25 years of biologic therapy

2023 marks 25 years since the approval of the first biologic drug in rheumatology. In this Viewpoint, five rheumatology researchers discuss how biologic therapy has transformed clinical practice, reflecting on their own experience, past and current challenges and what the future might hold for biologic drugs.

Biosimilars have an important place in the treatment of rheumatic conditions. The non-inferiority of biosimilars to bio-originators is ensured, but full and effective clinical adoption of these agents nonetheless requires consideration of several important issues, including the need for shared decision-making and a potential nocebo effect.

Since entering the clinic 25 years ago, biologic TNF inhibitors have transformed the outlook for people with rheumatoid arthritis and set the standard for all other targeted therapies. Despite changes to the therapeutic landscape, TNF inhibitors look set to remain an important treatment option for the foreseeable future.

Drug-free remission is a treatment goal in rheumatoid arthritis that can be achieved by tapering and discontinuation of biologic DMARDs. However, newly published real-world evidence suggests that DMARD discontinuation occurs less frequently than results of clinical trials suggest, so it is important to question what the ultimate goal of treatment should be.

IL-17 signalling regulates both protective and harmful immune responses; therefore, its complete inhibition can have adverse effects. Detailed consideration and fine-tuning of IL-17-inhibition strategies is needed to selectively regulate disease outcomes.

Among the wide range of drugs now available for the treatment of psoriatic arthritis, the best option for an individual patient remains unclear. Emerging real-world evidence from several Nordic registries suggests that differences exist in the response rates to different classes of biologic and targeted synthetic DMARDs in psoriatic arthritis.

The new ACR guideline for the treatment of juvenile idiopathic arthritis provides an update on several important topics, including management of oligoarthritis, temporomandibular joint arthritis and systemic-onset arthritis. Overall, the new guideline reflects changes in practice, but also highlights a concerning lack of high-quality evidence.

The 2021 ACR guideline for the treatment of rheumatoid arthritis provides an update on several important topics, including the use of targeted synthetic DMARDs (tsDMARDs). But how does the new guideline compare to EULAR recommendations, and is the growing importance of tsDMARDs adequately accounted for?

Limited data suggest associations between air pollution and rheumatic disease risk and outcomes. More sophisticated research is needed to clarify the conditions under which air pollution might influence the health of people with rheumatic disease, including their response to biologic drugs.

The TNF–TNF receptor signalling network has pleiotropic effects that can both promote and protect against immune-mediated diseases. Modulation of this network through the use of TNF receptor-targeting biologic drugs holds promise for treating various diseases, including TNF inhibitor-refractory diseases.

Vaccines are important tools for protection against infectious diseases, particularly in patients undergoing immunosuppression (including DMARD therapy). This Review discusses the effects of DMARDs on vaccine immunogenicity, focusing on influenza and SARS-CoV-2 vaccines, and potential mechanisms underlying these effects.

This Review provides an overview of the complement system and its role in a range of rheumatic and autoimmune diseases, and examines the rapidly expanding landscape of complement therapeutics in these settings, as well as prospects for improving their clinical use.

Long-term treatment with the anti-resorptive drug denosumab results in a continuous gain in bone mineral density, whereas denosumab withdrawal results in a transient overshoot in bone turnover, with rapid bone loss. This Perspective explores the potential mechanisms underlying these effects.

In this Review, Psarras, Wittmann and Vital discuss evidence of the production of type I interferons by cells and tissues other than haematopoietic cells. These interferons can have local effects, and their roles in the pathogenesis of systemic lupus erythematosus suggest the value of interferon-blocking therapies for treatment of this condition.

In this Review, the authors summarize the pathophysiological mechanisms of IL-1-mediated autoinflammation. They describe the epidemiological and clinical features of autoinflammatory diseases, challenges associated with diagnostics and disease management, and current and future therapies for targeting the IL-1 pathway.

Targeted therapies, including biologic DMARDs and Janus kinase inhibitors, can interfere with the mechanisms of pathological bone metabolism in inflammatory arthritis. In this Review, the authors discuss the effects of these therapies on local and generalized bone changes.

Regulatory T (T_reg) cells have crucial roles in peripheral tolerance and limiting inflammation, and IL-2 is an important cytokine for T_reg cell differentiation, activity and homeostasis. In this Review, Kolios, Tsokos and Klatzmann provide an overview of T_reg cell and IL-2 involvement in rheumatic diseases and how modulating IL-2 signalling and T_reg cell biology might provide novel treatment avenues.

Various drugs used in rheumatoid arthritis management have anti-inflammatory effects that can hinder atherosclerosis development and progression. However, these drugs can also concurrently have different pro-atherogenic effects, complicating the relationship between these drugs and cardiovascular involvement in rheumatoid arthritis.

The immunogenicity of a biologic agent can have clinical consequences in terms of response to therapy and risk of adverse events. In this Review, the authors summarize the latest data on the immunogenicity of biologic agents for various rheumatic indications.

In this Perspective article, the authors recount the earliest stages of translational research into IL-6 biology and the subsequent development of therapeutic IL-6 pathway inhibitors for the treatment of autoimmune rheumatic diseases and potentially numerous other indications.

Pharmacomicrobiomics studies investigating the effect of variations within the human gut microbiome on drugs have provided insights into therapeutics used for inflammatory arthritis, which could facilitate microbiome-based precision medicine approaches in rheumatology.

This Evidence-Based Guideline presents the first Pan American League of Associations for Rheumatology recommendations for the management of axial spondyloarthritis, addressing therapeutic targets, the use of pharmacological and non-pharmacological interventions and monitoring of patients.

The potential for the co-occurrence of spondyloarthritis and inflammatory bowel disease means that gastroenterologists must identify articular manifestations and rheumatologists must identify intestinal manifestations. This Review describes the progress in the treatment of patients with both spondyloarthritis and inflammatory bowel disease.

In systemic lupus erythematosus, renal involvement is known as lupus nephritis and it is associated with mortality and morbidity. This Review compares and contrasts the existing management guidelines for lupus nephritis and describes emerging therapeutic approaches and the feasibility of precision medicine.

Pope et al. review the current management (including both screening and treatment) of organ-based manifestations of systemic sclerosis as well as overall disease modification, with a focus on evidence from clinical trials and consensus recommendations.

This Evidence-Based Guideline presents the latest treatment recommendations for medication selection in psoriatic arthritis (PsA), covering the six clinical domains of PsA, related conditions and associated comorbidities, and reflecting important advances in the field since the previous update.

Axial spondyloarthritis, an immune-mediated inflammatory disease, is characterized by chronic back pain, joint stiffness and fatigue that can severely affect the quality of life. This Review summarizes the progress in the pharmacological management of this disease, including newly approved biologic DMARDs.

Advances in understanding the pathogenic mechanisms of primary Sjögren syndrome (pSS) and the development of new outcome measures are aiding drug development for this disease. This Review describes current treatments and highlights promising candidates for future therapies for pSS.

Despite the clinical success of therapeutics that inhibit TNF, gaps remain about the biology of this pleiotropic cytokine. This Review explores the latest discoveries related to TNF signalling pathways, TNF-induced gene expression, and the homeostatic and pathogenic functions of TNF, as well as the implications of these findings for therapeutics for TNF-mediated diseases.

This article reviews what is known about the role of the IL 23–IL 17 immune pathway at different stages in the development and progression of chronic immune-mediated inflammatory diseases, in particular rheumatoid arthritis and spondyloarthritis. The author draws on findings from disease-specific animal models and humanex vivostudies as well as data from clinical trials of therapies targeting the IL 23–IL 17 axis.

IL-6 has been linked to numerous inflammatory conditions (such as rheumatoid arthritis), and many IL-6-directed therapies are currently in development. The authors outline the basic biology of IL-6 and IL-6 signalling pathways before discussing the clinical implications of targeting IL-6 in the context of rheumatic diseases. Current and future indications for the use of IL-6-targeted therapies and safety of these agents are discussed.

In this article the authors review the 'BAFF/APRIL system', a complex of the cytokines BAFF and APRIL, their receptors and signalling pathways. The efficacy of belimumab, an anti-BAFF biologic agent used in clinical trials for SLE, is used to develop an argument that the BAFF/APRIL system is an important regulator of autoimmunity. Future therapies for SLE could fine-tune these cytokine signalling pathways to regulate autoreactive B cell survival and autoimmunity.

Although advances in therapy of rheumatoid arthritis (RA) have greatly improved disease outcomes, a considerable portion of patients still do not attain clinical remission. Thus, new treatments targeting a range of cytokines and cell types are being explored. This Review outlines these novel approaches to RA therapy.

The presence of anti-drug antibodies (ADA) can result in the loss of response to anti-TNF biologic agents in patients with rheumatoid arthritis. In this article, van Schouwenburg et al. outline the limitations of current assays for ADA detection and discuss how studying the immune responses caused by the different anti-TNF biologic agents could lead to strategies to help reduce or prevent the development of ADA.

In the past decade, the introduction of targeted biologic therapies has revolutionized the treatment of rheumatic diseases. Patents for many of these key biologic agents will soon expire, and the introduction of biosimilar versions is likely to lead to substantial cost savings. Focusing on targeted therapies for rheumatic diseases, the authors describe biosimilar agent manufacture, safety and efficacy concerns, and the current worldwide status of regulations for the approval of biosimilar drugs.

IL-1 has an important role in the pathogenesis of many hereditary and non-hereditary autoinflammatory diseases. This Review examines the biological functions of IL-1 and the use of IL-1-targeting agents in the treatment of various human diseases.

Interleukin-17 has been implicated in the pathogenesis of inflammatory arthritis. Evidence from animal models and preliminary results from trials in human disease highlight the emergence of this proinflammatory cytokine as a target for RA therapy.

Tumor necrosis factor (TNF) is expressed at high levels in synovial tissue from patients with RA. Through preclinical studies, animal model studies and human trials, this cytokine was the first to be fully validated as a therapeutic target for RA. Several approaches to blocking TNF have been developed, demonstrating considerable benefit in most of the patients treated.