Assessment of real-life patient handling experience of AVT02 administered subcutaneously via autoinjector in patients with moderate to severe active rheumatoid arthritis: an open-label, single-arm clinical trial, then an extension phase of AVT02 administered with a prefilled syringe.

BACKGROUND: This study investigated the ability of patients, naïve to adalimumab treatment and self-injection with an autoinjector (AI), to successfully self-administer AVT02, an adalimumab biosimilar, using a custom, ergonomic AI (Alvotech hf., Reykjavik, Iceland). RESEARCH DESIGN AND METHODS: This was a single-arm, open-label study, consisting of an 8-week active period and 48-week extension phase. Patients with moderate to severe rheumatoid arthritis (RA) self-administered 40 mg AVT02 subcutaneously via AI in the active period, followed by prefilled syringe in the extension phase. The primary endpoint was the percentage of successful self-injections up to Week 8. Usability and robustness of the AI were evaluated in the active period; safety, efficacy, pharmacokinetic and immunogenicity data were assessed throughout the study. RESULTS: The AI success rate was 100%. No handling events were noted up to Week 8. Both Ctrough measurements and immunogenicity profile were in line with expectations from previous studies, with no unexpected safety signals. CONCLUSIONS: This study demonstrated that AVT02-AI can be successfully and reliably used for repeated self-injections of AVT02 by moderate to severe RA patients, despite no previous experience of adalimumab self-administration. The extension phase provides long-term efficacy and safety data for AVT02 in RA. STUDY IDENTIFIER: NCT04224194.

Gender equity in academic rheumatology, current status and potential for improvement: a cross-sectional study to inform an EULAR task force.

OBJECTIVES: Evidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology. METHODS: This cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by χ2 test and t-test. RESULTS: Data from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work-life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement. CONCLUSIONS: There are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.

2019 EULAR points to consider for the assessment of competences in rheumatology specialty training.

BACKGROUND AND AIM: Striving for harmonisation of specialty training and excellence of care in rheumatology, the European League Against Rheumatism (EULAR) established a task force to develop points to consider (PtCs) for the assessment of competences during rheumatology specialty training. METHODS: A systematic literature review on the performance of methods for the assessment of competences in rheumatology specialty training was conducted. This was followed by focus groups in five selected countries to gather information on assessment practices and priorities. Combining the collected evidence with expert opinion, the PtCs were formulated by the multidisciplinary task force, including rheumatologists, medical educationalists, and people with rheumatic and musculoskeletal diseases. The level of agreement (LoA) for each PtC was anonymously voted online. RESULTS: Four overarching principles and 10 PtCs were formulated. The overarching principles highlighted the importance of assessments being closely linked to the rheumatology training programme and protecting sufficient time and resources to ensure effective implementation. In the PtCs, two were related to overall assessment strategy (PtCs 1 and 5); three focused on formative assessment and portfolio (PtCs 2-4); three focused on the assessment of knowledge, skills or professionalism (PtCs 6-8); one focused on trainees at risk of failure (PtC 9); and one focused on training the trainers (PtC 10). The LoA (0-10) ranged from 8.75 to 9.9. CONCLUSION: These EULAR PtCs provide European guidance on assessment methods throughout rheumatology training programmes. These can be used to benchmark current practices and to develop future strategies, thereby fostering continuous improvement in rheumatology learning and, ultimately, in patient care.

Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud's phenomenon and systemic sclerosis.

Capillaroscopy is a non-invasive and safe tool which allows the evaluation of the morphology of the microcirculation. Since its recent incorporation in the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for systemic sclerosis together with its assessed role to monitor disease progression, capillaroscopy became a 'mainstream' investigation for rheumatologists. Given its increasing use by a variety of physicians internationally both in daily practice to differentiate primary from secondary Raynaud's phenomenon, as well as in research context to predict disease progression and monitor treatment effects, standardisation in capillaroscopic image acquisition and analysis seems paramount. To step forward to this need, experts in the field of capillaroscopy/microcirculation provide in this very consensus paper their view on image acquisition and analysis, different capillaroscopic techniques, normal and abnormal capillaroscopic characteristics and their meaning, scoring systems and reliability of image acquisition and interpretation.

Patients with rheumatoid arthritis facing sick leave or work disability meet varying regulations: a study among rheumatologists and patients from 44 European countries.

OBJECTIVES: To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system's performance, across European countries. METHODS: We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates. RESULTS: Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (ß=-0.5 (95% CI -0.9 to -0.2) and ß=-0.5 (95% CI -1.0 to -0.1), respectively). The Scandinavian and Bismarckian system scored best on patients' and rheumatologists' perceptions of regulations and system performance. CONCLUSIONS: There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country's wealth.

Gender differences in early systemic sclerosis patients: a report from the EULAR scleroderma trials and research group (EUSTAR) database.

OBJECTIVES: To describe differences in clinical presentation between men and women in a large group of patients with early (<3 years' duration) systemic sclerosis (SSc) according to disease subsets. METHODS: A cross-sectional analysis of the prospective EULAR Scleroderma Trial and Research database (EUSTAR) was performed. Patients fulfilling preliminary ACR 1980 classification criteria for SSc, with less than 3 years from the first non-Raynaud's symptom at first entry, were selected. A group of patients with less than 3 years from the first SSc symptom, including Raynaud's phenomenon, was also analysed. SSc related variables, including antibodies, SSc subsets, disease activity and organ involvement were included. Descriptive and bivariate analyses were performed. RESULTS: A total of 1,027 patients were included, 90% Caucasian, 80% women, and 40% with diffuse cutaneous disease. In early stages of SSc, men showed more frequently than women active disease, diffuse cutaneous subset, anti-Scl-70 antibodies, elevated acute phase reactants, muscular and pulmonary involvement. Differences between men and women were confirmed in the limited, but not in the diffuse SSc subset. The results were similar when 650 patients with less than three years from the first SSc symptom, including Raynaud's phenomenon, were analysed. CONCLUSIONS: In early stages of SSc, men present signs and symptoms of more severe disease. In the limited disease subset, men might appear with clinical features and organ involvement similar to those of the diffuse subgroup. In clinical practice, the identification of such differences might help to select the appropriate management for each particular patient.

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study.

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001). Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review.

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice.

Definition and Reliability Assessment of Elementary Ultrasonographic Findings in Calcium Pyrophosphate Deposition Disease: A Study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force.

OBJECTIVE: To define the ultrasonographic characteristics of calcium pyrophosphate crystal (CPP) deposits in joints and periarticular tissues and to evaluate the intra- and interobserver reliability of expert ultrasonographers in the assessment of CPP deposition disease (CPPD) according to the new definitions. METHODS: After a systematic literature review, a Delphi survey was circulated among a group of expert ultrasonographers, who were members of the CPPD Ultrasound (US) Outcome Measures in Rheumatology (OMERACT) subtask force, to obtain definitions of the US characteristics of CPPD at the level of fibrocartilage (FC), hyaline cartilage (HC), tendon, and synovial fluid (SF). Subsequently, the reliability of US in assessing CPPD at knee and wrist levels according to the agreed definitions was tested in static images and in patients with CPPD. Cohen's κ was used for statistical analysis. RESULTS: HC and FC of the knee yielded the highest interobserver κ values among all the structures examined, in both the Web-based (0.73 for HC and 0.58 for FC) and patient-based exercises (0.55 for the HC and 0.64 for the FC). Kappa values for the other structures were lower, ranging from 0.28 in tendons to 0.50 in SF in the static exercise and from 0.09 (proximal patellar tendon) to 0.27 (triangular FC of the wrist) in the patient-based exercise. CONCLUSION: The new OMERACT definitions for the US identification of CPPD proved to be reliable at the level of the HC and FC of the knee. Further studies are needed to better define the US characteristics of CPPD and optimize the scanning technique in other anatomical sites.

Multiobserver Reliability of Ultrasound Assessment of Salivary Glands in Patients with Established Primary Sjögren Syndrome.

OBJECTIVE: To evaluate the multiobserver reliability of salivary gland ultrasonography (SGUS) for scoring greyscale (GS) parenchymal inhomogeneity and parenchymal color Doppler (CD) signal in patients with established primary Sjögren syndrome (pSS). METHODS: The study comprised 2 multiobserver reliability assessments in patients with pSS in 2 European centers. The first reliability exercise was performed on 24 patients with pSS and 8 controls who were independently evaluated with GS and CD US by 5 observers at the Institute of Rheumatology, Belgrade, Serbia. The second reliability exercise was carried out on 10 patients with pSS who were independently assessed with GS and CD US by 8 observers at the Hospital G.U. Gregorio Marañón, Madrid, Spain. SGUS parenchymal inhomogeneity and parenchymal CD signal were semiquantitatively scored using a 4-grade scoring system. The multiobserver agreement was calculated by the overall agreement and Light's κ statistics. RESULTS: A total of 640 SGUS examinations were performed in the first reliability exercise and a total of 320 examinations in the second reliability exercise. Multiobserver reliability was good (κ = 0.71-0.79) to excellent (κ = 0.81-0.82) for GS parenchymal inhomogeneity in both exercises. There was a moderate (κ = 0.53-0.58) to good (κ = 0.70) multiobserver reliability for parenchymal CD signal in the first exercise. However, there was no agreement or only a fair agreement (κ = 0.03-0.29) for parenchymal CD signal in the second exercise. CONCLUSION: US may be a reliable technique in the multiobserver scoring of GS parenchymal inhomogeneity of major SG in patients with established pSS. CD scoring of SG needs further standardization to be used in multicenter studies.

Assessment of clinical efficacy and safety in a randomized double-blind study of etanercept and sulfasalazine in patients with ankylosing spondylitis from Eastern/Central Europe, Latin America, and Asia.

Despite the demonstrated efficacy of etanercept for the treatment of ankylosing spondylitis (AS), sulfasalazine is often prescribed, especially in countries with limited access to biologic agents. The objective of this subset analysis of the ASCEND trial was to compare the efficacy of etanercept and sulfasalazine in treating patients with AS from Asia, Eastern/Central Europe, and Latin America. A total of 287 patients, 190 receiving etanercept 50 mg once weekly and 97 receiving sulfasalazine 3 g daily, from eight countries were included in this subset analysis. Differences in disease activity and patient-reported outcomes assessing health-related quality-of-life (HRQoL) parameters in response to treatment were analyzed using the Cochran-Mantel-Haenszel test for categorical efficacy endpoints and analysis of covariance model for continuous variables. At week 16, a significantly greater proportion of patients receiving etanercept achieved ASAS20 (79.0 %) compared with patients receiving sulfasalazine (61.9 %; p = 0.002). At week 16, treatment with etanercept also resulted in significantly better responses than sulfasalazine for ASAS40 (64.7 vs. 35.1 %; p < 0.001), ASAS5/6 (48.1 vs. 26.3 %; p < 0.001), proportion of patients achieving 50 % response in Bath AS Disease Activity Index (65.8 vs. 42.3 %; p < 0.001), partial remission (35.3 vs. 17.5 %; p = 0.002), and all HRQoL parameters. Both treatments were well tolerated. Etanercept was significantly more effective than sulfasalazine in the treatment of patients with AS from Asia, Central/Eastern Europe, and Latin America.

An OMERACT reliability exercise of inflammatory and structural abnormalities in patients with knee osteoarthritis using ultrasound assessment.

OBJECTIVE: To assess whether ultrasonography (US) is reliable for the evaluation of inflammatory and structural abnormalities in patients with knee osteoarthritis (OA). METHODS: Thirteen patients with early knee OA were examined by 11 experienced sonographers during 2 days. Dichotomous and semiquantitative scoring was performed on synovitis characteristics in various aspects of the knee joint. Semiquantitative scoring was done of osteophytes at the medial and lateral femorotibial joint space or cartilage damage of the trochlea and on medial meniscal damage bilaterally. Intra- and interobserver reliability were computed by use of unweighted and weighted κ coefficients. RESULTS: Intra- and interobserver reliability scores were moderate to good for synovitis (mean κ 0.67 and 0.52, respectively) as well as moderate to good for the global synovitis (0.70 and 0.50, respectively). Mean intra- and interobserver reliability κ for cartilage damage, medial meniscal damage and osteophytes ranged from fair to good (0.55 and 0.34, 0.75 and 0.56, 0.73 and 0.60, respectively). CONCLUSIONS: Using a standardised protocol, dichotomous and semiquantitative US scoring of pathological changes in knee OA can be reliable.

Access to biologic treatment for rheumatoid arthritis in Central and Eastern European (CEE) countries.

BACKGROUND: The aim of this study was to assess and compare patients' access to biologic anti-RA drugs in selected Central and Eastern European (CEE) countries and to analyze the determinants of differences between countries. MATERIAL/METHODS: This is a multi-country survey study, based on a combination of desk research and direct contact with national RA stakeholders. Data was collected using a pre-defined questionnaire. Affordability was measured using an affordability index, calculated comparing the index of health care expenditures to the price index, using Poland as an index of 1. RESULTS: The percentage of patients on biologic treatment in 2009 was highest in Hungary (5% RA patients on biologic treatment), followed by Slovenia (4.5%), Slovakia (3.5%), Czech Republic (2.92%), Romania (2.2%), Estonia (1.8%), and Croatia, Serbia, Poland (below 1.5%). Infliximab, etanercept, adalimumab and rituximab were included in the reimbursement system in all countries, but abatacept and tocilizumab were included only in Slovakia. In Slovenia, public payer covered 75% of the price, and 25% is covered by supplementary health insurance; in Bulgaria public payer covered 50% of etanercept and adalimumab costs, and 75% of rituximab cost. In other countries, biologic drugs are reimbursed at 100%. Affordability index for biologic drugs was the lowest in Slovenia (0.4). In each country national guidelines define which patients are eligible for biologic treatment. Disease Activity Score (DAS28) of over 5.1 and failure of 2 or more disease-modifying anti-RA drugs, including methotrexate, are commonly used criteria. CONCLUSIONS: The most important factors limiting access to biologic anti-RA treatment in the CEE region are macroeconomic conditions and restrictive treatment guidelines.

Are COX-2 inhibitors preferable to combined NSAID and PPI in countries with moderate health service expenditures?

RATIONALE: In developed countries, cyclooxygenase 2 (COX-2) inhibitors were shown to be less costly than the combination of non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) in treatment of patients with high risk of serious gastrointestinal (GI) adverse effects. It is questionable if such results apply to developing countries where health service costs are lower and there is high discrepancy between generic and patent protected drug prices. We analysed the direct cost of treatment with generic NSAIDs in combination with PPIs versus branded COX-2 inhibitors in patients with high risk of serious GI adverse effects from the perspective of the public health service in Serbia. METHODS: Total cost of treatment of serious GI complications and the use of NSAID+PPI versus COX-2 inhibitors were calculated. A model for estimation of cost of treatment of NSAID+PPI versus COX-2 inhibitors which included the probability of developing serious GI adverse effects was developed. RESULTS: Total cost of treatment of serious GI adverse effects resulted in an average of $814/patient. Considering the relative risk of such adverse effects for patients with four or more risk factors, the least costly treatment over 6 months was the use of celecoxib ($487). Compared with diclofenac+omeprazole, cost savings were estimated at $59 and $22 per patient with celecoxib and etoricoxib, respectively. CONCLUSION: Cost savings may be achieved by using COX-2 inhibitors in patients at high risk of GI adverse effects even in countries with moderate health care service expenditures. Such possibility requires further investigation.

Indices of the Scleroderma Assessment Questionnaire (SAQ) can be used to demonstrate change in patients with systemic sclerosis over time.

OBJECTIVE: This study aims to estimate the value of the Scleroderma Assessment Questionnaire (SAQ) to demonstrate change in patients (pts) with systemic sclerosis (SSc) over time. METHODS: Sixty pts with SSc were evaluated at two occasions, 12 months apart. Pts were divided into three subgroups according to criteria of improved, unchanged or deteriorated status of vascular, respiratory, gastrointestinal and musculosceletal system. All pts filled in the SAQ as part of both evaluations, and the Index of Vascular Status (IVS), Index of Respiratory Status (IRS), Index of Gastrointestinal status (IGS) and Index of Musculoskeletal Status (IMSS) were calculated. Average index scores for particular organ system at the beginning and after the follow-up period in all subgroups of pts were compared. RESULTS: The mean value of IVS decreased significantly in pts with objectively improved vascular status (1.91 vs. 1.29, p=0.01), but increased in pts with deteriorated status (1.54 vs. 2.13, p=0.003). In the subgroup of pts with unchanged vascular morphology or function, the IVS did not change significantly either (1.84 vs. 1.77, p=0.36). The mean value of IRS decreased significantly in pts with objectively improved lung function (1.08 vs. 0.62, p=0.027), and increased in pts with deteriorated function (0.69 vs. 1.12, p=0.012). In the subgroup of pts with unchanged pulmonary function, the IRS did not change significantly (0.13 vs. 0.14, p=0.18). A statistically significant decrease in mean IGS value was found in pts who were treated with prokinetics (1.20 vs. 0.70, p<0.001). In pts who were not treated with prokinetics, an increase of IGS was observed (0.58 vs. 0.76, p=0.002). Differences between mean values of the IMSS were statistically significant in subgroups of pts with improved (1.28 vs. 0.90, p=0.004) or deteriorated musculoskeletal status (0.98 vs. 1.44, p=0.012), but not in pts with unchanged condition of this organ system (0.72 vs. 0.68, p=0.498). CONCLUSION: The SAQ is a sensitive measurement to demonstrate change in patients with SSc over time.