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sandra_navarra.png

Sex: Female

Education:
Doctor of Medicine, University of Santo Tomas, 1980
Bachelor of Psychology, Philippine Women’s University, 1975

Field of Specialization:
Rheumatology
Autoinflammatory Diseases
Rheumatoid arthritis
Rheumatic Diseases

Researches:

Article title: Patterns of Medication Use in Systemic Lupus Erythematosus – A Multi‐Centre Cohort Study
Authors: Rangi Kandane‐Rathnayake, Worawit Louthrenoo, Shue‐Fen Luo, Yeong‐Jian J. Wu, et al.
Publication title: Arthritis Care and Research, July 2021

Abstract:
Objectives
Evidence for the utility of medications in settings lacking randomised trial data can come from studies of treatment persistence. We examined patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicentre longitudinal cohort.

Methods
Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLEDAI-2K) and medication details, captured at every visit from 2013-18, were used. Medications were categorised as glucocorticoids (GC), anti-malarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity.

Results
Data from 19,804 visits of 2,860 patients were analysed. Eight medication categories were observed: no treatment; GC, AM or IS only; GC+AM; GC+IS; AM+IS and GC+AM+IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits and biologicals in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with time-adjusted mean SLEDAI-2K≥10 had lower discontinuation of GC and higher discontinuation of IS.

Conclusion
Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.
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Article title: Prevention of infective complications in systemic lupus erythematosus: A systematic literature review for the APLAR consensus statements
Authors: Kenji Oku, Laniyati Hamijoyo, Nuntana Kasitanon, Meng Tao Li, et al.
Publication title: International Journal of Rheumatic Diseases 24(6), May 2021

Abstract:
Systemic lupus erythematosus (SLE) is a more common autoimmune rheumatic disease in the Asia‐Pacific region. The prognosis of SLE remains unsatisfactory in some Asian countries because of delayed diagnosis, limited access to medications, increased complications and issues of tolerability and adherence to treatment. The Asia‐Pacific League of Associations for Rheumatology SLE special interest group has recently published a set of consensus recommendations on the management of SLE for specialists, family physicians, specialty nurses, and other healthcare professionals in the Asia‐Pacific region. This article reports a systematic literature review of the infective complications of SLE in Asia and evidence for prevention of these infections by pre‐emptive antimicrobial therapy and vaccination.
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Article title: Independent associations of lymphopenia and neutropenia in patients with systemic lupus erythematosus: a longitudinal, multinational study
Authors: Rangi Kandane-Rathnayake, Worawit Louthrenoo, Vera Golder, Shue-Fen Luo, et al.
Publication title: Rheumatology, March 2021

Abstract:
Objective: The prevalence and associations of leucopenia in SLE remain incompletely understood. We evaluated associations of disease activity and medication use with leucopenia (lymphopenia and neutropenia) in a multinational, prospectively followed SLE cohort. Methods: Data from the Asia Pacific Lupus Collaboration cohort, in which disease activity and medications were prospectively captured from 2013-18, were used. Predictors of lymphopenia (lymphocyte count<0.8 x 109/L) and neutropenia (neutrophil count<1.5 x 109/L) were examined using multiple failure, time-dependent survival analyses. Results: Data from 2,330 patients and 18,287 visits were analysed. One thousand three hundred twelve patients (43.7%) had at least one episode of leucopenia. 867 patients (37.2%) had lymphopenia, observed in 3,065 (16.8%) visits, and 292 (12.5%) patients had neutropenia, in 622 (3.4%) visits. After multivariable analyses, lymphopenia was associated with overall disease activity, ESR, serology, prednisolone, azathioprine, methotrexate, tacrolimus, cyclophosphamide and rituximab use. Methotrexate and ciclosporin were negatively associated with neutropenia. Lupus low disease activity state (LLDAS) was negatively associated with both lymphopenia and neutropenia. Conclusion: Both lymphopenia and neutropenia were common in SLE patients but were differentially associated with disease and treatment variables. Lymphopenia and neutropenia should be considered independently in studies in SLE.
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Article title: The Asia-Pacific League of Associations for Rheumatology consensus statements on the management of systemic lupus erythematosus
Authors: Chi Chiu Mok, Laniyati Hamijoyo, Nuntana Kasitanon,Der Yuan Chen, et al.
Publication title: Rheumatology, March 2021

Abstract:
Systemic lupus erythematosus (SLE) is prevalent in Asia and carries a variable prognosis among patients across the Asia-Pacific region, which could relate to access to health care, tolerability of medications, and adherence to therapies. Because many aspects of SLE are unique among patients from this region, the Asia-Pacific League of Associations for Rheumatology developed the first set of consensus recommendations on the management of SLE. A core panel of 13 rheumatologists drafted a set of statements through face-to-face meeting and teleconferences. A literature review was done for each statement to grade the quality of evidence and strength of recommendation. 29 independent specialists and three patients with SLE were then recruited for a modified Delphi process to establish consensus on the statements through an online voting platform. A total of 34 consensus recommendations were developed. Panellists agreed that patients with SLE should be referred to a specialist for the formulation of a treatment plan through shared decision making between patients and physicians. Remission was agreed to be the goal of therapy, but when it cannot be achieved, a low disease activity state should be aimed for. Patients should be screened for renal disease, and hydroxychloroquine is recommended for all Asian people with SLE. Major organ manifestations of SLE should be treated with induction immunosuppression and subsequently maintenance; options include cyclophosphamide, mycophenolate mofetil, azathioprine, and calcineurin inhibitors, in combination with glucocorticoids. Biologics, combination regimens, plasma exchange, and intravenous immunoglobulins should be reserved for cases of refractory or life-threatening disease. Anticoagulation therapy with warfarin is preferred to the direct oral anticoagulants for thromboembolic SLE manifestations associated with a high-risk antiphospholipid antibody profile.
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Article title: Mortality and adverse events of special interest with intravenous belimumab for adults with active, autoantibody-positive systemic lupus erythematosus (BASE): a multicentre, double-blind, randomised, placebo-controlled, phase 4 trial
Authors: Saira Z Sheikh, Morton A Scheinberg, James Cheng-Chung Wei, Dana Tegzova, et al.
Publication title: The Lancet Rheumatology 3(2), December 2020

Abstract:
Background Belimumab is approved for the treatment of active systemic lupus erythematosus (SLE). Although clinical trials showed a favourable benefit–risk profile, numerical differences in the incidence of mortality and adverse events of special interest (AESIs) have been reported. We assessed the frequency of these events in patients with SLE receiving belimumab or placebo plus standard therapy. Methods BASE was a double-blind, randomised, placebo-controlled, phase 4 trial done in 33 countries. Adults with active SLE were randomly assigned (1:1) to receive intravenous belimumab (10 mg/kg) or placebo, plus standard therapy, for 48 weeks. The primary endpoints were incidences of all-cause mortality and AESIs during the on-treatment period (first-to-last study drug dose + 28 days). Safety analyses were done in the as-treated population (patients grouped by actual treatment received >50% of the time). This study was registered with ClinicalTrials.gov (NCT01705977). Findings Between Nov 27, 2012, and July 28, 2017, we randomly assigned 4018 patients. The as-treated population included 2002 patients in the belimumab group versus 2001 in the placebo group. Ten (0·50%) patients in the belimumab group died versus eight (0·40%) in the placebo group (difference 0·10%, 95% CI −0·31 to 0·51). Incidences were similar in the belimumab and placebo groups for serious infections (75 [3·75%] of 2002 vs 82 [4·10%] of 2001; difference −0·35%, 95% CI −1·55 to 0·85), opportunistic infections and other infections of interest (36 [1·80%] vs 50 [2·50%]; −0·70%, −1·60 to 0·20), non-melanoma skin cancers (4 [0·20%] vs 3 [0·15%]; 0·05%, −0·21 to 0·31) and other malignancies (5 [0·25%] vs 5 [0·25%]; 0·00%, −0·31 to 0·31). A higher proportion of patients in the belimumab group than in the placebo group had infusion and hypersensitivity reactions (8 [0·40%] vs 2 [0·10%]; 0·30%, −0·01 to 0·61), serious depression (7 [0·35%] vs 1 [0·05%]; 0·30%, 0·02 to 0·58), treatment-emergent suicidality (28 [1·42%] of 1972 patients vs 23 [1·16%] of 1986; 0·26%, −0·44 to 0·96), and sponsor-adjudicated serious suicide or self-injury (15 [0·75%] of 1972 patients vs 5 [0·25%] of 1986; post hoc difference 0·50%, 0·06 to 0·94). Interpretation In line with previously published data, incidences of all-cause mortality and AESIs were similar in patients given belimumab and placebo, except for serious infusion or hypersensitivity reactions, serious depression, treatment-emergent suicidality, and sponsor-adjudicated serious suicide or self-injury events. Funding GSK.
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Article title: Drivers of Satisfaction With Care for Patients With Lupus
Authors: Meenakshi Jolly, Bhavika Sethi, Courtney O'Brien, Winston Sequeira, et al.
Publication title: ACR Open Rheumatology 1(10), November 2019

Abstract:
Objective: Quality of life (QOL) and quality of care (QOC) in systemic lupus erythematosus (SLE) remains poor. Satisfaction with care (SC), a QOC surrogate, correlates with health behaviors and outcomes. This study aimed to determine correlates of SC in SLE. Methods: A total of 1262 patients with SLE were recruited from various countries. Demographics, disease activity (modified Systemic Lupus Erythematosus Disease Activity Index for the Safety of Estrogens in Lupus Erythematosus: National Assessment trial [SELENA-SLEDAI]), and QOL (LupusPRO version 1.7) were collected. SC was collected using LupusPRO version 1.7. Regression analyses were conducted using demographic, disease (duration, disease activity, damage, and medications), geographic (eg, China vs United States), and QOL factors as independent predictors. Results: The mean (SD) age was 41.7 (13.5) years; 93% of patients were women. On the univariate analysis, age, ethnicity, current steroid use, disease activity, and QOL (social support, coping) were associated with SC. On the multivariate analysis, Asian participants had worse SC, whereas African American and Hispanic patients had better SC. Greater disease activity, better coping, and social support remained independent correlates of better SC. Compared with US patients, patients from China and Canada had worse SC on the univariate analysis. In the multivariate models, Asian ethnicity remained independently associated with worse SC, even after we adjusted for geographic background (China). No associations between African American or Hispanic ethnicity and SC were retained when geographic location (Canada) was added to the multivariate model. Canadian patients had worse SC when compared with US patients. Higher disease activity, better social support, and coping remained associated with better SC. Conclusion: Greater social support, coping, and, paradoxically, SLE disease activity are associated with better SC. Social support and coping are modifiable factors that should be addressed by the provider, especially in the Asian population. Therefore, evaluation of a patient's external and internal resources using a biopsychosocial model is recommended. Higher disease activity correlated with better SC, suggesting that the latter may not be a good surrogate for QOC or health outcomes.
Full text link: https://tinyurl.com/suudxz8e

Article title: Lupus education for physicians and patients in a resource-limited setting
Authors: Sandra V. Navarra, Leonid Zamora, Ma. Theresa M. Collante
Publication title: Clinical Rheumatology 39(1), November 2019

Abstract:
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of manifestations and potential to affect several organ systems. Complications arise from both disease and medications especially glucocorticoids, significantly contributing to overall morbidity and mortality. SLE predominantly affects patients during their prime productive years resulting in substantial economic burden on the patient, caregivers, and society due to direct, indirect, and intangible costs. This illness burden is compounded in developing countries with limited resources due to various disparities in healthcare delivery. Physician education and practical referral and endorsement guidelines adapted to the local setting reinforce continuity and coordinated care. Likewise, patient education, self-help programs, and shared decision-making are essential best practice in the clinics. Both physician education and patient education improve overall outcomes in chronic diseases like SLE. As a developing country with very few rheumatologists and/or lupus specialists, efficient healthcare delivery for most Filipino lupus patients remains elusive. We describe our experience in confronting these challenges through development of strategies which focus on physician and patient education. Key Points • Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a highly variable course, requiring specialized, individualized, and coordinated care by a healthcare team. • Health disparities and limited resources significantly contribute to illness burden on the patient, family, and society. • Physician education on SLE must commence at undergraduate medical school, be integrated in Internal Medicine and Pediatrics, and reinforced through specialized training in Rheumatology and related specialties. • Patient education and empowerment are integral to improving healthcare outcomes especially in a resource-limited setting.
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Article title: Evaluation of remission definitions for systemic lupus erythematosus: a prospective cohort study
Authors: Vera Golder, Rangi Kandane-Rathnayake, Hoi Mbbs, Chang Gung
Publication title: The Lancet Rheumatology 1(2), October 2019

Abstract:
Background Validated outcome measures are needed from which to derive treatment strategies for systemic lupus erythematosus (SLE). However, no definition of remission for SLE has been widely adopted. The Definitions of Remission in Systemic Lupus Erythematosus (DORIS) group has proposed a framework with multiple potential definitions of remission. In this study, we aimed to assess the attainability and effect on disease outcomes of the DORIS definitions of remission, compared with the lupus low disease activity state (LLDAS), in patients with SLE. Methods In this prospective cohort study, we enrolled patients with SLE from 13 international centres that are part of the Asia Pacific Lupus Collaboration. Eligible patients were older than 18 years and fulfilled one of two classification criteria for SLE (1997 American College of Rheumatology criteria or the 2012 Systemic Lupus International Collaborating Clinics criteria). Visits were according to clinical need, with a minimum frequency of one visit per 6 months. We assessed attainment of remission on the basis of the eight DORIS definitions of remission, which varied in terms of serological activity, glucocorticoid use, and use of immunosuppresive agents; attainment of LLDAS; and disease flares at each visit. Irreversible organ damage accrual was recorded annually. Our primary aim was to assess exposure of patients to each of the remission definitions or LLDAS, and the respective association of these states with accrual of irreversible organ damage as the primary outcome measure. Occurrence of disease flares was the key secondary outcome. We used time-dependent Cox proportional hazards models and generalised linear models to assess DORIS definitions of remission and LLDAS in terms of their association with damage accrual and disease flares. Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients with SLE were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Remission, depending on DORIS definition, was achieved in 581 (4·6%) to 4546 (35·8%) of 12 689 visits. Spending 50% or more of observed time in any remission state was associated with a significant reduction in damage accrual, except for the two most stringent remission definitions, for which the frequency of attainment was lowest. Remission definitions disallowing serological activity were associated with the greatest reductions in disease flares. LLDAS was more attainable than any remission definition and was associated with a similar magnitude of protection from damage accrual and disease flares. Sustained remission and LLDAS were associated with a wider spread of effect sizes for reduction in risk of damage. By analysing patients who met the definition for LLDAS but not remission, we found that LLDAS was significantly associated with reduction in damage accrual, independent of all definitions of remission, except the least stringent. Interpretation Attainment of remission was associated with significant reductions in damage accrual and disease flares. LLDAS was more achievable than remission based on the DORIS criteria, but was similarly protective. Remission definitions with less stringency might be insufficiently distinct from LLDAS to substantially affect outcome measures, and further studies are needed to distinguish the protective effects of the various remission definitions.
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Article title: Risk factors for herpes zoster infection among Filipinos with systemic lupus erythematosus
Authors: Leonid Zamora and Sandra V. Navarra
Publication title: International Journal of Rheumatic Diseases 2019(00):1-6, September 2019

Abstract:
Aim: To identify clinical risk factors associated with herpes zoster (HZ) infections in systemic lupus erythematosus (SLE). Methods: A case‐control study ofHZ infection was performed in SLE patients seen at the University of Santo Tomas Lupus Clinics from 2009‐2014. Cases were matched 1:2 to SLE controls without HZinfection for age, sex, and disease duration. Clinical characteristics, SLE disease activity, and immunosuppressive use were compared. Results: Sixty‐five SLE patients(61,93.8%female) who developed HZ were matched with 130 SLE patients without HZ. Mean age was 36.75 years (±1.35; P=1.00) for the case group; mean SLE disease duration at first HZ infection was 6.1years (±3.3;P = .919). Four patients had more than 1 episode of HZ. There was localized HZ in 63/65(97%), and 2(3%) disseminated HZ infections. The case group received higher doses of prednisone 64/65 (P=.012), mean prednisone dose18.62mg/d(±1.48,P < .001) and more were exposed to cyclophosphamide (Cyc) (19/65; P < .001) compared to the control group's mean prednisone dose of 11.73mg/d(±1.16); there was Cyc use in 7/130 patients.Cyc in addition to mycophenolate mofetil (MMF)use among lupus nephritis patients conferred the highest risk for HZ infection occur‐rence. Hydroxychloroquine (HCQ) use reduced the risk for HZ by 87%(adjusted odds ratio 0.13, P = .003). Conclusion: Immunosuppressives and corticosteroid use are risk factors associated with the development of HZ in SLE.The risk for HZ increases among patients given intravenous Cyc and MMF for lupus nephritis. SLE disease activity did not show a direct association with HZ occurrence. HCQ use appeared to have a protective role against HZ infection.
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Article title: Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study
Authors: Vera Golder, Rangi Kandane-Rathnayake, Molla M. Huq, Hieu T. Nim, et al.
Publication title: The Lancet Rheumatology 1(2), September 2019

Abstract:
Background Treat-to-target strategies have improved outcomes in single-organ diseases with simple clinical or laboratory endpoints. A lack of validated endpoints has prevented adoption of treat to target for complex multiorgan conditions, such as systemic lupus erythematosus (SLE). We report the first prospective study undertaken to specifically validate a treat-to-target endpoint for SLE. Methods In this prospective cohort study, patients aged 18 years or older with SLE were recruited from 13 centres in eight countries and followed prospectively. Patients with at least two visits over the study period no more than 6 months apart were included in the longitudinal analysis. Patients with no visits in the final year of the study were censored from their last visit. Attainment of the lupus low disease activity state (LLDAS) was assessed at each visit. The primary outcome measure was accrual of irreversible end-organ damage, defined as at least a 1-point increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We used time-dependent hazard regression models and generalised linear models to measure the association between LLDAS (attainment at any timepoint, cumulative time in LLDAS, and sustained LLDAS) with accrual of irreversible end-organ damage or flare (key secondary outcome). This study is registered with ClinicalTrials.gov, NCT03138941. Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Attainment of LLDAS at any timepoint was associated with reduction in damage accrual (hazard ratio 0·59, 0·45–0·76; p<0·0001) and subsequent flare (0·65, 95% CI 0·56–0·75; p<0·0001). Cumulative time in LLDAS was associated with improved outcomes: compared with patients with less than 50% of observed time in LLDAS, those with at least 50% of observed time in LLDAS had reduced risk of damage accrual (0·54, 0·42–0·70; p<0·0001) and flare (0·41, 0·35–0·48; p<0·0001). Similarly, increased durations of sustained LLDAS were associated with incremental reductions in the risk of damage accrual. The association of LLDAS with reduced damage accrual was observed regardless of pre-existing damage or disease activity at study entry. Interpretation LLDAS attainment is associated with significant protection against flare and damage accrual in SLE. These findings validate LLDAS as an endpoint for clinical studies in SLE. Funding The Asia Pacific Lupus Collaboration received project support grants from UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.
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Article title: Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: A Phase III study extension
Authors: Ronald van Vollenhoven, Sandra V. Navarra, Roger A. Levy, Mathew Thomas, et al.
Publication title: Rheumatology (Oxford, England) 59(2), July 2019

Abstract:
Objective: This extension study of the Phase III, randomized, placebo-controlled Belimumab International SLE Study (BLISS)-52 and BLISS-76 studies allowed non-US patients with SLE to continue belimumab treatment, in order to evaluate its long-term safety and tolerability including organ damage accrual. Methods: In this multicentre, long-term extension study (GlaxoSmithKline Study BEL112234) patients received i.v. belimumab every 4 weeks plus standard therapy. Adverse events (AEs) were assessed monthly and safety-associated laboratory parameters were assessed at regular intervals. Organ damage (SLICC/ACR Damage Index) was assessed every 48 weeks. The study continued until belimumab was commercially available, with a subsequent 8-week follow-up period. Results: A total of 738 patients entered the extension study and 735/738 (99.6%) received one or more doses of belimumab. Annual incidence of AEs, including serious and severe AEs, remained stable or declined over time. Sixty-nine (9.4%) patients experienced an AE resulting in discontinuation of belimumab or withdrawal from the study. Eleven deaths occurred (and two during post-treatment follow-up), including one (cardiogenic shock) considered possibly related to belimumab. Laboratory parameters generally remained stable. The mean (s.d.) SLICC/ACR Damage Index score was 0.6 (1.02) at baseline (prior to the first dose of belimumab) and remained stable. At study year 8, 57/65 (87.7%) patients had no change in SLICC/ACR Damage Index score from baseline, indicating low organ damage accrual. Conclusion: Belimumab displayed a stable safety profile with no new safety signals. There was minimal organ damage progression over 8 years. Trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00424476 (BLISS-52), NCT00410384 (BLISS-76), NCT00732940 (BEL112232), NCT00712933 (BEL112234).
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Article title: Development of the Asia Pacific Lupus Collaboration cohort
Authors: Rangi Kandane-Rathnayake, Vera Golder, Worawit Louthrenoo, Shue-Fen Luo, et al.
Publication title: International Journal of Rheumatic Diseases 22(suppl_1), November 2018

Abstract:
Aim The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. Method The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3‐ to 6‐monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient‐reported quality of life (Short‐form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. Results The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat‐to‐target (T2T) endpoint, and reported several retrospective and cross‐sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. Conclusion The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.
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Article title: A prospective international study on adherence to treatment in 305 patients with flaring SLE: Assessment by drug levels and by self‐administered questionnaires
Authors: Nathalie Costedoat‐Chalumeau, Frederic Houssiau, Peter Izmirly, Véronique Le Guern, et al.
Publication title: Clinical Pharmacology & Therapeutics 103(6), September 2017

Abstract:
Nonadherence to treatment is a major cause of lupus flares. Hydroxychloroquine (HCQ), a major medication in systemic lupus erythematosus, has a long half-life and can be quantified by HPLC. This international study evaluated nonadherence in 305 lupus patients with flares using drug levels (HCQ<200ng/ml or undetectable desethylchloroquine), and self-administered questionnaires (MASRI<80% or MMAS-8<6). Drug levels defined 18.4% of the patients as severely nonadherent. In multivariate analyses, younger age, non-use of steroids, higher BMI and unemployment were associated with nonadherence by drug level. Questionnaires classified 39.9% of patients as nonadherent. Correlations between adherence measured by questionnaires, drug level, and physician assessment were moderate. Both methods probably measured two different patterns of nonadherence: self-administered questionnaires mostly captured relatively infrequently missed tablets, while drug levels identified severe nonadherence (i.e., interruption or erratic tablet intake). The frequency with which physicians miss nonadherence, together with under-reporting by patients, suggests that therapeutic drug monitoring is useful in this setting. This article is protected by copyright. All rights reserved.
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Article title: SAT0282 Frequency and Predictors of Attainment of The Lupus Low Disease Activity State (LLDAS) in A Cross Sectional Study of Sle Patients in The Asia Pacific
Authors: V. Golder, Rangi Kandane-Rathnayake, Alberta Hoi, W. Louthrenoo, et al.
Publication title: Annals of the Rheumatic Diseases 75(Suppl 2):770.1-770, June 2016

Abstract:
Background Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by fluctuating disease activity. A low disease activity endpoint, the Lupus Low Disease Activity State (LLDAS), was recently reported and retrospective validation showed that time spent in LLDAS translated into reduced damage accrual (Franklyn, Ann Rheum Dis, 2015). A large prospective study to validate LLDAS in a multiethnic cohort of lupus patients from the Asia Pacific Region is underway. Objectives To describe the frequency and identify the predictors of fulfilling criteria for LLDAS in baseline visit data from a large multinational multiethnic cohort of patients with SLE in nine Asia Pacific countries. Methods Prospectively collected baseline visit data from 1846 SLE patients enrolled in a longitudinal study were analysed cross sectionally against the recently published definition of LLDAS, and patient characteristics associated with LLDAS attainment determined. Results LLDAS criteria were met by 44% of patients at a single baseline visit. Stepwise multivariable logistic regression revealed that patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95% CI 0.19–0.49, p<0.001). Likewise, discoid rash (OR 0.66, 95% CI 0.49–0.89, p=0.006), renal disease (OR 0.60, 95% CI 0.48–0.75, p<0.001), elevated double stranded DNA (OR 0.65, 95% CI 0.53–0.81, p<0.001) or hypocomplementaemia (OR 0.52, 95% CI 0.40–0.67, p<0.001) were negatively associated with LLDAS attainment. Significant differences in LLDAS attainment between countries were observed, and higher national social wealth as measured by the Gross Domestic Product per capita was positively associated with LLDAS (OR 1.57, 95% CI 1.25–1.98, p<0.001). Conclusions Low disease activity was observed in less than half of SLE patients at a single point in time. Disease duration and phenotype, as well as national social wealth, were predictive of LLDAS attainment. Disclosure of Interest None declared
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Article title: OP0092 Remission in Sle: Consensus Findings from a Large International Panel on Definitions of Remission in SLE (DORIS), Cynthia Aranow, G. Bertsias, E. Bonfá, et al.
Authors: Ronald van Vollenhoven,
Publication title: Annals of the Rheumatic Diseases 74(Suppl 2):103.2-103, June 2015

Abstract:
Background Treat-to-target recommendations identified “remission” as a target in SLE but recognize that there is no generally accepted definition for remission in this disease. Objectives To achieve consensus, in a large multi-party international panel, on potential definitions for remission in SLE. Methods An international expert panel of sixty rheumatologists, nephrologists, dermatologists, clinical immunologists, and patient representatives participated in preparatory exercises, a full-day face-to-face meeting, and follow-up exercises and electronic voting rounds. Results Eight key statements regarding remission in SLE achieved >90% agreement (table). There were different viewpoints on the required duration of remission. In addition, the panel expressed strong support (>90%) for the following principles which will guide the further development of remission definitions: I. A definition of remission in SLE will be worded as follows: Remission in SLE is a durable state characterized by [a definition of: absence of symptoms, signs, abnormal labs, (serology)] Ia. Remission-off-therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials. Ib. Remission-on-therapy allows patients to be treated with maintenance antimalarials, stable, low-dose steroids (prednisone ≤5 mg/d), maintenance immunosuppressives and/or stable (maintenance) biologics. II. Assessment of clinical symptoms and signs should be based on a validated index, e.g., clinical-SLEDAI =0, BILAG D/E only, clinical ECLAM =0; supplemented with PhysGA <0.5 (0-3), and with labs included. III. For testing the construct validity of each potential remission definition the most appropriate outcomes (dependent variables) are: Death, Damage, Flares, and HR-QOL measures. Conclusions The work of this international consensus panel provides a framework for testing individual definitions of remission against longer-term outcomes.
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Article title: Treat-to-target in systemic lupus erythematosus: recommendations from an international task force
Authors: Ronald van Vollenhoven, Marta Mosca, George Bertsias, David Isenberg, et al.
Publication title: Annals of the Rheumatic Diseases 73(6), April 2014

Abstract:
The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.
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Article title: SAT0197 Baseline laboratory characteristics from the combined placebo groups in the bliss trials are predictive of severe flare at 24 weeks
Authors: Muhammad Helmi Petri, Ronald van Vollenhoven, Roger A Levy, Sandra V Navarra, et al.
Publication title: Annals of the Rheumatic Diseases 71(Suppl 3):538-538, January 2014

Abstract:
Background Identification and validation of potential serologic biomarkers of clinically meaningful SLE flare are major unmet medical needs in clinical practice and trials. Objectives To examine biomarker predictors of SLE flares at baseline in the combined placebo groups from the belimumab BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) phase 3 trials. Methods The BLISS trials enrolled patients with active SLE (SELENA SLEDAI ≥6) who were autoantibody positive (antinuclear antibody [ANA] or anti-double-stranded DNA [anti-dsDNA]), on stable standard therapy for 30 d, and without severe active lupus nephritis or CNS SLE. Patients were randomized to placebo, or belimumab 1 or 10 mg/kg, plus standard therapy. Changes in prednisone were allowed early in the trials, but had to be within 25% or 5 mg of baseline dose. Flare (moderate-severe) was defined as 1 new BILAG A or 2 new B scores, or by modified SLE Flare Index (SFI). Laboratory biomarkers evaluated included ANA, anti-dsDNA, anti-Smith, complement (C) 3, C4, C-reactive protein (CRP), proteinuria >0.5 g/24 h, immunoglobulin, B- and T-cell subsets, and B-lymphocyte stimulator (BLyS) quartile levels. The proportion of placebo patients with abnormal tests who developed a new flare was compared with the proportion without a flare. Meaningful difference was defined as: ≥10% absolute difference (% flare - % no flare) or nominal p values for pairwise comparison (likelihood ratio test); and ≥50% increase ([% flare - % no flare]/% no flare). Results By wk 24 in the placebo group (n=562), 25.3% of patients (n=142) had a flare by BILAG and 12.8% (n=72) by SFI. Predictors of wk-24 flare (% with vs without flare) are shown in the table. Conclusions SLE patients on standard therapy with low C3/4, positive CRP, proteinuria >0.5 g/24 h, positive anti-dsDNA or anti-Smith, or BLyS ≥2 ng/mL were at increased risk for SLE flare over 24 wk. Flare definitions (BILAG and SFI) had high concordance regarding predictors; univariate risk factors were the same for both definitions at 24 wk. Study limitations: laboratory tests were defined as categorical variables (present/absent) and time-varying nature of the characteristics over the 24 wk was not examined. The data suggest serologic tests predict clinically meaningful flare over 24 wk, and may be useful in the identification of patients at greater risk for flares in clinical practice and trials.
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Article title: SAT0204 Predictors for SLE flares: Baseline disease activity and demographic characteristics from the bliss trials' combined placebo groups
Authors: Ronald van Vollenhoven, Roger A Levy, Muhammad Helmi Petri, Sandra V Navarra, et al.
Publication title: Annals of the Rheumatic Diseases 71(Suppl 3):540-541, January 2014

Abstract:
Background Predicting which SLE patients are at increased risk for clinically meaningful flares may be useful in making management decisions. Objectives To identify demographic and disease-related predictors for flares. Methods Baseline demographic and SLE-related disease activity characteristics were evaluated for their ability to predict new SLE flares by wk 24 in the combined dataset of 562 patients receiving placebo + standard therapy from the belimumab BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) phase 3 trials. Flare (moderate-severe) was defined according to the modified SLE Flare Index (SFI) or as the development of 1 new BILAG A or 2 new B organ domain scores. Baseline variables included race, age, gender, BMI, SELENA-SLEDAI (SS; mean score, range, and 24 items with ≥30/group), PGA, BILAG A-E scores, ACR diagnostic criteria, SLICC damage index, SLE duration, and concurrent medications. A ≥10% absolute difference (% flare - % no flare) or ≥50% increase ([% flare - % no flare]/% no flare) was considered clinically meaningful. Results By wk 24, 142 patients (25.3%) receiving placebo had a flare by BILAG and 72 (12.8%) by SFI. By both flare indices, SS ≥12, serologic markers, and moderate-severe disease activity involving renal, hematologic, and vasculitic domains were predictors of flare, as was prednisone use (table). Immunosuppressives, antimalarials, and other concomitant medications did not predict flare. Conclusions SLE patients on standard therapy alone with moderate-severe renal, vasculitic, hematologic, or serologic disease activity were at increased risk of having a clinically meaningful flare over 24 wk.
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Article title: Overview of lupus nephritis management guidelines and perspective from Asia
Authors: Desmond Yap, Sandra V. Navarra, Zhi-Hong Liu, Ming-Hui Zhao, et al.
Publication title: International Journal of Rheumatic Diseases 16(6):625-36, December 2013

Abstract:
Lupus nephritis (LN) is a common and important manifestation of systemic lupus erythematosus (SLE). Evidence suggests higher rates of lupus renal involvement in Asian populations, and maybe more severe nephritis, compared with other racial or ethnic groups. The management of LN has evolved considerably over the past three decades, based on observations from clinical studies that investigated different immunosuppressive agents including corticosteroids, cyclophosphamide, azathioprine, mycophenolic acid, calcineurin inhibitors and novel biologic therapies. This is accompanied by improvements in both the short-term treatment response rate and long-term renal function preservation. Treatment guidelines for LN have recently been issued by rheumatology and nephrology communities in U.S.A. and Europe. In view of the racial difference in disease manifestation and response to therapy, and the substantial disease burden in Asia, a panel of 15 nephrologists and rheumatologists from different Asian regions with extensive experience in lupus nephritis - the Steering Group for the Asian Lupus Nephritis Network (ALNN) - met and discussed the management of lupus nephritis in Asian patients. The group has also reviewed and deliberated on the recently published recommendations from other parts of the world. This manuscript summarizes the discussions by the group and presents consensus views on the clinical management and treatment of adult Asian patients with LN, taking into account both the available evidence and expert opinion in areas where evidence remains to be sought.
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Article title: Risk of tuberculosis with anti-tumor necrosis factor-α therapy: Substantially higher number of patients at risk in Asia
Authors: Sandra V. Navarra, Boxiong Tang, Liangjing Lu, Hsiao-Yi Lin, et al.
Publication title: International Journal of Rheumatic Diseases 17(3), October 2013

Abstract:
To assess the potential risk of tuberculosis (TB) in patients treated with anti-tumor necrosis factor-alpha (TNF-α) agents in Asia. Absolute risk increase (ARI) of TB was estimated for three widely used anti-TNF-α therapies using published standardized incidence ratios (SIR) from the French Research Axed on Tolerance of bIOtherapies registry and incidence (absolute risk [AR]) of TB in Asia. Assuming an association of increased TB risk with anti-TNF-α therapy and country TB AR (incidence), the ARI of TB by country was calculated by multiplying the SIR of the anti-TNF-α therapy by the country's TB AR. The numbers needed to harm (NNH) for each anti-TNF-α agent and numbers needed to treat (NNT) to reduce one TB event using etanercept therapy instead of adalimumab or infliximab were also calculated for each country. The ARI of TB with anti-TNF-α therapies in Asian countries is substantially higher than Western Europe and North America and the difference between etanercept versus the monoclonal antibodies becomes more evident. The NNH for Asian countries ranged from 8 to 163 for adalimumab, 126 to 2646 for etanercept and 12 to 256 for infliximab. The NNT to reduce one TB event using etanercept instead of adalimumab therapy ranged from 8 to 173, and using etanercept instead of infliximab therapy the NNT ranged from 13 to 283. Higher numbers of patients are at risk of developing TB with anti-TNF-α therapy in Asia compared with Western Europe and North America. The relative lower risk of TB with etanercept may be particularly relevant for Asia, an endemic area for TB.
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Article title: Baseline Predictors of Systemic Lupus Erythematosus Flares: Data From the Combined Placebo Groups in the Phase III Belimumab Trials
Authors: Michelle A. Petri, Ronald van Vollenhoven, Jill Buyon, Roger A. Levy, et al.
Publication title: Arthritis & Rheumatology 65(8), August 2013

Abstract:
Objective: To identify predictors of moderate-to-severe systemic lupus erythematosus (SLE) flare in 562 patients treated with standard therapy alone in phase III belimumab trials, and to evaluate the impact of standard therapies on preventing flares. Methods: Post hoc analysis assessed baseline demographics, disease activity, and biomarkers in patients with and those without flare at treatment weeks 24 and 52. Severe flare was defined by the modified SLE Flare Index (SFI) and the development of any new British Isles Lupus Assessment Group (BILAG) A domain score. Severe and moderate flare was defined by development of 1 new BILAG A domain score or 2 new BILAG B domain scores. Baseline characteristics associated with a ≥10% absolute difference or a ≥50% increase in flare rates were considered predictive. Results: Frequencies of flares over 52 weeks according to the SFI, any new BILAG A domain score, and 1 new BILAG A domain score or 2 new BILAG B domain scores were 23.7%, 23.1%, and 32.0%, respectively. Flare predictors by univariate analysis on all 3 indices at weeks 24 and 52 were a score ≥12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI); anti-double-stranded DNA (anti-dsDNA) positivity; proteinuria (≥0.5 gm/24 hours); BILAG renal, vasculitic, and hematologic scores; elevated C-reactive protein levels; and B lymphocyte stimulator (BLyS) levels ≥2 ng/ml. Independent predictors by multivariate analysis at week 52 were SELENA-SLEDAI and/or BILAG renal involvement and anti-dsDNA ≥200 IU/ml (on all 3 indices); SELENA-SLEDAI and/or BILAG neurologic and vasculitic involvement (on 2 indices: any new BILAG A domain score and 1 new BILAG A domain score or 2 new BILAG B domain scores); BLyS levels ≥2 ng/ml (on 2 indices: the SFI and 1 new BILAG A domain score or 2 new BILAG B domain scores); and low C3 level (on the SFI). Baseline medications did not significantly decrease or increase moderate-to-severe SLE flare risk. Conclusion: Patients who were receiving standard SLE therapy and had renal, neurologic, or vasculitic involvement, elevated anti-dsDNA or BLyS levels, or low C3 had increased risk of clinically meaningful flare over 1 year. Hydroxychloroquine use was not predictive.
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Article title: THU0298 Consensus Definition of a Low Disease Activity State in Systemic Lupus Erythematosus
Authors: C. S. Lau, Mandana Nikpour, Sandra V. Navarra, W. Louthrenoo, et al.
Publication title: Annals of the Rheumatic Diseases 72(Suppl 3):A267-A267, June 2013

Abstract:
Background In systemic lupus erythematosus (SLE), organ damage, morbidity and mortality are the result of acute or sustained disease activity. The diversity of clinical features of active SLE makes quantification of disease activity problematic. The definition of a low disease activity state in rheumatoid arthritis has resulted in it being widely applied in research and clinical practice, but in SLE there is currently no such definition and thus no related outcome data. In contrast, clinicians often intuitively recognize a state of low SLE disease activity, wherein patients’ disease activity is low and treatment burden acceptable. No empirical definition of a low disease activity state in SLE has been described. Objectives To define a ‘lupus low disease activity state’ (LLDAS), for subsequent validation using prospective cohort data. Methods Firstly, we defined LLDAS conceptually as follows: ‘A state which, if sustained, is associated with a low likelihood of adverse outcome’, considering both disease activity and medication safety. Next, a panel of experts from Hong Kong, China, Philippines, Thailand, Singapore, Indonesia and Australia individually generated items for potential inclusion in a definition of LLDAS. These items were scored on a 5-point scale, then reduced using the Delphi method. Six experts participated in the first round of Delphi, and items with a mean score ≥ 3 were retained. Eleven experts then participated in a consensus meeting using the nominal group technique, and in a second round of Delphi, in which items with an mean score ≥ 4 were retained. Results Fifty-six ‘unique’ items were initially generated. These fell into two domains: (i) descriptions of disease activity, and (ii) descriptions of medication use. Following two rounds of Delphi, unanimous agreement on the preliminary definition of LLDAS was reached. The final list of five items defining LLDAS comprised: Conclusions We have generated a definition of LLDAS. The definition of LLDAS will be validated in a large prospective multicenter Asian-Pacific lupus cohort, using outcomes including organ damage and death, and refined in response to subsequent findings. Once validated, LLDAS may serve alone, or in combination with variables such as patient reported outcomes, as a treatment target in SLE clinical practice, research, and clinical trials. Disclosure of Interest None Declared
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Article title: Cross-cultural validation of a disease-specific patient-reported outcome measure for lupus in Philippines
Authors: Sandra V. Navarra, , RMDV Tanangunan, RA Mikolaitis-Preuss, M Kosinski, et al.
Publication title: Lupus 22(3), January 2013

Abstract:
Objective LupusPRO is a disease-targeted patient-reported outcome measure that was developed and validated among US patients with systemic lupus erythematosus (SLE). We report the cross-cultural validation results of the LupusPRO English-language version among Filipino SLE patients.Method The 43-item LupusPRO was pretested in 15 SLE individuals, then administered to 106 SLE patients, along with short-form SF36 and the EQ5D visual analogue scale. A mail/drop-back LupusPRO and change in health status item survey were returned within two to three days. Demographics, clinical and serological characteristics, disease activity and damage measured by PGA, SELENA-SLEDAI, LFA Flare, and SLICC-ACR SLE damage index (SDI) were collected. Internal consistency reliability (ICR), test-retest reliability (TRT), convergent validity (corresponding SF36 domains) and criterion validity (against general health and disease activity measures) were tested. Reported p values are two tailed.ResultsA total of 121 Filipino SLE subjects (95% women, median age 31.0 ± 16 years) with at least a high school level of English instruction participated. Median (IQR) PGA, SLEDAI and SDI were 0.0 (1.0), 2.0 (10) and 0 (1), respectively. ICR exceeded 0.7 for all domains except the lupus symptoms domain. TRT was greater than 0.85 for all LupusPRO domains. Convergent and criterion validity were observed against corresponding SF36 domains and disease activity measures. The tool was well received by patients. Confirmatory factor analysis showed good fit.Conclusion English LupusPRO has fair psychometric properties among SLE patients in the Philippines, and is now available for inclusion in clinical trials and longitudinal studies to test responsiveness to change.
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Article title: Safety profile of belimumab: Pooled data from placebo-controlled phase 2 and 3 studies in patients with systemic lupus erythematosus
Authors: DJ Wallace, S Navarra, MA Petri, A Gallacher, et al.
Publication title: Lupus 22(2), December 2012

Abstract:
Safety data were pooled and analyzed from one phase 2 and two phase 3 double-blind, placebo-controlled, repeat-dose systemic lupus erythematosus (SLE) trials of belimumab 1, 4 (phase 2 only), and 10 mg/kg. Types and rates of adverse events (AEs) were similar across treatment groups. Rates of patients experiencing any serious AE were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and belimumab 1, 4, and 10 mg/kg, respectively; rates of serious infusion reactions (including hypersensitivity reactions) occurring on the same days as infusions were 0.4%, 0.9%, 0%, and 0.9%, and rates of serious infections were 5.5%, 7.1%, 6.3%, and 5.3%. Malignancy rates/100 patient-years (excluding non-melanoma skin cancer) were 0.29 with placebo vs. 0.20 with all belimumab doses combined; mortality rates/100 patient-years were 0.43 vs. 0.73. These data support the conclusion that belimumab in combination with standard SLE therapy was generally well tolerated in a predominantly autoantibody-positive population with active SLE. ClinicalTrials.gov identifiers: LBSL02: NCT00071487; BLISS-52: NCT00424476; BLISS-76: NCT00410384.
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Article title: Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: Combined results from two phase III trials
Authors: Susan Manzi, Jorge Sánchez-Guerrero, Joan T. Merrill, Richard Furie, et al.
Publication title: Annals of the Rheumatic Diseases 71(11):1833-1838, May 2012

Abstract:
Objective To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. Methods Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) organ domain scores. Results At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA–SLEDAI, and immunological by SELENA–SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA–SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (≤16%) at baseline, including the SELENA–SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA–SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. Conclusions Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.
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Article title: Systemic lupus erythematosus following HPV immunization or infection?
Authors: HF Soldevilla, SFR Briones, SV Navarra
Publication title: Lupus 21(2):158-61, February 2012

Abstract:
Background and purpose: The link between autoimmunity and infectious agents has been strongly suggested by reports of lupus or lupus-like syndromes following immunization. This report describes three patients with either newly diagnosed systemic lupus erythematosus (SLE) or SLE flare, following vaccination for human papilloma virus (HPV). CASE 1: A 17-year-old female completed two doses of HPV vaccine uneventfully. Two months later, she developed arthralgias with pruritic rashes on both lower extremities, later accompanied by livedo reticularis, bipedal edema with proteinuria, anemia, leucopenia, hypocomplementemia and high titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA). Kidney biopsy showed International Society of Nephrology/Renal Pathology Society Class III lupus nephritis. She was started on high dose steroids followed by pulse cyclophosphamide therapy protocol for lupus nephritis, and subsequently went into remission. CASE 2: A 45-year-old housewife, previously managed for 11 years as having rheumatoid arthritis, had been in clinical remission for a year when she received two doses of HPV immunization. Four months later, she developed fever accompanied by arthritis, malar rash, oral ulcers, recurrent ascites with intestinal pseudo-obstruction, and behavioral changes. Cranial MRI showed vasculitic lesions on the frontal and parietal lobes. Laboratory tests showed anemia with leucopenia, hypocomplementemia, proteinuria, ANA positive at 1:320, and antibodies against dsDNA, Ro/SSA, La/SSB and histone. She improved following pulse methylprednisolone with subsequent oral prednisone combined with hydroxychloroquine. CASE 3: A 58-year-old housewife diagnosed with SLE had been in clinical remission for 8 years when she received two doses of HPV immunization. Three months later, she was admitted to emergency because of a 1-week history of fever, malar rash, easy fatigability, cervical lymph nodes, gross hematuria and pallor. Laboratory exams showed severe anemia, thrombocytopenia, active urine sediments, and hypocomplementemia. Despite pulse steroid therapy, blood transfusions, intravenous immunoglobulin and aggressive resuscitative measures, she expired a day after hospital admission. Summary: These cases narrate instances of the onset or exacerbation of lupus following HPV immunization suggesting adjuvant-induced autoimmunity. On the other hand, there are reports of higher incidence of HPV infection in SLE, with the infection per se possibly contributing to disease activity. Thus, the benefit of HPV immunization may still outweigh the risk among these individuals.
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Article title: Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: Prevalence, incidence, clinical features, and mortality
Authors: Rupert Jakes, Sang-Cheol Bae, Worawit Louthrenoo, Chi-Chiu Mok, et al.
Publication title: Arthritis Care & Research 64(2):159-68, February 2012

Abstract:
Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease with a wide spectrum of manifestations, shows considerable variation across the globe, although there is little evidence to indicate its relative prevalence in Asia. This review describes its prevalence, severity, and outcome across countries in the Asia-Pacific region. We conducted a systematic literature search using 3 groups of terms (SLE, epidemiology, and Asia-Pacific countries) of EMBase and PubMed databases and non-English language resources, including Chinese Wanfang, Korean KMbase, Korean College of Rheumatology, Japana Centra Revuo Medicina, Taiwan National Digital Library of Theses and Dissertations, and Taiwanese, Thai, and Vietnamese journals. The review showed considerable variation in SLE burden and survival rates across Asia-Pacific countries. Overall crude incidence rates (per 100,000 per year) ranged from 0.9-3.1, while crude prevalence rates ranged from 4.3-45.3 (per 100,000). Higher rates of renal involvement, one of the main systems involved at death, were observed for Asians (21-65% at diagnosis and 40-82% over time) than for whites. While infections and active SLE were leading causes of death, a substantial proportion (6-40%) of deaths was due to cardiovascular involvement. The correlation between the Human Development Index and 5-year survival was 0.83. This review highlights the need to closely monitor Asian SLE patients in Asian countries for renal and cardiovascular involvement, especially those who may not receive proper treatment and are therefore at greater risk of severe disease. We hope this will encourage further research specific to this region and lead to improved clinical management.
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Article title: Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G
Authors: Michelle M. A. Fernando, Jan Freudenberg, Annette Lee, David Lester Morris, et al.
Publication title: Annals of the Rheumatic Diseases 71(5):777-84, January 2012

Abstract:
Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon. These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.
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Article title: Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: A randomised, placebo-controlled, phase 3 trial
Authors: Sandra V. Navarra, Renato Antonio Guzman Moreno, Alberto E. Gallacher, Stephen Hall, et al.
Publication title: The Lancet 377(9767):721-31, February 2021

Abstract:
Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus. Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476. 867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10-2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30-2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07-2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21-2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93-2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09-2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15-2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18-2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease. Human Genome Sciences and GlaxoSmithKline.
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Article title: Studies of Filipino patients with systemic lupus erythematosus: Autoantibody profile of first-degree relatives
Authors: Sandra V. Navarra, M. I. Ishimori, E. A. Uy, Laniyati Hamijoyo, et al.
Publication title: Lupus 20(5):537-43 December 2010

Abstract:
This study surveyed the frequency of autoantibodies among un-affected first-degree relatives (FDRs) of Filipino systemic lupus erythematosus (SLE) patients compared with healthy un-related Filipino controls. The sensitivity, specificity and predictive value of the autoantibodies for SLE diagnosis were also assessed in this Filipino cohort. Filipino patients included in the University of Santo Tomas (UST) Lupus Database and un-affected FDRs were recruited. Healthy controls included those with no known personal or family history of autoimmune disease. The following autoantibodies were tested in all subjects: anti-nuclear antibody (ANA), anti-dsDNA, anti-Ro/SSA, anti-chromatin, anti-thyroid microsome, and anti-cardiolipin antibodies. Participants included 232 SLE patients, 546 FDRs, and 221 healthy controls. Median age of patients was 27 (range 8-66) years with median disease duration of 27.5 (range 1-292) months. Median age of FDRs was 42.0 (range 5-87) years. Compared with healthy controls, there were significantly more FDRs with positive ANA at titers 1 : 40 to 1 : 160 (p < 0.001) and 1 : 320 (p = 0.003), anti-Ro/SSA (4.94% versus 0.45%, p = 0.003), and anti-dsDNA ≥ 5.0 IU/ml (4.58% versus 1.36%, p = 0.031). ANA titer ≥1  :  160, anti-dsDNA, anti-Ro/SSA and anti-chromatin had the highest predictive value for SLE diagnosis. These findings reinforce the role of genetic influence in SLE risk among Filipinos, with a significant proportion of un-affected FDRs of SLE patients testing positive for autoantibodies compared with healthy Filipino controls. A longitudinal observational study in this same cohort will determine which proportion of these un-affected FDRs will evolve into clinical SLE disease in the future.
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Article title: Infections in systemic lupus erythematosus
Authors: Sandra V. Navarra and M. S. N. Leynes
Publication title: Lupus 19(12):1419-24, October 2010

Abstract:
Infections are an important cause of morbidity and mortality in systemic lupus erythematosus (SLE). Survival rates for SLE patients in developing countries are comparatively lower than those reported in industrialized countries, with early death from infection and active disease. In addition to the role of immunosuppressive agents in enhancing susceptibility to infection, infectious agents are also known to trigger lupus disease expression and activity. The endemicity of certain infections like tuberculosis further poses a special health issue in developing countries.
Full text available upon request to the author

Article title: Breast lymphoma in Sjögren’s syndrome complicated by acute monocular blindness
Authors: Helmar F. Soldevilla, Ramon Miguel M. Molina, Sandra V. Navarra
Publication title: International Journal of Rheumatic Diseases 13(2):164-70, May 2010

Abstract:
A 69-year-old hypertensive woman presented with eye and mouth dryness, bilateral parotid gland enlargement, associated with anasarca and proteinuria. Family history was notable for malignancies including breast, nasopharyngeal and colon cancers. Physical exam disclosed hypertension, bilaterally enlarged, firm, non-tender parotid glands, fine bibasilar crackles and bipedal edema. Anti Ro/Sjögren's syndrome antigen A antibody was positive, with negative tests for anti La/Sjögren's syndrome antigen B and anti-nuclear antibody (ANA). Chest radiographs showed basal infiltrates. Sjögren's syndrome associated with glomerulonephritis and interstitial lung disease was diagnosed, and she received pulse methylprednisololone followed by oral prednisone with dramatic improvement. Two months later, while on prednisone 5 mg/day, she returned to the clinic with an enlarging fixed non-tender right breast mass. She underwent modified radical mastectomy of the right breast, and pathologic report revealed diffuse, small cell, non-Hodgkin's lymphoma of the breast; axillary lymph nodes were negative for tumor. She opted for alternative therapy and did not return to the clinic until 7 months later when she developed sudden monocular blindness in the right eye with no other systemic manifestations. Magnetic resonance imaging (MRI) revealed swelling and enhancement of intracanalicular and pre-chiasmatic segments of the right optic nerve and right side of the optic chiasm. Considerations were Devic's disease versus metastases. She received pulse methylprednisolone therapy (1 g/day for 3 days) with partial recovery of vision. She is scheduled for lymphoma chemotherapy to include rituximab.
Full text available upon request to the author

Article title: Impact of Systemic Lupus Erythematosus on Health, Family, and Work: The Patient Perspective
Authors: Don Robinson, Daniel Aguilar, Melissa Schoenwetter, Robert W. Dubois, et al.
Publication title: Arthritis Care & Research 62(2):266-73, February 2010

Abstract:
Qualitative research among patients with systemic lupus erythematosus (SLE) can identify aspects of the disease relevant to clinical research and practice. A phenomenological, mixed-method approach was used to investigate these disease-driven health issues. A convenience sample of patients with SLE from Los Angeles County, California was recruited from a private, community-based rheumatology practice for participation in focus groups and interviews. Semistructured discussions explored disease manifestations and impact. A self-administered questionnaire evaluated the occurrence and importance of disease issues previously identified from literature. Patient health issues were identified through convergence using 1) qualitative analysis of focus group transcripts and 2) quantitative analysis of the questionnaire. Patients were also asked about their ability to accurately recall disease experiences. Focus group participants (n = 23) had a mean age of 43 years and a mean disease duration of 8 years; 19 (83%) were women and 14 (61%) were white. The most frequent health issues identified by focus group transcript analysis were pain (83%), fatigue (61%), work or school impairment (48%), skin manifestations (43%), and skin sensitivity (43%). Questionnaire findings were similar: the most frequent health issues were inability to do previous activities (87%), fatigue (87%), pain (87%), and work or school impairment (83%). Most interviewed patients (7 of 10) reported an ability to accurately recall disease issues between 24 hours and 7 days. SLE patients reported signs and symptoms that could significantly impact their functioning in daily life. Treatments that substantially improve these disease manifestations would offer considerable benefit to patients, treating physicians, and general society.
Full text available upon request to the author

Article title: Salmonella infections in patients with systemic lupus erythematosus: A case series
Authors: Jovie G. Gerona and Sandra V. Navarra
Publication title: International Journal of Rheumatic Diseases 12(4):319-23, December 2009

Abstract:
Systemic lupus erythematosis (SLE) patients are highly susceptible to infections. We aim to present our experience regarding the manifestations and outcomes of Salmonella infections in a group of Filipino SLE patients. This study reviewed the medical records of Filipino SLE patients with documented Salmonella infection seen at the Rheumatology Clinics of the University of Santo Tomas (UST) Hospital, Manila, Philippines from 2002 to 2009. Included were 12 patients (11 female), with mean age of 25.75 years (range 11-53 years) and average SLE disease duration 4.45 years to Salmonella infection. Five had septic arthritis (knee in 4, hip in 1), one of whom had concomitant typhoid fever. Another two patients had typhoid fever only. Sepsis syndrome was noted in three. One patient each had soft tissue abscess and meningitis. Salmonella typhi was isolated in seven patients, Salmonella sp. in four, and S. enteritidis in one patient. Two patients developed acute respiratory distress syndrome (ARDS), another had mixed Salmonella and Klebsiella pneumonia. Eleven patients were on high-dose steroids for active disease, including one patient with antecedent first infusion of cyclophosphamide plus rituximab. Management consisted of antimicrobials and adjunct surgery for arthritis and abscess. Except for three patients with Salmonella sepsis, all other patients improved with appropriate therapy.
Full text available upon request to the author

Article title: Gigantomastia in a patient with systemic lupus erythematosus successfully treated by reduction mammoplasty
Authors: A. E. Lanzon and Sandra V. Navarra
Publication title: Lupus 18(14):1309-12, October 2009

Abstract:
The objective of the study was to describe a Filipino woman with systemic lupus erythematosus (SLE) who developed gigantomastia associated with hyperoestrogenemia and successfully treated by reduction mammoplasty. A 37-year-old Filipino woman with SLE of 5-year duration presented with enlargement of breasts, which became more noticeable and progressive during disease flares requiring increased steroid dose (+ or - 40 mg/day). Following control of the last SLE flare, with prednisone effectively tapered to 15 mg/day, she consented to surgical breast reduction. Preoperative physical examination recorded the right and left breast measurement of 61 cm and 54.5 cm from sternal notch to nipple tip, respectively. serum oestrogen assay was elevated. She successfully underwent reduction mammoplasty with free nipple graft, with an uneventful postoperative course. The breast tissue oestrogen and progesterone receptor assays were strongly positive. In the succeeding months, SLE disease remained stable with prednisone tapered to 10 mg daily. This case illustrates a rare occurrence of gigantomastia associated with hyperoestrogenemia in a patient with SLE, successfully treated with reduction mammoplasty.
Full text available upon request to the author

Article title: Survey of vitamin D levels among post-menopausal Filipino women with osteoporosis
Authors: Anne-Annette P. Raso, Sandra V. Navarra, Julie Li-Yu, Tito Torralba
Publication title: International Journal of Rheumatic Diseases 12(3):225-9, September 2009

Abstract:
To determine the prevalence of vitamin D inadequacy in a group of Filipino post-menopausal women with osteoporosis. Seventy otherwise healthy post-menopausal Filipino women seen at the University of Santo Tomas Hospital, Section of Rheumatology, were diagnosed with osteoporosis by central dual-energy X-ray absorptiometry (DXA) technique. Levels of serum 25-hydroxyvitamin D were measured using enzyme-linked immunosorbent assay. The mean age of this population was 70 +/- 8 years, with an average of 22 +/- 10 years since menopause, and mean body mass index (BMI) of 22 +/- 1 kg/m(2). Only 30% (21/70) were on calcium plus vitamin D supplementation. Overall serum 25-hydroxyvitamin D levels ranged from 48-128 nmol/L, with a mean of 87 +/- 20.48 nmol/L. Serum 25-hydroxyvitamin D levels were divided as follows: 80-140 nmol/L (adequate), 25-79 nmol/L (inadequate/insufficient), and < 25 nmol/L (deficient). Sixty-four percent (45/70) of subjects had adequate levels while 36% (25/70) had inadequate levels of 25-hydroxyvitamin D. There were no subjects with deficient levels of 25-hydroxyvitamin D. Fischer's exact test did not show a significant association between BMD and 25-hydroxyvitamin D (P = 0.4804). Among this group of women with post-menopausal osteoporosis, only 36% had insufficient levels of 25-hydroxyvitamin D, with none of the subjects having deficient 25-hydroxyvitamin D levels. The majority (64%) had normal serum 25-hydroxyvitamin D levels--comparatively higher than that reported in the literature. These results suggest the possible contribution of factors other than vitamin D deficiency in post-menopausal Filipino women with osteoporosis.
Full text available upon request to the author

Article title: Central nervous system infections in Filipino patients with systemic lupus erythematosus
Authors: Pauline Jea Vargas, Gentry King, Sandra V. Navarra
Publication title: International Journal of Rheumatic Diseases 12(3):234-8, September 2009

Abstract:
Infections including those of the central nervous system (CNS) are a major contributor to morbidity and mortality in systemic lupus erythematosus (SLE). This case series describes the etiology, contributing factors and outcomes of CNS infections in a group of Filipino patients with SLE. Retrospective case series. We reviewed the medical records of SLE patients diagnosed and confined for a CNS infection at the University of Santo Tomas Hospital in Manila, Philippines, from 1997 to 2007. A total of 23 SLE patients (22 females) diagnosed with CNS infection were included in this study. The mean age was 25.8 years (range 12-51) at SLE diagnosis, and 30.9 years (range 14-58) at CNS infection, with a mean disease duration of 55 months (range 7-125). Nineteen cases (82.6%) were meningitis, and four (17.4%) were diagnoses of brain abscess. The etiologic agents were identified as Cryptococcus neoformans in seven (30.4%), Mycobacterium tuberculosis in seven (30.4%), Streptococcus pneumoniae in two (8.7%), Salmonella sp. in one (4.4%), Corynebacterium bovis with Actinomyces sp. in one (4.4%), and no isolate in five (21.7%). The average daily prednisone dose was 28.9 mg (range 0-60 mg); 10 patients had recently received pulse cyclophosphamide, and two were on mycophenolate mofetil at the time of infection. Most cases had active SLE; the lone patient in disease remission had S. pneumoniae meningitis post-splenectomy. The most common presentation was headache (100%) and fever (87%). The infection resolved completely in nine patients (39.1%), and resolved with sequelae in two patients (8.7%); 12 patients (52.2%) died. We described the etiology and outcomes of CNS infections in a group of Filipino patients with SLE. Risk factors included active SLE in the majority of cases requiring moderate- to high-dose steroids and other immunosuppressants like cyclophosphamide. Although C. neoformans and M. tuberculosis were the most common etiologic agents, it is just as important to search for less common organisms which can produce disease in highly susceptible hosts. A high index of suspicion and early appropriate management are crucial to favorable outcome among these patients.
Full text available upon request to the author

Article title: Severe hip and knee pain in a man with chronic tophaceous gout
Authors: Maria Cristina C. Tolin and Sandra V. Navarra
Publication title: International Journal of Rheumatic Diseases 12(1):57-60, April 2009

Abstract:
Gout is a common rheumatologic condition with characteristic clinical presentations during the acute arthritis and chronic tophaceous stages. Because of this, there is a tendency to overlook rare but important conditions which are independent of, but can co-exist with gout. This case of severe hip and knee pain in a patient with tophaceous gout takes the reader on a problem-solving exercise which simulates the analytical processes and decisions made in the clinic.
Full text available upon request to the author

Article title: Genetic determinants of basal C-reactive protein expression in Filipino Systemic Lupus Erythematosus families
Authors: Benjamin Rhodes, Andrew Wong, Sandra V. Navarra, Charles A. C. Villamin
Publication title: Genes & Immunity 9(2):153-60, April 2008

Abstract:
Basal C-reactive protein (CRP) is a heritable trait associated with long-term cardiovascular disease risk. Existing studies leave ambiguity over the key functional polymorphisms and fail to adjust for trans-acting effects. In a novel cohort of 285 Filipino systemic lupus erythematosus probands and their first-degree relatives, we quantified serum CRP and typed a dense map of CRP single-nucleotide polymorphisms (SNPs), along with SNPs in the interleukin-1 beta, interleukin-6 and apolipoprotein E genes. Ten CRP SNPs demonstrated association with basal CRP in a regression model (P=0.011-0.002). These delineated two haplotypes associated with high and low basal CRP expression (P=0.002). Differences in allele frequency were seen compared with Caucasian populations, enabling us to argue for an independent genetic effect from a phylogenetically distinct haplotype tagged by SNP rs1800947. We demonstrated an association between Apo epsilon 2 and higher basal CRP. Interleukin-6 genotype was associated with basal CRP, highlighting a role for acute-phase cytokines even in basal expression. Identifying these trans-acting variants may improve the use of basal CRP as a predictor cardiovascular risk, and increase our power to detect associations between CRP and disease.
Full text available upon request to the author

Article title: Presenting manifestations and clinical syndromes of Filipino patients with systemic lupus erythematosus
Authors: Charles A. C. Villamin and Sandra V. Navarra
Publication title: Modern Rheumatology 18(2):161-4, February 2008

Abstract:
The aim of this study was to describe the presenting clinical manifestations and syndromes of Filipino patients on diagnosis of systemic lupus erythematosus (SLE). We performed a retrospective review of medical records of Filipino SLE patients included in the lupus database of the University of Santo Tomas (UST) in Manila, Philippines. All patients fulfilled the American College of Rheumatology criteria for SLE. The following data were recorded: (1) demographic profile, (2) clinical manifestations on SLE diagnosis, and (3) clinical syndromes prior to and during fulfillment of diagnostic criteria for SLE and disease interval from diagnosis of a clinical syndrome to SLE diagnosis. Clinical data of 1,070 patients entered into the UST lupus database as of October 2005 were analyzed. The average age at SLE diagnosis was 28.5 +/- 11.5 (range 5-71) years, with 1,025 female and 45 male subjects. The most common presenting manifestation was arthritis (68%), followed by malar rash (49%), renal involvement (47%), photosensitivity (33%), and oral ulcers (33%). The following clinical syndromes were recorded prior to or during SLE diagnosis: nephrotic syndrome (30%), undifferentiated connective tissue disease (UCTD) (22%), autoimmune hemolytic anemia (AIHA) (6%), and idiopathic thrombocytopenic purpura (ITP) (6%). Among these, AIHA preceded the diagnosis of SLE at the longest interval (20.3 +/- 30.6, range 1-194 months). In this large database of Filipino patients with SLE, the most common presenting manifestation was arthritis, with renal involvement occurring in almost 50%. Among the clinical syndromes, nephrotic syndrome was the most common, whereas AIHA recorded the longest interval preceding SLE diagnosis, at an average of 20.3 months. Our findings are similar to data from other countries and emphasize the broad range of manifestations of SLE. The findings also reinforce the need to establish and maintain SLE databases to enhance awareness, early diagnosis, and more efficient management of the disease.
Full text link: https://tinyurl.com/4nve2afc

Article title: Association of baseline disease and patient characteristics with response to etoricoxib and indomethacin for acute gout
Authors: Sandra V. Navarra, Bernard R. Rubin, Qinfen Yu, Steven S. Smugar
Publication title: Current Medical Research and Opinion 23(7):1685-91, August 2007

Abstract:
Disease history and clinical features can influence treatment response in patients with acute gout. The purpose of this pooled subgroup analysis was to assess the association of baseline disease and patient characteristics with response to treatment in acute gout using data from two identical studies. Patients > or = 18 years of age with onset of acute gout within 48 h associated with moderate, severe, or extreme pain involving less than four joints were eligible for inclusion in the primary studies, and were randomized to etoricoxib 120 mg once daily (N = 178) or indomethacin 50 mg three times daily (N = 161). The primary and secondary efficacy endpoints were analyzed using an analysis of covariance model to detect potential differential treatment responses across several subgroups: joint involvement (mono-articular vs. oligo-articular), baseline pain severity (moderate vs. severe), concomitant allopurinol and/or colchicine use (users vs. nonusers), age (< 45, 45-55, and > 55 years), gender, and race (white or other). Overall, etoricoxib and indomethacin demonstrated comparable efficacy across all subgroups. Compared with patients with oligo-articular disease, those with mono-articular disease had significantly greater improvements in patient assessment of pain, patient global assessment of response to therapy (PGART), investigator global assessment of response to therapy (IGART), and study joint tenderness (p < 0.001 for all). Greater improvements were seen in patient assessment of pain (p < 0.001) and study joint tenderness (p < 0.05) for severe/extreme baseline pain compared with moderate baseline pain. Concomitant use of colchicine and/or allopurinol was associated with significantly worse IGART (p < 0.05). This pooled subgroup analysis demonstrated significantly greater response of acute gout to either etoricoxib or indomethacin among those with monoarticular disease, severe/extreme baseline pain, and non-use of colchicine and/or allopurinol. These results should be interpreted in the context of a pooled subgroup analysis with a limited sample size, and with the understanding that associations identified in such analyses do not define causation. Despite limitations, the results provide insights into the types of patients more likely to respond better to anti-inflammatory medication, and reiterate the importance of earlier effective control of the disease.
Full text available upon request to the author

Article title: A survey of psychosocial attributes of Filipino patients with systemic lupus erythematosus
Authors: Julie LI-YU and Sandra V Navarra
Publication title: APLAR Journal of Rheumatology 10(2):107-111, June 2007

Abstract:
Aim: To describe various domains of psychosocial attributes among Filipino patients with systemic lupus erythematosus (SLE). Methods: This is a cross-sectional survey of SLE patients seen at a tertiary centre in Manila, Philippines in 2005. All patients completed self-administered questionnaires: Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), and Optimism and Pessimism Scales. Spearman rank correlation coefficient was used to determine association between levels of depression and anxiety. Results: A total of 275 female SLE patients with mean age of 32.57 years ± 12.26 SD (range 19–68) completed the questionnaires. Various levels of depression, anxiety as well as optimism/pessimism were disclosed by patients. There was a significant association between degree of depression and anxiety, P = 0.000, but not with age at time of survey (P = 0.099) nor disease duration (P = 0.584). Areas of concern in the interpersonal domain included ‘irritability’, and ‘having none or lost interest in sex.’ In the socio-cultural domain, prevalent indicators of ‘indecisiveness’, ‘worthlessness’, and ‘self-criticism’ ranged from 42.7% to 47.7%. Descriptors of situational domain included guilt and punishment feelings, loss of energy, concentration difficulty, and tiredness/fatigue; notably 15.3% harboured suicidal thoughts. Conclusions: This survey among Filipino SLE patients further identified areas of concern in the various interpersonal, socio-cultural and situational domains which may significantly impact on patients’ and caregivers’ adjustment to the illness, and may thus influence the approach as well as overall response to management of these patients.
Full text available upon request to the author

Article title: Role of infectious agents in autoimmunity
Authors: Sandra V. Navarra
Publication title: Future Rheumatology 2(3):321-328, June 2007

Abstract:
The primary purpose of the immune system is to protect the body against a plethora of microorganisms, which are readily recognized as foreign under normal circumstances. However, the immune system must also be able to distinguish the protein fragments of these microorganisms from those of its own self-antigens through mechanisms of immune tolerance. In addition to genetic susceptibility crossing this precarious line between responses to foreign versus self antigens may lead to autoimmunity.
Full text available upon request to the author

Article title: Pulmonary arterial hypertension among Filipino patients with connective tissue diseases
Authors: Paul Santos Estrella, Sandra V. Navarra, Yih Chang Lin
Publication title: Modern Rheumatology 17(3):224-7, February 2007

Abstract:
We describe the clinical features, therapies, and clinical course of pulmonary arterial hypertension (PAH) in a group of Filipinos with connective tissue diseases (CTDs). We retrospectively reviewed the records of patients diagnosed with PAH by a two-dimensional echocardiogram as a tricuspid regurgitant jet of more than 25 mmHg. All patients had underlying CTDs, defined by the American College of Rheumatology criteria, and were seen at the rheumatology clinics of the University of Santo Tomas Hospital and the St. Luke's Medical Center, Philippines. Of the 33 patients (32 women) included in the analysis, there were 14 patients with systemic lupus erythematosus (SLE), 12 with scleroderma, 5 with mixed connective tissue disease (MCTD), 1 with primary antiphospholipid syndrome (APS), and 1 with dermatomyositis. The average age at PAH diagnosis was 38 +/- 14 years (mean +/- SD), and the mean duration of illness from CTD to PAH diagnosis was 53 +/- 52 months. Twelve patients had died at the time of this report, with a median duration of 15 months (range 1-57 months) from PAH diagnosis to mortality: six of these had scleroderma, five with SLE, and one with APS. The following therapies were used in this group of patients: low molecular weight heparin, warfarin, calcium-channel blockers, aspirin, cyclophosphamide, bosentan, iloprost, and sildenafil. We have described the clinical profile of PAH in a group of Filipino patients with CTDs, most commonly SLE. Various forms of pharmacologic therapies were used among these patients. Mortality remains high, particularly among those with underlying scleroderma. Early recognition and treatment are crucial in order to provide a better outcome for these patients.
Full text available upon request to the author

Article title: Clinical problem-solving: ‘persistent knee arthritis and prolonged fever in a lupus patient’
Authors: Emmanuel C. Perez and Sandra V. Navarra
Publication title: APLAR Journal of Rheumatology, November 2006

Abstract:
Salmonella infections occur more frequently among immunocompromised patients such as those with systemic lupus erythematosus (SLE), with high propensity for extra-intestinal, including osteoarticular, involvement. Hemarthrosis following trauma, typhoid fever and septic arthritis of the knee developed in a 20-year-old female lupus patient with pulmonary hypertension, maintained on corticosteroids and warfarin. This article takes the reader through the clinical problem-solving process with an SLE patient whose illness is confounded by prolonged fever, with manifestations indistinguishable from that of either lupus activity and/or an infection. Early diagnosis, appropriate antibiotics, and if necessary, surgical intervention are essential principles of management to improve prognosis and prevent long-term disabilities such as destructive arthropathy.
Full text link: https://tinyurl.com/98uff2ch

Article title: An overview of clinical manifestations and survival of systemic lupus erythematosus patients in Asia
Authors: Sandra V. Navarra and Jacqueline O. King
Publication title: APLAR Journal of Rheumatology, November 2006

Abstract:
Aim: To provide an overview of the clinical manifestations, survival and causes of mortality of systemic lupus erythematosus (SLE) patients in Asia.

Methods: Literature retrieval utilized the following sources: (i) computerized bibliographic database of the National Library of Medicine (MEDLINE 1986–2006) by PubMed; (ii) articles on SLE published in journals of national medical or rheumatology societies; and (iii) abstracts presented in national, regional and international rheumatology and SLE conferences. The available materials were cited to summarize and extrapolate data deemed most representative of each Asian country.

Results: The average age at SLE diagnosis ranged from 24–33 years, with a ratio ranging from 8–28 females to one male. Cutaneous and musculoskeletal manifestations were the most frequently observed, ranging from 45–98% and 36–85%, respectively. Renal involvement ranged from 6–100% (overall), or 26–74% (excluding presenting manifestations, and data obtained from a renal centre). Survival rates ranged from 65–98% at 5 years, and 50–84% at 10 years, with a trend for improved survival in more recent reports. Infection and active SLE disease were the predominant causes of mortality, with renal and central nervous system involvement as the main organs involved at time of death.

Summary: This overview substantiates the potential vastness of clinical material on SLE in Asia, and reinforces the need for concerted efforts to encourage more research designed to address special issues and develop a more efficient health care delivery system tailored to the Asian lupus patient.
Full text link: https://tinyurl.com/5he8a3e3

Article title: Clinical experience with infliximab among Filipino patients with rheumatic diseases
Authors: Sandra V. Navarra, Anne-Annette Raso, Juan Javier Lichauco, Perry P. Tan
Publication title: APLAR Journal of Rheumatology, July 2006

Abstract:
Aim: To describe the clinical experience with infliximab among Filipino patients with rheumatic diseases, specifically disease indications, dose regimens, clinical response, and adverse events.

Methods: We reviewed the data on Filipino patients who were given infliximab by rheumatologists for a rheumatic disease indication. The case report form included demographic profile, underlying rheumatic disease, comorbidities, concurrent medications, dose and frequency of infliximab, physicians’ assessment of clinical response, and adverse events. The frequency of doses, intervals between doses, and discontinuation status were recorded.

Results: Included were 64 patients (35 females), with a mean age of 44 years. Most (41%) had rheumatoid arthritis, followed by psoriasis/psoriatic arthritis (31.2%) and ankylosing spondylitis (17.2%). Average disease duration from diagnosis to initiation of infliximab therapy was 7.6 years ± 6.7 SD. Among 35 patients, the interval between maintenance infusions ranged from 6 to 13.6 weeks, with a mean of 8.27 weeks. Clinical response was good to excellent in more than 80% of patients. Discontinuation rate was 10.9% and 28.1% at 3 and 12 months, respectively. Infusion-related adverse events were mild and transient, and 14 (21.8%) cases of infection resolved with appropriate therapy. Infliximab was temporarily withheld in five (7.8%) patients with active tuberculosis.

Summary: These findings substantiate the superior clinical efficacy of infliximab and manageable adverse events among Filipinos with rheumatic diseases. It also demonstrates dose regimens in clinical practice in a third world setting with limited resources.
Full text link: https://tinyurl.com/pzxdwp8s

Article title: Philippine guidelines on the screening for tuberculosis prior to the use of biologic agents
Authors: Juan Javier T. Lichauco, Sandra A. Tankeh-Torres, Sandra V. Navarra, Leonila F. Dans
Publication title: APLAR Journal of Rheumatology, July 2006

Abstract:
Aim: To develop practice guidelines in tuberculosis screening of patients and their households and close contacts, prior to the use of biologic agents.

Method: A technical research committee formulated an evidence-based draft, based on existing literature regarding the tests used in tuberculosis screening among immunocompromised patients. The evidence-based draft was then circulated to an expert panel. An en banc meeting of the panelists was held and a consensus was declared if more than 50% agreed on a recommendation. Issues not resolved by consensus were discussed by correspondence and voted upon. The guidelines were presented in a public forum and feedback by stakeholders were reviewed and integrated into the final draft.

Recommendations: 1. Patients for biologic therapy should be screened for latent and active tuberculosis prior to initiating treatment. 2. All patients who are candidates for biologic agents should be screened by tuberculin skin test for latent TB, and a chest radiograph for active tuberculosis. 3. Household and close contacts of candidate patients should be screened for active tuberculosis. 4. All household and close contacts of candidate patients should be screened for active TB using chest radiograph. 5. Treat latent and active tuberculosis according to local guidelines. 6. Delay treatment with biologic agents in patients with latent or active tuberculosis. 7. Administer tuberculosis prophylaxis to the patient for biologic therapy exposed to household contacts with active tuberculosis.

Conclusion: These recommendations emphasize the importance of screening patients, household and close contacts for latent and active tuberculosis prior to initiating biologic therapy.
Full text link: https://tinyurl.com/dpx5unws

Article title: Immune therapy of lupus: What is on the horizon?
Authors: Sandra V. Navarra
Publication title: Nephrology Dialysis Transplantation 21(3):579-581, March 2006

Abstract:
No available
Full text link: https://tinyurl.com/p6mnmhz9

Article title: Risk factors for stroke among Filipino patients with systemic lupus erythematosus
Authors: Candice Marie C. Reyes and Sandra V. Navarra
Publication title: APLAR Journal of Rheumatology, May 2005

Abstract:
Aim: To describe the risk factors for stroke among Filipino patients with systemic lupus erythematosus (SLE).

Methods: This study retrospectively reviewed the medical records of Filipino patients with SLE seen at the Section of Rheumatology, Clinical Immunology and Osteoporosis of the University of Santo Tomas Hospital from 1998 to 2003. Assessment was made on the presence of known risk factors for stroke including age, hypertension, diabetes mellitus, dyslipidemia, personal or family history of coronary artery disease, family history of stroke, and SLE-related factors such as antiphospholipid syndrome (APS) and nephrotic syndrome.

Results: Of a total of 449 patients, 25 recorded 26 stroke events during the course of their SLE. Twenty-four female patients and one male had a mean age at stroke occurrence of 38.08 ± 15.45 SD years, with a mean duration from SLE diagnosis to stroke event of 62.48 ± 54.58 SD months. Infarction was implicated in 19 of 26 (73%) events, four (16%) had transient ischemic attack, two (8%) had intracerebral haemorrhage, and one had amaurosis fugax. Eighteen (72%) had systemic arterial hypertension, three (12%) had diabetes mellitus, and nine (36%) had dyslipidemia. A significant family or personal history was present in eight (32%), and there were no smokers. Twenty-one patients were on corticosteroid treatment with an average prednisone dose of 13.02 ± 10.95 SD mg/day. Nine (36%) were on immunosuppressive therapy prior to stroke, and two were on hydroxychloroquine. APS was diagnosed in three (12%), four (16%) each had nephrotic syndrome and extra-CNS vasculitis. Hypocomplementemia was present in six (24%).

Conclusion: Hypertension, dyslipidemia, and family or personal history were the predominant risk factors in this series, although SLE-related factors also possibly contributed to the occurrence of stroke, particularly in the younger patients.
Full text available upon request to the author

Article title: Normative bone mineral density values in Filipino women
Authors: Tito P. Torralba, Millicent Y. Tan-Ong, Sandra V. Navarra, Sarah H. Dy, et al.
Publication title: APLAR Journal of Rheumatology, April 2004

Abstract:
Objective: To obtain reference values of bone mineral density (BMD) for Filipino women in order to make a population-specific diagnosis of osteoporosis.

Method: Sudy design: Cross-sectional. Setting: Osteoporosis Unit, Joint and Bone Center, Section of Rheumatology and Clinical Immunology, Department of Medicine, University of Santo Tomas Hospital, Manila, Philippines. Participants: 442 healthy Filipino women volunteers recruited from the outpatient department, Rheumatology and Clinical Immunology Clinic of the University of Santo Tomas Hospital and from within the University of Santo Tomas campus. Subjects with known underlying illness or conditions or intake of drugs that predispose to osteoporosis were excluded from the study. Intervention: Bone mineral density (BMD) measurements, expressed in grams per square centimenter of the lumbar spine, non-dominant femur and non-dominant forearm were done in 442 consecutive healthy Filipino women using the LUNAR DPX-IQ machine.

Results: Means and standard deviations of BMD measurements at each site were calculated using Kwikstat software Version 3.6, Release 7. Results were grouped in decades to serve as reference per decade.

Conclusion: Bone mineral density measurements of these 442 healthy Filipino women may serve as an initial reference guide for the diagnosis of osteoporosis in Filipino women.
Full text available upon request to the author

Article title: Efficacy and Safety Profile of Treatment with Etoricoxib 120 mg Once Daily Compared with Indomethacin 50 mg Three Times Daily in Acute Gout: A Randomized Controlled Trial
Authors: Bernard R. Rubin, Robert Burton, Sandra Navarra, Joseph Antigua, et al.
Publication title: Arthritis & Rheumatology 50(2):598-606, March 2004

Abstract:
To evaluate the efficacy and safety of etoricoxib and indomethacin in the treatment of patients with acute gout. A randomized, double-blind, active-comparator study was conducted at 42 sites. A total of 189 men and women (> or =18 years of age) who were experiencing an acute attack (< or =48 hours) of clinically diagnosed gout were treated for 8 days with etoricoxib, 120 mg/day (n = 103), or indomethacin, 50 mg 3 times a day (n = 86). The primary efficacy end point was the patient's assessment of pain in the study joint (0-4-point Likert scale) over days 2-5. Safety was assessed by adverse experiences (AEs) occurring during the trial. Etoricoxib demonstrated clinical efficacy comparable to that of indomethacin in terms of the patient's assessment of pain in the study joint. The difference in the mean change from baseline over days 2-5 was -0.08 (95% confidence interval -0.29, 0.13) (P = 0.46), which fell within the prespecified comparability bounds of -0.5 to 0.5. Secondary end points over the 8-day study, including the onset of efficacy, reduction in signs of inflammation, and patient's and investigator's global assessments of response to therapy, confirmed the comparable efficacy of the two treatments. The etoricoxib-treated patients had a numerically lower incidence of AEs (43.7%) than did the indomethacin-treated patients (57.0%) and a significantly lower incidence of drug-related AEs (16.5% versus 37.2%; P < 0.05). Etoricoxib at a dosage of 120 mg once daily was confirmed to be an effective treatment for acute gout. Etoricoxib was comparable in efficacy to indomethacin at a dosage of 50 mg 3 times daily, and it was generally safe and well tolerated.
Full text link: https://tinyurl.com/25bmmnt6
Article title: Infectious agents in arthritis and autoimmunity
Authors: Sandra V. Navarra
Publication title: Modern Rheumatology 13(2):97-102, June 2003

Abstract:
The distinctions between infection, chronic arthritis, and autoimmune diseases have steadily blurred over the past decades. The proposed pathomechanisms underlying these interesting associations include putative pathways from infection to innate and adaptive immunity, molecular mimicry, and certain microbial and host factors. This article further reviews the spectrum of microbial agents implicated in some rheumatic diseases and cites the potential clinical application of this expanding field of knowledge in the prevention and treatment of chronic inflammatory and autoimmune diseases.
Full text available upon request to the author

Article title: Renal Microtophi in a Patient with Lupus Nephritis and Tophaceous Gout
Authors: Sandra V. Navarra, Sue Celle T. Saavedra, Antonio V. Cayco
Publication title: JCR Journal of Clinical Rheumatology 7(4):268-72, September 2001

Abstract:
This case describes a 58-year-old female with systemic lupus erythematosus (SLE) and coexistent chronic tophaceous gout. A renal biopsy showed concurrent lupus nephritis and renal medullary microtophi, confirmed by electron and polarizing microscopy, respectively. Whereas clinical SLE and gout have already been shown to be rarely associated, this case further illustrates the presentation of these two diseases in a single renal specimen. In this patient the gout began shortly after menopause without known risk factors and before any overt renal disease or signs of SLE. The tophaceous gout antedating the SLE, as well as the apparently benign course of illness, suggest that the pathologic effects of SLE and gout on the kidneys are based on independent mechanisms and may not necessarily aggravate each other. Treatment of the gout with allopurinol may have contributed to improved renal function.
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Article title: Popliteal Arterial Hemorrhage in a Chronic Renal Failure Patient with Destructive Arthropathy
Authors: Sandra V. Navarra, Lyndon J.Q. Llamado, Tito Torralba
Publication title: JCR Journal of Clinical Rheumatology 5(4):224-7, September 1999

Abstract:
Popliteal arterial hemorrhage is a rare but potentially devastating complication of markedly deformed joints. This report describes a 57-year-old Filipino man with chronic renal failure and destructive arthropathy caused by crystal deposition and /or a neuropathic joint, who presented with the complication of acute popliteal arterial hemorrhage. The case illustrates a rare combination of articular diseases underlying a completely altered joint structure and biomechanics, resulting in an acute popliteal arterial tear and hemorrhage.
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Article title: Successful Use of Diltiazem in Calcinosis Caused by Connective Tissue Disease
Authors: Tito Torralba, Julie Li-Yu, Sandra V. Navarra
Publication title: JCR Journal of Clinical Rheumatology 5(2):74-8, May 1999

Abstract:
The mechanism for calcinosis in connective tissue disease remains unclear. Various therapies such as warfarin, colchicine, steroids, and bisphosphonates have been tried. However, despite some benefit in early cases, improvement generally is not seen in advanced cases of calcinosis. Several recent studies strongly suggest a favorable response of calcinosis to diltiazem, a calcium channel antagonist. This report concerns two Filipino women, one with dermatomyositis, the other with undifferentiated connective tissue disease, who showed significant reduction of widespread calcinosis after treatment with diltiazem.
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Article title: Tuberculosis among Filipino patients with systemic lupus erythematosus
Authors: Sandra V. Navarra, Emmanuel Edwin R. Dy, Caroline G. Arroyo, Tito Torralba
Publication title: Seminars in Arthritis and Rheumatism 26(3):628-34, December 1996

Abstract:
A retrospective review of the clinical records of 54 patients with systemic lupus erythematosus (SLE) and documented tuberculosis (TB) infection seen at the University of Santo Tomas Hospital was accomplished. There were 53 women and one man, with a mean age of 32.2 +/- 10 years and a total of 57 TB occurrences. Pulmonary involvement was recorded in 42 (74%): upper lungfield in 25, mid to lower lungfield in 7, and miliary pattern or diffuse infiltrates in 10. TB arthritis was noted in 8, osteomyelitis in 4, and soft tissue abscesses in 4. Central nervous system involvement consisted of brain abscesses (tuberculomas) in two and meningitis in one. Two patients each had TB lymphadenitis, genitourinary TB, ileocecal TB, and TB peritonitis. Hepatobiliary and cutaneous TB occurred in one patient each. Eight of 10 patients with disseminated or miliary TB died primarily of respiratory failure; six of these eight patients also had some form of extrapulmonary involvement. Using the Wilcoxon rank-sum test, there were significant differences in the mean SLE Disease Activity Index (SLEDAI) and Severity of Disease Index (SDI) scores between those with limited TB (SLEDAI 24 +/- 7 SD; SDI 19 +/- 18 SD) versus those with extensive TB (SLEDAI 41 +/- 16 SD; SDI 36 +/- 21 SD), P < .05. There was no significant difference in the average daily prednisone dose (mg) between those with limited TB (25 +/- 17 SD) versus those with extensive TB (31 +/- 16 SD). The contributory role of tuberculous infection in the morbidity and mortality of patients with SLE must be emphasized, especially in areas endemic for TB.
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