Biologic Therapies

Introduction

Advances in biotechnology, a greater understanding of the immunopathogenesis of rheumatoid arthritis (RA) and a desire for more effective therapeutics have led to the development of a class of therapeutic agents called biologic/cytokine-directed therapies. These specifically targeted biopharmaceuticals have taken aim at cellular subsets, adhesion molecules, class II major histocompatability complex (MHC) molecules, T-cell and B-cell receptors, costimulatory molecules and a variety of cytokines. Extensive studies with these new agents have moved the field forward in determining the operative roles and relative importance of integral elements of the immune response in the perpetuation of inflammatory disorders.

While many of these agents have either been instructive or disappointing, many have shown impressive clinical efficacy. Despite a large number of clinical trials using monoclonal antibodies to target T-cell subsets, most of these failed to make it to the market because of limited efficacy and unacceptable toxicities (e.g., lymphopenia, cytokine-release syndrome, etc.). The dose-related toxicity of cyclosporine has also made this T cell directed therapy unacceptable to many. Nonetheless, a modified approach targeting costimulatory signaling of T cells has led to the successful agent abatacept (see Blockade of T-Cell Costimulatory Pathways).

Humoral hyperactivity is one of the characteristic aberrant immune responses seen in RA. B-cell activation and hyperactivity result in hypergammaglobulinemia and excessive autoantibody production that include rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies, both of which have been linked to the pathogenesis of the disease. For many years, the importance of this humoral overdrive has fluctuated, but has gained relevance with the development of B-cell–specific monoclonal antibodies such as rituximab (see B-Cell Targeted Therapies).

Cytokine-directed therapies have been developed because of their specific but broader immunologic benefits in primary and secondary inflammatory events. They have become popular because of their ease of use and significant effects on clinical, radiographic and functional outcomes in RA. As regulatory and terminal effector molecules, cytokines are thought to underlie the amplified dysregulated immune response that contributes to the magnitude and chronicity of manifest inflammatory disease. For example, the proinflammatory cytokines tumor necrosis factor-alpha (TNFα ) and interleukin (IL) IL-1 are responsible for the activation of numerous cell types, the release of cytokines and inflammatory mediators, the induction of adhesion molecules and the migration of cells to sites of inflammation (Figure 12-1). Within the joint, a constitutive balance of proinflammatory and anti-inflammatory regulatory cytokines exists (Figure 12-2). However, with rheumatoid inflammation, an imbalance evolves favoring an inflammatory milieu.

While the manipulation of cytokine activity has been therapeutically successful, it has not resulted in a disease cure, likely because it does not affect the underlying cause of autoimmunity. Proinflammatory cytokine activity may be abrogated by soluble receptor constructs (e.g., etanercept) or monoclonal antibodies (e.g., adalimumab, infliximab), cytokine receptor blockade (e.g., tocilizumab) or by induction of anti-inflammatory cytokine activity (Figure 12-3).

The success of cytokine therapies underscores the merits of approaching inflammatory diseases with more complete yet efficient and specific therapies. The relative ease of delivery, specificity and affinity for target molecules/tissues and biologically suitable half-lives have made these therapies effective and therefore attractive to clinicians and patients alike. In the course of developing most cytokine therapies, the biologic plausibility, safety and efficacy of most cytokine drug development has focused on RA. The availability of a well-defined, common, homogenous disorder with validated outcome measures has made RA an attractive arena for the development and marketing of these new agents.

In addition to the TNF-blocking therapies (e.g., adalimumab, etanercept, infliximab, certolizumab, golimumab), other cytokine-directed therapies have been approved or are currently being developed. These include a variety of mechanistic approaches to IL-1 inhibition (seeInterleukin-1 Inhibitors), IL-6 blockade (see Interleukin-6 Inhibitors) and inhibition of other potential targets, such as IL-15 and IL-17.

The dosage and administration details for currently FDA-approved IV/SC biologics are listed in Table 12-1.

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Indications for Biologic Therapies

The introduction and approval of many new biologic therapies have favorably impacted the lives of many individuals with a variety of inflammatory disorders and have begun to change the standard of care for RA. Foremost among these have been the tumor necrosis factor (TNF) inhibitors (e.g., etanercept, infliximab, certolizumab and golimumab). Despite these therapeutic advances, payers, managed-care providers and, in some cases, concerned physicians have limited the use of these agents because of concerns about safety or cost. These impediments to use lessened because of the growing worldwide use and experience with biologics, impressive clinical data, associations with reduced mortality rates and numerous safety reviews.

The TNF inhibitors have been approved for use in RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, pediatric ulcerative colitis, plaque psoriasis, hidradenitis suppurativa and uveitis, with each TNF inhibitor indicated for a subset of these conditions. In RA, cytokine therapies are generally indicated for patients who have not shown an adequate response to a reasonable dose and duration of methotrexate (MTX) or other traditional (disease-modifying antirheumatic drug) DMARDs. These agents are approved to control the signs and symptoms of RA and reduce structural (radiographic) damage. In addition, both etanercept and infliximab have a quality-of-life indication based on 2-year data showing improvement in functional outcome measures (e.g., health assessment questionnaire (HAQ)). None of the currently marketed TNF inhibitors require previous DMARD or biologic therapy prior to their use. However, only etanercept, adalimumab, and certolizumab have been approved for use without concomitant MTX.

Anakinra, abatacept, rituximab and tocilizumab share some of the same indications as the TNF inhibitors. In addition, anakinra is indicated for the treatment of cryopyrin-associated periodic syndromes, and rituximab is approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and granulomatosis with polyangiitis. Unlike the TNF inhibitors, rituximab is only approved for use in those patients who have had an inadequate response to one or more TNF inhibitor, and tocilizumab and anakinra are only approved for patients who have failed one or more DMARD. Abatacept has a broad label similar to the anti-TNF therapies.

Biologic agents should only be considered when an aggressive approach to the disease is warranted and the merits of such an approach have been studied, proven, and advocated. Guidelines have been suggested to better define the appropriate use of biologic drugs, especially in early disease or when MTX or other DMARDs yielded partial or nonresponses. The 2021 American College of Rheumatology (ACR) guideline for the management of RA (Pharmacotherapy and Management Guidelines for Rheumatoid Arthritis) position biologics for use after a suboptimal response to MTX monotherapy in patients with low, moderate, or high disease activity.

Screening for Latent Tuberculosis (TB)

Although the 2021 ACR guideline contains no recommendations on tuberculosis screening, the 2015 ACR guideline recommends screening to identify latent TB infection (LTBI) in all RA patients being considered for treatment with biologic agents or JAK inhibitors, regardless of the presence of risk factors for LTBI. The patient’s medical history should be assessed to identify risk factors for TB. The guideline recommends the tuberculin skin test (TST) or interferon-gamma-release assays (IGRAs) as the initial test in all patients starting biologic agents, regardless of risk factors for LTBI. Most healthcare providers use an IGRA test (eg, the QuantiFERON®-TB Gold Test). The TST must be read within 48 to 72 hours by a health care professional and is considered positive if there is ≥5 mm induration. The guideline recommends the IGRA over the TST in patients who had previously received a Bacille Calmette-Guérin (BCG) vaccination, due to the high false-positive test rates with the TST. Patients with a positive initial or repeat TST should have a chest radiograph and, if suggestive of active TB, a sputum examination to check for the presence of active TB. RA patients with a negative screening TST or IGRA may not need further evaluation in the absence of risk factors and/or clinical suspicion for TB.