Cytochrome P450 activity in rheumatoid arthritis patients during continuous IL-6 receptor antagonist therapy.

BACKGROUND: Inflammation suppresses cytochrome P450 (CYP) enzyme activity, and single-dose interleukin 6 receptor antagonists (anti-IL-6R) reverse this effect. Here, we assess the impact of continuous anti-IL-6R therapy in patients with rheumatoid arthritis. METHODS: In a clinical pharmacokinetic trial, the Basel cocktail was administered before and after 3 and 12 weeks of anti-IL-6R therapy to assess CYP enzyme activity (registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021). In a retrospective study, the 4ß-hydroxycholesterol/cholesterol ratio was measured as a biomarker for CYP3A4 activity before and after 3 and 6 months of anti-IL-6R therapy. The control group was patients initiating a tumor necrosis factor alfa (TNF-α) inhibitor. RESULTS: In the clinical pharmacokinetic trial (n = 3), midazolam metabolic ratio (CYP3A4) was inconclusive due to the limited sample size. Midazolam AUC and Cmax indicate a weak impact on CYP3A4 activity after 3 weeks of anti-IL-6R therapy compared to baseline (AUC geometric mean ratio (GMR): 0.80, 95% CI: 0.64-0.99 and Cmax GMR: 0.58, 95% CI: 0.37-0.91), which returns to baseline levels after 12 weeks of therapy (AUC GMR 1.02, 95% CI: 0.72-1.46 and Cmax GMR 1.03, 95% CI 0.72-1.47). No effect on the 4ß-hydroxycholesterol/cholesterol ratio was observed in the retrospective study. CONCLUSION: Based on sparse data from three patients, continuous anti-IL-6R therapy seems to cause an acute but transient increase in CYP3A4 activity in rheumatoid arthritis patients, which may be due to a normalization of the inflammation-suppressed CYP activity. Further studies are warranted to understand the mechanism behind this putative transient effect. Trial registration Registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021.

Complement Proteins L-Ficolin and M-Ficolin Are Increased in Patients With Axial Spondyloarthritis and Decrease After Tumor Necrosis Factor Inhibitor Treatment.

OBJECTIVE: We have previously reported elevated levels of the complement lectin pathway proteins L-ficolin and H-ficolin in patients with axial spondyloarthritis (axSpA) compared with healthy controls. The aim of the present study was to investigate these biomarkers in a cross-sectional cohort of patients suffering from low back pain (LBP). Further, we aimed to investigate changes in lectin pathway protein levels after initiation of adalimumab (ADA; a tumor necrosis factor inhibitor) in a longitudinal cohort of patients with axSpA. METHODS: Lectin pathway protein levels (mannan-binding lectin [MBL], collectin liver 1, H-ficolin, L-ficolin, M-ficolin, MBL-associated serine protease [MASP]-1, MASP-2, MASP-3, MBL-associated protein 19 [MAp19], and MAp44) in EDTA plasma were determined in 2 well-characterized cohorts: (1) a clinical cross-sectional cohort of patients with LBP, including patients with axSpA (n = 23), patients with unspecific LBP (uLBP) with ≥ 1 SpA features (n = 55), and patients with uLBP without SpA features or magnetic resonance imaging findings suggestive of axSpA (n = 64); and (2) a randomized double-blinded, placebo-controlled trial cohort of patients with axSpA (n = 49) initiating ADA therapy. Lectin pathway protein levels were determined using immunoassays. RESULTS: Plasma levels of L-ficolin and M-ficolin were significantly increased in the cross-sectional cohort of newly diagnosed patients with axSpA compared with clinically relevant controls with uLBP (all P < 0.05). Both L-ficolin and M-ficolin decreased significantly after ADA therapy (P < 0.05). CONCLUSION: L-ficolin and M-ficolin levels are elevated in newly diagnosed patients with axSpA compared with clinically relevant controls. Both L-ficolin and M-ficolin levels decrease significantly after initiating ADA therapy. These findings provide new insights into the inflammatory processes in axSpA and support the involvement of complement in axSpA pathogenesis.

Infliximab biosimilar-to-biosimilar switching in patients with inflammatory rheumatic disease: clinical outcomes in real-world patients from the DANBIO registry.

OBJECTIVE: Successful uptake of biosimilars in rheumatology is limited by lack of real-world evidence regarding effectiveness of biosimilar-to-biosimilar switching. We investigated infliximab biosimilars CT-P13-to-GP1111 switching among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). METHODS: Observational cohort study from the DANBIO registry. Patients were classified as originator-naïve or originator-experienced. Retention rates of 1-year GP1111 treatment were explored (Kaplan-Meier). We identified baseline factors (at the time of switch) associated with withdrawal of GP1111 (multivariable Cox-regression analyses with HRs including originator treatment history). Changes in subjective and objective measures of disease activity 4 months before and after the switch were assessed in individual patients. RESULTS: Of 1605 patients (685 RA, 314 PsA and 606 AxSpA, median disease duration was 9 years, 37% in Clinical Disease Activity Index/Ankylosing Spondylitis Disease Activity Score remission), 1171 were originator-naïve. Retention rates at 1-year were 83% (95% CI: 81% to 85%) and 92% (95% CI: 90% to 95%) for the originator-naïve and originator-experienced, respectively. GP1111 retention rates were higher in originator-experienced compared to originator-naïve with RA (HR=0.4 (95% CI: 0.2 to 0.7)) and PsA (HR=0.2 (95% CI: 0.1 to 0.8)), but not significantly for AxSpA: HR=0.6 (95% CI: 0.3 to 1.2). Lower disease activity was associated with higher retention. Changes in disease activity preswitch and postswitch were close to zero. CONCLUSION: This real-world observational study of more than 1600 patients with inflammatory arthritis showed high 1-year retention following a nationwide infliximab biosimilar-to-biosimilar switch. Retention was higher in originator-experienced and in patients with low disease activity, suggesting outcomes to be affected by patient-related rather than drug-related factors.

The effect of medical cannabis on cognitive functions: a systematic review.

BACKGROUND: Cannabis-based medicines are widely used in the treatment of a number of medical conditions. Unfortunately, cognitive disturbances are often reported as adverse events, although conversely, cognitive improvements have been reported. Hence, the objective of the present study was to identify, critically appraise and synthesise research findings on the potential impact of cannabis-based medicines on cognitive functioning. METHODS: Four databases (EMBASE, PsycINFO, PubMed and Scopus) were systematically searched. Studies were included if they provided findings on the impact of cannabis-based medicines in controlled settings on cognitive functioning measured by recognised cognitive tests in human adults. Study participants were required to be their own case-control, and neither studies on abuse, abstinences, patients with severe neurodegenerative diseases nor cancer-related pain conditions were included. Screening, risk of bias assessment and data extraction were conducted independently by two researchers. Findings were tabulated and synthesised by outcome. FINDINGS: Twenty-three studies were included, comprising a total of N = 917. Eight studies used Sativex as the cannabis-based medicine two used Epidiolex, two other studies used sprays, three studies used gelatine capsules, five smoked cannabis, two other and finally one studied cannabis withdrawal. Fifteen studies reported non-significant findings; six reported cognitive impairments; one study found cognitive improvement and a single study found improvement following withdrawal. Thirteen studies had cognitive or neuropsychological functioning as the primary outcome. CONCLUSIONS: Due to a large heterogeneity and methodological limitations across studies, it is not possible to make any definite conclusions about the impact of cannabis-based medicines on cognitive functioning. However, the majority of high-quality evidence points in the direction that the negative impact of cannabis-based medicines on cognitive functioning is minor, provided that the doses of THC are low to moderate. On the other hand, long-term use of cannabis based medicines may still adversely affect cognitive functioning. In the studies that found impaired cognitive functioning to be significant, all of the test scores were either within the normal range or below what would be characterised as a neuropsychologically cognitive impairment.

Differences in topographical location of sacroiliac joint MRI lesions in patients with early axial spondyloarthritis and mechanical back pain.

BACKGROUND: Early diagnostics of axial spondyloarthritis (axSpA) remains a challenge. Traditional imaging one-plane sacroiliac joint (SIJ) MRI assessment is used. By introducing a two-plane assessment system, the objective was to analyse the differences in SIJ MRI changes in early axSpA compared with changes in patients with mechanical back pain (MBP) by exploring the differences in volume and location. METHODS: MRIs in the early diagnostic state of 25 axSpA patients (mean age 31.3 years) and 59 MBP patients (mean age 32.3 years) were included. The MRIs were assessed by two readers regarding the distribution of bone marrow edema (BME) in 14 joint portions and structural changes in six joint portions in addition to SIJ anatomical variations and lumbar spine disc degeneration. RESULTS: AxSpA patients had a significantly higher overall BME sumscore (volume) of 25.1 compared to MBP patients 6.8, p < 0.005. The MBP group had the highest prevalence (66%) and sumscore (5.7) in the middle anterior sacrum. The axSpA group had significantly higher prevalence and sumscores in all joint portions except the three cartilaginous anterior sacral joint portions, including the ligamentous compartments (prevalence 40-60% compared to 8-15%, p both < 0.005). The axSpA group had also a significantly higher prevalence of erosions and fatty marrow disposition, but there were no differences in the prevalence of anatomical variations except the bipartite iliac bony plate. CONCLUSIONS: AxSpA patients demonstrated a widespread distribution of both inflammatory and structural changes, including high BME occurrence in the ligamentous joint portions whereas patients with MBP had the highest occurrence of BME in the middle anterior sacrum. These findings may help differentiate axSpA patients from other back pain conditions in the early diagnostic phase.

Musculoskeletal pain in psoriasis-relation to inflammation and additional value of ultrasound in psoriatic arthritis classification.

OBJECTIVE: To investigate and compare clinical features and US signs of inflammation in joints and entheses in patients with psoriasis with and without musculoskeletal pain, and the additional value of US in classification of PsA. Furthermore, to explore the association between such findings and patient-reported outcomes (PROs) and the performance of screening-questionnaires for identifying patients with PsA. METHODS: Patients with psoriasis (n = 126) recruited from a nationwide survey were evaluated at one of four rheumatology departments. The evaluation included clinical examination, laboratory tests, radiography, greyscale and colour Doppler US of 48 joints and 12 entheses, PROs, and four screening questionnaires for PsA. Patients were classified with Classification for PsA (CASPAR), US-modified CASPAR, and US-only criteria. RESULTS: When subgroups of self-reported pain (63%), no pain (29%) and diagnosed PsA (9%) were compared, patients with pain had higher tenderness-related clinical scores (tender joints, entheses and FM points) and US greyscale sum-scores, compared with 'no pain' patients. PROs were negligibly moderately correlated with pain-related clinical scores (Spearman's rho = 0.11-0.59, all patients), and negligibly weakly with US sum-scores (rho = 0.01-0.34). More patients could be classified as PsA when US synovitis/enthesitis was included as an entry criterion (US-modified CASPAR, 66% of all patients) compared with conventional CASPAR (35%) or US-only criteria (52%). Sensitivities of screening questionnaires were low for fulfilment of CASPAR (0.23-0.66), US-modified CASPAR (0.17-0.57), and US-only (0.20-0.57) criteria. CONCLUSION: Self-reported pain in psoriasis is related to US inflammation. US-modified CASPAR criteria identified almost twice as many patients as conventional CASPAR criteria. Screening questionnaires showed limited value.

Pregnancy-related sacroiliac joint findings in females with low back pain: a four-year magnetic resonance imaging follow-up study.

BACKGROUND: Pregnancy-related pain may be associated with sacroiliac joint (SIJ) changes, detectable by magnetic resonance imaging (MRI). PURPOSE: To analyze the prevalence and course of SIJ MRI and clinical findings in women referred with low back pain and relate these to pregnancy. MATERIAL AND METHODS: A retrospective follow-up study from a longitudinally collected cohort comprising 328 women. RESULTS: Women reporting debut of pain in relation to a pregnancy (PP group) tended to have a higher baseline prevalence of all investigated MRI findings, cumulated positive SIJ tests, and a potential fulfilment of the spondyloarthritis diagnosis compared to remainders. The prevalence of subchondral bone marrow edema (BME), any SIJ MRI finding, and potential fulfilment of the spondyloarthritis diagnosis were significantly higher in the PP group compared to women who had not been pregnant. In the total study group, the prevalence of ≥1 MRI finding increased over the four-year study period from 34% to 47% (P<0.001), driven by increasing prevalence of BME (25% to 32%; P=0.008) and fatty marrow deposition (FMD) (20% to 25%; P=0.020). In addition, the BME volume score increased. Over time, the PP group had persisting high prevalence of buttock pain and total MRI findings and their FMD volume score increased, but there were no between-group differences in MRI variables at follow-up. CONCLUSION: Overall, the prevalence of MRI findings increased over time. Although the PP group had different clinical and SIJ MRI characteristics cross-sectional at baseline compared to remainders, longitudinal analyses revealed that these diminished over time.

Impact of the COVID-19 pandemic on treat-to-target strategies and physical consultations in >7000 patients with inflammatory arthritis.

OBJECTIVES: To explore the impact of the COVID-19 pandemic on treat-to-target strategies (disease activity, remission rates) and access to physical consultations in patients with inflammatory rheumatic disease, as well as to explore characteristics of patients with/without physical consultations in the clinic and the impact of early vs established disease. METHODS: Patients with RA, PsA or axial SpA (axSpA) prospectively followed in the nationwide DANBIO registry answered online questionnaires and reported patient-reported outcomes (PROs) in June and November 2020. Patient characteristics, disease activity and physical consultations in the clinic before and during the pandemic were identified in DANBIO [all patients and subgroups with early disease (disease duration ≤2 years)]. In individual patients, changes in PROs before and during the pandemic were calculated. Characteristics of patients with/without physical consultations were described (age, gender, education level, comorbidities, disease duration, treatment). RESULTS: We included 7836 patients (22% of eligible patients), 12% of which had early disease. PROs were stable before and during the pandemic, with median changes approximating zero, as well as in patients with early disease. Remission rates were stable. The relative decrease in the number of patients with physical consultations was 21-72%, which was highest in axSpA. Characteristics of patients with/without physical consultations were similar. Self-reported satisfaction with treatment options and access was >70%; the preferred contact form was physical consultation (66%). CONCLUSION: In this nationwide study performed during the first 8 months of the pandemic, patient satisfaction was high and the PROs and remission rates remained stable despite the remarkable reduction in physical consultations, as well as in patients with early disease. Characteristics of patients with/without physical consultations appeared similar.

Comparative effectiveness of two adalimumab biosimilars in 1318 real-world patients with inflammatory rheumatic disease mandated to switch from originator adalimumab: nationwide observational study emulating a randomised clinical trial.

OBJECTIVES: In 2018, a nationwide mandatory switch from originator to biosimilar adalimumab was conducted in Denmark. The available biosimilar was GP2017 (Hyrimoz) in Eastern regions and SB5 (Imraldi) in Western regions. We aimed to assess the comparative effectiveness of GP2017 versus SB5 in patients with rheumatoid arthritis (RA)/psoriatic arthritis (PsA)/axial spondyloarthritis (AxSpA). METHODS: Observational cohort study based on the DANBIO registry with geographical cluster pseudo-randomisation, analysed by emulating a randomised clinical trial. Main outcome was adjusted 1-year treatment retention (Cox regression). Furthermore, 6 months' remission rates (logistic regression), reasons for withdrawal and back-switching to originator were investigated (overall and stratified by indication). RESULTS: Overall, of 1570 eligible patients, 1318 switched and were included (467 RA/321 PsA/530 AxSpA); 623 (47%) switched to GP2017, 695 (53%) to SB5. Baseline characteristics of the two clusters were largely similar, but some differences in registration practice were observed. The combined 1-year retention rate for the two biosimilars was 89.5%. Compared with SB5, estimated risk of withdrawal for GP2017 was lower (HR 0.60; 95% CI 0.42 to 0.86) and 6 months' remission rate was higher (OR 1.72; 95% CI 1.25 to 2.37). Stratified analyses gave similar results (statistically significant for RA). During 1 year, 8.5% and 12.9% withdrew GP2017 and SB5, respectively (primarily lack of effect and adverse events), of whom 48 patients (3.6%) back-switched. CONCLUSION: This head-to-head comparison of GP2017 versus SB5 following a mandatory switch from the originator indicated differences in effectiveness in routine care. This may reflect a true difference, but other explanations, for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.

Self-protection strategies and health behaviour in patients with inflammatory rheumatic diseases during the COVID-19 pandemic: results and predictors in more than 12 000 patients with inflammatory rheumatic diseases followed in the Danish DANBIO registry.

AIMS: In Danish patients with inflammatory rheumatic diseases to explore self-protection strategies and health behaviour including adherence to disease-modifying antirheumatic treatment (DMARD) during the initial phase of the COVID-19 pandemic and again after the reopening of the society started. Furthermore, to identify characteristics of patients with high levels of anxiety and self-isolation. METHODS: Patients in routine care followed prospectively in the nationwide DANBIO registry were invited to answer an online questionnaire regarding disease activity and COVID-19 infection, behaviour in March and June 2020. Responses were linked to patient data in DANBIO. Characteristics potentially associated with anxiety, self-isolation and medication adherence (gender/age/diagnosis/education/work status/comorbidity/DMARD/smoking/EQ-5D/disease activity) were explored with multivariable logistic regression analyses. RESULTS: We included 12 789 patients (8168 rheumatoid arthritis/2068 psoriatic arthritis/1758 axial spondyloarthritis/795 other) of whom 65% were women and 36% treated with biological DMARD. Self-reported COVID-19 prevalence was 0.3%. Patients reported that they were worried to get COVID-19 infection (March/June: 70%/45%) and self-isolated more than others of the same age (48%/38%). The fraction of patients who changed medication due to fear of COVID-19 were 4.1%/0.6%. Female gender, comorbidities, not working, lower education, biological treatment and poor European Quality of life, 5 dimensions were associated with both anxiety and self-isolation. CONCLUSION: In >12 000 patients with inflammatory arthritis, we found widespread anxiety and self-isolation, but high medication adherence, in the initial phase of the COVID-19 pandemic. This persisted during the gradual opening of society during the following months. Attention to patients' anxiety and self-isolation is important during this and potential future epidemics.

Reduced Humoral Response of SARS-CoV-2 Antibodies following Vaccination in Patients with Inflammatory Rheumatic Diseases-An Interim Report from a Danish Prospective Cohort Study.

Background/Purpose: In light of the current COVID-19 pandemic, whether patients with rheumatic musculoskeletal disease (RMD) treated with conventional (cs) or biologic (b) disease-modifying drugs (DMARDs) exhibit an adequate immune response to the currently available SARS-CoV-2 vaccinations remains a major concern. There is an urgent need for more SARS-CoV-2 vaccine efficacy data to inform healthcare providers on the potential need for a booster vaccine. We established the 'Detection of SARS-CoV-2 antibodies in Danish Inflammatory Rheumatic Outpatients' study (DECODIR) in March 2021 in order to assess and compare the immunoglobulin G (IgG response) of the SARS-CoV-2 BNT162b2 vaccine (Pfizer, Groton, CT, USA/BioNTech, Mainz, Germany) and mRNA-1273 vaccine (Moderna, Cambridge, MA, USA) administered as part of the national vaccine roll out in patients with RMDs, irrespective of treatment. Patients' SARS-CoV-2 IgG level was used as proxy to determine vaccination response. Methods: The study is a longitudinal prospective cohort study in which the SARS-CoV-2 antibody response was measured and compared at baseline and at six weeks following vaccination. The study population consisted of patients with rheumatoid arthritis (RA), spondyloarthropathies (SpA), or psoriatic arthritis (PsA) receiving their outpatient treatment at the Danish Hospital for Rheumatic Diseases, Sonderborg. Bloods, patient reported outcome measurements (PROMS), clinical data, and treatment information (cs/bDMARD) were collected at baseline/6 weeks and documented in the Danish DANBIO registry. Commercially available antibody tests (ThermoFisher, Waltham, MA, USA) were used, and SARS-CoV-2 IgG levels were reported in EliA U/mL. Sufficient IgG response was defined as ≥10 EliA U/mL (manufacturers cut-off). Associations between antibody response, age, gender, disease (RA/PsA/SpA), no treatment or cs/bDMARD treatment, and disease activity were tested using proportional odds regression and bootstrapped tests of medians. Results were reported using mean, median (IqR), and bootstrapped 95% confidence interval (CI) of the median. Results: A total of 243 patients were included. We observed a significant increase in IgG levels (median of <0.7 EliA U/mL at baseline versus 34.5 EliA U/mL at 6 weeks). Seventy-two patients (32%) had an insufficient IgG response. The median IgG level in patients treated with cs/bDMARD combination therapy was significantly lower compared to patients without any DMARD treatment (12 EliA U/mL vs. 92 EilA U/mL (p < 0.01)). Conclusion: Patients treated with a combination of cs/bDMARD are at significantly higher risk of an inadequate response to SARS-CoV-2 vaccines as measured by IgG level compared to patients without DMARD treatment. IgG SARS-CoV-2 are only part of the immune response, and further data are urgently needed. At present, our results may inform healthcare providers and policy makers on the decision for the need of a booster vaccine in this particular patient group.

The utility of magnetic resonance imaging lesion combinations in the sacroiliac joints for diagnosing patients with axial spondyloarthritis. A prospective study of 204 participants including post-partum women, patients with disc herniation, cleaning staff, runners and healthy persons.

OBJECTIVES: To investigate the diagnostic utility of different combinations of SI joint MRI lesions for differentiating patients with axial SpA (axSpA) from other conditions with and without buttock/pelvic pain. METHODS: A prospective cross-sectional study included patients with axSpA (n = 41), patients with lumbar disc herniation (n = 25), women with (n = 46) and without (n = 14) post-partum (birth within 4-16 months) buttock/pelvic pain and cleaning assistants (n = 26), long-distance runners (n = 23) and healthy men (n = 29) without pain. Two independent readers assessed SI joint MRI lesions according to the Spondyloarthritis Research Consortium of Canada MRI definitions and pre-defined MRI lesion combinations with bone marrow oedema (BME) and fat lesions (FAT), respectively. Statistical analyses included the proportion of participants with scores above certain thresholds, sensitivity, specificity, positive and negative predictive values and likelihood ratios. RESULTS: BME adjacent to the joint space (BME@joint space) was most frequent in axSpA (63.4%), followed by women with post-partum pain (43.5%), but was present in nearly all groups. BME adjacent to fat lesions (BME@FAT) and BME adjacent to erosions (BME@erosion) were only present in axSpA patients and in women with post-partum pain, but scores ≥3 and ≥4, respectively, were only seen in axSpA patients. FAT@erosion was exclusively recorded in axSpA patients. FAT@joint space and FAT@sclerosis were present in most groups, but with higher scores in the axSpA group. CONCLUSION: BME@joint space and FAT@joint space were frequent in axSpA but also in other conditions, reducing the diagnostic utility. FAT@erosion, and BME@FAT, BME@erosion and FAT@sclerosis above certain thresholds, were exclusively seen in axSpA patients and may thus have diagnostic utility in the differentiation of axSpA from other conditions.

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. METHODS: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. RESULTS: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. INTERPRETATION: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

What Level of Inflammation Leads to Structural Damage in the Sacroiliac Joints? A Four-Year Magnetic Resonance Imaging Follow-Up Study of Low Back Pain Patients.

OBJECTIVE: Sacroiliac (SI) joint bone marrow edema (BME) is considered to be pivotal in the detection of early spondyloarthritis. However, the link between BME and development of spondyloarthritis-related bone remodeling remains unclear. This study was undertaken to investigate the evolution of BME and structural lesions in the SI joints over time. METHODS: Baseline and 4-year follow-up magnetic resonance imaging scans were conducted in 604 patients ages 18-40 years who were referred with low back pain to an outpatient spine clinic. Eight SI joint regions were scored for BME and categorized as absent, limited (<25% of subcortical bone region), intermediate (25-50%), or extensive (>50%). Structural lesions including erosions and fat lesions were scored as absent or present. RESULTS: SI joint BME was seen at either time point (baseline or at 4 years) in 41% of participants but was persistent at both time points in only 16% of participants. Structural SI joint lesions developed according to the extent of BME at baseline: limited, intermediate, and extensive BME (as compared to absent BME) were independently associated with erosion at follow-up with odds ratios (ORs) of 3, 5, and 46, respectively, and with fat lesions (ORs 3, 7, and 33, respectively). In regions with limited and intermediate BME at baseline, 60% and 50% had resolved by follow-up, respectively, while only 2% and 7% had evolved into extensive BME by follow-up. CONCLUSION: While extensive SI joint BME was a strong independent predictor of development of structural lesions, limited and intermediate BME were mostly transient and only rarely evolved into extensive BME or structural lesions. These findings enhance our understanding of the natural development of SI joint lesions and indicate different progression patterns for limited/intermediate versus extensive BME, possibly due to different etiologies.

Magnetic Resonance Imaging of Lesions in the Sacroiliac Joints for Differentiation of Patients With Axial Spondyloarthritis From Control Subjects With or Without Pelvic or Buttock Pain: A Prospective, Cross-Sectional Study of 204 Participants.

OBJECTIVE: To evaluate whether different types of sacroiliac (SI) joint lesions identified by magnetic resonance imaging (MRI) could differentiate axial spondyloarthritis (SpA) from conditions with buttock or pelvic pain attributable to other reasons, including postpartum women and healthy subjects. METHODS: The study was designed as a prospective, cross-sectional study involving 204 participants, comprising patients with axial SpA (n = 41) and control groups of subjects with or without SI joint pain, including patients with lumbar disc herniation (n = 25), women with (n = 46) or without (n = 14) postpartum buttock/pelvic pain (having given birth within the preceding 4-16 months), hospital cleaning staff (n = 26), long-distance runners (n = 23), and healthy men (n = 29). Participants underwent clinical examination and MRI, and MRIs were evaluated in a blinded manner by 2 readers according to the Spondyloarthritis Research Consortium of Canada (SPARCC) SI joint inflammation and structural lesion scores. SPARCC score cutoff levels were defined as scores above a certain threshold. Primary analyses were based on reader agreement with regard to the presence of SI joint pathologic features on MRI ("concordant reads"). Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: SI joint ankylosis and backfill were detected by MRI only in patients with axial SpA (32% and 37%, respectively), while bone marrow edema (BME) and fat lesions were seen in all non-axial SpA control groups (3-39% with BME and 4-14% with fat lesions). SI joint erosion was present only in patients with axial SpA and in women with postpartum buttock/pelvic pain (at erosion score cutoffs of >1 and >4, 61% and 34%, respectively, in patients with axial SpA, and 9% and 2%, respectively, in women with postpartum buttock/pelvic pain). A SPARCC BME score of ≥5 was present only in patients with axial SpA (56%) and in women with postpartum buttock/pelvic pain (24%), while fat lesions were present, albeit rarely, at high SPARCC cutoff scores in nearly all groups. Of the 38 women from the non-postpartum control groups who had given birth (mean time since birth 9.7 years), 2 (5%) had BME, whereas none had SI joint erosion or fat lesions, and none had a BME score of ≥4. CONCLUSION: BME and fat lesions were most pronounced in patients with axial SpA, but also occurred in other groups, particularly women with postpartum buttock/pelvic pain. Erosion above a certain SPARCC score threshold as well as backfill and ankylosis were highly specific for axial SpA.

Effect of Magnetic Resonance Imaging vs Conventional Treat-to-Target Strategies on Disease Activity Remission and Radiographic Progression in Rheumatoid Arthritis: The IMAGINE-RA Randomized Clinical Trial.

Importance: Whether using magnetic resonance imaging (MRI) to guide treatment in patients with rheumatoid arthritis (RA) improves disease activity and slows joint damage progression is unknown. Objective: To determine whether an MRI-guided treat-to-target strategy vs a conventional clinical treat-to-target strategy improves outcomes in patients with RA in clinical remission. Design, Setting, and Participants: Two-year, randomized, multicenter trial conducted at 9 hospitals in Denmark. Two hundred patients with RA in clinical remission (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] <3.2 and no swollen joints) were enrolled between April 2012 and June 2015. The final follow-up visit was April 2017. Interventions: Patients were randomly allocated (1:1) to an MRI-guided vs a conventional treat-to-target strategy. In the MRI-guided group, the treatment goal was absence of MRI bone marrow edema combined with clinical remission, defined as DAS28-CRP of 3.2 or less and no swollen joints. In the conventional group, the treatment goal was clinical remission. Main Outcomes and Measures: Co-primary outcomes were proportions of patients achieving DAS28-CRP remission (DAS28-CRP <2.6) and with no radiographic progression (no increase in total van der Heijde-modified Sharp score) at 24 months. Significance testing for the primary outcome was based on 1-sided testing. Secondary outcomes were clinical and MRI measures of disease activity, physical function, and quality of life. Results: Of 200 patients randomized (133 women [67%]; mean [SD] age, 61.6 [10.5] years; median baseline DAS28-CRP, 1.9 [interquartile range, 1.7-2.2]; van der Heijde-modified Sharp score, 18.0 [interquartile range, 7.0-42.5]), 76 patients (76%) in the MRI-guided group and 95 (95%) in the conventional group completed the study. Of these, 64 (85%) vs 83 (88%), respectively, reached the primary clinical end point (risk difference, -4.8% [1-sided 95% CI, -13.6% to + ∞; 1-sided P = .19]) and 49 (66%) vs 58 (62%), respectively, reached the primary radiographic end point (risk difference, 4.7% [1-sided 95% CI, -7.0% to + ∞; 1-sided P = .25). Of 10 key secondary end points, 8 were null and 2 showed statistically significant benefit for the MRI treat-to-target group. Seventeen patients (17%) in the MRI-guided treat-to-target group and 6 patients (6%) in the conventional treat-to-target group experienced serious adverse events. Conclusions and Relevance: Among patients with RA in clinical remission, an MRI-guided treat-to-target strategy compared with a conventional treat-to-target strategy did not result in improved disease activity remission rates or reduce radiographic progression. These findings do not support the use of an MRI-guided strategy for treating patients with RA. Trial Registration: ClinicalTrials.gov Identifier: NCT01656278.

To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry.

OBJECTIVES: Real-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised. METHODS: Observational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted). RESULTS: 1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months' preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers' clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective. CONCLUSION: Seventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects.

Divergent effects on macrophage biomarkers soluble CD163 and CD206 in axial spondyloarthritis.

The chronic joint inflammation in axial spondyloarthritis (axSpA) is characterized by infiltration of activated macrophages. The haptoglobin-hemoglobin receptor CD163 and the mannose receptor CD206 are strongly expressed on M2c and M2a macrophages, respectively. We measured the soluble forms of the receptors (sCD163 and sCD206) in plasma (PL) in two axSpA cohorts. All patients fulfil the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axSpA and/or the 1984 modified New York criteria for ankylosing spondylitis. The first cohort included anti-TNF-α treated patients with active axSpA (n = 30); the second cohort included patients in early disease stages (n = 38). Plasma sCD163 and sCD206 were both within the reference interval of healthy controls (HC), but sCD163 decreased slightly during anti-TNF-α treatment [baseline: 1.49 mg/L (IQR: 1.22-1.77 mg/L, 12 weeks: 1.29 (IQR: 1.09-1.57) mg/L, 20 weeks: 1.25 (IQR: 0.99-1.75) mg/L, 52 weeks: 1.39 (IQR: 1.15-1.78) mg/L], while sCD206 increased [baseline: 0.17 (IQR: 0.13-0.21) mg/L, 12 weeks: 0.19 (0.16-0.23) mg/L, 20 weeks: 0.20 (0.14-0.24) mg/L, 52: 0.19 (IQR: 0.14-0.23) mg/L], pointing toward a shift in polarization of involved macrophages. Plasma levels of sCD206 proved significantly higher in patients with early disease stages and definite radiological sacroiliitis (n = 10). This was not the case for sCD163. A significant increase in response to anti-TNF-α treatment, could suggest sCD206 as a marker of response to anti-TNF-α treatment, however, the potential for the two macrophage markers as diagnostic and prognostic indicators of disease in axSpA is weak.

Development and Validation of MRI Sacroiliac Joint Scoring Methods for the Semiaxial Scan Plane Corresponding to the Berlin and SPARCC MRI Scoring Methods, and of a New Global MRI Sacroiliac Joint Method.

OBJECTIVE: To develop semiaxial magnetic resonance imaging (MRI) scoring methods for assessment of sacroiliac joint (SIJ) bone marrow edema (BME) in patients with axial spondyloarthritis, and to compare the reliability with equivalent semicoronal scoring methods. METHODS: Two semiaxial SIJ MRI scoring methods were developed based on the principles of the semicoronal Berlin and Spondyloarthritis Research Consortium of Canada (SPARCC) methods. A global quadrant-based method was also developed. Baseline and 12-week MRI of the SIJ from 51 patients participating in a randomized double-blind placebo-controlled trial of adalimumab 40 mg every other week versus placebo were scored by the semiaxial and the corresponding semicoronal methods. Results were compared by linear regression analysis. The reproducibility and sensitivity were evaluated by intraclass correlation coefficients (ICC) and smallest detectable change [SDC, absolute values and percentage of the highest observed score (SDC-HOS)]. RESULTS: Interreader and intrareader ICC were moderate to very high for semiaxial scoring methods (baseline 0.83-0.88 and 0.85-0.97; change 0.33-0.78), while high to very high for semicoronal scoring methods (baseline 0.90-0.92 and 0.93-0.97; change 0.77-0.89). Association between semiaxial and semicoronal scores were high for both the Berlin and SPARCC method (baseline: R2 = 0.93 and 0.88; change: R2 = 0.82 and 0.87, respectively), while lower for the global method (baseline: R2 = 0.79; change: R2 = 0.54). The SDC-HOS were 9.8-18.6% and 5.9-10.7% for the semiaxial and semicoronal methods, respectively. CONCLUSION: Detection of SIJ BME in the semiaxial scan plane is feasible and reproducible. However, a slightly lower reliability of all 3 semiaxial methods supports the general practice of using the coronal scan-plane in therapeutic studies.

A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry.

OBJECTIVES: According to guidelines, a nationwide non-medical switch from originator (INX, Remicade) to biosimilar infliximab (Remsima, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry. METHODS: Disease activities 3 months before and after switch and changes over time were calculated. Flare was defined as change in 28 Joint Disease Activity Score (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude and adjusted retention rates were compared with a historic cohort of INX-treated patients. RESULTS: Eight hundred and two patients switched (403 RA/120 PsA/279 AxSpA; 51% women, age (median (IQR): 55 (44-66)) years). Follow-up was 413 (339-442) days. Prior INX treatment duration was 6.8 (4.3-9.5) years. Disease activities were similar 3 months before/after switch. Crude 1-year CT-P13 retention rate (84.1 (95% CI 81.3 to 86.5)) was similar to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), p=0.22). The adjusted absolute retention rates were 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 to 88.8), respectively (p=0.03). In total 132 patients withdrew (lack of effect: 71/132=54%, adverse events: 37/132=28%). Patients with previous INX treatment duration >5 years had longer CT-P13 retention. CONCLUSION: In 802 arthritis patients treated with INX for median >6 years, a nationwide non-medical switch to CT-P13 had no negative impact on disease activity. Adjusted 1-year CT-P13 retention rate was slightly lower than for INX in a historic cohort.