European biologics registers

Over the last 15 years, the European biologics registers have greatly increased our knowledge of the safety and effectiveness of biologic therapies in daily practice. They have convincingly shown that tumour necrosis factor (TNF) inhibitors do not increase the overall risk of solid or lymphoproliferative tumours. However, a slight increase in the risk of skin cancer cannot be ruled out. A higher risk of serious infections compared to csDMARDs has been identified which has to be taken into account in clinical care. The registers have identified the great impact of uncontrolled high disease activity on the risks of myocardial infarction, stroke, and overall mortality which underlines the importance of tight disease control. By their clinical effectiveness, the biologic agents therefore have the potential to prevent adverse outcomes. Overall, a favourable benefit-risk profile of TNFi and other biological agents has been observed, with some specific precautions in defined patient groups.

Combination therapy in rheumatoid arthritis

The therapeutic armamentarium available for treatment of rheumatoid arthritis (RA) has changed significantly over the past 30 years, transforming the therapeutic landscape and prognosis for a substantial proportion of patients with RA. Combination therapies represent an important therapeutic paradigm for management of rheumatoid arthritis. The rationale for combination therapies is clear and demonstrated to bring treatment benefit to patients achieving lower disease activity scores and reduced radiologic progression according to ‘treat-to-target’ principles. A rigorous evidence-based debate is required involving not only parameters related to disease activity scores and radiologic progression, but related to the cost-effectiveness analysis of using many of these newer agents compared to older csDMARDs. This chapter addresses the evidence related to the utilization of combination strategies for the management of RA as compared to monotherapy.

The use of JAK inhibitors in the treatment of rheumatoid arthritis

Low molecular weight, orally available, ‘small molecules’ which target and inhibit components of the Janus family tyrosine kinase (JAK) enzyme inflammatory signalling cascade have been lately considered as an important alternative to biologic therapies for rheumatoid arthritis (RA). JAK signalling is used by a number of pro-inflammatory cytokines known to be involved in RA pathogenesis, notably IL-6. Therefore, several JAK inhibitors with variable degrees of selectivity and specificity for the JAK enzymes have been investigated in treatment of RA. To date, two JAK inhibitors, tofacitinib and baricitinib, have been approved for treatment of RA in certain regions. This chapter discusses the safety, efficacy, trials, and future directions of these two JAK inhibitors.

Interleukin-6 inhibitors

Interleukin 6 (IL-6) is a pleiotropic cytokine which has diverse biological activity, with wide-ranging effects on the immune system, homeostasis, and metabolism. It is the most abundant pro-inflammatory cytokine in the synovial joints and sera of patients with active rheumatoid arthritis (RA) and has been found to play a central role in the pathogenesis of the disease, causing joint inflammation and destruction, as well as systemic manifestations. Inhibition of IL-6 signalling has been investigated and developed as a potential treatment strategy for RA. Clinical trials have demonstrated the efficacy and safety of tocilizumab, a humanized monoclonal antibody directed against the IL-6 receptor, showing therapeutic benefit both in early RA and those considered to have refractory disease. The success of tocilizumab has spurred the development of an array of new biologic agents targeting the IL-6 pathway in RA.

Self-management: A patient’s perspective

This chapter is written by an expert patient who works with medical professionals. It covers a personal experience of being diagnosed and the psychosocial effects that arose from this period of time. It highlights the requirements for self-management in terms of retaining autonomy, models the definitions of self-management, and discusses the outcomes of different approaches. All chronic illness support, including self-management programmes, require an ongoing relationship between the patient and provider, including considerations of individual barriers; therefore the necessity for both social and medical support for patients’ self-management is also discussed, including differing needs for people from marginalized backgrounds, and suggestions on improving programmes is deliberated.

Fatigue

Fatigue in rheumatoid arthritis (RA) is associated with inflammation, pain, disability, sleep, depression, and health beliefs, implying complex, multicausal pathways comprising differing combinations of variables. From a patient perspective, it is a common, overwhelming, and distressing symptom. From a societal perspective, fatigue is a significant predictor of high healthcare costs and the main reason for work disability and loss. This chapter will highlight the role of patients in establishing the importance of the symptom, including the proposal that it should be measured in studies of RA whenever possible. Acknowledgement of fatigue as a patient priority is a relatively recent development, and highlights the value of collaborating with patients in shaping the research agenda. There will be discussion of the scale of fatigue in RA, including data on prevalence and descriptions of its nature and impact. Research has established the unpredictable and unearned nature of RA-related fatigue with its physical, cognitive, and emotional components, and identified the associated individual and societal burden. This will be followed by conceptual models informing our understanding of the biology of rheumatoid arthritis-related fatigue, the role of bioinformatics, and the challenges of unravelling the mechanisms of this multidimensional symptom. Finally, the evidence for interventions and treatments to alleviate fatigue will be presented, with a focus on non-pharmacological approaches to support fatigue self-management.

Disease activity assessment in rheumatoid arthritis

The major clinical hallmarks of rheumatoid arthritis (RA) are articular swelling, joint pain, and morning joint stiffness. Disease activity assessment is pivotal when following patients with RA throughout the course of their disease, and especially when assessing improvement or deterioration upon institution of the necessary therapies. To prevent an adverse outcome, it is essential to diagnose the disease early and to start treatment with disease-modifying antirheumatic drugs (DMARDs) immediately after diagnosis. Adhering to the treat-to-target approach, which is a central strategy irrespective of the type of treatment available and the therapy applied, requires consistency in using validated composite measures of disease activity. Rather than a mere matter of using specific therapies, it is also a matter of using tools for disease activity assessment to guide therapeutic decision-making. This enables offering and achieving the best possible outcomes for RA patients.

Pre-rheumatoid arthritis

The typical evolution of rheumatoid arthritis (RA) is that a person, with genetic risk factors, develops autoantibodies and subclinical inflammation under relevant environmental influences. There are indications that the primary site of the pathology is at mucosal surfaces (e.g. in the gums, lungs, and/or the gut), after which the disease translocates to the joints. Preclinical RA can be defined at the phase during which no clinically apparent features are present (i.e. no symptoms of inflammatory arthritis or clinically apparent joint swelling) but during which RA related biologic derangements such as the presence of autoantibodies are present. This chapter presents an overview of the risk factors, stages, and events occurring during the pre-RA phase. A better understanding of the factors involved will enable more accurate prediction of RA at the individual level and selection of high-risk individuals for inclusion in preventive studies. Several pharmacologic and non-pharmacologic studies aiming to prevent or delay the onset of RA in at-risk individuals are currently underway. It is hoped that such interventions in the pre-RA and indeed in the preclinical-RA phases will allow us to reduce the risk of RA and prevent RA developing in at least a proportion of at-risk patients.

Clinical recommendations

This chapter will review the most important recommendations that are relevant for evidence-based clinical practice. The main focus will be on recommendations that are specific to rheumatoid arthritis (RA) but some recommendation on special topics (e.g. biosimilars) will also be addressed. The literature to support evidence-based medicine is enormous, but the scientific quality may differ across studies. Recommendations based on systematic literature research may support evidence-based practice. Both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have published several important evidence-based recommendations. Further, task forces independent of these organizations have also presented important recommendations to support best practice. New treatment strategies have also improved RA care to an extent where remission has become an achievable goal for the majority of patients with RA. Important principles in the new treatment strategies are ‘window of opportunity’ which imply early initiation of disease-modifying antirheumatic drugs (DMARDs) before the onset of damage, and further ‘treat-to-target’ which is a strategy for follow-up with focus on reaching a predefined target, and where DMARD treatment is adjusted if the target is not achieved. Patients with early disease are monitored with ‘tight controls’, and with use of composite disease activity measures that includes joint counts.

Prevention of rheumatoid arthritis

The field of rheumatology has made major contributions to medicine through the identification of cellular and molecular targets. Moreover, early treatment is associated with improved outcomes of rheumatoid arthritis (RA). This observation led to the assumption that a window of opportunity exists, in which the disease is most susceptible to disease-modifying treatment. Although this window of opportunity has yet to be precisely defined significant progress has been achieved in this area. This includes the recognition of an at-risk state, characterized by disease specific autoantibodies in serum and inflammatory joint pain. This chapter describes the current state-of-the-art of RA prevention highlighting the importance of risk stratification. At this moment the best starting position for preventive studies is inclusion of patients at high risk of developing RA, such as those subjects who fulfil the European League Against Rheumatism (EULAR) definition of arthralgia at risk for RA.