Initial glucocorticoid bridging in rheumatoid arthritis: does it affect glucocorticoid use over time?

OBJECTIVES: To compare the use of glucocorticoids (GC) over time in patients with rheumatoid arthritis (RA) who were or were not treated initially with GC bridging therapy. METHODS: Data from the BeSt, CareRA and COBRA trials were combined in an individual patient data (IPD) meta-analysis. We compared GC use between bridgers and non-bridgers at 12, 18 and 24 months from baseline with mixed-effects regression analysis. Secondary outcomes were mean cumulative GC dose until 24 months after baseline with and without the bridging period, Disease Activity Score based on 28 joints (DAS28) over time and number of disease-modifying antirheumatic drug (DMARD) changes. RESULTS: 252/625 patients (40%) were randomised to GC bridging (bridgers). Excluding the period of bridging, later GC use was low in both groups and cumulative doses were similar. Mean DAS28 was similar between the groups, but bridgers improved more rapidly (p<0.001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio 0.59 (95% CI 0.38 to 0.94)). GC use was higher in the bridgers at t=12 months (OR 3.27 (95% CI 1.06 to 10.08)) and the bridging schedules resulted in a difference in cumulative GC dose of 2406 mg (95% CI 1403 to 3408) over 24 months. CONCLUSION: In randomised trials comparing GC bridging and no GC bridging, bridgers had a more rapid clinical improvement, fewer DMARD changes and similar late use of GC compared with non-bridgers. GC bridging per protocol resulted, as could be expected, in a higher cumulative GC dose over 2 years.

Long-term mortality in treated-to-target RA and UA: results of the BeSt and IMPROVED cohort.

OBJECTIVES: To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA). METHODS: The BeSt (BehandelStrategieën) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)≤2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed. RESULTS: Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy. CONCLUSIONS: After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor.

Unmet need in rheumatology: reports from the Advances in Targeted Therapies meeting, 2023.

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.

Antibodies against advanced glycation end-products and malondialdehyde-acetaldehyde adducts identify a new specific subgroup of hitherto patients with seronegative arthritis with a distinct clinical phenotype and an HLA class II association.

OBJECTIVE: In rheumatoid arthritis (RA) around two-thirds of patients are autoantibody positive for rheumatoid factor, anti-citrullinated protein antibodies and/or anti-carbamylated protein antibodies. The remaining seronegative subgroup of patients is clinically heterogeneous and thus far, biomarkers predicting the disease course are lacking. Therefore, we analysed the value of other autoantibodies in RA directed against malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE). METHODS: In sera of 648 patients with RA and 538 patients without RA from the Leiden Early Arthritis Clinic, anti-MAA and anti-AGE IgG antibody levels were measured using ELISA. Associations between genetic risk factors, acute phase reactants, radiological joint damage, remission and anti-PTM positivity were investigated using regression, correlation and survival analyses. RESULTS: Anti-AGE and anti-MAA were most prevalent in RA (44.6% and 46.1% respectively) but were also present in non-RA arthritis patients (32.9% and 30.3% respectively). Anti-AGE and anti-MAA antibodies were associated with HLA-DRB1*03 within seronegative RA (OR=1.98, p=0.003, and OR=2.37, p<0.001, respectively) and, for anti-AGE also in non-RA arthritis patients (OR=2.34, p<0.001). Presence of anti-MAA antibodies was associated significantly with markers of inflammation, erythrocyte sedimentation rate and C reactive protein, in all groups independent of anti-AGE. Interestingly, the presence of anti-AGE and anti-MAA antibodies was associated with radiological progression in patients with seronegative RA, but not evidently with sustained drug-free remission. CONCLUSIONS: Anti-AGE and anti-MAA were present in around 45% of RA patients and 30% of non-RA arthritis patients, and although not specific for RA, their presence associated with HLA, inflammation and, for RA, with clinical outcomes especially in patients with seronegative RA.

The long-term course of the Health Assessment Questionnaire in patients with systemic sclerosis.

Objective: The Health Assessment Questionnaire-Disability Index is an important outcome measure reflecting functional disability, but knowledge on its course over time in patients with systemic sclerosis is scarce. Therefore, we investigated the long-term course of the Health Assessment Questionnaire-Disability Index and its association with baseline characteristics in systemic sclerosis patients. Methods: Systemic sclerosis patients, fulfilling the European League Against Rheumatism and the American College of Rheumatology 2013 criteria, were included from the Leiden Combined Care in Systemic Sclerosis cohort with annual assessments including the Scleroderma Health Assessment Questionnaire-Disability Index (range = 0-3). The course of the Health Assessment Questionnaire-Disability Index was evaluated over the total follow-up (baseline to last available Health Assessment Questionnaire-Disability Index) and between yearly visits. Based on a minimal clinical important difference of 0.22, courses were categorized into worsening, stable or improvement. The course of the Health Assessment Questionnaire-Disability Index over time was evaluated with linear mixed models. Baseline characteristics were compared between patients with a worsening or improvement of the Health Assessment Questionnaire-Disability Index over the total follow-up period with logistic regression analyses. Results: A total of 517 systemic sclerosis patients were included, with a median follow-up of 7 years (interquartile range = 4-9; 2649 visits) and a baseline Health Assessment Questionnaire-Disability Index of 0.625 (interquartile range = 0.125-1.25). On group level, the Health Assessment Questionnaire-Disability Index is stable with an annual increase of 0.019 (95% confidence interval = 0.011 to 0.027). Looking at subgroups, patients >65 years or who died/were physically unable to come during follow-up had a worse mean Health Assessment Questionnaire-Disability Index. In individual courses from baseline to the last follow-up, the proportions of patients with a clinically meaningful worsening, stable or improved Health Assessment Questionnaire-Disability Index were 35%, 42% and 23%, respectively. Patients with immunosuppressants (odds ratio = 0.5, 95% confidence interval = 0.3 to 0.9) or gastrointestinal involvement (odds ratio = 0.6, 95% confidence interval = 0.4 to 0.9) at baseline showed a reduced chance of worsening of the Health Assessment Questionnaire-Disability Index over the total follow-up period. Conclusion: Over time, the average course of the Health Assessment Questionnaire-Disability Index was stable in systemic sclerosis patients. However, individual courses vary, with worsening occurring in one-third. Worsening occurred less often in individuals using immunosuppressants or with gastrointestinal involvement at baseline.

Anti-topoisomerase, but not anti-centromere B cell responses in systemic sclerosis display active, Ig-secreting cells associated with lung fibrosis.

OBJECTIVES: Almost all patients with systemic sclerosis (SSc) harbour autoantibodies. Anti-topoisomerase antibodies (ATA) and anti-centromere antibodies (ACA) are most prevalent and associate with distinct clinical phenotypes. B cell responses underlying these phenotypes are ill-defined. To understand how B cell autoreactivity and disease pathology connect, we determined phenotypic and functional characteristics of autoreactive B cells in ATA-positive and ACA-positive patients. METHODS: Levels and isotypes of autoantibodies secreted by ex vivo cultured peripheral blood mononuclear cells from patients with ATA-positive (n=22) and ACA-positive (n=20) SSc were determined. Antibody secreting cells (ASCs) were isolated by cell sorting and cultured separately. Correlations were studied between the degree of spontaneous autoantibody production and the presence and degree of interstitial lung disease (ILD). RESULTS: Circulating B cells secreting either ATA-immunoglobulin G (IgG) or ACA-IgG on stimulation was readily detectable in patients. The ATA response, but not the ACA response, showed additional secretion of autoreactive IgA. ATA-IgG and ATA-IgA were also secreted spontaneously. Additional cell sorting confirmed the presence of ATA-secreting plasmablasts. The degree of spontaneous ATA-secretion was higher in patients with ILD than in those without (p<0.001) and correlated with the degree of pulmonary fibrosis (p<0.001). CONCLUSION: In contrast to ACA-positive patients, ATA-positive patients show signs of recent activation of the B cell response that hallmarks this disease. The degree of activation correlates with the presence and severity of ILD, the most deleterious disease manifestation. This could explain differential responsiveness to B cell depleting therapy. The abundant and spontaneous secretion of ATA-IgG and ATA-IgA may point toward a continuously activating trigger.

Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis.

OBJECTIVES: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may affect this. METHODS: Data from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (≥3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome. RESULTS: The probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended. CONCLUSIONS: Based on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low.

Systematic literature review of observational cohorts and clinical trials into the success rate of glucocorticoid discontinuation after their use as bridging therapy in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the success rate of glucocorticoid (GC) discontinuation during follow-up in observational cohorts and clinical trials using temporary GC as part of initial therapy ('bridging') in newly diagnosed patients with rheumatoid arthritis (RA). METHODS: Systematic literature searches were conducted to identify observational cohorts and clinical trials including patients with RA treated with initial GC bridging therapy, defined as discontinuation of GC within 1 year. Patient percentages still using GC were considered the reverse of successful discontinuation. Random effects meta-analyses were performed stratified by time point. RESULTS: The scoping literature search for observational cohort studies could not identify studies answering the research question. The literature search for clinical trials identified 7160 abstracts, resulting in 10 included studies, with varying type and dose of GC and varying tapering schedules, of which 4 reported sufficient data on GC discontinuation or use after the bridging phase. The pooled proportion of patients who were still or again using GC was 22% (95% CI 8% to 37%, based on four trials) at 12 months and 10% at 24 months (95% CI -1 to 22, based on two trials). Heterogeneity was substantial (I²≥65%). CONCLUSION: The success rate of GC discontinuation after bridging as part of initial treatment of RA has been described in a limited number of studies. Reports on observational cohorts did not answer the research question. In clinical trials, protocolised discontinuation was mostly successful, although 22% of the patients who started GC bridging therapy still or again used GC at 12 months, and 10% at 24 months.

Dissociation in SLE: A part of lupus fog?

INTRODUCTION: Lupus fog is ill-defined. We aimed to study whether lupus fog is the result of dissociation by studying the prevalence of dissociation and dissociative fog in patients with SLE and neuropsychiatric manifestations of inflammatory and non-inflammatory origin. METHODS: Patients visiting the tertiary referral center for neuropsychiatric systemic lupus erythematosus (NPSLE) of the LUMC between 2007-2019 were included. Patients were classified as having neuropsychiatric symptoms of inflammatory or non-inflammatory origin. Dissociation was studied using the Dissociative Experience Scale-II (DES), in which the presence of 28 dissociative symptoms is rated (0-100% of the time), of which one question assesses the presence of a dissociative fog directly. Average scores are calculated and scores ≥ 25 are considered indicative of a dissociative disorder. A score of ≥ 30 on question 28 (dissociative fog) was considered indicative for the presence of a fog. Summary scores in the general adult population range from 4.4 to 14. Multiple regression analysis (MRA) was performed to study the association between inflammatory neuropsychiatric symptoms and dissociation. DES results are presented as median (range) and MRA as B and 95% confidence interval (CI). RESULTS: DES questionnaires were available for 337 patients, of which 69 had an inflammatory NPSLE phenotype (20%). Mean age in the total study population was 43 ± 14 years and the majority was female (87%). The median dissociation score was 7.1 (0-75) and did not differ between patients with neuropsychiatric symptoms of inflammatory or non-inflammatory origin (B: -0.04 (95% CI: -0.17; 0.09)). 35 patients (10%) had a score indicative of a dissociative disorder. The most common type of dissociation was absorption/imagination. 43 patients (13%) reported a dissociative fog. DISCUSSION: In most patients with SLE and neuropsychiatric symptoms, dissociative symptoms are within normal range, regardless of underlying etiology. Dissociative fog is present, but uncommon. Lupus fog is most likely not associated with dissociation.

White matter hyperintensities associate with cognitive slowing in patients with systemic lupus erythematosus and neuropsychiatric symptoms.

OBJECTIVE: To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter hyperintensity (WMH) volumes. METHODS: Patients attending the Leiden University Medical Centre NPSLE clinic between 2007 and 2015 without large brain infarcts were included (n=151; 42±13 years, 91% women). In a multidisciplinary consensus meeting, neuropsychiatric symptoms were attributed to systemic lupus erythematosus (SLE) (NPSLE, inflammatory (n=24) or ischaemic (n=12)) or to minor/non-NPSLE (n=115). Multiple regression analyses were performed to compare cognitive function between NPSLE phenotypes and to assess associations between brain and WMH volumes and cognitive function cross-sectionally. RESULTS: Global cognitive function was impaired in 5%, learning and memory (LM) in 46%, executive function and complex attention (EFCA) in 39% and psychomotor speed (PS) in 46% of all patients. Patients with inflammatory NPSLE showed the most cognitive impairment in all domains (p≤0.05).Higher WMH volume associated with lower PS in the total group (B: -0.14 (95% CI -0.32 to -0.02)); especially in inflammatory NPSLE (B: -0.36 (95% CI -0.60 to -0.12). In the total group, lower total brain volume and grey matter volume associated with lower cognitive functioning in all domains (all: 0.00/0.01 (0.00;0.01)) and lower white matter volume associated with lower LM, EFCA and PS (all: 0.00/0.01 (0.00;0.01)). CONCLUSION: We demonstrated that an association between brain and WMH volumes and cognitive function is present in patients with SLE, but differs between (NP)SLE phenotypes. WMHs associated with PS especially in inflammatory NPSLE, which suggests a different, potentially more severe underlying pathophysiological mechanism of cognitive impairment in this phenotype.

Fatigue in patients with systemic lupus erythematosus and neuropsychiatric symptoms is associated with anxiety and depression rather than inflammatory disease activity.

INTRODUCTION: We aimed to investigate risk factors for fatigue in patients with systemic lupus erythematosus (SLE) and neuropsychiatric symptoms in order to identify potential interventional strategies. METHODS: Patients visiting the neuropsychiatric SLE (NPSLE) clinic of the Leiden University Medical Center between 2007-2019 were included. In a multidisciplinary consensus meeting, SLE patients were classified as having neuropsychiatric symptoms of inflammatory origin (inflammatory phenotype) or other origin (non-inflammatory phenotype). Fatigue was assessed with the SF-36 vitality domain (VT) since 2007 and the multidimensional fatigue inventory (MFI) and visual analogue scale (VAS) since 2011. Patients with a score on the SF-36 VT ≥1 standard deviation (SD) away from the mean of age-related controls of the general population were classified as fatigued; patients ≥2 SD away were classified as extremely fatigued. Disease activity was measured using the SLE disease activity index-2000. The influence of the presence of an inflammatory phenotype, disease activity and symptoms of depression and anxiety as measured by the hospital anxiety and depression scale (HADS) was analyzed using multiple regression analyses corrected for age, sex and education. RESULTS: 348 out of 371 eligible patients filled in questionnaires and were included in this study . The majority was female (87%) and the mean age was 43 ± 14 years. 72 patients (21%) had neuropsychiatric symptoms of an inflammatory origin. Fatigue was present in 78% of all patients and extreme fatigue was present in 50% of patients with an inflammatory phenotype vs 46% in the non-inflammatory phenotype. Fatigue was similar in patients with an inflammatory phenotype compared to patients with a non-inflammatory phenotype on the SF-36 VT (ß: 0.8 (95% CI -4.8; 6.1) and there was less fatigue in patients with an inflammatory phenotype on the MFI and VAS (ß: -3.7 (95% CI: -6.9; -0.5) and ß: -1.0 (95% CI -1.6; -0.3)). There was no association between disease activity and fatigue, but symptoms of anxiety and depression (HADS) associated strongly with all fatigue measurements. CONCLUSION: This study suggests that intervention strategies to target fatigue in (NP)SLE patients may need to focus on symptoms of anxiety and depression rather than immunosuppressive treatment.

Changes in selected haematological parameters associated with JAK1/JAK2 inhibition observed in patients with rheumatoid arthritis treated with baricitinib.

OBJECTIVE: To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing. METHODS: Data were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492). RESULTS: Mean absolute neutrophil counts decreased (-1.36×109/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×109/L) within 1 month, then decreased to baseline (weeks 12-24). Mean platelet counts increased at week 2 (+51×109/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (-0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure). CONCLUSIONS: Moderate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.

Predictive factors for treatment-related mortality and major adverse events after autologous haematopoietic stem cell transplantation for systemic sclerosis: results of a long-term follow-up multicentre study.

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) improves survival in systemic sclerosis (SSc) with poor prognosis, but is hampered by treatment-related mortality (TRM). OBJECTIVE: To evaluate event-free survival (EFS), TRM, response to treatment, disease progression and patient characteristics associated with events. METHODS: All patients treated with HSCT for SSc in The Netherlands until 2017 (n=92) were included. Data on skin involvement (modified Rodnan skin score (mRSS), pulmonary function (forced vital capacity (FVC) and diffusion capacity of the lungs for carbon monoxide (DLCO)), extent of interstitial lung disease on high-resolution CT using Goh scores and left ventricular ejection fraction (LVEF) were collected at baseline, 1, 2 and 5 years. Occurrence of events, defined as death or major organ failure, were collected until 2019. As control, a comparison between patients treated with cyclophosphamide (CYC) and patients with HSCT who participated in the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial was performed. RESULTS: Median follow-up was 4.6 years. EFS estimates at 5, 10 and 15 years were 78%, 76% and 66%, respectively. Twenty deaths occurred. Mean FVC, DLCO, mRSS and Goh scores all improved significantly. Disease progression occurred in 22 patients. Frequency of TRM decreased over time and occurred more often in males. Events were independently associated with male sex, LVEF <50% and older age. In ASTIS, patients treated with HSCT (n=23) 7 events occurred versus 13 in the CYC group (n=22). CONCLUSION: Our data confirm long-term efficacy of HSCT in improving survival, skin and lung involvement in SSc. Male sex, lower LVEF and older age at baseline were identified as risk factors for events.