Saud University, Riyadh during the period 1990-2014 was carried out retrospectively. Demographic, clinical, haematological and immunological parameters along with therapy, complications and outcome were retrieved from patients' medical charts. Different characteristics were compared between the three groups of AAV; GPA (Granulomatosis with polyangiitis), MPA (Microscopic polyangiitis) and EGPA (Eosinophilic granulomatosis with polyangiitis). RESULTS: We identified 34 AAV patients (21 males: 13 females; 31 Saudis: 3 non-Saudis) comprising of 23 GPA, 2 MPA and 9 EGPA cases. The mean age of onset was 42.1±17.6 years (range 11-75) and mean duration of disease was 8.7± 5.1 years (range 1-20). The most frequently affected system was pulmonary in all AAV (73.5%), GPA (65.2%) and EGPA (100%) while it was renal in MPA (100%) patients. Ophthalmological and upper airways involvement was higher in GPA. Neurological involvement was higher in EGPA (p<0.05). ANCA were detected in 79.4% of AAV patients, of them c-ANCA were 77.8% and p-ANCA 22.2%. ANCA was positive in 91.3% GPA, 100% MPA and 44.4% EGPA patients. In GPA c-ANCA were detected in 80.9% and p-ANCA in 17.4%, in MPA, c-ANCA were detected in 50% and p-ANCA in 50%, in EGPA, c-ANCA were observed in 75% and p-ANCA in 25%. GPA patients had PR3 specificity in 93.3%, and MPO in 6.7%, PR3 was present in all MPA patients (100%), while EGPA patients had MPO (100%). Therapy administered were corticosteroids (100%), intravenous cyclophosphamide (58.8%), azathioprine (50%) and rituximab (11.8%). Infections were noted in 29.4%. CONCLUSIONS: The 10-year survival in our AAV patients was 95%. ANCA pattern was similar to Caucasian AAV patients and different from Japanese and Chinese AAV patients.

An eosinophilic variant granulomatosis with polyangiitis involving the dura, bilateral orbits, and mastoids.

Granulomatosis with polyangiitis (GPA) formerly called Wegener's granulomatosis is a chronic necrotizing granulomatous inflammatory disease with systemic vasculitis involving the upper and lower respiratory tract, and kidneys. The typical histopathology is that of necrotizing granulomatous inflammation with palisading histiocytes, neutrophils, and lymphocytes. We report a case of a 57-year-old lady presenting with left eye swelling, left ear pain and discharge, but with no pulmonary or renal symptoms. Investigations revealed positive cytoplasmic antineutrophil cytoplasmic antibodies  and proteinase 3 antibodies. The CT and MRI showed meningeal thickening and bilateral structural changes of the orbits and mastoids. Lacrimal gland biopsy showed non necrotizing granulation with an eosinophilic infiltration. She was diagnosed with eosinophilic variant of GPA of the eyes and mastoid bones bilaterally extending to dura and sparing the lungs and kidneys. She responded to corticosteroids and rituximab.

Fertility, ovarian failure, and pregnancy outcome in SLE patients treated with intravenous cyclophosphamide in Saudi Arabia.

Intravenous cyclophosphamide (IV CYC) has been and still used for treatment of severe manifestations of systemic lupus erythematosus (SLE), a disease occurring predominantly in women. IV CYC has been shown to predispose patients to ovarian failure and adverse pregnancy outcomes. We studied the impact of prior IV CYC treatment on ovarian function and pregnancy in our SLE patients, in terms of amenorrhea, fertility, and pregnancy outcome over a 26-year period. The study included 535 women (319 married), out of which 188 received IV CYC and 347 did not. Sixty-one patients experienced amenorrhea; the rate of amenorrhea in IV CYC user group (28.2 %; n = 53) was significantly higher than that in non-IV CYC group (3.7 %; n = 8) (P < 0.05). The type of amenorrhea was assessed in 99 women receiving IV CYC. Thirty-four (34.3 %) of them developed amenorrhea which was transient in 21 (21.2 %) and sustained in 13 (13.1 %) women. The older age at the time of receiving IV CYC and its higher cumulative dose were found to be risk factors for amenorrhea. Among married women, 48 of 99 (48.5 %) in IV CYC group conceived 90 pregnancies and 128 of 220 (58.2 %) in non-IV CYC group conceived 293 pregnancies. The rates of abortions, fetal loss, and live births between the two groups were similar; however, women with prior IV CYC had significantly more preterm births. Prior IV CYC was no barrier to conception; pregnancy outcome was favorable but associated with amenorrhea and preterm deliveries.

Haematological abnormalities in systemic lupus erythematosus.

OBJECTIVES: This study was conducted to evaluate the frequency and pattern of haematological abnormalities (HA) in SLE patients at the time of diagnosis and last follow-up, and their relationship with organ involvement. PATIENTS AND METHODS: This retrospective study included patients who were diagnosed and treated for SLE from 1982 to 2008 at King Khalid University hospital, Riyadh. Demographic and haematological parameters at diagnosis and the last follow-up, disease manifestations, organ involvement and clinical hematological complications were recorded. Association of HA with organ involvement was explored by multivariate analysis. RESULTS: A total of 624 patients (90.7% females, mean age 34.3±11.9 years) were studied. HA were present in 516 (82.7 %) patients at the time of diagnosis. Anemia was the most frequent HA in 63.0% patients followed by lymphopenia in 40.3%, leukopenia in 30.0%, thrombocytopenia in 10.9% and autoimmune hemolytic anemia (AIHA) in 4.6% patients. Deep vein thrombosis and pulmonary embolism were diagnosed in 7.4% and 2.6% patients respectively. After a mean follow-up of 9.3±5.3 years, 329/491 (67%) patients still had some HA present. Anemia remained the most common abnormality (51.7% patients) followed by lymphopenia in 33.1%, and thrombocytopenia in 4.8% patients. Leucopenia was associated with oral ulcers (p=0.021) and alopecia (p=0.031), anemia with renal disease (p=0.017), AIHA with neurological involvement (p=0.003), elevated IgG with malar rash (p=0.027), and low C3 with serositis (p=0.026). CONCLUSION: HA are very common at the time of diagnosis and during follow-up in SLE, and some of these abnormalities are associated with organ damage. This information may help in better management planning of SLE patients.

Herpes Zoster Infections in SLE in a University Hospital in Saudi Arabia: Risk Factors and Outcomes.

Patients with SLE carry an increased risk of infection that account for 11-23% of all hospitalized patients and 50% of all SLE patients develop major infections during the course of their disease. Globally Herpes Zoster has been reported as the most frequent viral infection in SLE patients. We determined the clinical spectrum, disease sequelae and the risk factors associated with the development of Herpes Zoster in patients with SLE and their outcomes. Retrospective case control study of Herpes Zoster infections was done in SLE patients between 1982 and 2006. Cases were matched 1:2 to controls for age, race, sex and duration of follow up. Clinical features of the cases from the time of lupus diagnosis to the time of Zoster were compared to their respective controls over similar time periods. Thirty two SLE cases were compared to sixty four controls. Cases were more likely to have received cyclophosphamide (P = .0223) and intravenous methylprednisolone pulse therapy (P = .0026), MMF (P < .02), had leucopenia (P = .0407) and hemolytic anemia (P = .0344). More cases than controls had lupus nephritis, cerebritis, thrombocytopenia but the differences did not reach statistical significance. The mean oral prednisolone dose and proportion of patients receiving immunosuppressives including pulse methylprednisolone therapy, IV Cyclophosphamide and mycophenolate was significantly higher in patients with active SLE compared to patients with SLE in remission at the time of Herpes Zoster (P < .05). Disseminated Zoster developed in patients with active SLE (7/9) compared to patients with SLE in remission (0/23). None of the patients had postherpetic neuralgia or bacterial super infection. Immunosuppressive medications were discontinued at the time of diagnosis of Zoster in 19 of 32 patients and all patients received antiviral medications.There were no permanent neurologic deficits or deaths. We conclude that Herpes Zoster infections occur at increased frequency among patients with SLE and carry significant morbidity. Immunosuppressive therapy and severe manifestations of lupus may be risk factors for the development of Herpes Zoster although not necessarily at the time of disease flare or immunosuppressive therapy. Our study suggests that although Herpes Zoster occurs frequently in patients with SLE, it has a relatively benign course.

Lupus nephritis among 624 cases of systemic lupus erythematosus in Riyadh, Saudi Arabia.

The aim of this article is to study the prevalence, clinicolaboratory features, WHO histological types, therapy and renal outcome of lupus nephritis (LN) in Saudi Arabia. During the 27-year-period (1980-2006), 299 (47.9%) cases of LN were identified among the 624 cases of systemic lupus erythematosus (SLE) follow-up at King Khalid University Hospital, Riyadh. The female:male ratio in LN was 8.3:1, with a mean age of 32 years and a mean age of onset of 23 years. The WHO renal histological types were; Class I (1%), Class II (18.1%), Class III (10%), Class IV (37.1%), Class V (11.7%), and Class VI (2.7%). Azathioprine was given to 43.1% and pulse cyclophosphamide to 65.6% in combination with other drugs. Remission was seen in 226 (75.6%) patients, renal flares in 14 (4.7%), end stage renal disease (ESRD) in 27 (9.0%), death in 18 (6.0%), and 14 (4.7%) lost follow-up. The 5- and 10-year patient survival rates in our whole LN cohort by Kaplan-Meier analysis were 96% and 95%, respectively. The survival did not differ significantly in different LN classes nor did it differ significantly during the three periods of presentation (1980-1990, 1991-2000, and 2001-2006; P > 0.05). The risk factors for poor survival were found to be older age at onset (>50-years age; P = 0.034), ESRD (P = 0.000), and low C3 (P = 0.022). The risk factors for progression to ESRD were older age at onset (>50-years age; P = 0.037), hypertension (P = 0.009), elevated serum creatinine (P = 0.000), and proliferative LN (Classes III, IV; P = 0.013, P = 0.039). Different treatment modalities did not have significant effect on survival in the whole LN cohort (P = >0.05). However, pulse cyclophosphamide favored remission in Classes II, III, IV, and V (P = 0.023). The main causes of death were renal failure (50%) and infections (44.4%).

Immunogenicity of singlet oxygen modified human DNA: implications for anti-DNA antibodies in systemic lupus erythematosus.

Reactive oxygen species (ROS)-modified DNA has been shown to be a better and more discriminating immunogen than native DNA (nDNA) for the production of anti-DNA autoantibodies in SLE (systemic lupus erythematosus). Among ROS, the role of hydroxyl radical (.OH) in the induction of damage and modification of nDNA has been extensively studied while such documentation implicating singlet oxygen ((1)O(2)) in inducing immunogenicity in nDNA leading to the production of anti-double-stranded (ds) DNA autoantibodies in SLE is not yet available. This prospective study was undertaken to evaluate the immunogenicity of healthy human dsDNA modified with (1)O(2) generated by methylene blue plus radiant light. Female rabbits were immunized with (1)O(2)-modified human dsDNA to raise anti-dsDNA antibodies. (1)O(2)-modified anti-dsDNA rabbit immune sera and the (1)O(2)-modified anti-dsDNA rabbit purified immunoglobulin G (IgG) were tested against a variety of dsDNA antigenic substrates through direct enzyme-linked immunosorbent assay (ELISA). The immunogenicity of (1)O(2)-modified human dsDNA was further evaluated by studying its immunoreactivity with SLE patients' sera and SLE patients' purified anti-dsDNA IgG. As compared to healthy human sera, (1)O(2)-modified anti-dsDNA rabbit immune sera as well as the (1)O(2)-modified anti-dsDNA rabbit purified IgG demonstrated a strong affinity towards (1)O(2)-modified human dsDNA(.)(1)O(2)-modified human dsDNA proved to be potentially more immunogenic against SLE patients' whole sera and SLE patients' purified IgG as compared to healthy human sera. Our findings suggest that (1)O(2) may also be inducing immunogenicity in native dsDNA resulting in the production of anti-dsDNA autoantibodies as seen in SLE patients.

Results of delivery in umbilical cord prolapse.

OBJECTIVE: To review the peripartum clinical course of patients whose pregnancies were complicated by umbilical cord prolapse and to evaluate its impact on neonatal outcome. METHODS: All cases of cord prolapse managed in King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between 1990-2000 were identified. There were 111 patients identified among 55,789 deliveries. Each maternal and fetal chart was reviewed for parity, age, gestational age, fetal presentation, status of membranes, time from diagnosis to delivery, mode of delivery, baby weight, Apgar scores and cord blood hydrogen ion concentration (PH). The data collected was analyzed using Gold Stat Software Package, and statistical significance was established by using analysis of variance and Chi-square. RESULTS: The incidence of cord prolapse was found to be one in 503 cases (1.99 per thousand deliveries) in our study. Seventy-two (64.9%) of the fetuses were in vertex presentation and 39 (35.1%) were non-vertex, including breech and transverse presentations. Ninety one point nine percent were singletons and 8% were twins. At the time of diagnosis in 15 (13.5%) membranes were artificially ruptured and in 96 (86.5%), they were spontaneously ruptured. The cervix was fully dilated in 10% and minimally dilated in 100 (90%). Regarding mode of delivery, 7 (6.5%) were vaginal deliveries and 104 (93.5%) were cesarean sections. The interval from diagnosis to delivery ranged from 10 minutes to >20 minutes. Six (5.4%) of the babies were delivered in 10 minutes, 49 (44.1%) in 20 minutes and 56 (50.5%) in more than 20 minutes. Apgar score was less than 7 in 44 (39.6%) of the babies at one minute and in 5 (4.5%) of the babies at 5 minutes. Cord PH was less than 7 in 2 (1.8%) cases and more than 7 in 109 (98.2%). Forty-one (36.9%) of the babies were admitted in neonatal intensive care unit. There was no perinatal mortality in our study group. CONCLUSION: In our review, we found that cord prolapse is not associated with higher rates of perinatal mortality or morbidity and our study supports clinical management of cord prolapse by cesarean section. The interval from diagnosis to delivery may not be the only determinant of neonatal outcome.