[CAR T-cell therapy in rheumatology-What we know so far?] / CAR-T-Zell-Therapie in der Rheumatologie ­ Was wissen wir bisher?

Autoreactive B­cells play a key role in the pathogenesis of autoimmune diseases, such systemic lupus erythematosus (SLE). An efficient depletion of B­cells therefore plays a special role in autoimmune diseases, especially in cases with a severe course of the disease. Treatment with chimeric antigen receptor (CAR) T­cells, which was originally developed for the treatment of B­cell lymphomas and leukemias, provides the possibility to deplete B­cells even in deep tissues. The initial results from case series with this procedure for SLE, myositis and systemic sclerosis were very positive. This review article gives an overview of the course, mechanism of action, results so far and the research agenda of CAR T­cell therapy in autoimmune diseases.

2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

OBJECTIVE: To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION: This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

Health Care Utilization for Musculoskeletal Issues During the Prediagnosis Period in Psoriatic Arthritis: A Population-Based Study.

OBJECTIVE: Information about the prediagnosis period in psoriatic arthritis (PsA) is limited. The present study was undertaken to compare health care utilization related to musculoskeletal issues during a 5-year period prior to the diagnosis of PsA versus that of subjects with no prior inflammatory arthritis within a primary care setting. METHODS: We conducted a population-based, matched cohort study using electronic medical records and administrative data in Ontario, Canada. Age- and sex-matched cohorts of PsA patients and comparators from the same family physicians were assembled. Comparators were not allowed to have prior spondyloarthritis, ankylosing spondylitis, or rheumatoid arthritis billing code diagnoses. The study outcomes included health care utilization and costs related to nonspecific musculoskeletal issues during a 5-year period prior to the index date. RESULTS: We studied 462 PsA patients and 2,310 matched comparators. The odds ratio (OR) related to visiting a primary care physician for nonspecific musculoskeletal issues in patients with PsA was 2.14 (95% confidence interval 1.73-2.64) in the year immediately preceding the index date and was similarly elevated up to 5 years prior. The OR related to using other musculoskeletal-related health care services, including musculoskeletal specialists visits, joint injections, joint imaging, and emergency department visits, was higher in PsA as early as 5 years preceding the index date. Total and musculoskeletal-related health care costs prior to the index date were higher for patients with PsA versus comparators. CONCLUSION: A prodromal PsA phase characterized by nonspecific musculoskeletal symptoms may exist. Further study is needed to determine if this represents a window for earlier diagnosis of PsA.

[IgG4-related disease: Diagnostic criteria evolution toward the 2019 ACR/EULAR classification criteria]. / Maladie associée aux IgG4 : des critères « diagnostiques ¼ aux critères de classification ACR/EULAR 2019.

The concept of IgG4-related disease (IgG4-RD) has recently been individualized in the early 2000s, but most of the organ involvements are known since more than 100 years. IgG4-RD is a non-malignant fibroinflammatory disorder, characterized by peculiar immunological and pathological abnormalities, which can affect virtually all organs or tissues. Diagnostic criteria have been proposed and have evolved rapidly, with general or organ specific criteria. An international and multidisciplinary group assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) has recently developed and validated a set of classification criteria called 2019 ACR/EULAR classification criteria for IgG4-related disease. The objective of this review is to discuss the evolution from organ specific and general diagnostic criteria toward the 2019 ACR/EULAR classification criteria, as well as respective benefits and limits of these criteria. The use of the 2019 ACR/EULAR classification criteria will help to better define homogeneous group of IgG4-RD patients in future clinical, epidemiological and basic science research studies on the disease.

[Remarkable medical advances in rheumatology : may be ]. / Une révolution thérapeutique en rhumatologie : oui, mais .

The development of new drugs is a significant activity in a university hospital that favors access to therapeutic novelties to patients. Rheumatology, whose drug armamentarium was poor in the 1980s, has benefited from the huge progresses of immunology in the 1980-1990s, allowing a therapeutic revolution in whom the academic hospital of Liège (CHU Liège) has been strongly implicated. First protocols with anti-TNF-? monoclonal antibodies have been applied in 1997. Sixty-one protocols have been initiated in rheumatoid arthritis, 12 in ankylosing spondylitis, 10 in psoriatic arthritis, 9 in systemic erythematosus lupus, 3 in giant cell arteritis, 1 in polymyalgia rheumatica, 5 in osteoarthritis and 4 in osteoporosis. Potential and pitfalls will be discussed disease by disease and also by drug categories. The balance remains globally positive, but remission is far from be reached.

La recherche clinique médicamenteuse est une activité importante dans un hôpital universitaire. Elle valide des nouveautés thérapeutiques et fait bénéficier les patients de traitements novateurs bien avant leur mise sur le marché. La rhumatologie est une discipline dont l'arsenal thérapeutique était pauvre dans les années 1980, et les immenses progrès de l'immunologie, réalisés entre 1980 et 1995, lui ont permis de vivre une véritable révolution thérapeutique à laquelle notre service a amplement participé. C'est en 1997 que les premiers traitements par anticorps monoclonaux anti-TNF-? (les traitements dits biologiques) ont été utilisés au CHU de Liège. Soixante et une études seront initiées dans la polyarthrite rhumatoïde, 12 dans la spondylarthrite ankylosante, 10 dans la polyarthrite psoriasique, 9 dans le lupus érythémateux disséminé, 3 dans l'artérite temporale de Horton, une dans la pseudopolyarthrite rhizomélique, une dans la sclérodermie, 5 dans l'arthrose, 4 dans l'ostéoporose. Les espoirs et les déceptions observées dans les différentes indications, et avec les différentes molécules, sont analysées. Le bilan est globalement positif, mais les résultats encore insuffisants que pour arriver au concept de rémission.

Era of biosimilars in rheumatology: reshaping the healthcare environment.

Compared with the original approved biological drug on which it is based, a biosimilar has highly similar physicochemical characteristics and biological activity, as well as equivalent efficacy and no clinically meaningful differences in safety and immunogenicity. Before they are approved, biosimilars must undergo a rigorous development process using state-of-the-art technologies to establish biosimilarity to the reference biological product. After approval, biosimilars must comply with good pharmacological practices for biological drugs. Several biosimilar disease-modifying antirheumatic drugs (bsDMARDs) based on the tumour necrosis factor inhibitors adalimumab, etanercept and infliximab have been approved for use in patients with rheumatic diseases. Substantial cost savings can be made if biological-naive patients begin treatment with bsDMARDs, and patients receiving original biological DMARDs (bDMARDs) are switched to bsDMARDs. Despite the consistently similar efficacy, safety and immunogenicity of bsDMARDs relative to their respective original bDMARDs, switching from a reference bDMARD to a bsDMARD can result in nocebo responses, such as subjective increase of disease activity and pain-related adverse events. This may have a negative impact on adherence to bsDMARDs in clinical trials and clinical practice. To ensure optimal and rational integration of bsDMARDs into rheumatology practice and realise the full cost-saving efficacy of these drugs, rheumatologists must be aware that careful communication of the cost-saving efficacy and safety of bsDMARDs to their patients is the key to a successful long-term switch to bsDMARD therapy.

[Improvement of prognosis by timely treatment : Requirement: initial presentation within 6 weeks]. / Verbesserung der Prognose durch frühzeitige Therapie : Forderung: Erstvorstellung in 6 Wochen.

Rheumatoid arthritis (RA) is one of the most frequent chronic inflammatory rheumatic diseases and when untreated leads to chronic tissue destruction and increased mortality. Due to innovative systemic treatment strategies established over the last 20-25 years, the prognosis has considerably improved in terms of disease and socioeconomic burdens, symptoms, long-term prognosis, ability to work and mortality; however, as a rule a prerequisite is long-term and continuous treatment. A medicinal cure of RA is still not in view. For many patients this means the long-term use of very expensive medications. In addition to hemato-oncology, rheumatology has become the second most expensive discipline in Germany in terms of cost per patient. Convincing data from many studies imply that an early start of treatment within the first few weeks after clinical onset of symptoms improves the prognosis, reduces the necessity for expensive drugs and thereby considerably decreases medical costs. This results in the requirement that every patient with symptoms of arthritis must be seen by a rheumatologist within the first 6 weeks following initial manifestation of the disease. Such an improvement in treatment can only be achieved in Germany if the numbers of rheumatologists and trained healthcare professionals in practices such as clinics are considerably increased. This is not only in the interests of patients but also in the interests of the health insurance companies because the investment in the healthcare infrastructure with internistic rheumatologists will result in substantial economic benefits for the cost bearer. It must be the common task of all players in healthcare policy, cost bearers and internistic rheumatologists to provide optimal conditions in medical as well as economical terms.

[Biosimilars antibodies: positioning compared to originators - the experience in rheumatology and the biosimilars of trastuzumab in oncology]. / Anticorps biosimilaires versus princeps - L'expérience en rhumatologie et les biosimilaires du trastuzumab en oncologie.

Biosimilars have demonstrated their equivalence with biologic originators, according to rigorous specifications imposed by the regulatory agencies, the FDA and the EMA. Their development is justified by the very high cost of biopharmaceuticals, and strong incentives for their prescription lead us to hope substantial savings, allowing to finance other innovative molecules. Trastuzumab marked history of the treatment of breast cancer. Four biosimilars of trastuzumab are available for routine use and we will detail the key points of their development.

TITLE: Anticorps biosimilaires versus princeps - L'expérience en rhumatologie et les biosimilaires du trastuzumab en oncologie. ABSTRACT: Les biosimilaires sont des produits ayant montré leur équivalence avec le traitement biologique de référence, selon un cahier des charges strict imposé par les agences d'enregistrement, la FDA et l'EMA. Leur développement et leur utilisation sont justifiés par le coût très élevé des biomédicaments, et de fortes incitations à leur prescription font espérer des économies substantielles, permettant le financement d'autres molécules innovantes. Le trastuzumab a marqué l'histoire des traitements du cancer du sein, quatre biosimilaires étant désormais disponibles pour une utilisation en routine. Nous détaillerons ici les points clés de leur développement.

Fibromyalgia and small fiber neuropathy: the plot thickens!

Several groups of investigators have described the presence of small fiber neuropathy in fibromyalgia patients. This writing discusses how this new finding could renovate fibromyalgia concept, diagnosis, and treatment. Predominant rheumatology thinking proposes fibromyalgia as a "centralized pain syndrome." An alternative hypothesis views fibromyalgia as a stress-related dysautonomia with neuropathic pain features. Dorsal root ganglia may be the key autonomic-nociceptive short-circuit sites. The recent recognition of small fiber neuropathy in a large subgroup of fibromyalgia patients reinforces the dysautonomia-neuropathic hypothesis and validates fibromyalgia pain. These new findings support fibromyalgia as a primarily neurological entity, nevertheless, rheumatologist will likely remain the best equipped specialist to diagnose fibromyalgia and differentiate it from other multi-symptomatic rheumatic syndromes. Skin biopsy and corneal confocal microscopy will probably become useful fibromyalgia diagnostic tests. Dorsal root ganglia sodium channel blockers are potential fibromyalgia analgesic medications. Subgroups of young girls with "autoimmune neuropathic fibromyalgia" may respond to immunoglobulin therapy. Multimodal intervention directed to regain autonomic nervous system resilience will likely remain the cornerstone for fibromyalgia therapy.

Global research trends in stem cells for osteoarthritis: a bibliometric and visualized study.

AIM: There have been increased interests in the use of stems cells in the research of osteoarthritis (OA). The present study aimed to investigate the global status and trends in this field. METHOD: Publications related to stem cells search in OA from 1994 to 2017 were retrieved from the Science Citation Index-Expanded Web of Science. The source data were studied and indexed using a bibliometric methodology. For visualized study, VOS viewer software was used to conduct bibliographic coupling, co-authorship, co-citation and co-occurrence analysis and to analyze the publication trends in stem cells for OA research. RESULT: A total of 1933 articles were included. The relative research interests and number of publications were globally increasing per year. The USA made the highest contributions to the global research with the most citations and the highest H-index. The journal Osteoarthritis and Cartilage had the highest publication number. The Tokyo Medical and Dental University, University of Pittsburgh and Shanghai Jiaotong University were the most contributive institutions. Studies could be divided into four clusters: mechanism study, animal study, clinical trials and tissue engineering. The clinical studies were predicted to be the next popular topic in this field. CONCLUSION: The number of publications about stem cells for OA would be increasing based on the current global trends. The USA was the largest contributor in this field. Most efforts could be put into clinical studies involving mesenchymal stem cells for OA, which may be the next hot spots in OA and stem cells research.

Overdiagnosis and overtreatment in rheumatology: a little caution is in order.

Overdiagnosis is a term coined by experts in cancer screening to point to indolent cancers detected by screening that would have never led to manifest health problems. Overdiagnosis leads to unnecessary medical care (overtreatment), anxiety and cost. In rheumatology overdiagnosis and overtreatment are hardly discussed but likely present. This viewpoint examines how our prevailing views on the management of inflammatory rheumatic diseases may relate to overdiagnosis and overtreatment. Six paradigms of modern rheumatology will be discussed: early diagnosis, intensive treatment, remission, prognosis and risk stratification, evidence-based rheumatology, and precision medicine. It is concluded that, in spite of the enormous progress that they have brought, all paradigms bear the intrinsic dangers of overdiagnosis and overtreatment. So a little caution is in order.

Total Joint Arthroplasty in Patients with Inflammatory Rheumatic Diseases.

Since its introduction, total joint arthroplasty (TJA) has improved the quality of life of patients with degenerative joint disorders. In the last decades, a number of conventional and biological disease-modifying antirheumatic drugs have become available for the treatment of patients with inflammatory rheumatic diseases (IRD), leading to a reduction in the need to undergo TJA. However, TJA is still frequently performed in IRD patients. Both rheumatologists and orthopedics should be aware that patients with IRD have a peculiar perioperative risk profile due to disease-related, patient-related, and surgery-related risk factors. On the basis of current evidence, TJA is a safe procedure for IRD patients as long as an accurate risk stratification and a multidisciplinary approach are applied. We here describe the current strategies for an appropriate surgical management of osteoarthritis in IRD patients and the fascinating opening perspectives that surgeons and clinicians may expect in the future.

From supernatants to cytokines: a personal view on the early history of IL-1, IL-1Ra, TNF and its inhibitor in rheumatology.

Long-term cell cultures developed early in the twentieth century allowed identification in their supernatants of biological mediators subsequently defined as migration factors, interferons, lymphokines, monokines, cytokines and interleukins. In rheumatology, early in the 1930s, synovial cell cultures revealed two major distinct populations, i.e. synovial fibroblasts and monocyte-macrophages. Discovery of the interstitial collagenase (MMP-1) and its role in tissue destruction, such as in rheumatoid arthritis (RA), raised the question of the cellular source for this enzyme. My personal interest in the field was driven by the lack of understanding for the link between tissue destruction and immunology. This triggered our seminal contribution to the field, establishing in 1976-79 at the Arthritis Unit (Massachusetts General Hospital, with SM Krane) that a mononuclear factor (MCF, around 15 kDa) produced by stimulated macrophage, under direct contact with activated T cells, induced large amounts of collagenase and prostaglandin E2 (PGE2, a bone resorbing agent) in human synovial fibroblasts from RA patients. Our original "MCF" biological observations preceded cloning, and recombinant IL-1ß confirmed the biological activity of the purified natural IL-1. Following my return to Geneva in 1980 and searching for a high level of IL-1 in urine and serum of patients with high fever or Still's disease, to our surprise-"a finding of absence"-we found that IL-1 was masked by a factor of approximately 17 kDa and first presented this in 1984 at the Fourth International Lymphokine Workshop. In 1987, before IL-Ra cloning, my co-worker P Seckinger and I demonstrated first-time observation in cytokine biology that the mechanism was due to the inhibition of IL-1 binding the cell surface receptor, leading to the concept of IL-1 receptor antagonist (IL-1Ra). Having reported in 1985 that TNF/cachectin also induced collagenase and PGE2 in human synovial cells, we found that IL-1Ra did not block TNF-α but was due to another inhibitor. As other investigators, we confirmed that this inhibitory factor was a soluble TNF receptor. The years between the 1970s and 1990s were probably the most exciting period in the field of cytokines and cytokine antagonists; it gave rise to two concepts in the cytokine field-one of the receptor antagonist, and the other of soluble receptor antagonists.

[Rheumatology. Checkpoint-induced autoimmunity - birth of a new disease]. / Rhumatologie. Autoimmunité induite par des checkpoints ­ naissance d'une nouvelle maladie.

Tumor cells express checkpoint proteins in order to prevent an immune reaction by T-cells. Checkpoint inhibitors are successfully used in oncology to unleash a cytotoxic immune response. Unfortunately this treatment increasingly leads to immune-related adverse events which resemble various primary autoimmune disorders known in rheumatology. Potentially, checkpoint dysfunction also underlies rheumatic diseases which would open the way for new treatment options to restore immune tolerance.

En exprimant certaines molécules régulatrices (dénommées « checkpoints ¼) à leur surface, les tumeurs parviennent à éviter la reconnaissance par le système immunitaire. L'inhibition de ces checkpoints peut donc permettre une réponse immunitaire, médiée par les lymphocytes T, contre les cellules tumorales. L'utilisation croissante des « checkpoint inhibitors ¼ en oncologie a permis d'augmenter considérablement la survie des patients, mais a également engendré des effets indésirables autoimmuns ressemblant sur le plan clinique aux maladies primaires que l'on connaît en rhumatologie. Des traitements corrigeant une dysfonction des checkpoints pourront probablement dans le futur également traiter des maladies autoimmunes et rétablir l'immunotolérance.

Patterns of Systemic Treatment for Psoriatic Arthritis in the US: 2004-2015.

OBJECTIVE: To examine trends in the use of systemic disease-modifying antirheumatic drugs (DMARDs) among patients with psoriatic arthritis (PsA) in the US. METHODS: Using claims data (2004-2015) from a large US commercial health plan, we identified patients with PsA who initiated DMARD therapy. We examined baseline patient characteristics and initial treatment patterns. We then assessed changes in the DMARD regimen over the 12-month period after the first DMARD initiation date. Using Poisson regression, we estimated age- and sex-adjusted incidence rates of treatment changes in each calendar year. RESULTS: We identified 9,222 PsA patients who initiated DMARD therapy (42.8% biologic DMARDs [bDMARDs] and 57.2% conventional synthetic DMARDs [csDMARDs]). Initiators of bDMARDs were younger than those initiating csDMARDs (mean ± SD age 48 ± 13 versus 52 ± 14 years) and generally had fewer comorbidities, but a higher proportion of bDMARD initiators received nonsystemic treatments for psoriasis at baseline. Methotrexate was the most frequently used DMARD, constituting 80.6% of csDMARD initiations. Etanercept (49.1%) was the most commonly prescribed bDMARD, followed by adalimumab (34.4%). During the 12-month followup after the first DMARD initiation, 20.1% of bDMARD initiators and 31.1% of csDMARD initiators had their initial DMARD regimen modified, with an increasing trend in treatment modifications over the 11-year study period (P = 0.03). Overall, 5.3% of patients discontinued treatment, but the rates of discontinuation decreased over time (P < 0.001). CONCLUSION: In this large cohort of PsA patients with DMARD initiation, more than 40% were treated with a bDMARD. We found an increasing trend in treatment modification after use of the initial DMARD and a decreasing trend in complete DMARD discontinuation over the past decade.

Valoración previa a la inmunosupresión farmacológica en Reumatología / (Pre-assessment of pharmacological immunosuppression in Rheumatology)

ResumenEn los últimos 15 años se han desarrollado terapias y esquemas terapéuticos para inducir la remisión a la gran mayoría de enfermedades reumatológicas. La mejoría clínica lograda se consigue a expensas de una inmunosupresión más agresiva y específica, lo que conlleva un aumento en el riesgo de infecciones. La principal causa de muerte de las enfermedades autoinmunes, en los primeros 5 años de evolución, es la infección secundaria a la inmunosupresión. El objetivo del presente trabajo fue elaborar un documento de consenso con el afán de reducir este riesgo, basado en la mejor evidencia médica disponible, utilizando los recursos disponibles en el hospital para disminuir la morbimortalidad de los pacientes que reciben estas terapias. Contar con un documento de consenso permitirá minimizar los efectos secundarios y mejorar la acción terapéutica, con mayores oportunidades de remisión y una más adecuada utilización del recurso institucional.

AbstractIn the last 15 years therapies and therapeutic schemes have been developed to induce remission to the vast majority of rheumatologic diseases. The clinical improvement achieved is at the cost of a more aggressive and specific immunosuppression, which leads to an increase in the risk of infections. The main cause of death of autoimmune diseases in the first 5 years of evolution is infection secondary to immunosuppression. The objective of the present study was to develop a consensus document with the aim of reducing this risk of infection, based on the best available medical evidence, using the resources available in our hospital to reduce the morbidity and mortality of patients receiving these therapies. Having a consensus document will allow us to minimize side effects and improve therapeutic action with greater opportunities for referral and better utilization of institutional resources.

Neurological Complications of Therapeutic Monoclonal Antibodies: Trends from Oncology to Rheumatology.

PURPOSE OF REVIEW: This review is to describe the scope of neurological complications associated with monoclonal antibody-based therapies, applied across medical specialties, to demonstrate the common and rare neurological syndromes that may be encountered in clinical practice according to the therapeutic agent being receive, and to explain appropriate work-up, diagnosis, and management of drug complications, as supported by the literature. RECENT FINDINGS: The number of commercially available, evidence-based therapeutic monoclonal antibodies continues to expand. In oncology, immune checkpoint inhibitors are particularly important, as a wide range of central and peripheral nervous system complications are described. In rheumatology, anti-TNF alpha drugs remain associated with demyelinating syndromes. The number of therapeutic monoclonal antibodies encountered in practice continues to grow, as does the number of described neurological complications. Recognition of a possible drug complication is key, as these are typically complex patients at risk of other causes of neurological injury. Identification of a complication of therapy often leads to intervention and a change in management.

[Anti-IL-6 : new therapeutic trends]. / Rhumatologie. Anti-IL-6 : nouvelles perspectives thérapeutiques.

The anti-IL-6 tocilizumab is a recognized treatment in rheumatoid arthritis and in systemic juvenile idiopathic arthritis. Almost ten years after its first use, there is more information about its security profile and its indication should be extended to other systemic inflammatory diseases, such as the giant cell arteritis. New molecules targetting the IL-6 pathway are under validation : sarilumab, sirukumab and olokizumab. Here is a brief state of the future outlook and trends of this therapeutic class.

Le tocilizumab (Actemra) est un anticorps monoclonal anti-IL-6 reconnu comme traitement de la polyarthrite rhumatoïde et de l'arthrite juvénile idiopathique systémique après échec du méthotrexate. Presque dix ans après sa mise sur le marché, on dispose davantage d'informations quant à son profil de sécurité et son indication devrait s'étendre à d'autres maladies systémiques inflammatoires, telles que l'artérite gigantocellulaire. De nouvelles molécules inhibant la voie de l'IL-6, le sarilumab, le sirukumab et l'olokizumab sont également en cours de validation. Voici une revue des perspectives à venir pour cette classe thérapeutique.