American College of Rheumatology Guidance for the Management of Pediatric Rheumatic Disease During the COVID-19 Pandemic: Version 2.

OBJECTIVE: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus. RESULTS: To date, 39 guidance statements have been approved by the task force. Those with similar recommendations were combined to form a total of 33 final guidance statements, all of which received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n = 5) or high consensus (n = 28). CONCLUSION: These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated.

Collaborative study for the establishment of Infliximab Biological Reference Preparation Batch 1.

Two preparations of the chimeric anti-Tumour Necrosis Factor (TNF) monoclonal antibody Infliximab were formulated and lyophilised at the National Institute for Biological Standards & Control (NIBSC) prior to evaluation in a collaborative study for their suitability to serve as a World Health Organization (WHO) International Standard (IS)/European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for the potency assay of Infliximab. Twenty-six laboratories tested the preparations using different in vitro cell-based bioassays (TNF-α neutralisation, antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity) and binding assays. Amongst them, 19 laboratories performed cell-based bioassays. The results of this study indicated that the candidate preparation coded 16/170 was suitable to serve as an International Standard for Infliximab based on the data obtained for biological activity. This candidate standard was established in 2017 as the first International Standard for Infliximab with an assigned potency for TNF neutralisation activity of 500 IU per ampoule. In the same study, the suitability of preparation 16/170 of Infliximab to serve as the European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for the Infliximab potency assay as described in the Ph. Eur. monograph on Infliximab concentrated solution (2928) was also evaluated. The corresponding analysis, based on the measurement of the inhibitory action of anti-human TNF (Infliximab) on the cytotoxic activity of TNF-alpha, was performed using data from a subset of 9 laboratories using the TNF-alpha-sensitive fibrosarcoma cell line WEHI-164. The results obtained were compared to those obtained from different cell-based neutralisation assays that were used by other laboratories in the context of establishing the 1st World Health Organization (WHO) International Standard (IS) for Infliximab. Based on the analyses, preparation 16/170 was adopted by the Ph. Eur. Commission in June 2018 as Infliximab BRP batch 1 with an assigned potency of 500 IU per ampoule.

Batch-to-Batch Consistency of SB4 and SB2, Etanercept and Infliximab Biosimilars.

BACKGROUND: Biosimilars must meet stringent regulatory requirements, both at the time of authorization and during their lifecycle. Yet it has been suggested that divergence in quality attributes over time may lead to clinically meaningful differences between two versions of a biologic. Therefore, this study investigated the batch-to-batch consistency across a range of parameters for released batches of the etanercept biosimilar (SB4) and infliximab biosimilar (SB2). METHODS: SB4 (Benepali®) and SB2 (Flixabi®) were both developed by Samsung Bioepis and are manufactured in Europe by Biogen at their facility in Hillerød, Denmark. A total of 120 batches of SB4 and 25 batches of SB2 were assessed for consistency and compliance with specified release parameters, including purity, post-translational glycosylation (SB4 only), protein concentration, and biological activity. RESULTS: The protein concentration, purity, tumor necrosis factor-α (TNF-α) binding, and TNF-α neutralization of all batches of SB4 and SB2 were within the strict specification limits set by regulatory agencies, as was the total sialic acid (TSA) content of all batches of SB4. CONCLUSIONS: Quality attributes of SB4 and SB2 batches showed little variation and were consistently within the rigorous specifications defined by regulatory agencies.

2018 update of the EULAR recommendations for the management of hand osteoarthritis.

Since publication of the European League Against Rheumatism (EULAR) recommendations for management of hand osteoarthritis (OA) in 2007 new evidence has emerged. The aim was to update these recommendations. EULAR standardised operating procedures were followed. A systematic literature review was performed, collecting the evidence regarding all non-pharmacological, pharmacological and surgical treatment options for hand OA published to date. Based on the evidence and expert opinion from an international task force of 19 physicians, healthcare professionals and patients from 10 European countries formulated overarching principles and recommendations. Level of evidence, grade of recommendation and level of agreement were allocated to each statement. Five overarching principles and 10 recommendations were agreed on. The overarching principles cover treatment goals, information provision, individualisation of treatment, shared decision-making and the need to consider multidisciplinary and multimodal (non-pharmacological, pharmacological, surgical) treatment approaches. Recommendations 1-3 cover different non-pharmacological treatment options (education, assistive devices, exercises and orthoses). Recommendations 4-8 describe the role of different pharmacological treatments, including topical treatments (preferred over systemic treatments, topical non-steroidal anti-inflammatory drugs (NSAIDs) being first-line choice), oral analgesics (particularly NSAIDs to be considered for symptom relief for a limited duration), chondroitin sulfate (for symptom relief), intra-articular glucocorticoids (generally not recommended, consider for painful interphalangeal OA) and conventional/biological disease-modifying antirheumatic drugs (discouraged). Considerations for surgery are described in recommendation 9. The last recommendation relates to follow-up. The presented EULAR recommendations provide up-to-date guidance on the management of hand OA, based on expert opinion and research evidence.

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.

Escenario actual de los medicamentos biocomparables en México: posicionamiento del Colegio Mexicano de Reumatología, 2016 / Current state of biosimilars in Mexico: The position of the Mexican College of Rheumatology, 2016

El presente documento refleja el posicionamiento del Colegio Mexicano de Reumatología y de expertos sobre el uso de medicamentos biocomparables (conocidos como biosimilares en otros países) en enfermedades reumáticas. En resumen, este posicionamiento considera que si bien los biocomparables deben considerarse como intercambiables, no es ética la sustitución automática de medicamentos sin previo aviso en pacientes estables durante el seguimiento; que la aprobación de un biocomparable debe llevarse a cabo solo después de revisar exhaustivamente las pruebas preclínicas y clínicas señaladas por la ley mexicana; que debe modificarse la forma de enfatizar en su nomenclatura que se trata de un medicamento biotecnológico innovador o biocomparable de manera clara; que no es adecuado elegir como tratamiento un biocomparable basándose únicamente en aspectos económicos ni realizarse la extrapolación de indicaciones basándose únicamente en la aprobación obtenida por el innovador y en ausencia de datos de seguridad y eficacia para el biocomparable

The present document is a position statement of the Mexican College of Rheumatology on the use of biosimilars in rheumatic diseases. This position considers that biosimilars should be considered as interchangeable, that automatic substitution without previous notice in stable patients during follow-up is not ethical, that the approval of a biosimilar should only be given after exhaustive review of preclinical and clinical data marked by Mexican regulations, that it should be clearly stated in the nomenclature of biologic drugs which is the innovator and which is the biosimilar, that it is not correct to choose a biosimilar as treatment based only on economic reasons or extrapolate indications based only on the approval of the innovator and in the absence of safety and efficacy data for the biosimilar

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty.

OBJECTIVE: This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). METHODS: A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. RESULTS: The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. CONCLUSION: This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

"Official View" on Glucocorticoids in Rheumatoid Arthritis: A Systematic Review of International Guidelines and Consensus Statements.

OBJECTIVE: To describe the perception of the current role of systemic glucocorticoids in the management of rheumatoid arthritis (RA) by examining their importance and the current level of evidence in recent guidelines, and to identify open questions to be addressed in future guidelines and research projects. METHODS: We conducted a systematic literature review using the databases Ovid Embase, PubMed Medline, and Cochrane Library for guidelines on the pharmacologic treatment of RA. Retrieved articles were evaluated regarding their quality using the Appraisal of Guidelines for Research and Evaluation II tool and scrutinized for all relevant information concerning the use of glucocorticoids. RESULTS: All guidelines agree that glucocorticoids, especially if given at low doses and for a short duration, are an appropriate option in the treatment of RA. However, many recommendations remain vague, as reliable and detailed evidence is scarce. Important aspects of glucocorticoid therapy are partially or completely neglected, and the existing nomenclature is not used uniformly. Quality evaluation revealed flaws in many articles, concerning not only glucocorticoid-specific recommendations but also guideline quality in general. CONCLUSION: Current recommendations for use of glucocorticoids in the management of RA are suboptimal. More rigorous evaluation of doses, timing, and duration of their use is needed. Existing nomenclature on glucocorticoid therapy should be used uniformly.

Biosimilar monoclonal antibodies: preclinical and clinical development aspects.

Biological drugs and their originated biosimilars are large, highly complex molecules derived from living cells or organisms. Traditional medicines, by contrast, are usually simple molecules of low molecular weight, synthesised by chemical means. The distinct complexities and methods of manufacture create an important difference between biosimilars and conventional generic drugs: while chemical generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biological therapies are inherently variable, creating unavoidable differences between even subsequent batches of the same product. An expiring patent does not necessarily mean that the manufacturing process of the originator product becomes available to the biosimilar developers (for instance, the relevant cell line clone and growth medium). Therefore, it cannot be guaranteed that biosimilar products are identical to their reference product on a molecular level. This difference has important implications for the regulation and licensing of biosimilars. While conventional generic drugs require only a limited comparison and demonstration of identical chemical structure to the reference product, biosimilars require far more rigorous testing. In general, there must be a thorough comparison of structural and functional characteristics between biosimilar and originator drug. Stepwise nonclinical in vitro and in vivo approaches are recommended to evaluate the similarity of both drugs and any identified micro-heterogeneities must then be assessed for their impact on safety and clinical performance. Subsequently, clinical pharmacokinetic (PK) studies need to be performed in order to demonstrate a similar PK profile, prior to conducting clinical efficacy trials.

The majority of patients do not store their biologic disease-modifying antirheumatic drugs within the recommended temperature range.

OBJECTIVE: To monitor whether biologic DMARD (bDMARD) home storage temperatures comply with the manufacturers' Summary of Product Characteristics (SmPC) recommendations. METHODS: This observational study included consenting adult patients from eight Dutch pharmacies who received their bDMARDs with a validated temperature logger. Patients were instructed to store their packages according to standard label instructions and to return the temperature logger(s) after use. Primary outcome was defined as the proportion of patients that stored their bDMARDs within the SmPC recommended temperature range. In addition, the proportion of patients storing bDMARDs below 0°C or above 25 °C for longer than two consecutive hours was estimated. RESULTS: A total of 255 (87.0%) patients (mean age 53.2 (s.d.; 13.1) years, 51.4% female) returned their temperature logger(s) to the pharmacy. Of these, 17 patients (6.7%) stored their bDMARD within the recommended temperature range. The proportion of the patients that stored their bDMARD for more than 2 h consecutive time below 0°C or above 25°C was respectively 24.3% (median duration: 3.7 h (IQR 2.2 h; range 2.0-1,097.1 h) and 2.0% (median duration: 11.8 h (IQR 44.3 h; range 2.0-381.9 h). CONCLUSION: The majority of patients do not store their bDMARDs within the SmPC-recommended temperature range.

[Intra-articular injection of cortisone]. / Intraartikuläre Injektion mit Kortison.

Intra-articular injections with glucocorticoids are standard procedures according to therapy guidelines in many rheumatic conditions. There is increasing evidence from clinical trials on the treatment of rheumatoid arthritis that more patients will attain the target of remission using a combination of systemic medication and intra-articular injections with glucocorticoids compared to systemic medication alone. Intra-articular injections with glucocorticoids play an important role in the therapeutic management of pediatric rheumatic diseases. In many countries competency in performing intra-articular injections is among the important skills necessary for certification as a specialist in rheumatology.

[Injection treatment with hyaluronic acid]. / Injektionsbehandlung mit Hyaluronsäure.

This article presents the spectrum of indications for the use of hyaluronic acid (HA) based on the recommendations of the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), the Osteoarthritis Research Society International (OARSI), the International Institute for Health and Clinical Excellence (NICE) and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) taking the reality of patient care in Europe into account.

[Acupuncture Therapy versus Disease-modifying Antirheumatic Drugs for the Treatment of Ankylosing Spondylitis--a Meta-analysis]. / Akupunktur versus krankheitsmodifizierende Antirheumatika in der Behandlung der ankylosierenden Spondylitis--eine Metaanalyse.

BACKGROUND: We conducted a meta-analysis evaluating the efficacy and safety of acupuncture compared to disease-modifying antirheumatic drugs in patients with ankylosing spondylitis. METHODS: Four databases including Pubmed, EMBASE, Cochrane library, and ISI Web of Science were searched in December 2014, taking also the reference section into account. Randomized controlled trials that aimed to assess the efficacy of acupuncture therapy were identified. The inclusion criteria for the outcome measurements were the clinical effect, ESR, occipital wall test, chest expansion, CRP and finger ground distance. Finally, six studies met these inclusion criteria. Two reviewers screened each article independently and were blinded to the findings of each other. RESULTS: We analyzed data from 6 RCTs involving 541 participants. Acupuncture therapy could further improve the clinical effect (OR = 3.01; 95% CI, 1.48-6.13; P = 0.002) and reduce ESR level (SMD = -0.77; 95% CI, -1.46 to -0.08; P = 0.03) compared to DMARDs; a combination of acupuncture and DMARDs could further improve clinical effect (OR = 3.20, 95% CI, 1.36-7.54; P = 0.008), occipital-wall distance (SMD = -0.84; 95% CI, -1.37 to -0.31; P = 0.002), chest expansion (SMD = 0.38; 95% CI, 0.16-0.60; P = 0.0009), and finger-ground distance (SMD = -0.48; 95% CI, -0.87 to -0.09; P = 0.02) as compared to DMARDs treatment alone. CONCLUSIONS: Our findings support that acupuncture therapy could be an option to relieve symptoms associated with AS. These results should be interpreted cautiously due to the generally poor methodological qualities of the included trials.

Proposal for a new nomenclature of disease-modifying antirheumatic drugs.

In light of the recent emergence of new therapeutics for rheumatoid arthritis, such as kinase inhibitors and biosimilars, a new nomenclature for disease-modifying antirheumatic drugs (DMARDs), which are currently often classified as synthetic (or chemical) DMARDs (sDMARDS) and biological DMARDs (bDMARDs), may be needed. We propose to divide the latter into biological original and biosimilar DMARDs (boDMARDs and bsDMARDs, respectively, such as abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab or tocilizumab, but also emerging ones like clazakizumab, ixekizumab, sarilumab, secukinumab or sirukumab) and the former into conventional synthetic and targeted synthetic DMARDs (csDMARDs and tsDMARDs, respectively). tsDMARDs would then constitute only those that were specifically developed to target a particular molecular structure (such as tofacitinib, fostamatinib, baricitinib or apremilast, or agents not focused primarily on rheumatic diseases, such as imatinib or ibrutinib), while csDMARDs would comprise the traditional drugs (such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, gold salts and others). The proposed nomenclature may provide means to group and distinguish the different types of DMARDs in clinical studies and review articles.

Anti-tumor necrosis factor patent expiration and the risks of biocopies in clinical practice.

Biosimilars that were not compared in clinical trials with the compound innovator are not true biosimilars (biocopies) and are associated with risks that the clinical rheumatologist should be aware of before generalized use. This article comments on various aspects surrounding the use of such biocopies in clinical rheumatology.