Overview of biologic agents in the rheumatic diseases

INTRODUCTION — Advances in molecular biology, immunology, and drug development since the late 1990s have led to a variety of new treatment approaches to rheumatoid arthritis and other systemic inflammatory diseases associated with autoimmunity. The major biologic approaches in clinical use, including both medications made by molecular biologic techniques and small molecule kinase inhibitors, include agents that:

●Interfere with cytokine function, signal transduction, or production

●Inhibit the "second signal" required for T-cell activation

●Deplete B cells

An overview of biologic agents, biosimilar medications with near identity to the original biologic agents, and small molecule kinase inhibitors used in the management of patients with rheumatic disorders is reviewed here. The role of cytokines in the immune system and in rheumatic disease pathogenesis, the management strategies for individual diseases, and a fuller discussion of the efficacy and safety of these agents are presented in detail separately (see "The adaptive cellular immune response: T cells and cytokines"). (See relevant disease-specific topic reviews.)

T CELL SUBSETS AND CYTOKINES — T helper (Th) cell subsets each secrete an array of specific cytokines, which then influence the development and perpetuation of systemic inflammation. Th cells and their cytokines can be categorized into two general subsets, termed Th1 and Th2, which differ in how they affect the immune system. The cytokines generated by Th1 or Th2 cells respectively inhibit the cellular function of the other phenotype [1,2]. Additional cell types, termed Th17 cells and regulatory T cells (T reg), have also been described. Th cell differentiation and function are described in detail separately. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets'.)

Briefly, the following major subsets are important and of particular interest in the regulation of normal immune function and immune-mediated disorders:

●Th1 cells – Th1 lymphocytes participate in a broad variety of inflammatory responses, including cell-mediated inflammation in rheumatoid arthritis, psoriasis, psoriatic arthritis, acute allograft rejection, graft-versus-host disease, and others. Some of the proinflammatory mediators produced by Th1 cells include interferon gamma (IFNg), tumor necrosis factor (TNF), and interleukin (IL) 2. IFNg and IL-2 can inhibit Th2 cell proliferation.

●Th2 cells – Th2 lymphocytes stimulate antibody production by B cells and augment eosinophil responses. The activation of Th2 cells contributes to the development of chronic graft-versus-host disease, systemic lupus erythematosus, and systemic sclerosis. A partial list of mediators produced by Th2 includes IL-4, -5, -10, and -13. IL-4 and IL-10 can inhibit Th1 cytokine production.

●Th17 cells – Th17 cells differentiate from naïve T cells in response to antigen, transforming growth factor (TGF) beta, IL-6, and IL-23 [3,4]. Th17 cells secrete a cytokine, IL-17, which in concert with other cytokines affects inflammation, cartilage, and bone metabolism [5].

●T reg cells – T reg cells function largely to regulate other T cells. They may have critical functions in multiple rheumatic diseases, including giant cell arteritis, granulomatosis with polyangiitis, rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis, Sjögren's disease, and other conditions. T reg cells also differentiate under the influence of antigen and TGF beta, and they have a protective function through IL-10 and TGF beta [5]. While not yet clinically tested as cell-based therapy, their capacity to reduce inflammation and autoimmunity are the subject of interest in this context.

A number of anti-cytokine therapies have been developed as therapeutic agents based in part on these observations.

ANTICYTOKINE APPROACHES — Several specific anticytokine therapies for the treatment of autoimmune diseases have been introduced into clinical practice.

Nomenclature — Abbreviations placed at the ends of the names of therapeutic agents convey specific information relating to their structure [6]:

●"-cept" refers to fusion of a receptor to the Fc part of human immunoglobulin G1 (IgG1)

●"-mab" indicates a monoclonal antibody (mAb)

●"-ximab" indicates a chimeric mAb

●"-zumab" indicates a humanized mAb

●"-umab" indicates a fully human mAb

In late 2021, an expanded collection of four suffixes was introduced to accommodate the increasing number of mAbs, to decrease sound-alikes, and to provide information about modifications to the immunoglobulin structure [7]. These suffixes are to be used instead of "mab" for mAbs developed from 2022 onward (see "Overview of therapeutic monoclonal antibodies", section on 'Naming conventions'):

●"tug" is used for full-length unmodified immunoglobulins that recognize a single epitope (monospecific)

●"bart" is used for full-length monospecific immunoglobulins with engineered constant regions or any point mutation introduced by engineering

●"mig" is used for bispecific or multispecific immunoglobulins with any structure

●"ment" is used for monospecific immunoglobulin variable region fragments

Types of therapeutic molecules — To downregulate or inhibit the effector functions of cytokines in vivo, three general approaches have been used:

●Soluble receptor antagonists – Soluble receptor antagonists can be truncated forms of the cell surface receptor that are devoid of the transmembrane and intracytoplasmic domains. However, these molecules retain binding affinities that are comparable to those of full-length membrane-bound receptors. The prototypical soluble receptor antagonist is etanercept, a fusion protein comprised of the p75 tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1. (See 'Etanercept' below.)

Soluble receptor molecules such as etanercept bind their target cytokine while it is in serum, thereby inhibiting the cytokine's ability to interact with its cell surface receptors. Soluble fusion proteins must remain in the circulation for at least several days to achieve their therapeutic effects. The half-life of etanercept is longer than that of the native soluble receptor because the receptor binds tightly to the IgG-Fc [8]

●Monoclonal antibodies to cytokines or their receptors – The second approach to the downregulation of cytokine function has been the use of mAbs [9]. mAbs also have a higher affinity for a given cytokine compared with soluble receptors (eg, etanercept) that target the same molecule.

Therapeutic mAbs used to treat patients with rheumatologic diseases typically consist of the Fc portion of human IgG1 (sometimes IgG4) and chimeric, humanized, or fully human Fab fragments. Examples of mAbs employed in the treatment of rheumatic disease are infliximab, adalimumab, ustekinumab, and secukinumab. Certolizumab, a polyethylene glycolated (PEGylated) Fab fragment that does not contain an Fc portion, has also been developed, as have other therapeutic antibodies derived from IgG2 and IgG4. (See 'TNF inhibition' below and 'Ustekinumab' below and 'Secukinumab' below.)

●Cell surface receptor antagonist proteins – Recombinant cell surface receptor antagonists are biologically inactive proteins that compete with a cytokine for binding to the cytokine's membrane receptor [10]. Examples of cell surface receptor antagonists in the rheumatic diseases are anakinra and rilonacept, recombinant antagonists of the interleukin (IL) 1 receptor (see 'IL-1 inhibition' below). Another mAb against a receptor is brodalumab, an anti-IL-17 receptor antibody. (See 'IL-17 inhibition' below.)

Receptor antagonists must bind greater than 90 percent of the receptors on the cell surface to be effective. Large doses of the antagonist are required for such an effect.

Another approach, which more indirectly targets an array of cytokines, is the use of orally administered small molecule drugs, produced by traditional manufacturing techniques, which are designed to inhibit selected cytoplasmic protein tyrosine kinases, such as Janus kinase (JAK), which mediates signaling from membrane cytokine receptors. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders".)

BIOLOGIC CYTOKINE INHIBITORS

TNF inhibition — Five tumor necrosis factor (TNF) inhibitors are available for the treatment of rheumatoid arthritis and a number of other rheumatic and other immune-mediated diseases in the United States and worldwide. (See 'Etanercept' below and 'Infliximab' below and 'Adalimumab' below and 'Certolizumab' below and 'Golimumab' below.)

These drugs have been the subject of numerous trials and other studies, including multiple meta-analyses. As an example, a systematic literature review and meta-analysis of TNF-blocking agents for rheumatoid arthritis indicated that these agents used in monotherapy were equally efficacious and similar to methotrexate regarding clinical signs. When used in combination with methotrexate, they were better than methotrexate alone [11]. Thus, the combination of a TNF blocker and methotrexate was superior to either methotrexate or a TNF blocker alone, and the TNF blockers were relatively safe compared with methotrexate. The use and evidence for the efficacy of these agents in rheumatoid arthritis and other disorders are described in detail separately in the UpToDate topics on treatment of individual diseases, including rheumatoid arthritis, psoriatic arthritis and psoriasis, spondyloarthritis, inflammatory bowel disease, and others. (See appropriate topic reviews.)

The potential adverse effects of the TNF inhibitors are also described in detail separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

Biosimilar forms of several TNF inhibitors have become commercially available in many countries, and additional biosimilar agents are in development. (See 'Biosimilars for biologic agents' below.)

Etanercept — Etanercept is a soluble p75 TNF receptor fusion protein that consists of two p75 TNF receptors bound to the Fc portion of immunoglobulin G (IgG). Thus, the medication is bivalent (one etanercept molecule binds two TNF molecules). Etanercept is administered once or twice weekly via subcutaneous injection.

Etanercept is used for the treatment of a number of forms of inflammatory arthritis and other conditions, including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. However, etanercept is not effective for ulcerative colitis and Crohn disease. (See appropriate topic reviews on the treatment of specific diseases.)

Biosimilars of etanercept have received regulatory approval in Europe, South Korea, and other countries [12]. (See 'Biosimilars for biologic agents' below.)

Infliximab — Infliximab is a chimeric monoclonal antibody (mAb) directed against TNF. The term "chimeric" refers to the use of both murine and human components of the drug. With infliximab, the kappa chain variable region (VK) and heavy chain variable region (VH) domains of the antigen-binding portion of the molecule are murine, and the constant Fc domain is human. Infliximab is administered via intravenous infusion approximately every six weeks once a steady state has been achieved.

The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) approved a subcutaneous version of a biosimilar infliximab, which is also available in Canada and Korea [13,14].

Infliximab is effective for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn disease, and ulcerative colitis. (See appropriate topic reviews on the treatment of specific diseases.)

Biosimilar forms of infliximab, such as infliximab-dyyb, have been approved in a number of countries worldwide, with all the indications of the legacy (originator) compound [12]. (See 'Biosimilars for biologic agents' below.)

Adalimumab — Adalimumab is a recombinant fully human mAb that is administered subcutaneously rather than by intravenous infusion. The recommended interval between administrations is every two weeks. Adalimumab is associated with a lower risk of anti-drug antibody formation compared with infliximab, possibly by virtue of its fully human construction. Nevertheless, anti-drug antibodies occur upon treatment with adalimumab, which can be reduced by concomitant methotrexate treatment [15]. They are directed against the idiotype and can be neutralizing. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Adalimumab-induced human anti-human antibodies'.)

Adalimumab has been approved for use in rheumatoid arthritis, plaque psoriasis, Crohn disease, pediatric Crohn disease, ulcerative colitis, psoriatic arthritis, hidradenitis suppurativa, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, and noninfectious intermediate, posterior, and panuveitis (see appropriate topic reviews on the treatment of specific diseases). Adalimumab biosimilars have been approved in numerous countries and regions, including in India [12], Canada, Europe [16], and the United States [17].

Certolizumab — Certolizumab pegol is a humanized anti-TNF-alpha antibody Fab' fragment that is chemically linked to polyethylene glycol. The medication neutralizes membrane-associated and soluble TNF-alpha. Certolizumab pegol is administered every two weeks by subcutaneous injection, and dosing at four-week intervals can be effective in some patients for maintenance therapy.

Certolizumab pegol is formally approved in the United States for use in Crohn disease and rheumatoid arthritis, as well as psoriatic arthritis and ankylosing spondylitis, and it has been used in uveitis and ulcerative colitis. Like the other TNF inhibitors it is available worldwide. (See appropriate topic reviews on the treatment of specific diseases.)

In addition, the EMA has approved a label change for certolizumab pegol, making it the first anti-TNF for potential use in women with chronic rheumatic disease during both pregnancy and breastfeeding, based on two trials [18,19]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tumor necrosis factor inhibitors'.)

Golimumab — Golimumab is a human IgG1 kappa mAb specific for human TNF-alpha that neutralizes TNF-alpha activity. Golimumab binds to both the soluble and transmembrane bioactive forms of human TNF-alpha. It is administered once monthly by subcutaneous injection.

Golimumab has been available for use in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis in a number of countries. (See appropriate topic reviews on the treatment of specific diseases.)

IL-1 inhibition — Interleukin (IL) 1 inhibitors such as anakinra are available commercially for use in patients with rheumatoid arthritis and other forms of inflammatory arthritis. However, their relatively modest effect on inflammatory arthritis in rheumatoid arthritis compared with other biologic agents, such as the TNF inhibitors, has resulted in their being used only rarely for this disease. These agents are also used in systemic-onset juvenile idiopathic arthritis and adult-onset Still's disease, as well as other conditions. The biology, adverse effects, and other factors related to the various IL-1 inhibitors are discussed in detail separately. (See "Interleukin 1 inhibitors: Biology, principles of use, and adverse events".)

Anakinra and two other IL-1 inhibitors, canakinumab and rilonacept, through their effect on the inflammasome (a critical mediator of autoinflammatory conditions), are effective for the treatment of autoinflammatory conditions such as cryopyrin-associated periodic syndromes (CAPS), TNF receptor-1 associated periodic syndrome (TRAPS), and familial Mediterranean fever, and are used to treat these conditions. (See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)" and "Cryopyrin-associated periodic syndromes and related disorders" and "Management of familial Mediterranean fever", section on 'Interleukin 1 inhibition'.)

IL-1 inhibition also has a role in the treatment of selected patients with acute gouty arthritis, as well as pseudogout. (See "Treatment of gout flares", section on 'Resistant or refractory disease' and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Resistant disease'.)

A variety of approaches to IL-1 inhibition, including receptor antagonism and IL-1 binding, have been employed.

Anakinra — Anakinra is a recombinant human IL-1 receptor antagonist (rHuIL-1Ra), which unlike the native protein is not glycosylated and has an additional N-terminal methionine. Anakinra is available for the treatment of rheumatoid arthritis but is significantly less potent in most patients with rheumatoid arthritis than TNF inhibitors [20,21]. Unlike conventional disease-modifying antirheumatic drugs (DMARDs; eg, methotrexate), anakinra is not recommended in a combination regimen with a TNF inhibitor or other biologic agents because of an increased frequency of serious adverse events, including serious infections [22,23]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Resistant to standard therapies'.)

Anakinra may be more effective in the treatment of autoinflammatory conditions, including TRAPS (see "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)"). It is also used for the treatment of systemic juvenile idiopathic arthritis and adult-onset Still's disease, and in selected patients with recurrent pericarditis (see "Systemic juvenile idiopathic arthritis: Treatment" and "Treatment of adult-onset Still's disease" and "Recurrent pericarditis", section on 'Other immune therapy'). In the European Union, anakinra is approved to treat signs and symptoms of rheumatoid arthritis in combination with methotrexate in patients who have not responded adequately to methotrexate alone, and CAPS [24].

Anakinra has also been approved by the US Food and Drug Administration (FDA) and EMA for the treatment of coronavirus disease 2019 (COVID-19). (See "COVID-19: Management in hospitalized adults", section on 'Baricitinib and JAK inhibitors'.)

Canakinumab — Canakinumab, an anti-IL-1beta (anti-IL-1b) mAb with a longer half-life than anakinra, has also been employed in autoinflammatory conditions and in settings in which IL-1 inhibition is beneficial (eg, acute gout in which contraindications to conventional therapies exist) [25].

In the United States and the European Union, canakinumab is approved for four types of periodic fever syndromes in adults and children aged two and above: CAPS, TRAPS, hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), and familial Mediterranean fever; as well as for adult-onset Still's disease; systemic juvenile idiopathic arthritis (Still's disease; in children, aged two and above); and gouty arthritis [26,27].

Rilonacept — Rilonacept is a human IgG1 Fc antibody with bispecific arms; these bind IL-1b. Like the other IL-1 inhibitors, it is available for use in patients with CAPS and related conditions such as the Muckle-Wells syndrome, another rare autoinflammatory disease. Although the manufacturer of rilonacept applied for FDA approval for gout, this approval was not granted. Nevertheless, like the other IL-1 inhibitors, it is sometimes used in this disease. Rilonacept is also approved for use in the United States for recurrent pericarditis. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Rilonacept' and "Recurrent pericarditis", section on 'Interleukin 1 inhibitors'.)

IL-6 inhibition — IL-6 has both proinflammatory and antiinflammatory effects and has been successfully targeted for the treatment of rheumatoid arthritis and other rheumatic diseases [28]. The cytokine activates T cells, B cells, macrophages, and osteoclasts and is a pivotal mediator of the hepatic acute phase response. In concert with TNF-alpha and IL-1, IL-6 promotes vascular endothelial growth factor (VEGF) and metalloproteinase production [29].

IL-6 binds to both soluble and membrane-bound receptors and leads to the transduction of intracellular signals through the interaction of this complex with gp130, mediating gene activation and a wide range of biologic activities [29,30].

The biology, principles of use, and adverse effects of therapeutic IL-6 inhibitors are described in detail separately. (See "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects".)

Tocilizumab — Tocilizumab is a humanized anti-human IL-6 receptor antibody of the IgG1 subclass. The medication is made by grafting the complementarity determining regions of a mouse anti-human IL-6 receptor mAb onto human IgG1. Tocilizumab binds to both the membrane-bound and soluble forms of human IL-6 receptor (IL-6R), thereby inhibiting the action of the cytokine/receptor complex and interfering with the cytokine's effects.

Tocilizumab is used for rheumatoid arthritis, juvenile idiopathic arthritis and Castleman disease. (See "Systemic juvenile idiopathic arthritis: Treatment", section on 'Interleukin 6 inhibitors' and "HHV-8-negative/idiopathic multicentric Castleman disease", section on 'IL-6 inhibitors' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'IL-6 inhibitor therapies' and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy'.)

Tocilizumab has also shown benefit in giant cell arteritis (approved for this indication in the United States and Europe) as well as interstitial lung disease associated with systemic sclerosis (approved in the United States) [31] (see "Treatment of giant cell arteritis", section on 'Tocilizumab' and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Tocilizumab'). It is also used in patients with COVID-19 and patients with cytokine release syndrome associated with chimeric antigen receptor (CAR)-T cell therapy. (See "COVID-19: Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg, tocilizumab)' and "Cytokine release syndrome (CRS)", section on 'CAR-T cell-associated CRS'.)

Sarilumab — Another human mAb, sarilumab, is a fully human recombinant mAb of the IgG1 subclass that binds to the IL-6R and acts as an IL-6R antagonist. It is directed against both the membrane-bound and soluble IL-6R and is available in the United States and the European Union for the treatment of rheumatoid arthritis. In the United States, sarilumab has also been approved for the treatment of refractory polymyalgia rheumatica [32]. It is administered by subcutaneous injection every two weeks [33-35].

IL-17 inhibition — IL-17, which is produced by Th17 cells, amplifies production of multiple cytokines and stimulates keratinocytes, synoviocytes, macrophages, fibroblasts, and neutrophils [36]. Antibodies that target the IL-17 pathways have been developed and are marketed for the treatment of several conditions in which the IL-17 pathway has a role, including psoriasis and psoriatic arthritis, spondyloarthritis, and other immune-mediated diseases.

Secukinumab — Secukinumab is a fully human IgG1 kappa mAb against IL-17 [37]. It is commercially available for use in psoriasis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, hidradenitis suppurativa, and inflammatory bowel disease. It has also been used in uveitis [37]. Its efficacy in rheumatoid arthritis (for which it has not been approved) appears to be modest, and comparatively less than in these other conditions, based upon limited study [38].

Secukinumab is administered by monthly subcutaneous injection after several loading doses [39]. An intravenous form of secukinumab is also available [40].

Ixekizumab — Ixekizumab, a humanized mAb against IL-17A, has been granted FDA and EMA approval for the treatment of psoriasis and has been effective for psoriatic arthritis as well. It has also been granted EMA approval for psoriatic arthritis.

Bimekizumab — Bimekizumab, a humanized mAb against IL-17A and IL-17F, has been granted EMA approval for the treatment of plaque psoriasis, psoriatic arthritis, and non-radiographic and radiographic axial spondyloarthritis [41]. Bimekizumab is also approved in Canada and the US for plaque psoriasis [42].

IL-12/23 blockade

Ustekinumab — Ustekinumab is a human IgG1 kappa mAb that binds to the p40 subunit shared by IL-12 and IL-23. It is available for use in the treatment of psoriasis and psoriatic arthritis [43]. It is administered every 12 weeks by subcutaneous injection after several loading doses.

Ustekinumab interferes with the binding of the proinflammatory cytokines IL-12 and IL-23 to their cell surface receptors. Biologic effects of IL-12 and IL-23 include natural killer (NK) cell activation, CD4+ T-cell differentiation and activation. Ustekinumab also interferes with the expression of monocyte chemotactic protein (MCP)-1, TNF-alpha, interferon-inducible protein-10 (IP-10), and IL-8.

Ustekinumab is also approved by the EMA for the treatment of adult patients with moderately to severely active Crohn disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF-alpha antagonist or have medical contraindications to such therapies [44].

Guselkumab — Guselkumab is a human IgG1 mAb directed against the p19 subunit of IL-23 and is thus specific for IL-23, not binding to IL-12. It is highly efficacious in psoriasis and also works in psoriatic arthritis. It has been approved for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. It has been approved by the FDA and EMA for use in psoriatic arthritis.

Risankizumab — Risankizumab is a humanized IgG1 mAb directed against the p19 subunit of IL-23 [45-47]. It was approved by the FDA and EMA for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy and subsequently approved for the treatment of psoriatic arthritis. It is administered subcutaneously 4 weeks apart for the first 2 doses, then every 12 weeks, and may be administered alone or in combination with conventional synthetic DMARDs.

COSTIMULATION BLOCKADE — A biologic agent, abatacept, that targets a key pathway in T-cell costimulation is available for use in rheumatoid arthritis (and psoriatic arthritis) and is under study in other rheumatic diseases. CD28 and CTLA-4 (CD152) are important in the regulation of T-cell activation and function; they help control some of the cross-talk between T cells, on which they are primarily expressed, and antigen-presenting cells, on which they interact with their ligands, CD80 and CD86 (also termed B7-1 and B7-2) [48]. CD28 binding has been found to decrease the activity of regulatory T cells (T reg) and to increase T effector cell activity, while CTLA-4 may, by contrast, ultimately activate T effector cells without suppressing T reg activity [49]. Thus, targeting of these pathways can impact immune function. (See "Transplantation immunobiology", section on 'T cell costimulation'.)

Abatacept — Abatacept is a soluble fusion protein comprising CTLA-4 and the Fc portion of immunoglobulin G1 (IgG1) (CTLA4-Ig). Abatacept is available for use in the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis. Abatacept can be administered by either weekly subcutaneous injection or by monthly intravenous infusion following several loading doses. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept'.)

Abatacept prevents CD28 from binding to its counter-receptor, CD80/CD86, due to its higher affinity for CD80/CD86. This prevents the suppression of T reg activity and prevents increased T effector cell activity [49]. Administration of CTLA4-Ig or successful transfer of its gene also prevents or ameliorates collagen-induced arthritis in mice, and it is beneficial in transplantation models [50,51].

B-CELL DEPLETION AND INHIBITION — Biologic agents that can deplete B cells (eg, rituximab) or inhibit factors that activate B cells (belimumab) are used for the treatment of a range of rheumatic and other diseases. In addition to their central role in antibody production, B cells present antigen to T cells, activate T cells, and promote the production of proinflammatory cytokines, including interleukin (IL) 1, IL-4, IL-6, IL-8, IL-10, and IL-12; tumor necrosis factor (TNF)-alpha; vascular endothelial growth factor (VEGF); monocyte chemotactic protein (MCP); and macrophage migration inhibitory factor (MIF) [52]. (See "Normal B and T lymphocyte development".)

Rituximab — Rituximab, a chimeric immunoglobulin G1 (IgG1) monoclonal antibody (mAb), is used to treat lymphoproliferative disorders and several rheumatic diseases. It eliminates CD20-positive B cells, induces complement mediated cytotoxicity, and stimulates apoptosis but has little and/or nonspecific effects on existing protective autoantibody titers, with a profound negative effect on de novo antibody formation (eg, following COVID-19 vaccination). It is probable that some combination of these effects accounts for its activity in autoimmune disease [53]. It is usually administered as a short series of typically two or four intravenous infusions every four to six months or at longer intervals as needed. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Incorporation of rituximab'.)

In addition to treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia, rituximab is indicated for treating rheumatoid arthritis and granulomatosis with polyangiitis and microscopic polyangiitis. It has also been used in systemic lupus erythematosus, systemic sclerosis, and other forms of vasculitis as well as myositis, although it is not formally approved by regulatory agencies for any of these other conditions. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

Implications of rituximab use in patients during the COVID-19 pandemic are described separately. (See "COVID-19: Care of adult patients with systemic rheumatic disease".)

Belimumab — Belimumab is an anti-B lymphocyte stimulator (BLyS) mAb which binds to soluble BLyS, preventing its binding and stimulation of B cells [52]. It is available for use for the treatment of systemic lupus erythematosus and is being studied in other conditions, such as Sjögren's disease. Belimumab is administered by intravenous infusion every four weeks after therapy is initiated with several more frequent loading doses. It is also available for subcutaneous injections. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults".)

Anifrolumab — Anifrolumab is a first-in-class global type 1 interferon inhibitor approved by the FDA for systemic lupus erythematosus in addition to standard of care [54].

BIOSIMILARS FOR BIOLOGIC AGENTS

●Definitions – The World Health Organization (WHO) defines a biosimilar as a "biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product" [55]. "Similarity" is defined as the "absence of a relevant difference in the parameter of interest."

A biosimilar (unlike a "biomimic" or "biocopy," which are medications marketed in some countries) has the same primary amino acid sequence as the reference product and has undergone rigorous analytic and clinical testing in comparison with its reference product [56].

●Availability – Multiple biosimilar agents have been approved by regulatory agencies in several countries and regions, and their availability is growing. Copies of biologic agents, including several of the tumor necrosis factor (TNF) inhibitors, rituximab, and other therapeutic molecules, have been marketed and are under development for use in the rheumatic diseases. The availability of each of these agents and approved indications for their use will depend upon regulatory requirements in different regions and local patent laws and patent expiration dates [57-59].

Commercially available products that have received regulatory designation as biosimilar (eg, infliximab, etanercept, adalimumab, and rituximab) in the United States, Canada, and some other countries are described in the drug information monograph (Lexicomp) included within UpToDate for the legacy (originator) biologic agent [57,60-64]. (See "Infliximab (including biosimilars): Drug information" and "Etanercept (including biosimilars available in Canada): Drug information" and "Adalimumab (including biosimilars): Drug information".)

An updated list of biologic products and biosimilars approved by the US Food and Drug Administration (FDA) is available through the FDA Center for Drug Evaluation and Research [65], and updated information regarding biosimilars approved by the European Medicines Agency (EMA) is also available [66,67].

●Equivalence with bio-originators – The American College of Rheumatology (ACR) has issued a "white paper" that recommends the use of biosimilars for patients with rheumatic diseases [68]. The ACR report highlights the scientific rigor with which the FDA and other regulatory agencies outside of the United States have evaluated these agents, including the process of extrapolation of indications.

The data supporting the use of biosimilar TNF-alpha inhibitors are particularly robust:

•A 2016 systematic review described the results of 19 observational studies and clinical trials that compared biosimilar TNF-alpha inhibitors with their reference biologic products, including infliximab, etanercept, and adalimumab [69]. The studies included patients with rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Pharmacokinetic measurements for the respective biosimilar drugs and their reference products were within defined equivalence margins, and similar clinical responses and adverse events were found for biosimilars their reference drugs. Two studies documented immunologic cross-reactivity between products, and similar efficacy and safety were observed in four cohort studies in which patients were switched from the reference product to a biosimilar medication.

•A subsequent meta-analysis described the results of 25 clinical trials of 10,642 patients with rheumatoid arthritis that compared biosimilar TNF-alpha inhibitors with their reference biologic products, including infliximab, etanercept, and adalimumab [70]. Biosimilars were equivalent to reference biologics in terms of disease activity (ACR 20 response; relative risk [RR] 1.01) and patient function (Health Assessment Questionnaire Disability Index [HAQ-DI] scores; standardized mean difference -0.04).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY

●Biologic targeting for rheumatologic disease treatment – The major biologic approaches to treatment of the rheumatologic diseases include agents that (see 'Anticytokine approaches' above):

•Interfere with cytokine function

•Interfere with interferon function

•Inhibit the "second signal" required for T-cell activation

•Deplete B cells

●Biologic therapeutic agents for rheumatologic disease – The following biologic treatment strategies are employed in rheumatic disease:

•Tumor necrosis factor (TNF) inhibition (see 'TNF inhibition' above)

•Interleukin (IL) 1 inhibition (see 'IL-1 inhibition' above)

•IL-6 inhibition (see 'IL-6 inhibition' above)

•IL-17 inhibition (see 'IL-17 inhibition' above)

•IL-12/23 inhibition (see 'IL-12/23 blockade' above)

•Costimulation blockade (see 'Costimulation blockade' above)

•B-cell depletion and inhibition of B-cell activation (see 'B-cell depletion and inhibition' above)

•Interferon type 1 inhibition

●Biosimilars – Copies of biologic agents that are no longer under patent protection are becoming available for use in multiple countries. These medications have the same amino acid sequences as the original reference molecules, and the regulatory regimens require these biosimilar agents to be highly similar in terms of quality, safety, and efficacy to the already-licensed reference biotherapeutic product. (See 'Biosimilars for biologic agents' above.)

●Janus kinase inhibitors – Tofacitinib, baricitinib, upadacitinib, peficitinib, and filgotinib are orally administered, highly targeted, small molecule pharmaceutical agents that inhibit Janus kinases (JAK), which are cytoplasmic protein tyrosine kinases that mediate signaling from an array of multiple cytokine receptors to the nucleus. Their therapeutic benefits and adverse effects in rheumatic diseases are generally similar to the biologic agents. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge John H Stone, MD, MPH, who contributed to an earlier version of this topic review.