Real-world effectiveness of golimumab in the treatment of patients with active rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis who failed initial TNF-α inhibitor therapy: a pooled analysis of European prospective observational studie.

OBJECTIVES: Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients often experience secondary non-response to a first-line tumour necrosis factor alpha inhibitor (TNFαi). This pooled analysis of six observational studies in Europe (GO-BEYOND program) provides an estimate of second-line golimumab (GLM) effectiveness for these rheumatic diseases. METHODS: The GO-BEYOND studies included common disease-specific endpoints allowing for a pooled analysis. Patients had discontinued one prior TNFαi (due to loss of efficacy, tolerability, or inconvenience) and were followed for 12 months after GLM initiation. Primary endpoints included the proportion of patients achieving low disease activity (LDA, DAS28-CRP<3.2) in RA, minimal disease activity (MDA, fulfilment of 5 of 7 outcome measures) in PsA, or low disease activity (ASDAS<2.1) in axSpA at 6 months. Disease activity at 3 and 12 months and quality of life (QoL; EQ-5D-3L) were also assessed. Adverse events were monitored. Protocol-specified analyses were based on observed data. RESULTS: In 712 patients, (n=325, RA; 186, PsA; 201, axSpA), mean age was 54 years, 64% were female, and median disease duration was 5 years. Primary endpoints were achieved in 58.3% (RA), 45.5% (PsA), and 45.4% (axSpA) of patients; disease activity improvements were observed at 3 and 12 months and EQ-5D-3L results showed improved QoL over time. The treatment persistence rate at 12 months was 67.8% of patients. No new safety signals were observed. CONCLUSIONS: This pooled analysis of the GO-BEYOND studies showed that treatment with GLM was effective and represented a valid second-line option for RA, PsA, and axSpA patients.

Sustained effectiveness and safety of subcutaneous tocilizumab over two years in the ARATA observational study.

OBJECTIVES: To investigate long-term effectiveness and safety of subcutaneous tocilizumab (TCZ-SC) in the routine clinical care of patients with rheumatoid arthritis (RA). METHODS: ARATA (ML29087) was a prospective, multicentre, observational study of adult patients with active RA initiating therapy with TCZ-SC. The primary effectiveness outcome was the proportion of patients achieving DAS28-ESR <2.6 at week 104. Additional efficacy outcomes included individual DAS28-dcrit responses (improvement of ≥1.8 from baseline), CDAI remission (≤2.8), and patient-reported outcomes (PROs), including Work Productivity and Activity Impairment scores. Adverse event rates were used to evaluate safety and tolerability. RESULTS: Between May 2014 and July 2018, 114 study centres in Germany enrolled 1,300 patients with RA who received at least one dose of TCZ-SC (mean age 57.3 [SD 12.5] years, mean DAS28-ESR of 4.9 [SD 1.3]). At week 104, 58.7% (365/622) patients achieved DAS28-ESR <2.6, 64.0% had an individual DAS28-dcrit response, and 31.4% (241/767) achieved CDAI remission. PROs, including patient global assessment, pain, and fatigue, showed marked improvements from baseline. Work outcomes, including absenteeism (missed work) and presenteeism (productivity while at work), also improved. Injection reactions were rare and no new safety signals occurred. Patients expressed a high level of satisfaction with treatment. Baseline patient characteristics and outcomes were similar for ARATA and ICHIBAN (an observational study of TCZ-IV in Germany), despite different formulations and time periods. CONCLUSIONS: The safety and effectiveness of TCZ-SC is maintained over 2 years during routine clinical care. TCZ-SC represents a convenient and effective option for RA patients who prefer SC administration.

The safety and effectiveness of tocilizumab in elderly patients with rheumatoid arthritis and in patients with comorbidities associated with age.

OBJECTIVES: To examine the safety and effectiveness of long-term tocilizumab treatment in elderly patients with rheumatoid arthritis (RA) and patients with age-associated comorbidities. METHODS: ICHIBAN (NCT01194401) was a prospective, non-interventional study that observed adult patients with active moderate-to-severe RA in German rheumatology clinics and practices for up to two years. Patients were to be treated according to the tocilizumab label. Here, we present safety and effectiveness data analysed according to patient age. RESULTS: Of the 3,164 patients treated with at least one dose of tocilizumab, 924 patients were <50 years old, 1496 patients were 50-65 years old, and 744 patients were >65 years old at baseline. Patients >65 years had the highest baseline DAS28-ESR, CDAI, and HAQ-DI scores, along with the highest burden of comorbidities, such as diabetes, coronary heart disease, anaemia, and renal insufficiency. Under treatment with tocilizumab, patients >65 years had similar improvements in DAS28-ESR, CDAI and patient-reported outcomes (fatigue, pain, sleeplessness) with similar glucocorticoid savings compared to patient groups <65 years. Patients >65 years with late-onset RA achieved similar reductions in disease activity compared to early-onset patients. Despite numerically higher rates of adverse events (AEs), serious AEs and serious infections in patients >65 years, there were similar rates of AEs leading to withdrawal. CONCLUSIONS: Elderly patients in ICHIBAN experienced improvements similar to younger patients in most effectiveness endpoints with only slightly higher rates of AEs, indicating an overall net-positive risk-benefit ratio of tocilizumab treatment regardless of patient age.

Characterisation of depressive symptoms in rheumatoid arthritis patients treated with tocilizumab during routine daily care.

OBJECTIVES: To assess whether tocilizumab treatment is associated with changes in depression symptoms in patients with rheumatoid arthritis (RA) during routine daily care. METHODS: We retrospectively analysed data from a German non-interventional study (ARATA) of adult, tocilizumab-naïve RA patients who initiated subcutaneous tocilizumab and were followed for 52 weeks. The Beck Depression Inventory II (BDI-II) was used to assess symptoms of depression and create baseline subgroups of no (BDI-II<14), mild (14-19), moderate (20-28), and severe (≥29) depression. Other key outcomes included Disease Activity Score-28 joints (DAS28), patient-reported outcomes (PROs), and adverse events. Mixed model repeated measures (MMRM) assessed the impact of DAS28 on BDI-II over time, and Pearson correlation analyses evaluated associations between changes from baseline. RESULTS: Of 474/1155 ARATA patients who completed the BDI-II at baseline, 47.7% had evidence of depression: 18.4% mild, 17.7% moderate, and 11.6% severe. 229 patients (48.3%) completed the BDI-II at both baseline and week 52. Two-thirds of patients with moderate or severe depression at baseline improved to a milder or no depression subgroup at week 52 (44/65 [67.7%]). Improvements in disease activity and PROs were observed in all subgroups, but patients with depression had lower response and higher adverse events rates. We observed an association between DAS28 and BDI-II over time in MMRM analyses, but the Pearson correlation for change from baseline was weak (r=0.10). CONCLUSIONS: Depression is common in patients receiving routine care for RA. Improvements in depressive symptoms in RA during tocilizumab therapy appear to be distinct from changes in disease activity.

Rituximab plus leflunomide in rheumatoid arthritis: a randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study).

OBJECTIVE: To investigate the efficacy and safety of rituximab + LEF in patients with RA. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators' control. RESULTS: Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders. CONCLUSION: The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring. TRIAL REGISTRATION: EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958.

ICHIBAN, a non-interventional study evaluating tocilizumab long-term effectiveness and safety in patients with active rheumatoid arthritis.

OBJECTIVES: We aimed to measure long-term effectiveness and safety of tocilizumab in patients with rheumatoid arthritis in daily German practice. METHODS: ICHIBAN was a prospective, multi-centre, non-interventional study (ML22928) that enrolled adult patients with active moderate to severe rheumatoid arthritis. Patients were to be treated according to tocilizumab label and observed for up to two years. Effectiveness outcomes included DAS28-ESR remission, EULAR response, CDAI and HAQ. RESULTS: Overall, 3164 patients received at least one dose of tocilizumab. Patient mean age was 55.5±13.1 years (74.8% female). At baseline, 72.1% of patients had at least one comorbidity. Approximately 50.9% of patients received concomitant csDMARDs, mostly methotrexate, and 80.7% received concomitant glucocorticoids (GCs). In patients receiving GCs at baseline, the mean dose decreased from 9.32±16.36 mg/d to 4.60±4.48 mg/d at week 104. In the effectiveness population with no prior TCZ (n=2902), 61.4% of patients achieved the primary outcome, DAS28-ESR remission. Improvements were seen as early as week 4. At week 104, 77.9% of patients had DAS28-ESR low disease activity, 89.6% achieved good or moderate EULAR response, and 29.5% achieved a CDAI-based remission. Effectiveness outcomes were similar in all previous therapy subgroups. The incidence of serious infections was similar to the rates in former studies involving tocilizumab. Patients receiving GC at baseline experienced slightly higher rates of treatment-related serious adverse events, mainly infections. No new safety signals were observed. CONCLUSIONS: Long-term effectiveness and safety in ICHIBAN were in line with previously reported tocilizumab efficacy and safety studies.

Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study.

OBJECTIVE: To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR). METHODS: In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug. RESULTS: At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40-CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity. CONCLUSION: Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study. TRIAL REGISTRATION NUMBER: NCT01751776.

Early and late responses in patients with rheumatoid arthritis who were conventional synthetic disease-modifying anti-rheumatic drug inadequate responders and were treated with tocilizumab or switched to rituximab: an open-label phase 3 trial (MIRAI).

OBJECTIVES: To evaluate early and late responses in biological-naïve patients with rheumatoid arthritis (RA) initiating tocilizumab and early tocilizumab non-responders who switched to rituximab. METHODS: In this open-label, non-randomised phase 3 study, RA patients with inadequate response to conventional synthetic DMARDs received tocilizumab 8 mg/kg intravenously at study begin and weeks 4, 8 and 12. After evaluation at week 16, early responders (Disease Activity Score based on 28 joints-erythrocyte sedimentation rate [DAS28-ESR] <2.6) completed the study; partial responders (DAS28-ESR decrease >1.2 or DAS28-ESR ≥2.6-≤3.2) were to continue tocilizumab through week 28; non-responders (DAS28-ESR decrease ≤1.2) switched to rituximab (1000 mg, weeks 16 and 18) with safety follow-up through week 66. RESULTS: Of 519 patients, 222 (42.8%) achieved early DAS28-ESR remission at week 16; 240 patients continued treatment, 213 (41.0%) received tocilizumab, and 27 (5.2%) switched to rituximab. At week 32 DAS28-ESR remission was achieved by 117/213 patients (54.9%) who continued tocilizumab and 4/27 patients (14.8%) who switched to rituximab; good EULAR response was achieved by 66.7% and 25.9% and CDAI remission by 19.2% and 14.8% of patients, respectively. Serious adverse events occurred through week 32 in 45/490 patients (9.2%) who received tocilizumab (serious infections, 2.7%) and through week 66 in 8/27 patients (29.6%) who switched to rituximab. CONCLUSIONS: Early response to tocilizumab was observed in 42.8% of patients. Half of early partial responders benefitted from continuing tocilizumab. Switching non-responders to rituximab seems feasible. No new safety signals were observed in patients treated with tocilizumab or switched to rituximab.

[Rheumatism and gastroenterology]. / Rheuma und Gastroenterologie.

BACKGROUND: Gastroenterological and rheumatological diseases often have a systemic character, with disease manifestations beyond the area affected by the disease. Common disease-relevant pathophysiological pathways, e.g. chronic inflammation, may present primarily as rheumatological or gastroenterological disease. Knowledge of disease-specific symptoms and signs beyond one's own area of expertise my lead to an earlier and more precise diagnosis, with the chance of a more focused therapy. AIM: The aim of this overview is to sensitize orthopedists as well as rheumatologists to gastroenterological signs and symptoms and give them a clinical guide to approaching an interdisciplinary patient. Targeted, clinically relevant questions are discussed and common disease entities are presented.

Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

OBJECTIVES: To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans , in a multicentre trial setting. METHODS: DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated. RESULTS: At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks. CONCLUSION: This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials. KEY POINTS: • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.

Long-term effects of secukinumab on MRI findings in relation to clinical efficacy in subjects with active ankylosing spondylitis: an observational study.

INTRODUCTION: A 28-week study suggested efficacy of the anti-interleukin-17A monoclonal antibody secukinumab in active ankylosing spondylitis (AS). MRI-assessed inflammation was reduced at weeks 6, 28. OBJECTIVE: To analyse the longer-term effects of secukinumab on MRI inflammatory and non-inflammatory spinal lesions in relation to its clinical efficacy in subjects with active AS. METHODS: Spinal MRI results (baseline, week 94) for 13 subjects with AS initially treated with secukinumab 2×10 mg/kg intravenously (n=10) or placebo (n=3) and receiving a secukinumab maintenance dose of 3 mg/kg IV every 4 weeks up to week 94 were evaluated by the Berlin score; inflammatory/non-inflammatory (fatty) changes were assessed at vertebral edges (VEs). Results were compared with clinical outcomes. RESULTS: Most of the 13 subjects assessed at week 94 had sustained clinical responses: 8 (62%) achieved Assessment of SpondyloArthritis international Society 20% (ASAS20), including 6 (46%) achieving ASAS40 responses, corresponding to 75% and 83% reductions in the Berlin score, respectively. In the 10 subjects treated with secukinumab throughout the study period, 79/91 (87%) inflammatory VEs at baseline resolved by week 94; new fatty lesions occurred in 39/796 (4.9%) of VEs; 87/124 (70%) VEs with fatty lesions at baseline remained unchanged; 30% were no longer visible. CONCLUSIONS: In this pilot study, secukinumab treatment up to 2 years yielded sustained clinical improvement accompanied by regression of spinal inflammation. The impact of secukinumab on the development of fatty changes and bone formation in AS will be assessed in larger trials. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov, number NCT00809159.

Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. METHODS: We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. FINDINGS: 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. INTERPRETATION: Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. FUNDING: Novartis.

German guidelines for the sequential medical treatment of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs.

The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease-modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice.

Real-World Effectiveness and Safety of SDZ ETN, an Etanercept Biosimilar, in Patients with Rheumatic Diseases: Final Results from Multi-Country COMPACT Study.

INTRODUCTION: COMPACT, a non-interventional study, evaluated the persistence, effectiveness, safety and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA), axial-spondyloarthritis (axSpA) or psoriatic arthritis (PsA) treated with SDZ ETN (etanercept [ETN] biosimilar) in Europe and Canada. METHODS: Patients (aged ≥ 18 years) who have been treated with SDZ ETN were categorised on the basis of prior treatment status (groups A-D): patients in clinical remission or with low disease activity under treatment with reference ETN or biosimilar ETN and switched to SDZ ETN; patients who received non-ETN targeted therapies and switched to SDZ ETN; biologic-naïve patients who started SDZ ETN after conventional therapy failure; or disease-modifying anti-rheumatic drug (DMARD)-naïve patients with RA considered suitable for treatment initiation with a biologic and started on treatment with SDZ ETN. The primary endpoint was drug persistence, defined as time from study enrolment until discontinuation of SDZ ETN treatment. RESULTS: Of the 1466 patients recruited, 844 (57.6%) had RA, 334 (22.8%) had axSpA and 288 (19.6%) had PsA. Patients had an ongoing SDZ ETN treatment at the time of enrolment for an observed average of 138 days (range 1-841); 22.7% of patients discontinued SDZ ETN through 12 months of study observation. Overall, all the patients receiving SDZ ETN showed good treatment persistence at 12 months with discontinuation rates of 15.2%, 25.7% and 27.8% in groups A, B and C, respectively. Across all patient groups, no major differences were observed in the disease activity and PRO scores between baseline and month 12. Injection-site reactions were low across the treatment groups. CONCLUSION: These results support the effectiveness and safety of SDZ ETN treatment in patients with RA, axSpA or PsA in real-life conditions. The treatment persistence rates observed were consistent with previously published reports of patients treated with reference or other biosimilar ETN. No new safety signals were identified.

The US7 score is sensitive to change in a large cohort of patients with rheumatoid arthritis over 12 months of therapy.

PURPOSE: To determine the sensitivity to change of the US7 score among RA patients under various therapies and to analyze the effect of each therapeutic option over 1 year. To estimate predictors for development of destructive bone changes. METHODS: Musculoskeletal ultrasound (US7 score), DAS28, CRP and ESR were performed in 432 RA patients at baseline and after 3, 6 and 12 months. The cohort was divided into four sub-groups: first-line DMARDs (Group 1; 27.3%), therapy switch: DMARDs to second DMARDs (Group 2; 25.0%), first-line biologic after DMARDs therapy (Group 3; 35.4%) and therapy change from biologic to second biologic (Group 4; 12.3%). RESULTS: The US7 synovitis and tenosynovitis sum scores in grey-scale (GSUS) and power Doppler ultrasound (PDUS) as well as ESR, CRP decreased significantly (p<0.05) after 12 months in group 1 to 3. Group 1+2 also illustrated a significant change of DAS28 after 1 year (p<0.001). Only in Group 4, the US7 erosion sum score decreased significantly from 4.3 to 3.6 (p=0.008) after 1 year. Predictors capable of forecasting US erosions after one year were: higher score of US7 synovitis (p<0.001), of US7 erosions in GSUS (p<0.001), as well as of DAS28 (p<0.001) at baseline. CONCLUSIONS: The comparable developments of the US7 score with clinical and laboratory data illustrates its potential to reflect therapeutic response. Therefore, the novel US7 score is sensitive to change. Patients who switched from one biologic to another exhibited a significant decline in erosions after 12 months, while the erosions scores in the other groups were stable.

Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study.

OBJECTIVE: To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA). METHODS: Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16. RESULTS: Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one). CONCLUSIONS: ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

Assessment of therapeutic response in ankylosing spondylitis patients undergoing anti-tumour necrosis factor therapy by whole-body magnetic resonance imaging.

OBJECTIVES: Multifocal musculoskeletal inflammation is common in ankylosing spondylitis (AS) and is effectively treated by expensive anti-TNF (tumour necrosis factor) therapy. This study evaluated assessment of response by whole-body (WB) MRI compared with clinical assessment in AS patients during etanercept therapy. METHODS: Ten patients with AS underwent a 12-month therapy with etanercept. Clinical markers were monitored [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP)] and patients underwent WBMRI (1.5 T, STIR and T1-weighted) at three different time points (0, 26 and 52 weeks). WBMRI was evaluated and correlated with clinical scores. RESULTS: The BASDAI index decreased under therapy from 5.5 ± 0.5 (week 0) to 1.7 ± 0.5 (week 52, P < 0.05). CRP declined from 15.7 ± 2.2 mg/dl (week 0) to 0.9 ± 0.9 mg/dl (week 52, P < 0.05). In WBMRI, the sum of all lesions showed a significant decrease from week 0 (38.9 ± 3.4) to week 52 (2.2 ± 0.9, 94.3 % reduction). WBMRI detected more areas of synovitis and enthesitis than clinical examination alone. CONCLUSIONS: AS activity significantly decreased under etanercept therapy, which was proven by clinical examination and WBMRI. WBMRI detected more inflammatory lesions than clinical examination alone. The results suggest that WBMRI improves the detection of inflammatory changes and the assessment of their course under therapy. KEY POINTS: • Multifocal musculoskeletal inflammation in AS is effectively treated by anti-TNF therapy. • Inflammatory lesions can be assessed by clinical examination and whole-body MRI. • AS activity significantly decreased under therapy as shown by WBMRI/clinical examination. • WBMRI detected more inflammatory lesions than clinical examination alone. • WBMRI improves detection of inflammatory changes and may help evaluation of therapy.

Evaluation of the novel ultrasound score for large joints in psoriatic arthritis and ankylosing spondylitis: six month experience in daily clinical practice.

BACKGROUND: To evaluate the utility of the recently introduced SOLAR score (sonography of large joints in Rheumatology), which has been validated in RA patients, in a cohort of patients with Psoriatic Arthritis (PsA) and Ankylosing Spondylitis (AS) presenting with involvement of large peripheral joints. METHODS: The recently established SOLAR score has been designed to determine the degree of inflammation in the shoulder, the elbow, the hip and the knee joint in patients suffering from RA. Since large joints are frequently involved in PsA and AS, synovitis and synovial vascularity were scored semiquantitatively (grade 0-3) by grey scale (GSUS) and power Doppler ultrasound (PDUS) utilizing the validated scoring system. Each joint was scanned from different angles, the knee joint for example was divided into four areas to score for synovitis: the suprapatellar longitudinal, the medial longitudinal, the lateral longitudinal, and the posterior region. Each area was scored from 0-3, so a maximum score of 12 could be achieved. PsA and AS patients presenting with peripheral joint disease involving large joints were examined at baseline, 3 and 6 months after initiation of local or systemic therapy (DMARDs/Biologics). For evaluation of the inflammatory status, the erythrocyte sedimentation rate (ESR) was determined. RESULTS: A cohort of 126 patients were enclosed, and 83 of these were followed for 6 months. At baseline before modification of the therapy, patients received DMARDs (n = 83), DMARDs plus biologics (n = 30), or biologic monotherapy (n = 29). Following intervention, all US scores demonstrated a marked improvement. The GSUS and the PDUS scores for all joint areas, except the PDUS score of the hip, exhibited a significant improvement (p < 0.05), while the GSUS of the knee showed even a highly significant (p < 0.001) change. The ESR displayed a significant decrease from 27 to 19 mm (p < 0.002) representing good treatment response. CONCLUSION: The SOLAR score, which has been recently introduced for RA patients, is a very suitable instrument for the qualitative and quantitative evaluation of large joint involvement in PsA and AS patients and allows for treatment monitoring.

The Sensitivity to Change of the ASAS Health Index in an Observational Real-Life Cohort Study.

OBJECTIVE: The Assessment of Spondyloarthritis international Society Health Index (ASAS HI) measures global functioning and health in patients with axial spondyloarthritis (axSpA) covering domains of physical, emotional, and social functioning. The main aim of this study was to investigate the sensitivity to change of ASAS HI in comparison with established variables of disease activity, function, and mental health. METHODS: Patients with axSpA from the disease register RABBIT-SpA with follow-up time of at least 12 months and available ASAS HI questionnaires were included. Patients received questionnaires addressing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), mental health (5-item World Health Organization Well-Being Index [WHO-5]), and global functioning (ASAS HI). Standardized response means (SRMs) were calculated to compare the sensitivity to change of different variables. RESULTS: Six hundred and sixty-seven patients were included, 552 treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and 115 with conventional synthetic DMARDs and/or nonsteroidal antiinflammatory drugs (control group). Between baseline and month 12, the mean ASAS HI declined from 6.9 to 5.1 in the bDMARD group and from 5.9 to 5.6 in the conventionally treated group. In the bDMARD group, the SRM of ASAS HI was 0.52, compared to 0.59 for BASFI, 0.65 for WHO-5, 0.73 for BASDAI, and 0.90 for ASDAS. The following ASAS HI domains were most frequently affected: pain (78% agreed), maintaining body position (75%), and energy/drive (73%). In the patients receiving bDMARDs, there was an improvement in all items. In the control group, the largest improvement was seen in pain. CONCLUSION: As expected, ASDAS and BASDAI as disease activity scores showed high sensitivity to change, whereas changes in physical function (BASFI), mental health (WHO-5), and the broader concept of functioning and health (ASAS HI) were moderate.

Methotrexate plus ustekinumab versus ustekinumab monotherapy in patients with active psoriatic arthritis (MUST): a randomised, multicentre, placebo-controlled, phase 3b, non-inferiority trial.

BACKGROUND: The role of methotrexate in combination with biological agents in patients with psoriatic arthritis remains unclear. The MUST phase 3b trial aimed to compare the efficacy of ustekinumab plus placebo with ustekinumab plus methotrexate in patients with active psoriatic arthritis. METHODS: In this investigator-initiated, randomised, multicentre, placebo-controlled, phase 3b non-inferiority trial done in 22 centres in Germany, patients with active psoriatic arthritis received open-label ustekinumab and were randomly assigned (1:1) to masked concomitant therapy with placebo or methotrexate (ongoing or new). The primary outcome was non-inferiority of mean Disease Activity Score-28 joints (DAS28) at week 24 for ustekinumab monotherapy (ustekinumab plus placebo) versus ustekinumab combination therapy (ustekinumab plus methotrexate), stratified by previous methotrexate treatment. The key secondary analysis was non-inferiority of DAS28 at week 52. The primary analysis was based on a stratified van Elteren test with an α of 2·5% and a non-inferiority margin of 12·5% by Mann-Whitney estimator. Adverse events and serious adverse events were assessed. This study is registered with ClinicalTrials.gov, NCT03148860. FINDINGS: Between Jan 24, 2017, and April 12, 2021, 186 patients with active psoriatic arthritis were screened, of whom 173 (93%) patients were enrolled and randomly assigned (1:1) to receive concomitant methotrexate therapy (n=88) or placebo (n=85). 84 patients were receiving methotrexate at baseline, and 89 patients had no previous methotrexate treatment. 166 (96%) patients (87 in the ustekinumab plus methotrexate group and 79 in the ustekinumab plus placebo group) were included in the safety and efficacy analyses at week 24 (69 [42%] female; 97 [58%] male; mean age 48·2 years [SE 1·1]). Ustekinumab plus placebo was non-inferior to ustekinumab plus methotrexate in DAS28 at week 24 (2·9 [SD 1·31] vs 3·1 [1·42]); the stratified Mann-Whitney estimator for treatment comparison was 0·5426 (95% CI 0·4545-0·6307). Non-inferiority for ustekinumab plus placebo was also observed in DAS28 at week 52. Serious adverse events occurred in seven (9%) patients in the ustekinumab plus placebo group and eight (9%) patients in the ustekinumab plus methotrexate group. No specific serious adverse events affected more than one patient, and there were no deaths. INTERPRETATION: Interleukin (IL)-12 and IL-23 inhibition with ustekinumab is an effective treatment for psoriatic arthritis independent of methotrexate use; concomitant methotrexate did not increase efficacy of ustekinumab (based on DAS28). On the basis of these data, there is no evidence to support the addition or maintainance of methotrexate when initiating ustekinumab in patients with active psoriatic arthritis. FUNDING: Janssen Cilag.