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OBJECTIVES: To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT). METHODS: Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking. RESULTS: In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks. CONCLUSIONS: Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice. TRIAL REGISTRATION NUMBER: EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815.
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OBJECTIVE: To evaluate the long-term sustainability of response to the Janus kinase inhibitor upadacitinib among patients with rheumatoid arthritis and an inadequate response or intolerance to biological disease-modifying antirheumatic drugs (bDMARD-IR) in the SELECT-BEYOND phase 3 trial. METHODS: Patients on background conventional synthetic DMARDs (csDMARDs) were treated once daily with upadacitinib 15 mg or placebo. Patients who completed the week 24 visit could enter a long-term extension of up to 5 years. The sustainability of response was assessed based on achievement of Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and Disease Activity Score 28-joint count using C-reactive protein (DAS28 (CRP)) targets and evaluated up to week 260 in all patients receiving the approved upadacitinib 15 mg dose, including those randomised to upadacitinib 15 mg and those who switched from placebo to upadacitinib 15 mg at week 12. RESULTS: In this bDMARD-IR population, 45% (n=104/229) and 79% (n=172/219) of patients treated with upadacitinib 15 mg plus background csDMARD(s) achieved CDAI remission or CDAI low disease activity (LDA) at any point during the 5-year study, respectively. Of those who achieved CDAI remission/LDA, 25%/43% maintained their initial response through 240 weeks of follow-up after first achieving response. Most patients who lost remission or LDA were able to recapture that response by the cut-off date. Similar overall results were observed for SDAI and DAS28 (CRP). No strong predictors of response were identified. CONCLUSIONS: Over three-quarters of bDMARD-IR patients achieved CDAI LDA with upadacitinib, and almost half of those maintained LDA through 240 weeks of follow-up. Remission was achieved by nearly half of all patients and maintained in approximately a quarter of those achieving remission. TRIAL REGISTRATION NUMBER: NCT02706847.
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Antirreumáticos , Artrite Reumatoide , Compostos Heterocíclicos com 3 Anéis , Humanos , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Masculino , Feminino , Antirreumáticos/uso terapêutico , Antirreumáticos/administração & dosagem , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto , Idoso , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/administração & dosagem , Índice de Gravidade de Doença , Método Duplo-CegoRESUMO
OBJECTIVES: To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up. METHODS: Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0-100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences. RESULTS: We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5-5.1)-8.0 (7.2-8.8) at 6 months, and in BASFI from 2.2 (1.4-3.1)-4.6 (3.6-5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis. CONCLUSION: In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.
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OBJECTIVES: This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort. METHODS: Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions. RESULTS: 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states. CONCLUSIONS: Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.
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BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.
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Autoanticorpos , Cinesinas , Lúpus Eritematoso Sistêmico , Feminino , Humanos , Masculino , Biomarcadores , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnósticoRESUMO
OBJECTIVE: This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA). METHODS: This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI ≥30 kg/m2. All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI. RESULTS: Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms. CONCLUSION: In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received. TRIAL REGISTRATION NUMBER: NCT01491815.
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Artrite Reumatoide , Metotrexato , Humanos , Metotrexato/uso terapêutico , Resultado do Tratamento , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Fatores de Risco , Obesidade/complicações , Obesidade/epidemiologia , Proteína C-ReativaRESUMO
OBJECTIVES: The reported prevalence of coeliac disease (CD) in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) varies in previous studies. We aimed to examine the prevalence of CD in patients with RA and JIA. METHODS: We searched Medline, Embase, Cochrane and Web of Science Core Collection between 1 January 1990 and 31 October 2022. In our primary analysis, the prevalence of biopsy-confirmed CD in RA and JIA patients was investigated. In secondary analyses, the prevalence of serological markers for CD was examined. Pooled weighted prevalences of CD and serological markers with 95% confidence intervals (95%CI) were calculated and quality of included studies was assessed. Meta-regression analysis was performed on publication year, sample size, CD prevalence in the general population, proportion of females, and quality assessment score. RESULTS: In this systematic review, 14 publications were deemed relevant for RA and 22 for JIA, with nine and 18 included in the primary analyses of CD prevalence, respectively. Among a total of 754 RA patients and 2077 patients with JIA, the weighted pooled prevalence estimates of biopsy-confirmed CD were 0.4% (95%CI=0.0-1.2) and 1.4% (95%CI=0.7-2.2), respectively. The pooled prevalence estimates of positive CD serology were 0.9% (95%CI=0.3-1.9) in RA and 5.4% (95%CI=2.5-9.2) in JIA. CONCLUSIONS: In this meta-analysis, we found a pooled prevalence of biopsy-confirmed CD in patients with RA and JIA comparable to that in the general population. Routine screening for CD is not warranted in RA but could be considered in JIA patients with additional risk factors for CD.
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Artrite Juvenil , Artrite Reumatoide , Doença Celíaca , Feminino , Humanos , Artrite Juvenil/diagnóstico , Artrite Juvenil/epidemiologia , Prevalência , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/epidemiologia , BiópsiaRESUMO
OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.
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Azatioprina , Lúpus Eritematoso Sistêmico , Humanos , Azatioprina/uso terapêutico , Tacrolimo/uso terapêutico , Rituximab/uso terapêutico , Metotrexato/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Imunossupressores/uso terapêutico , Ciclofosfamida/uso terapêutico , Hidroxicloroquina/uso terapêutico , Glucocorticoides/uso terapêutico , Inibidores Enzimáticos/uso terapêuticoRESUMO
The Advances in Targeted Therapies meets annually, convening experts in the field of rheumatology to both provide scientific updates and identify existing scientific gaps within the field. To review the major unmet scientific needs in rheumatology. The 23rd annual Advances in Targeted Therapies meeting convened with more than 100 international basic scientists and clinical researchers in rheumatology, immunology, infectious diseases, epidemiology, molecular biology and other specialties relating to all aspects of immune-mediated inflammatory diseases. We held breakout sessions in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpa), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and osteoarthritis (OA). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research. An overarching theme across all disease states is the continued need for clinical trial design innovation with regard to therapeutics, endpoint and disease endotypes. Within RA, unmet needs comprise molecular classification of disease pathogenesis and activity, pre-/early RA strategies, more refined pain profiling and innovative trials designs to deliver on precision medicine. Continued scientific questions within PsA include evaluating the genetic, immunophenotypic, clinical signatures that predict development of PsA in patients with psoriasis, and the evaluation of combination therapies for difficult-to-treat disease. For axSpA, there continues to be the need to understand the role of interleukin-23 (IL-23) in pathogenesis and the genetic relationship of the IL-23-receptor polymorphism with other related systemic inflammatory diseases (eg, inflammatory bowel disease). A major unmet need in the OA field remains the need to develop the ability to reliably phenotype and stratify patients for inclusion in clinical trials. SLE experts identified a number of unmet needs within clinical trial design including the need for allowing endpoints that reflect pharmacodynamic/functional outcomes (eg, inhibition of type I interferon pathway activation; changes in urine biomarkers). Lastly, within SSc and vasculitis, there is a lack of biomarkers that predict response or disease progression, and that allow patients to be stratified for therapies. There remains a strong need to innovate clinical trial design, to identify systemic and tissue-level biomarkers that predict progression or response to therapy, endotype disease, and to continue developing therapies and therapeutic strategies for those with treatment-refractory disease. This document, based on expert consensus, should provide a roadmap for prioritising scientific endeavour in the field of rheumatology.
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Artrite Psoriásica , Artrite Reumatoide , Espondiloartrite Axial , Lúpus Eritematoso Sistêmico , Osteoartrite , Reumatologia , Vasculite , Humanos , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Lúpus Eritematoso Sistêmico/terapia , Biomarcadores , Interleucina-23RESUMO
OBJECTIVES: This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE). METHODS: Adult patients with active SLE (n=249) were recruited from 29 hospitals in China and randomised 1:1:1:1 to receive subcutaneous telitacicept at 80 mg (n=62), 160 mg (n=63), 240 mg (n=62) or placebo (n=62) once weekly in addition to standard therapy. The primary endpoint was the proportion of patients achieving an SLE Responder Index 4 (SRI-4) response at week 48. Missing data were imputed using the last observation carried forward method. RESULTS: At week 48, the proportion of patients achieving an SRI-4 response was 75.8% in the 240 mg telitacicept group, 68.3% in the 160 mg group, 71.0% in the 80 mg group and 33.9% in the placebo group (all p<0.001). Significant treatment responses were observed in secondary endpoints, including a ≥4-point reduction on the Systemic Lupus Erythematosus Disease Activity Index, a lack of Physician's Global Assessment score worsening and a glucocorticoid dose reduction in the 240 mg group. Telitacicept was well tolerated, and the incidence of adverse events and serious adverse events was similar between the telitacicept and placebo groups. CONCLUSIONS: This phase 2b clinical trial met the primary endpoint. All telitacicept groups showed a significantly higher proportion of patients achieving an SRI-4 response than the placebo group at week 48, and all doses were well tolerated. These results support further investigations of telitacicept in clinical trials involving more diverse populations and larger sample sizes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02885610).
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Lúpus Eritematoso Sistêmico , Proteínas Recombinantes de Fusão , Adulto , Humanos , Método Duplo-Cego , Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Remission is the established therapeutic goal for patients with systemic lupus erythematosus (SLE) and is currently defined by the widely adopted Definition Of Remission In SLE (DORIS) criteria. Attainment of remission is rare in the clinical setting, thus an alternative, pragmatic treatment target of low disease activity, as defined by the Lupus Low Disease Activity State (LLDAS), provides a less stringent and more attainable treatment goal for a wider proportion of patients compared with DORIS remission. Randomized controlled trials and real-world analyses have confirmed the positive clinical benefits of achieving either DORIS remission or LLDAS. The treat-to-target (T2T) approach utilizes practical clinical targets to proactively tailor individual treatment regimens. Studies in other chronic inflammatory diseases using the T2T approach demonstrated significantly improved clinical outcomes and quality-of-life measures compared with established standard of care. However, such trials have not yet been performed in patients with SLE. Here we review the evolution of DORIS remission and LLDAS definitions and the evidence supporting the positive clinical outcomes following DORIS remission or LLDAS attainment, before discussing considerations for implementation of these outcome measures as potential T2T objectives. Adoption of DORIS remission and LLDAS treatment goals may result in favorable patient outcomes compared with established standard of care for patients with SLE.
Systemic lupus erythematosus (SLE) is a complex disease that can affect many organs. It can lead to life-threatening complications and poor quality of life. As SLE is very different in each person, it can be challenging to measure disease activity. Doctors are encouraged to set clinical targets to tailor treatment for each patient. Clinical targets include scoring systems that measure disease improvement. Remission is an established clinical target. When a patient is in remission, disease activity is controlled, and the patient does not experience any symptoms. As remission is difficult to achieve, experts developed a more realistic yet still favorable state. This is the lupus low disease activity state, when lupus symptoms are minimal on stable therapy. Doctors use remission and low disease activity in clinical trials to compare existing SLE drugs with new treatments, including biologic drugs. Biologics target key parts of the immune system to help suppress SLE. In this review, we looked at recent clinical trials and found that biologic drugs can help patients achieve remission or low disease activity. Patients who achieved these clinical targets had slower disease progression and improved quality of life. Clinical trials in SLE should continue to use remission and low disease activity targets to help compare treatments. Doctors are encouraged to use them in their routine clinics as treatment targets to measure SLE disease control. Low disease activity state may be particularly helpful as an initial target for patients who are not yet in remission.
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Drug development in lupus has improved over the past 10 years but still lags behind that of other rheumatic disease areas. Assessment of prospective lupus therapies in clinical trials has proved challenging for reasons that are multifactorial including the heterogeneity of the disease, study design limitations and a lack of validated biomarkers which greatly impacts regulatory decision-making. Moreover, most composite outcome measures currently used in trials do not include patient-reported outcomes. Given these factors, the Addressing Lupus Pillars for Health Advancement Global Advisory Committee members who serve on the drug development team identified an opportunity to convene a meeting to facilitate information sharing on completed and existing outcome measure development efforts. This meeting report highlights information presented during the meeting as well as a discussion on how the lupus community may work together with regulatory agencies to simplify and standardise outcome measures to accelerate development of lupus therapeutics.
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Lúpus Eritematoso Sistêmico , Humanos , Estudos Prospectivos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Projetos de Pesquisa , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. METHODS: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). RESULTS: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. CONCLUSIONS: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments. TRIAL REGISTRATION NUMBER: NCT01491815.
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Antirreumáticos , Artrite Reumatoide , Humanos , Certolizumab Pegol/uso terapêutico , Abatacepte/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Metotrexato/uso terapêutico , Quimioterapia Combinada , Resultado do TratamentoRESUMO
OBJECTIVE: The goals of this study were to assess the associations of severe nonadherence to hydroxychloroquine (HCQ), objectively assessed by HCQ serum levels, and risks of systemic lupus erythematosus (SLE) flares, damage, and mortality rates over five years of follow-up. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort is an international multicenter initiative (33 centers throughout 11 countries). The serum of patients prescribed HCQ for at least three months at enrollment were analyzed. Severe nonadherence was defined by a serum HCQ level <106 ng/mL or <53 ng/mL for HCQ doses of 400 or 200 mg/day, respectively. Associations with the risk of a flare (defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/American College of Rheumatology Damage Index [SDI] increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS: Of the 1,849 cohort participants, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/mL (244-566); 48 patients (7.3%) had severe HCQ nonadherence. No covariates were clearly associated with severe nonadherence, which was, however, independently associated with both flare (odds ratio 3.38; 95% confidence interval [CI] 1.80-6.42) and an increase in the SDI within each of the first three years (hazard ratio [HR] 1.92 at three years; 95% CI 1.05-3.50). Eleven patients died within five years, including 3 with severe nonadherence (crude HR 5.41; 95% CI 1.43-20.39). CONCLUSION: Severe nonadherence was independently associated with the risks of an SLE flare in the following year, early damage, and five-year mortality.
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Hidroxicloroquina , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Masculino , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Prednisona , Imunossupressores/uso terapêutico , Modelos de Riscos ProporcionaisRESUMO
Background: Studies on long-term consequences of COVID-19, commonly referred to as post-COVID condition, in patients with inflammatory rheumatic diseases are scarce and inconclusive. Furthermore, classifying patients with inflammatory rheumatic diseases as having post-COVID condition is complicated because of overlapping symptoms. Therefore, we investigated the risk of post-COVID condition and time until recovery, and compared the prevalence of symptoms seen in post-COVID condition, between patients with inflammatory rheumatic diseases and healthy controls, with and without a history of COVID-19. Methods: In this substudy we used data from an ongoing prospective cohort study in the Netherlands. All adult patients with inflammatory rheumatic diseases from the Amsterdam Rheumatology and Immunology Center in Amsterdam, the Netherlands, were invited to participate in the study between April 26, 2020, and March 1, 2021. All patients were asked, but not obliged, to recruit their own control participant of the same sex, of comparable age (< 5 years), and without an inflammatory rheumatic disease. Demographic and clinical data, including data on the occurrence of SARS-CoV-2 infections, were collected via online questionnaires. On March 10, 2022, all study participants received a questionnaire on the occurrence, onset, severity, and duration of persistent symptoms during the first 2 years of the COVID-19 pandemic, independent of their history of SARS-CoV-2 infection. Additionally, we prospectively monitored a subset of participants who had a PCR or antigen confirmed SARS-CoV-2 infection in the 2-month period surrounding the questionnaire in order to assess COVID-19 sequelae. In line with WHO guidelines, post-COVID condition was defined as persistent symptoms that lasted at least 8 weeks, started after the onset and within 3 months of a PCR or antigen-confirmed SARS-CoV-2 infection, and could not be explained by an alternative diagnosis. Statistical analyses included descriptive statistics, logistic regression analyses, logistic-based causal mediation analyses, and Kaplan-Meier survival analyses for time until recovery from post-COVID condition. In exploratory analyses, E-values were calculated to investigate unmeasured confounding. Findings: A total of 1974 patients with inflammatory rheumatic disease (1268 [64%] women and 706 [36%] men; mean age 59 years [SD 13]) and 733 healthy controls (495 [68%] women and 238 [32%] men; mean age 59 years [12]) participated. 468 (24%) of 1974 patients with inflammatory rheumatic disease and 218 (30%) of 733 healthy controls had a recent SARS-CoV-2 omicron infection. Of those, 365 (78%) of 468 patients with inflammatory rheumatic disease and 172 (79%) of 218 healthy controls completed the prospective follow-up COVID-19 sequelae questionnaires. More patients than controls fulfilled post-COVID condition criteria: 77 (21%) of 365 versus 23 (13%) of 172 (odds ratio [OR] 1·73 [95% CI 1·04-2·87]; p=0·033). The OR was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90-2·59]; p=0·12). Among those without a history of COVID-19, patients with inflammatory diseases were more likely to report persistent symptoms consistent with post-COVID condition than were healthy controls (OR 2·52 [95% CI 1·92-3·32]; p<0·0001). This OR exceeded the calculated E-values of 1·74 and 1·96. Recovery time from post-COVID condition was similar for patients and controls (p=0·17). Fatigue and loss of fitness were the most frequently reported symptoms in both patients with inflammatory rheumatic disease and healthy controls with post-COVID condition. Interpretation: Post-COVID condition after SARS-CoV-2 omicron infections was higher in patients with inflammatory rheumatic disease than in healthy controls based on WHO classification guidelines. However, because more patients with inflammatory rheumatic disease than healthy controls without a history of COVID-19 reported symptoms that are commonly used to define a post-COVID condition during the first 2 years of the pandemic, it is likely that the observed difference in post-COVID condition between patients and controls might in part be explained by clinical manifestations in the context of underlying rheumatic diseases. This highlights the limitations of applying current criteria for post-COVID condition in patients with inflammatory rheumatic disease, and suggests it might be appropriate for physicians to keep a nuanced attitude when communicating the long-term consequences of COVID-19. Funding: ZonMw (the Netherlands organization for Health Research and Development) and Reade foundation.
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OBJECTIVES: A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes. METHODS: Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset. RESULTS: Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2. CONCLUSION: Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.
Assuntos
Autoanticorpos , Lúpus Eritematoso Sistêmico , Humanos , Anticorpos Antinucleares , DNA , Imunossupressores , Aprendizado de MáquinaRESUMO
OBJECTIVES: To evaluate the time course of clinical response following anifrolumab treatment in patients with SLE. METHODS: A post hoc analysis was conducted using pooled data from phase III, randomised, 52-week, placebo-controlled, Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of intravenous anifrolumab (every 4 weeks, 48 weeks) in patients with moderate-to-severe SLE receiving standard therapy. Anifrolumab 300 mg and placebo groups were compared for British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response over time, time to sustained BICLA response, SLE Responder Index ≥4 (SRI(4)) response over time, time to sustained Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) response and change in glucocorticoid dosage over time. All p values for comparisons were nominal. RESULTS: Of the 726 evaluated patients (anifrolumab 300 mg, n=360; placebo, n=366), a greater proportion attained a BICLA response in the anifrolumab versus the placebo group from Week 8 (p<0.001); treatment group differentiation was maintained at all subsequent visits to Week 52. Consistently, more patients achieved a BICLA response sustained to Week 52 in the anifrolumab versus placebo group (HR=1.73, 95% CI 1.37 to 2.20). More patients attained SRI(4) response with anifrolumab than placebo from Week 12 (p=0.005). As early as Week 8, more patients achieved CLASI-A skin response sustained to Week 52 with anifrolumab versus placebo (HR=1.72, 95% CI 1.17 to 2.55). Glucocorticoid dosage reductions from baseline were greater in anifrolumab-treated versus placebo-treated patients from Week 20 (p=0.010) through Week 52. CONCLUSIONS: Anifrolumab treatment was associated with sustained improvements in overall SLE disease activity and skin responses versus placebo from Week 8, which likely led to greater glucocorticoid reductions in the anifrolumab versus placebo groups from Week 20. These findings provide insights to physicians and patients on when to expect potential clinical responses following anifrolumab treatment.
Assuntos
Lúpus Eritematoso Sistêmico , Tulipa , Humanos , Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
OBJECTIVE: To estimate direct and indirect costs associated with neuropsychiatric (NP) events in the Systemic Lupus International Collaborating Clinics inception cohort. METHODS: NP events were documented annually using American College of Rheumatology definitions for NP events and attributed to systemic lupus erythematosus (SLE) or non-SLE causes. Patients were stratified into 1 of 3 NP states (no, resolved, or new/ongoing NP event). Change in NP status was characterized by interstate transition rates using multistate modeling. Annual direct costs and indirect costs were based on health care use and impaired productivity over the preceding year. Annual costs associated with NP states and NP events were calculated by averaging all observations in each state and adjusted through random-effects regressions. Five- and 10-year costs for NP states were predicted by multiplying adjusted annual costs per state by expected state duration, forecasted using multistate modeling. RESULTS: A total of 1,697 patients (49% White race/ethnicity) were followed for a mean of 9.6 years. NP events (n = 1,971) occurred in 956 patients, 32% attributed to SLE. For SLE and non-SLE NP events, predicted annual, 5-, and 10-year direct costs and indirect costs were higher in new/ongoing versus no events. Direct costs were 1.5-fold higher and indirect costs 1.3-fold higher in new/ongoing versus no events. Indirect costs exceeded direct costs 3.0 to 5.2 fold. Among frequent SLE NP events, new/ongoing seizure disorder and cerebrovascular disease accounted for the largest increases in annual direct costs. For non-SLE NP events, new/ongoing polyneuropathy accounted for the largest increase in annual direct costs, and new/ongoing headache and mood disorder for the largest increases in indirect costs. CONCLUSION: Patients with new/ongoing SLE or non-SLE NP events incurred higher direct and indirect costs.
Assuntos
Transtornos Cerebrovasculares , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/terapia , Lúpus Eritematoso Sistêmico/complicações , Estudos Longitudinais , Etnicidade , BrancosRESUMO
OBJECTIVES: Glucocorticoid sparing is a key priority for SLE management. We evaluated the effects of sustained glucocorticoid tapering in patients with SLE. MATERIAL AND METHODS: This was a post hoc analysis of the randomized, placebo-controlled, 52-week phase 3 Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of anifrolumab (300 mg i.v. once every 4 weeks for 48 weeks) plus standard therapy in patients with moderate to severe SLE. In a cohort of patients receiving glucocorticoids (prednisone or equivalent) 10 mg or more per day at baseline, we assessed changes in glucocorticoid dosage, patient-reported outcomes (PROs) and safety. Outcome measures were compared between sustained glucocorticoid taper responders (7.5 mg or less per day by week 40 sustained through week 52) and non-responders, regardless of treatment group, and between patients receiving anifrolumab or placebo. RESULTS: Among the 726 patients in the TULIP trials, 375 patients received glucocorticoids 10 mg or more per day at baseline, and of these, 155 (41%) patients were sustained glucocorticoid taper responders. Compared with non-responders (n = 220), sustained glucocorticoid taper responders reduced their mean cumulative glucocorticoid dose by 32%, improved PRO scores, reduced blood pressure and experienced fewer serious adverse events. Sustained glucocorticoid tapering was achieved by 51% (96/190) of patients receiving anifrolumab vs 32% (59/185) receiving placebo. Compared with placebo, more anifrolumab-treated patients achieved both sustained glucocorticoid taper and reduced overall disease activity [38% (72/190) vs 23% (43/185)]. CONCLUSIONS: Sustained glucocorticoid tapering is associated with clinical benefits. Anifrolumab treatment has potential to reduce disease activity and glucocorticoid exposure, a key goal of SLE management. STUDY REGISTRATION: ClinicalTrials.gov identifier: NCT02446912 and NCT02446899.