Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

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.

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).

Patient experiences of muscle biopsy in idiopathic inflammatory myopathies: a cross-sectional survey.

INTRODUCTION: Muscle biopsy plays an important role in the diagnostic evaluation of individuals with suspected idiopathic inflammatory myopathies (IIM). However, variability in biopsy practices may result in a heterogenous patient experience. The existing literature offers limited insights into the experiences and perspectives of patients undergoing muscle biopsy. METHODS: This study employed a 27-item online survey to comprehensively characterise the experience of muscle biopsy among Australian patients, including their concerns, beliefs about procedure utility, information sources, physical sensations, perceived complications and recovery. RESULTS: A total of 111 Australian individuals who reported a diagnosis of IIM completed the survey, with data collected from March to June 2023. Most participants had inclusion body myositis (76/111, 68.5%) and had undergone one biopsy procedure (87/111, 78.4%) as part of their IIM work-up. Nine of the 111 respondents did not undergo a muscle biopsy. The procedure was well-tolerated by many respondents, however, a notable number of respondents experienced post-procedural pain lasting > 72 h (27/102, 26.5%), increasing weakness post-biopsy (13.7%), numbness at the biopsy site (18/102, 17.6%) and a recovery time beyond 3 days (36/102, 35.3%). A substantial minority (30/111, 27%) felt they were inadequately informed about the risks and benefits of the procedure. CONCLUSIONS: This survey highlights that although muscle biopsy is often well-tolerated, there are considerable patient concerns that are often inadequately addressed. Our findings underscore the need for improved patient-doctor communication and support throughout the biopsy process.

Impact of remission and low disease activity on health-related quality of life in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate the impact of remission and lupus low disease activity state (LLDAS) on health-related quality of life (HRQoL) in systemic lupus erythematosus. METHODS: Short-Form 36 (SF-36), three-level EQ-5D (EQ-5D-3L) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials were used. Duration in remission/LLDAS required to reach a HRQoL benefit ≥ minimal clinically important differences (MCIDs) during and post-treatment was determined using quantile regression and generalized estimating equations. RESULTS: Patients (n = 1684) were assessed every fourth week (15 visits). Four cumulative (ß = 0.60) or four consecutive (ß = 0.66) visits in remission were required to achieve a benefit ≥MCID in SF-36 physical component summary (PCS) scores, and six cumulative (ß = 0.44) or five consecutive (ß = 0.49) for a benefit ≥MCID in mental component summary (MCS) scores. Eight cumulative (ß = 0.30 for both) or eight consecutive (ß = 0.32 for both) visits in LLDAS were required for a benefit in PCS/MCS ≥MCID, respectively. For EQ-5D-3L index scores ≥MCID, six cumulative (ß = 0.007) or five consecutive (ß = 0.008) visits in remission were required, and eight cumulative (ß = 0.005) or six consecutive (ß = 0.006) visits in LLDAS. For FACIT-Fatigue scores ≥MCID, 12 cumulative (ß = 0.34) or 10 consecutive (ß = 0.39) visits in remission were required, and 17 cumulative (ß = 0.24) or 16 consecutive (ß = 0.25) visits in LLDAS. CONCLUSION: Remission and LLDAS contribute to a HRQoL benefit in a time-dependent manner. Shorter time in remission than in LLDAS was required for a clinically important benefit in HRQoL, and longer time in remission for a benefit in mental compared with physical HRQoL aspects. When remission/LLDAS was sustained, the same benefit was achieved in a shorter time.

Laboratory investigation results influence Physician's Global Assessment (PGA) of disease activity in SLE.

OBJECTIVE: To evaluate the impact of laboratory results on scoring of the Physician Global Assessment (PGA) of disease activity in systemic lupus erythematosus. METHODS: Fifty clinical vignettes were presented via an online survey to a group of international lupus experts. For each case, respondents scored the PGA pre and post knowledge of laboratory test results (pre-lab and post-lab PGAs). Agreement between individual assessors and relationships between pre-lab and post-lab PGAs, and PGAs and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) were determined. Respondents were also asked about factors they incorporate into their PGA determinations. RESULTS: Sixty surveys were completed. The inter-rater PGA reliability was excellent (pre-lab intraclass correlation coefficient (ICC) 0.98; post-lab ICC 0.99). Post-lab PGAs were higher than pre-lab PGAs: median (IQR) pre-lab PGA 0.5 (1.05), post-lab PGA 1 (1.3) (p<0.001), with a median (IQR) difference of 0.2 (0.45). In general, all abnormal labs including elevated anti-double stranded DNA antibody level (dsDNA) and low complement impacted PGA assessment. Cases with weakest correlations between pre-lab and post-lab PGA were characterised by laboratory results revealing nephritis and/or haematological manifestations. Both pre-lab and post-lab PGAs correlated with SLEDAI-2K. However, a significantly stronger correlation was observed between post-lab PGA and SLEDAI-2K. Multiple factors influenced PGA determinations. Some factors were considered by an overwhelming majority of lupus experts, with less agreement on others. CONCLUSIONS: We found excellent inter-rater reliability for PGAs in a group of international lupus experts. Post-lab PGA scores were higher than pre-lab PGA scores, with a significantly stronger correlation with the SLEDAI-2K. Our findings indicate that PGA scoring should be performed with knowledge of pertinent laboratory results.

Lupus Low Disease Activity State (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus.

OBJECTIVE: We evaluated the discriminant capacity of the Lupus Low Disease Activity State (LLDAS) in post-hoc analysis of data from the BLISS-52 and BLISS-76 trials of belimumab in systemic lupus erythematosus (SLE). METHODS: LLDAS attainment, discrimination between belimumab and placebo arms, and the effects in subgroups with high disease activity at recruitment were evaluated at week 52 using appropriate descriptive statistics, χ2 test and logistic regression. RESULTS: At week 52, for belimumab 10 mg/kg, 17.0% and 19.3% of patients who achieved a Systemic Lupus Erythematosus Responder Index-4 also attained LLDAS in BLISS-52 and BLISS-76, respectively. Significantly more patients attained LLDAS on belimumab 10 mg/kg compared with placebo (12.5% vs 5.8%, OR 2.32, p=0.02 for BLISS-52; 14.4% vs 7.8%, OR 1.98, p=0.04 for BLISS-76). In a subgroup analysis, the difference in week 52 LLDAS attainment between belimumab 10 mg/kg and placebo was greater in patients who had higher disease activity at baseline, compared with the overall group. CONCLUSIONS: LLDAS was able to discriminate belimumab 10 mg/kg from placebo in the BLISS-52 and BLISS-76 trials. Our findings support the validity of LLDAS as an outcome measure in SLE clinical trials.

Rituximab treatment in primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (PACNS) is a rare autoimmune vasculitis affecting the brain and spinal cord. Treatment with biological agents has revolutionised the treatment of many rheumatic conditions but there is scant literature regarding the use of biological agents in PACNS. We present three cases of PACNS treated with rituximab, including two cases of relapsed disease, and a literature review suggesting a role for rituximab in this condition.

Efficacy and safety of treat-to-target strategy studies in rheumatic diseases: A systematic review and meta-analysis.

BACKGROUND: The concept of treat-to-target (T2T), a treatment strategy in which treatment is directed to reach and maintain a defined goal such as remission or low disease activity (LDA), has been explored for several diseases including rheumatic diseases such as rheumatoid arthritis (RA). However, a comprehensive review of T2T in all rheumatic diseases has not recently been undertaken. OBJECTIVE: To perform a systematic review and meta-analysis of the efficacy and safety of a T2T strategy in the management of adult patients with inflammatory rheumatic diseases. METHODS: PUBMED, EMBASE and CINAHL were searched from January 1990 to December 2023 using key words related to a T2T strategy and rheumatic diseases; T2T strategy clinical trials or observational studies were included. Clinical, physical function and radiologic outcomes, cost-effectiveness, and adverse events (AEs) of the T2T strategies were investigated and a random-effect meta-analysis was conducted for the most commonly used outcomes in RA studies. RESULTS: The search identified 7896 studies, of which 66 fit inclusion criteria, including 50 in RA, 3 in psoriatic arthritis (PsA), 1 in spondyloarthritis (SpA) and 12 in gout. For the studies comparing a T2T strategy with usual care (UC) in RA, 83.3% (20/24) showed a T2T strategy could achieve significantly better clinical outcomes, and the meta-analysis showed that patients treated with a T2T strategy were more likely to be in remission (pooled RR: 1.68 (1.47-1.92), p<0.001] and achieve DAS-28 response (pooled standardised mean difference (SMD): 0.47 (0.26-0.69), P<0.001] at 1 year than patients treated with UC. Sensitivity analyses showed that a T2T strategy with a predefined treatment protocol had better clinical efficacy than that without protocol. In terms of improving physical function and health-related quality of life (HRQoL), 11/19 (57.9%) studies found a T2T strategy was significantly more likely to achieve these than UC, with the meta-analysis for the mean change of HAQ score supporting this conclusion (pooled SMD: 1.48 (0.46-2.51), p=0.004). Five out of 9 studies (55.6%) demonstrated greater benefit regarding radiographic progression from a T2T strategy. In terms of cost-effectiveness and AEs, 2/2 studies found a T2T strategy was more cost-effective than UC and 8/8 studies showed no tendency for AEs to occur more often with a T2T strategy. For the studies in PsA and SpA, a T2T strategy was also demonstrated to be more effective than UC in clinical and functional benefits, but not in radiologic outcomes. All gout studies showed that sUA level could be controlled more effectively with a T2T strategy, and 2 studies revealed that the T2T strategy could inhibit erosion development or crystal deposition. CONCLUSIONS: For patients with active RA, a T2T strategy has been shown in mulitple studies to increase the likelihood of achieving clinical response and improving HRQoL without increasing economic costs and AEs. Limited studies have shown clinical and functional benefits from T2T strategies in active PsA and SpA. A T2T strategy has also been found to improve clinical and radiologic outcomes in gout. T2T trials in other rheumatic diseases are lacking.

Real-world implications of IMACS malignancy screening guidelines for idiopathic inflammatory myopathies: An evaluation of compliance and economic impact at a tertiary referral center.

AIM: An inaugural set of consensus guidelines for malignancy screening in idiopathic inflammatory myopathy (IIM) were recently published by an international working group. These guidelines propose different investigation strategies based on "high", "intermediate" or "standard" malignancy risk groups. This study compares current malignancy screening practices at an Australian tertiary referral center with the recommendations outlined in these guidelines. METHODS: We conducted a retrospective analysis of newly diagnosed IIM patients. Relevant demographic and clinical data regarding malignancy screening were recorded. Existing practice was compared with the guidelines using descriptive statistics; costs were calculated using the Australian Medicare Benefit Schedule. RESULTS: Of the 47 patients identified (66% female, median age: 63 years [IQR: 55.5-70], median disease duration: 4 years [IQR: 3-6]), only one had a screening-detected malignancy. Twenty patients (43%) were at high risk, while 20 (43%) were at intermediate risk; the remaining seven (15%) had IBM, for which the proposed guidelines do not recommend screening. Only three (6%) patients underwent screening fully compatible with International Myositis Assessment and Clinical Studies recommendations. The majority (N = 39, 83%) were under-screened; the remaining five (11%) overscreened patients had IBM. The main reason for guideline non-compliance was the lack of repeated annual screening in the 3 years post-diagnosis for high-risk individuals (0% compliance). The mean cost of screening was substantially lower than those projected by following the guidelines ($481.52 [SD 423.53] vs $1341 [SD 935.67] per patient), with the highest disparity observed in high-risk female patients ($2314.29/patient). CONCLUSION: Implementation of the proposed guidelines will significantly impact clinical practice and result in a potentially substantial additional economic burden.

Role of intravenous immunoglobulins in systemic sclerosis (SSc): A systematic literature review.

BACKGROUND: Systemic sclerosis (SSc) is a heterogenous, multi-system autoimmune disease that causes progressive fibrosis of the skin and internal organs, resulting in high morbidity and mortality. Intravenous Immunoglobulin (IVIG) is a therapeutic option for SSc; however, reports of its efficacy have been variable, and its use across multiple organ manifestations of SSc has not been comprehensively reviewed. AIM: The aim of this study was to systematically assess the existing literature on the role of IVIG use across a range of SSc manifestations. METHODS: Medline, Embase, Cochrane, Web of Science and Scopus were searched from 01/01/2003-15/04/2024 using terms related to SSc and IVIG. Included studies were English-language full texts, where ≥5 adults with SSc received IVIG, and where a reportable outcome was documented. RESULTS: Of 418 potentially relevant records, 12 were included in this review, comprising 266 patients across one randomised control trial, two pilot studies, one open label study, seven retrospective studies and one case control study. Eighteen outcomes were documented across five different organ systems: cutaneous, respiratory, musculoskeletal, gastrointestinal, and other (clinical improvement and corticosteroid sparing benefit). Results showed a favourable effect of IVIG in reducing the extent of skin thickening, muscle and joint pain, gastrointestinal symptoms, steroid dosing and improving patient/physician reported quality of life. Whilst IVIG may appear to be less beneficial for respiratory disease, the stabilisation in pulmonary function tests and radiological features may be considered a positive outcome in itself. Limitations included a lack of high-quality studies, and the use of concomitant therapies in many studies, rendering the efficacy of IVIG alone difficult to ascertain. CONCLUSION: IVIG showed benefit in treating some manifestations of SSc, however there was a lack of convincing evidence for the efficacy in others. The lack of high-quality data highlights the need for further well-designed clinical trials to confirm these findings and inform guidelines for IVIG use.

Muscle biopsy practices in the evaluation of idiopathic inflammatory myopathies: An international survey of expert clinicians.

BACKGROUND: Muscle biopsy is an important test in the evaluation of individuals with suspected myopathy, including those with suspected idiopathic inflammatory myopathy (IIM). Various approaches, including open surgical biopsy, needle biopsy and conchotome forceps, have been reported. However the real-world utilisation of these approaches remains unclear. There are no established guidelines for the use of muscle biopsy, or selection of biopsy technique, in investigating IIM and international practices are not well-documented. This study describes current approaches to muscle biopsy amongst clinicians with expertise in IIM. METHODS: A survey regarding muscle biopsy practices was disseminated among members of the International Myositis Assessment and Clinical Studies (IMACS) group. Data were analysed using descriptive statistics. RESULTS: One-hundred and sixteen clinicians completed the survey, primarily rheumatologists. Open surgical biopsy was the most commonly employed technique (74.5 %), followed by needle (11.3 %) and conchotome (9.4 %) approaches. Clinical examination was the most common method of muscle selection, with 85.2 % of respondents reporting they 'always or almost always' relied on it. MRI and electromyography were also frequently utilised for muscle selection (51.9 %, 45.4 % respectively). There was variability in the perceived utility of muscle biopsy in certain clinical contexts, such as presence of myositis specific antibodies or cutaneous manifestations of dermatomyositis. While respondents generally reported low complication rates following muscle biopsy, non-diagnostic histopathology was commonly reported, regardless of procedural approach. CONCLUSION: Clinicians managing IIM report muscle biopsy to be well tolerated however, non-diagnostic results are common. Substantial heterogeneity regarding perceived indications for biopsy, procedural approaches, and muscle selection strategies were observed within this expert group. Future research is needed to establish best practice and determine the role of muscle biopsy in the context of continued advancements in serological profiling of IIM.

Diagnosing and characterizing inflammatory myopathies at an Australian tertiary public hospital: Resource utilization and direct healthcare costs.

AIM: To determine the direct health service costs and resource utilization associated with diagnosing and characterizing idiopathic inflammatory myopathies (IIMs), and to assess for limitations and diagnostic delay in current practice. METHODS: A retrospective, single-center cohort analysis of all patients diagnosed with IIMs between January 2012 and December 2021 in a large tertiary public hospital was conducted. Demographics, resource utilization and costs associated with diagnosing IIM and characterizing disease manifestations were identified using the hospital's electronic medical record and Health Intelligence Unit, and the Medicare Benefits Schedule. RESULTS: Thirty-eight IIM patients were identified. IIM subtypes included dermatomyositis (34.2%), inclusion body myositis (18.4%), immune-mediated necrotizing myopathy (18.4%), polymyositis (15.8%), and anti-synthetase syndrome (13.2%). The median time from symptom onset to diagnosis was 212 days (IQR: 118-722), while the median time from hospital presentation to diagnosis was 30 days (8-120). Seventy-six percent of patients required emergent hospitalization during their diagnosis, with a median length of stay of 8 days (4-15). The average total cost of diagnosing IIM was $15 618 AUD (STD: 11331) per patient. Fifty percent of patients underwent both MRI and EMG to identify affected muscles, 10% underwent both pan-CT and PET-CT for malignancy detection, and 5% underwent both open surgical and percutaneous muscle biopsies. Autoimmune serology was unnecessarily repeated in 37% of patients. CONCLUSION: The diagnosis of IIMs requires substantial and costly resource use; however, our study has identified potential limitations in current practice and highlighted the need for streamlined diagnostic algorithms to improve patient outcomes and reduce healthcare-related economic burden.

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.

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.