Association of the Spectrum of Cutaneous Lupus Erythematosus with Disease Activity and Systemic Manifestations in Patients with Systemic Lupus Erythematosus.

Background: Cutaneous involvement is common in systemic lupus erythematosus (SLE) patients and may be essential to the disease activity. This study aimed to describe cutaneous manifestations spectrum and determine the association of cutaneous lesions with the disease activity and systemic involvement among SLE patients in Malang, Indonesia. Methods: A cross-sectional study was conducted using 54 SLE patients from rheumatology outpatient clinic at Saiful Anwar General Hospital Malang, Indonesia. Cutaneous features were classified according to Gilliam and Sontheimer classification of cutaneous lupus. Disease activity and clinical manifestations were documented according to Mexican-SLE disease activity index (Mex-SLEDAI). Results: Among 54 subjects, 50% of the patients had cutaneous manifestations. Subacute cutaneous lupus erythematosus (SCLE) was observed in 11.1% of patients, and malar rash in 20.4%. Subjects with cutaneous lesions had significantly higher Mex-SLEDAI scores, especially those who had SCLE (p<0.001), malar rash (p=0.002), alopecia (p=0.002), and photosensitivity (p=0.032). Six patients (11.1%) had skin infections with higher disease activity (9[8-11]vs.2[0-4];p<0.001). SCLE was significantly associated with malar rash (OR 11.7[1.8-76.5]), vasculitis (OR 43.0[4.1-445.6]), and fatigue (OR 15.0[2.1-108.8]). Malar rash was associated with photosensitivity (OR 8.4[1.6-44.0]), while oral or nasal ulcer was associated with fatigue (OR 8.6 [1.4-54.6]). Vasculitis (OR 5.9[1.0-35.1]) and nephritis (OR 11.7 [1.8-76.5]) were associated with the presence of skin infection. Conclusion: SCLE and malar rash are the most common cutaneous lesions among subjects. Subjects with cutaneous lesions have relatively higher disease activity. Several skin lesions are also associated with SLE patients' systemic manifestations.

Randomised Clinical Trial Study: The Combination of Vitamin D and Curcumin Piperine Attenuates Disease Activity and Pro-inflammatory Cytokines Levels Insystemic Lupus Erythematosus Patients.

BACKGROUND: Curcumin-piperine might synergise with vitamin D to induce clinical remission in patients with systemic lupus erythematosus (SLE). OBJECTIVE: To observe the improvement of patients with SLE clinically and the levels of inflammatory cytokines after receiving supplements of curcumin-piperine and cholecalciferol (Vitamin D3). METHODS: Forty-five female SLE patients were included in a three-month double-blind, randomized controlled trial. Participants were classified into: Group I (400 IU cholecalciferol + placebo three times daily, n = 15), Group II (600 mg curcumin + 15,800 m piperine once daily and three times daily placebo, n = 15), and Group III (cholecalciferol 400 IU three times and 600 mg curcumin + 15,800 mg piperine once a day, n = 15). Mexican SLE disease activity score (Mex- SLEDAI), fatigue severity scale (FSS), TGF-ß, and IL-6 levels were measured from all patients before and after the treatments. RESULTS: Mex-SLEDAI, FSS, and IL-6 were reduced significantly, while TGF-ß serum levels were increased in all groups after the treatments (p <0.05). Changes in Mex-SLEDAI score (p = 0.003 and p = 0.008), FSS (p = 0.001 and p <0.001), and TGF-ß (p = 0.003 and p = 0.004) serum levels were significantly higher in group III compared to the group I or group II. On the other hand, changes in Mex-SLEDAI, FSS, IL-6, and TGF-ß serum levels were similar between groups I and II. CONCLUSION: Although vitamin D or curcumin-piperine alone could improve the clinical outcome and cytokines levels in SLE, curcumin-piperine combined with vitamin D had the best outcome in improving the disease activity and cytokines levels among patients with SLE. (ClinicalTrials.gov number, NCT05430087).

Secukinumab in Ankylosing Spondylitis Patients: A Cost-per-Responder Analysis from the Indonesian Health System Perspective.

OBJECTIVE: There are no publications that have demonstrated economic value for ankylosing spondylitis (AS) treatments in Indonesia. Cost per responder (CPR) is a lean method of economic evaluation. We estimated CPR from Indonesia's health system perspective following AS treatment with secukinumab relative to adalimumab, golimumab, and infliximab. METHODS: In the absence of head-to-head trials, a comparative evidence analysis was conducted in the form of matching-adjusted indirect comparison (MAIC) to estimate the response rate of various competing treatment options against secukinumab. This was followed by a CPR analysis that compared the cost per patient for a defined response level. RESULTS: Based on MAIC, patients on secukinumab had higher Assessment in Spondyloarthritis International Society (ASAS) 20 response (improvement of ≥ 20% and ≥ 1 unit in at least three domains on a scale of 10 and no worsening of ≥ 20% and ≥ 1 unit in remaining domain on a scale of 10) and ASAS 40 response (improvement of ≥ 40% and ≥ 2 units in at least three domains on a scale of 10 and no worsening at all in remaining domain) versus those on adalimumab, golimumab, and infliximab at week 24. The cost per ASAS 20 at week 24 for secukinumab was 75% lower than adalimumab, 65% lower than golimumab, and 80% lower than infliximab. The cost per ASAS 40 at week 24 for secukinumab was 77% lower than adalimumab, 67% lower than golimumab, and 83% lower than infliximab. Secukinumab dominated adalimumab, golimumab, and infliximab at week 24 and adalimumab at week 52, by being more efficacious at lower cost. Threshold analysis revealed that substantial reduction in efficacy or increase in cost of secukinumab would make secukinumab not cost effective, indicating the robustness of the results. CONCLUSION: This study demonstrated that if AS patients in Indonesia were treated with secukinumab instead of comparator therapies, more patients could be treated, and more patients would reach response to treatment for the same budget.

Factors Associated with Vaccine Breakthrough Incidence among Health Care Workers Vaccinated with Inactivated SARS-CoV2 Vaccine (CoronaVac).

BACKGROUND: Healthcare workers (HCWs) run a high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The HCWs are prone to the SARS-CoV-2 infection in the hospital despite being fully vaccinated. The present study aimed to address the factors associated with the coronavirus disease 2019 (COVID-19) vaccine breakthrough among HCWs. STUDY DESIGN: A prospective cohort study. METHODS: Participants were 184 HCWs receiving two doses of inactivated SARS-CoV-2 vaccine (CoronaVac, Sinovac Life Science). All participants were followed for six months. Confirmed COVID-19 was defined as positive SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR). Before undergoing RT-PCR, questionnaires were used to obtain information on demographic characteristics, profession, contact with COVID-19 cases, personal protective equipment (PPE), health protocols adherence, exercise, and nutritional habits. RESULTS: A number of 57 (31%) participants were COVID-19 positive. Close contact with COVID-19 cases (adjusted RR 6.82, 95% CI: 1.97, 47.98, P = 0.044), being a resident doctor (adjusted RR 4.72, 95% CI: 1.11, 20.11, P = 0.036), improper mask-wearing (adjusted RR 2.36, 95% CI: 1.15, 4.85, P = 0.019), and lower frequency of eating fruit and vegetables (adjusted RR 2.73, 95% CI: 1.34, 5.57, P = 0.006) increased the risk of vaccine breakthrough. Compared to single surgical masks, KN95 and N95 significantly reduced the risk of COVID-19 (adjusted RR 0.27, 95% CI: 0.07, 0.97, P = 0.045 and adjusted RR 0.25, 95% CI: 0.07, 0.87, P = 0.029), respectively. CONCLUSION: As evidenced by the obtained results, being a resident doctor, close contact with confirmed COVID-19 cases, health protocol incompliance, as well as the lower frequency of fruit and vegetable consumption were associated with the risk of vaccine breakthrough among HCWs. Appropriate strategies are needed to prevent the risk of SARS-CoV-2 infection among HCWs.

The Role of Vitamin D for Modulating the T Helper 1 Immune Response After the Coronavac Vaccination.

The purpose of this study was to observe the role of vitamin D levels with T helper 1 (Th1)-type cytokines, such as interferon γ (IFN-γ) and interleukin-12 (IL-12) efficacy, in those who had already received 2 injections of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccines (CoronaVac). We also observed if these cytokines played any significance in the CoronaVac effectiveness for preventing coronavirus disease 2019 (Covid-19) infection. One hundred ninety-four volunteers were monitored for 8 months upon receiving 2 inactivated SARS-CoV2 vaccination injections (CoronaVac, Sinovac Life Sciences). The rate of confirmed Covid-19 infections was the primary outcome. Six to 7 weeks after the second vaccine injection, and blood samples were obtained to measure the serum vitamin D, IFN-γ, and IL-12 levels. Low vitamin D level was defined if vitamin D level <30 ng/mL. Subjects with low vitamin D had lower IFN-γ and IL-12 levels (P = 0.04 and P = 0.04, respectively). The receiver operating characteristics curve analysis revealed that the area under curve for IFN-γ was 0.59, whereas IL-12 was 0.59 for predicting the low vitamin D levels. During follow-up, a higher incidence of Covid-19 infections was observed in subjects with low IFN-γ levels (P = 0.03). Kaplan-Meier survival analysis revealed that the cumulative hazard of confirmed Covid-19 cases was increased in subjects with low IFN-γ levels (log-rank test, P = 0.03). We concluded that lower vitamin D level was correlated with a lower Th1 immune response, whereas the adequate IFN-γ level was required to obtain better CoronaVac effectiveness.

Association Between the Effectiveness and Immunogenicity of Inactivated SARS-CoV2 Vaccine (CoronaVac) with the Presence of Hypertension among Health Care Workers.

OBJECTIVE: This study aimed to observe the association between the presence of hypertension with Covid-19 vaccine effectiveness among healthcare workers who received CoronaVac vaccination. METHODS: We conducted a prospective cohort study in Saiful Anwar General Hospital, Malang, Indonesia on 155 healthcare workers aged 18-59 years old who already received twice of the CoronaVac (Sinovac Life Science, Beijing, China) injection with 14-day intervals. Hypertension was diagnosed according to the 2020 International Society of Hypertension. Subjects were monitored for six months. The primary outcome was the rate of Covid-19 diagnosed by the pharyngeal swab for the real-time reverse transcription-polymerase chain reaction (RT-PCR) examination. The secondary endpoints were: (1) severity of Covid-19 among infected participants; (2) rate of hospitalizations; and (3) anti-SRBD antibody levels measured by ECLIA. RESULTS: Among 155 participants, 18.7% of them were diagnosed with hypertension, and 31.0% had the desirable BP target according to the current guidelines. Subjects with hypertension, especially those with uncontrolled blood pressure, had a higher incidence of Covid-19 infection than subjects without hypertension. Subjects with symptomatic Covid-19 and hospitalized because of Covid-19 were higher in participants with hypertension. The anti-SRBD antibody levels were lower in the second month after CoronaVac vaccination in hypertensive subjects. In contrast, comparable anti-SRBD levels were seen from both groups at sixth months after vaccination. CONCLUSION: Hypertension was associated with lower vaccine effectiveness in healthcare workers. Subjects with hypertension had a higher risk of being infected with Covid-19 despite getting a complete dose of vaccination and lower antibody production.

Association of the premature immunosenescence with the presence and severity of anemia among patients with systemic lupus erythematosus.

INTRODUCTION: One of the possible mechanisms that contribute to the development of anemia in systemic lupus erythematosus (SLE) is the presence of premature immunosenescence in SLE. This study aimed to observe the correlation between immunosenescence with anemia in SLE. METHODS: This research was a cross-sectional study with the subject was 60 women with SLE aged 16-45 years old. Subjects were recorded for the demographic and clinical data, complete blood counts, iron status (iron serum, total iron-binding capacity, and transferrin saturation), ferritin, inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), and anti-dsDNA levels. Immunosenescence was observed by measuring the senescent T cells from peripheral blood mononuclear cells (PBMC) by flow cytometry, counted as CD4+CD57+ and CD8+CD57+ T cells. Serum IL-2 and IFNγ as the cytokines associated with immunosenescence were also measured from all subjects. Subjects were divided into anemic and non-anemic groups according to the classification of anemia from WHO (Hb < 12 gr/dl). RESULTS: Anemic SLE patients had higher CD4+CD57+, CD8+CD57+, and IFNγ, while IL-2 was lower in SLE patients with anemia. Multivariate linear regression revealed that the decreasing levels of Hb were associated with the increase of CD8+CD57+ percentages and IFNγ levels. Anti-dsDNA, ESR, CRP, ferritin, iron serum, and transferrin saturation were correlated with CD8+CD57+. IFNγ level also correlated with the anti-dsDNA, iron serum, and ferritin levels. No correlation was found between the iron status and inflammatory markers with CD4+CD57+ percentages and IL-2 levels. Multivariate regression analysis showed that IFNγ was positively associated with anti-dsDNA and negatively associated with iron serum and transferrin saturation, while CD8+CD57+ percentages were positively associated with the ferritin levels. CONCLUSION: Immunosenescence is associated with anemia by modulating the inflammatory response and causing iron dysregulation in SLE.

Low levels of vitamin D were associated with coagulopathy among hospitalized coronavirus disease-19 (COVID-19) patients: A single-centered study in Indonesia.

BACKGROUND: This study was aimed to explore the association of vitamin D in the risk of coagulopathy in coronavirus disease-19 (COVID-19). METHODS: Clinical and laboratory findings were obtained from 50 confirmed COVID-19 patients hospitalized in Saiful Anwar General Hospital, Malang, Indonesia, from September to November 2020. Thrombotic events during hospitalization were recorded, and the ISTH disseminated intravascular coagulation (DIC) score was used to classify overt DIC. Hypovitaminosis D was defined by serum vitamin D level <49.92 nmol/L. RESULTS: Among 50 patients, 42 (84%) had hypovitaminosis D, and 6 (12%) developed thrombotic events. Vitamin D levels were lower in patients with thrombotic events (p=0.015), D-dimer >2 mg/L (p=0.006), ISTH DIC score 5 (p=0.020), admitted on ICU (p=0.002), and non-survivor groups (p=0.007). Multivariate analysis for the risk in increased D-dimer levels showed low vitamin D as the only significant risk factor with OR 1.8 (1.2-4.4), p=0.034. Low vitamin D also increased the risk for developing overt DIC with OR. 5.4 (1.0-30.2), p=0.039. Vitamin D level had negative correlations with ferritin (R=-0.316, p=0.044) and CRP (R=-0.530, p=0.000). CONCLUSIONS: In conclusion, a low level of vitamin D was found in most hospitalized COVID-19 patients and might be associated with the development of coagulopathy.

Association between senescence of T cells and disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients are predisposed to chronic immune activation, leading to accelerated immunosenescence. The aging of the immune system causes the T cells to express several senescence markers such as CD57 and KLRG1, which produce pro-inflammatory cytokine interferon γ (IFN-γ). Immunosenescence was associated with high morbidity and mortality in other diseases. This research was conducted to prove the association between senescent T cells and SLE disease activity. MATERIAL AND METHODS: This research was an observational cross-sectional study on 53 women aged 16-45 years diagnosed with SLE based on SLICC 2012 criteria. All subjects were recorded for demographic and clinical data, and their SLE disease activity index (SLEDAI) score was measured to evaluate disease activity. Active disease was defined as SLEDAI score ≥ 3. The CD57 antigen and KLRG1 expression on CD4+ and CD8+ T cells were calculated from peripheral blood mononuclear cells (PBMC) by flow cytometry. Interferon γ was measured from serum using ELISA. The comparison was done using the Mann-Whitney U test, and correlation was tested using the Spearman test. Associations between variables were calculated using linear regression models. RESULTS: Systemic lupus erythematosus patients with active disease had markedly higher CD4+KLRG1+ (3.1 [1.3-5.5]% vs. 0.3 [0.1-0.5]%), CD8+CD57+ (11.6 ±7.1% vs. 2.4 ±2.0%, p = 0.000), and CD8+KLRG1+ T cell percentages (13.7 ±7.5% vs. 0.3 ±0.1%, p = 0.000), and IFN- γ levels (208.9 [148.3-233.8] vs. 146.7 [130.2-210.8] pg/ml, p = 0.048), compared to the inactive patients. Positive correlation and association was found between the CD8+CD57+ and CD8+KLRG1+ percentages with the SLEDAI score (p = 0.007 and p = 0.007, for the linear regression analysis, respectively). CONCLUSIONS: Systemic lupus erythematosus patients showed significantly higher senescence T cell markers compared to controls, and the increase of T cell senescence, especially in the CD8 compartment, has some association with increased disease activity in patients with SLE.

Role of Lymphocytes CD4/CD8 Ratio and Immunoglobulin G Cytomegalovirus as Potential Markers for Systemic Lupus Erythematosus Patients with Periodontal Disease.

OBJECTIVES: The aim of the study was to analyze the correlation between periodontitis severity in systemic lupus erythematosus (SLE) with CD4/CD8 lymphocytes ratio and cytomegalovirus gamma immunoglobulin (IgG CMV) level. MATERIALS AND METHODS: This is a descriptive study using a cross-sectional approach that included 93 subjects who were diagnosed with SLE in Rheumatology Department, Saiful Anwar Hospital, during 2017 to 2019. Periodontitis severity was assessed by periodontal Index (PI). CD4/CD8 lymphocyte ratio was determined using flow cytometry and IgG CMV levels using enzyme-linked immunosorbent assay. STATISTICAL ANALYSIS: The differences among the three groups were analyzed using analysis of variance. Correlation among the groups was calculated using Spearman/Pearson correlation coefficient test, while regression analysis was done using Statistical Package for the Social Sciences. RESULTS: The mean of periodontitis severity and standard deviation in SLE was 2.66 ± 1.02. There were negative correlation between CD4/CD8 lymphocyte ratio with periodontal index (r = -0.971) and positive correlation between IgG CMV level with periodontal index (r = 0.977). CONCLUSIONS: Inverted CD4/CD8 ratio and IgG CMV were found associated with periodontitis severity in SLE patient. Further research was recomended that CD4/CD8 lymphocytes ratio and IgG CMV can be used as a potensial marker of periodontitis severity in SLE patients.

Factors associated with health care seeking behavior for musculoskeletal pain in Indonesia: A cross-sectional study.

AIM: To assess the factors defining healthcare-seeking behavior of people with musculoskeletal pain in the urban community of Malang City, East Java, Indonesia. METHODS: A cross-sectional survey was performed in Malang City, East Java, Indonesia. In total, 2067 participants aged 16-93 years were interviewed. The sociodemographic and socioeconomic factors of healthcare seeking behavior, musculoskeletal pain, disability, and adverse drug reactions were assessed using the validated Indonesian version of Community Oriented Program for the Control of Rheumatic Disease (COPCORD) protocol by International League of Associations for Rheumatology and the World Health Organization core questionnaire. Chi-square test was applied to assess the determinants of health-seeking behavior for musculoskeletal pain. RESULTS: Slightly more than one-third of the respondents (36%) with musculoskeletal pain, described as osteoarthritis, low back pain, gouty arthritis, soft tissue rheumatism, and autoimmune arthritis, were assessed for their health-seeking behavior. About 73% of all those participants sought treatment for their musculoskeletal symptoms. Treatment modality used was modern healthcare, traditional healthcare, self-treatment using traditional medication, self-treatment using modern medication with the proportions of 20.94%, 25.23%, 33.95%, 25.77%, respectively. Disability significantly affected health-seeking behavior as the major determinant (prevalence ratio [PR] 1.087, 95% CI 1.031-1.146, P = 0.002), followed by age (PR 1.043, 95% CI 1.000-1.087, P = 0.049). Healthcare-seeking behavior was associated with the presence of adverse drug reactions (P < 0.001). CONCLUSION: Factors associated with musculoskeletal pain health-seeking behavior were disability and age. Self and traditional healthcare treatment were further associated with an adverse drug reaction.