Association of sustained lupus low disease activity state with improved outcomes in systemic lupus erythematosus: a multinational prospective cohort study.

BACKGROUND: Validation of protective associations of the lupus low disease activity state (LLDAS) against flare, irreversible damage, health-related quality of life, and mortality has enabled the adoption of treat-to-target strategies in patients with systemic lupus erythematosus (SLE). Previous validation studies were of short duration, limiting the ability to detect longer term signals in flare rate and irreversible damage. In addition, previous studies have focused on percent time at target, rather than actual periods of time that are more useful in clinical practice and trials. We assessed long-term protective associations of LLDAS and remission, and specifically examined protective thresholds of sustained LLDAS and remission. METHODS: Patients aged 18 years or older with SLE were followed up from May 1, 2013, to Dec 31, 2020 in a prospective, multinational, longitudinal cohort study. Patients were recruited from 25 centres in 12 countries. Multi-failure time-to-event analyses were used to assess the effect of sustained LLDAS on irreversible damage accrual (primary outcome; measured with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and flare (key secondary outcome; measured with the SELENA Flare Index), with dose exposure and threshold effects studied. Sustained LLDAS or remission were defined as two or more consecutive visits over at least 3 months in the respective state. This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: 3449 patients were followed up for a median of 2·8 years (IQR 1·1-5·6), totalling 37 662 visits. 3180 (92·2%) patients were women, and 3031 (87·9%) were of Asian ethnicity. 2506 (72·7%) patients had sustained LLDAS at least once. Any duration of sustained LLDAS or remission longer than 3 months was associated with reduced damage accrual (LLDAS: hazard ratio 0·60 [95% CI 0·51-0·71], p<0·0001; remission: 0·66 [0·57-0·76], p<0·0001) and flare (LLDAS: 0·56 [0·51-0·63], p<0·0001; remission: 0·66 [0·60-0·73], p<0·0001), and increasing durations of sustained LLDAS corresponded to increased protective associations. Sustained DORIS remission or steroid-free remission were less attainable than LLDAS. INTERPRETATION: We observed significant protective associations of LLDAS and remission against damage accrual and flare, establish a threshold of 3 months sustained LLDAS or remission as protective, and demonstrate deepening protection with longer durations of sustained LLDAS or remission. FUNDING: The Asia Pacific Lupus Collaboration receives project support grants from AstraZeneca, Bristol Myers Squibb, EMD Sereno, GSK, Janssen, Eli Lilly, and UCB.

Association of systemic lupus erythematosus standard of care immunosuppressants with glucocorticoid use and disease outcomes: a multicentre cohort study.

BACKGROUND: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.

Comparison of Attainment and Protective Effects of Lupus Low Disease Activity State In Patients With Newly Diagnosed Versus Established Systemic Lupus Erythematosus.

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

SMART-SLE: serology monitoring and repeat testing in systemic lupus erythematosus-an analysis of anti-double-stranded DNA monitoring.

OBJECTIVE: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive. METHODS: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare. RESULTS: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009). CONCLUSION: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.

Impact of low disease activity, remission, and complete remission on flares following tapering of corticosteroids and immunosuppressive therapy in patients with systemic lupus erythematous: a multinational cohort study.

BACKGROUND: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission. METHODS: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission. FINDINGS: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare. INTERPRETATION: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months. FUNDING: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB.

'Not at target': prevalence and consequences of inadequate disease control in systemic lupus erythematosus-a multinational observational cohort study.

BACKGROUND: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes. METHODS: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI). RESULTS: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients. CONCLUSION: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.

Patterns of Medication Use in Systemic Lupus Erythematosus: A Multicenter Cohort Study.

OBJECTIVE: Evidence for the utility of medications in settings lacking randomized trial data can come from studies of treatment persistence. The present study was undertaken to examine patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicenter longitudinal cohort. METHODS: Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (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 analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics 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 a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs 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.

Lupus low disease activity state and remission and risk of mortality in patients with systemic lupus erythematosus: a prospective, multinational, longitudinal cohort study.

BACKGROUND: Treat-to-target goals for patients with systemic lupus erythematosus (SLE) have been validated to protect against organ damage and to improve quality of life. We aimed to investigate the association between lupus low disease activity state (LLDAS) and remission and risk of mortality in patients with SLE. We hypothesised that LLDAS has a protective association with mortality risk. METHODS: In this prospective, multinational, longitudinal cohort study, we used data from patients with SLE in the Asia Pacific Lupus Collaboration cohort collected between May 1, 2013, and Dec 31, 2020. Eligible patients were adults (aged ≥18 years) who met either the 1997 American College of Rheumatology modified classification criteria for SLE or the 2012 Systemic Lupus International Collaborating Clinics classification criteria. The primary outcome was all-cause mortality, and LLDAS, remission, and variations of remission with lower glucocorticoid thresholds were the primary exposure variables. Survival analyses were used to examine longitudinal associations between these endpoints and risk of mortality. This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: Among a total of 4106 patients in the cohort, 3811 (92·8%) patients were included in the final analysis (median follow-up 2·8 years [IQR 1·0-5·3]; 3509 [92·1%] women and 302 [7·9%] men), of whom 80 died during the observation period (crude mortality rate 6·4 deaths per 1000 person-years). LLDAS was attained at least once in 43 (53·8%) of 80 participants who died and in 3035 (81·3%) of 3731 participants who were alive at the end of the study (p<0·0001); 22 (27·5%) participants who died versus 1966 (52·7%) who were alive at the end of the study attained LLDAS for at least 50% of observed time (p<0·0001). Remission was attained by 32 (40·0%) of 80 who died and in 2403 (64·4%) of 3731 participants who were alive at the end of the study (p<0·0001); 14 (17·5%) participants who died versus 1389 (37·2%) who were alive at the end of the study attained remission for at least 50% of observed time (p<0·0001). LLDAS for at least 50% of observed time (adjusted hazard ratio 0·51 [95% CI 0·31-0·85]; p=0·010) and remission for at least 50% of observed time (0·52 [0·29-0·93]; p=0·027) were associated with reduced risk of mortality. Modifying the remission glucocorticoid threshold (<5·0 mg/day prednisolone) was more protective against mortality than current remission definitions (0·31 [0·12-0·77]; p=0·012), and glucocorticoid-free remission was the most protective (0·13 [0·02-0·96]; p=0·046). INTERPRETATION: LLDAS significantly reduced the risk of mortality in patients with SLE. Remission did not further reduce the risk of mortality compared with LLDAS, unless lower glucocorticoid thresholds were used. FUNDING: The Asia-Pacific Lupus Collaboration received funding from Janssen, Bristol Myers Squibb, Eli Lilly, and UCB for this study.

Rheumatoid arthritis management in the APLAR region: Perspectives from an expert panel of rheumatologists, patients and community oriented program for control of rheumatic diseases.

Rheumatoid arthritis (RA) is a major health burden in Asia Pacific affecting the quality of life of patients and consuming healthcare resources. According to recent estimates from the World Health Organization-International League Against Rheumatism-Community Oriented Program for Control of Rheumatic Diseases, prevalence is around 0.3%-0.5%. Management guidelines have helped to improve treatment across this diverse region. To gain better insight into current real-world management applications in view of these guidelines, virtual meetings were conducted in mid-2020 to explore perspectives of rheumatologists and patients, as well as discuss the impact of coronavirus disease 2019 on RA management. Patients and rheumatologists from Hong Kong, Malaysia, Singapore, the Philippines, Thailand, India, Pakistan, and Taiwan were included, representing a diverse mix of healthcare systems, wealth, ethnicity and culture. Despite many countries having prospered in recent years, similar challenges in RA diagnosis and treatment were identified. The daily impact and patient experience of RA were also similar across countries, marked by "silent" pain and disability, and universal misunderstanding of the disease. Late diagnosis and treatment, and barriers to access to appropriate treatment, remain problematic. The experience shared by Taiwan offers a glimmer of hope, however, wherein patient advocacy groups have succeeded in being included in policy-making decisions and securing access to advanced treatment. Real-world solutions that pay heed to the unique local needs and diversity of Asia Pacific are required to improve RA management, which will take time. In the interim, help can be sought from the trained, non-rheumatologist community to reduce some of the disease burden.

Does hydroxychloroquine improve patient reported outcomes in patients with lupus?

BACKGROUND: Hydroxychloroquine (HCQ) use is associated with less disease activity, flares, damage and improved survival in Systemic Lupus Erythematosus (SLE). However, its effect on patient reported health outcomes (PROs) such as quality of life (QOL) is not known. METHODS: International data from Study on Outcomes of Lupus (SOUL) from 2,161 SLE patients were compared by HCQ use. Disease activity and damage were assessed using SELENA-SLEDAI and SLICC-ACR/SDI. QOL was evaluated using LupusPRO and Lupus Impact Tracker (LIT). Linear regression analyses were performed with LupusPRO summary scores health related HRQOL, non-health related NHRQOL and LIT as dependent and HCQ use as independent variable. Analyses were undertaken to test mediation of effects of HCQ use on QOL through disease activity. RESULTS: Mean age was 40.5 ± 12.8 years, 93% were women. Sixty-three (1363/2161) percent were on HCQ. On univariate analysis, HCQ use was associated with (a) better QOL (LupusPRO-HRQOL: ß 6.19, 95% CI 4.15, 8.24, P ≤ 0.001, LupusPRO NHRQOL: ß 5.83, 95% CI 4.02, 7.64, P ≤ 0.001) and less impact on daily life (LIT: ß -9.37, 95% CI -12.24, -6.50, P ≤ 0.001). On multivariate and mediational analyses, the effects of HCQ on QOL were indirectly and completely mediated through disease activity. CONCLUSIONS: HCQ use in SLE is associated with better patient reported health outcomes (LupusPRO-HRQOL and NHRQOL and impact on daily life), and the effects are mediated through disease activity. This information can facilitate patients and physician's communication with decision-making regarding the use of HCQ for SLE management.

Practice Advisory on the Appropriate Use of NSAIDs in Primary Care.

Cyclo-oxygenase (COX)-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are important in managing acute and chronic pain secondary to inflammation. As a greater understanding of the risks of gastrointestinal (GI), cardiovascular (CV) and renal events with NSAIDs use has emerged, guidelines have evolved to reflect differences in risks among NSAIDs. Updated guidelines have yet to reflect new evidence from recent trials which showed similar CV event rates with celecoxib compared to naproxen and ibuprofen, and significantly better GI tolerability for celecoxib. This practice advisory paper aims to present consensus statements and associated guidance regarding appropriate NSAID use based on a review of current evidence by a multidisciplinary group of expert clinicians. This paper is especially intended to guide primary care practitioners within Asia in the appropriate use of NSAIDs in primary care. Following a literature review, group members used a modified Delphi consensus process to determine agreement with selected recommendations. Agreement with a statement by 75% of total voting members was defined a priori as consensus. For low GI risk patients, any nonselective NSAID plus proton pump inhibitor (PPI) or celecoxib alone is acceptable treatment when CV risk is low; for high CV risk patients, low-dose celecoxib or naproxen plus PPI is appropriate. For high GI risk patients, celecoxib plus PPI is acceptable for low CV risk patients; low-dose celecoxib plus PPI is appropriate for high CV risk patients, with the alternative to avoid NSAIDs and consider opioids instead. Appropriate NSAID prescription assumes that the patient has normal renal function at commencement, with ongoing monitoring recommended. In conclusion, appropriate NSAID use requires consideration of all risks.

Associations Between Classification Criteria Items in Systemic Lupus Erythematosus.

OBJECTIVE: A project aimed at developing new classification criteria for systemic lupus erythematosus (SLE) is based on weighted criteria that include both laboratory and clinical items. Combinations of certain symptoms may occur commonly in SLE, which provides an argument against independently counting these items. The current study was undertaken to evaluate the interrelationship between candidate criteria items in the International Early SLE cohort and in the Euro-Lupus cohort. METHODS: The International Early SLE cohort included 389 patients, who were diagnosed within 3 years prior to the study. Data on the ACR's 1997 update of the SLE revised criteria, the Systemic Lupus International Collaborating Clinics 2012 criteria, and on 30 additional items were collected. To evaluate the interrelationship of the criteria, a tetrachoric correlation was used to assess the degree of association between different manifestations in the same organ system. The correlations identified in the International Early SLE cohort were validated in the Euro-Lupus cohort. RESULTS: A few relevant correlations were observed among specific clinical cutaneous manifestations (in particular, malar rash correlated with photosensitivity, alopecia, and oral ulcers) and serologic manifestations (anti-Sm and anti-double-stranded DNA and anti-RNA polymerase, anti-Ro and anti-La, and antiphospholipid antibodies), and these results were validated in the Euro-Lupus cohort. The associations within the mucocutaneous domain, hematologic and the specific autoantibodies suggest that within a single domain only the highest ranking item should be counted to avoid overrepresentation. CONCLUSION: Some of the candidate SLE criteria cluster within domains. Given these interrelationships, multiple criteria within a domain should not be independently counted. These results are important to consider for the structure of new SLE classification criteria.

Risk factors for herpes zoster infection among Filipinos with systemic lupus erythematosus.

AIM: To identify clinical risk factors associated with herpes zoster (HZ) infections in systemic lupus erythematosus (SLE). METHODS: A case-control study of HZ 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 HZ infection 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 6.1 years (±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 dose 18.62 mg/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 11.73 mg/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 occurrence. 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.

Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension.

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).

Lupus education for physicians and patients in a resource-limited setting.

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.

Drivers of Satisfaction With Care for Patients With Lupus.

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.

Serotonin syndrome masquerading as disease flare in lupus nephritis with end-stage renal disease.

INTRODUCTION: Serotonin syndrome is a potentially life-threatening condition characterized by the triad of mental status changes, autonomic instability, and neuromuscular changes. We report a case of serotonin syndrome masquerading as disease flare in a lupus nephritis patient with end-stage renal disease receiving linezolid for the treatment of infected pseudoaneurysm. CASE REPORT: A 36-year-old female lupus nephritis patient on maintenance hemodialysis for end-stage renal disease had been on multiple antibiotics, including anti-tuberculosis medications, over the past month for infected pseudoaneurysm complicating her arteriovenous fistula. Due to minimal response, she underwent pseudoaneurysmal ligation and given linezolid. Two days later, she developed chest pain, tachycardia, hypertension, tremors, later accompanied by high-grade fever, diarrhea, insomnia, and body weakness. Although fully awake and oriented, she was markedly agitated, mildly icteric, had hyperreflexia and asthenia with proximal muscle strength graded 3/5 in all extremities. Blood counts revealed anemia and thrombocytopenia; ancillary tests showed aspartate aminotransferase markedly higher than alanine aminotransferase, elevated serum lactate dehydrogenase and creatine kinase, and low C3 levels. Intravenous hydrocortisone was started for a suspected lupus flare. On the background of linezolid, isoniazid, and tramadol administration, serotonin syndrome with rhabdomyolysis was strongly considered. Offending drugs were discontinued, resulting in the dramatic improvement of symptoms and improved strength and well-being. The steroid was successfully tapered to 5 mg/day and a week later, she remained afebrile without recurrence of symptoms. CONCLUSION: Serotonin syndrome should be considered in patients on multiple serotonergic agents on the background of end-stage renal disease. Prompt recognition and distinction from lupus activity can significantly impact management decisions.

Sex Differences in Quality of Life in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) predominantly affects women. Clinical phenotype and outcomes in SLE may vary by sex and are further complicated by unique concerns that are dependent upon sex-defined roles. We aimed to describe sex differences in disease-specific quality of life (QoL) assessment scores using the Lupus Patient-Reported Outcome (LupusPRO) tool in a large international study. METHODS: Cross-sectional data from 1,803 patients with SLE on demographics, self-identified sex status, LupusPRO, and disease activity were analyzed. The LupusPRO tool has 2 constructs: health-related QoL (HRQoL) and non-HRQoL. Disease activity and damage were evaluated using the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, respectively. Nonparametric tests were used to compare QoL and disease activity by sex. RESULTS: A total of 122 men and 1,681 women with SLE participated. The mean age was similar by sex, but the damage scores were greater among men. Men fared worse on the non-HRQoL social support domain than women (P = 0.02). When comparing disease and QoL among men and women ages ≤45 years, men were found to have greater damage and worse social support than women. However, women fared significantly worse on lupus symptoms, cognition, and procreation domains with trends for worse functioning on physical health and pain-vitality domains. CONCLUSION: In the largest study of a diverse group of SLE patients, utilizing a disease-specific QoL tool, sex differences in QoL were observed on both HRQoL and non-HRQoL constructs. Although men performed worse in the social support domain, women (especially those in the reproductive age group) fared worse in other domains. These observations may assist physicians in appropriately addressing QoL issues in a sex-focused manner.

A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis.

Calcineurin inhibitors added to standard-of-care induction therapy for lupus nephritis (LN) may increase complete renal remission (CRR) rates. The AURA-LV study tested the novel calcineurin inhibitor voclosporin for efficacy and safety in active LN. AURA-LV was a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial of two doses of voclosporin (23.7 mg or 39.5 mg, each twice daily) versus placebo in combination with mycophenolate mofetil (2 g/d) and rapidly tapered low-dose oral corticosteroids for induction of remission in LN. The primary endpoint was CRR at 24 weeks; the secondary endpoint was CRR at 48 weeks. Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. CRR at week 24 was achieved by 29 (32.6%) subjects in the low-dose voclosporin group, 24 (27.3%) subjects in the high-dose voclosporin group, and 17 (19.3%) subjects in the placebo group (OR=2.03 for low-dose voclosporin versus placebo). The significantly greater CRR rate in the low-dose voclosporin group persisted at 48 weeks, and CRRs were also significantly more common in the high-dose voclosporin group compared to placebo at 48 weeks. There were more serious adverse events in both voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively). These results suggest that the addition of low-dose voclosporin to mycophenolate mofetil and corticosteroids for induction therapy of active LN results in a superior renal response compared to mycophenolate mofetil and corticosteroids alone, but higher rates of adverse events including death were observed.

Development of the Asia Pacific Lupus Collaboration cohort.

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.