TNF-Blocking Therapies

Introduction

Tumor necrosis factor (TNF) has been shown to play a key role in the pathogenesis and amplified inflammatory response characteristic of RA. Therefore, tumor necrosis factor-alpha (TNFα ) is an attractive candidate for therapeutic manipulation. Several studies have showed an excess of TNF and TNF receptors (TNFRs) in rheumatoid synovium, substantial evidence of TNF-related proinflammatory events (e.g., additional cytokine induction, increased nitric oxide, collagenase, prostaglandins, increased adhesion molecules expression) in addition to evidence of spontaneous erosive synovitis in TNF overexpressing transgenic mice. TNFα is an attractive therapeutic target owing to its pleiotropic origins and plethora of proinflammatory effects. The most dramatic of these may be TNF-mediated endotoxic shock, cachexia and fever associated with sepsis.

Biologically specific therapies targeting TNFα have been studied and approved for use in a variety of inflammatory disorders, including juvenile arthritis, moderate-severe RA, early RA, psoriatic arthritis, psoriasis, ankylosing spondylitis and Crohn’s disease (Table 14-1). Moreover, clinical trials thus far have shown variable benefits in other inflammatory diseases, including ulcerative colitis, spondyloarthropathies, uveitis, and some granulomatous disorders (e.g., sarcoidosis, pyoderma gangrenosum). Further controlled trials are needed to establish the efficacy and safety of TNF inhibition in other inflammatory states.

In RA, scientific and clinical evidence demonstrates that blocking TNFα provides dramatic improvement in disease activity and quality of life, with less risk of radiographic progression. Five agents that inhibit TNFα have been approved for use in RA:

• A soluble dimeric p75 TNF-R IgG1-Fc fusion construct (etanercept)
• A chimeric anti-TNFα IgG1 monoclonal antibody (mAb) (infliximab)
• A human IgG1 anti-TNFα mAb (adalimumab)
• A human IgG1қ anti-TNFα mAb (golimumab)
• A pegylated Fab’ fragment of a humanized anti-TNFα mAb (certolizumab pegol).

Mechanism of Action

TNF and TNFRs are members of a family of molecules (including Fas-ligand/Fas, CD40 ligand/CD40) possessing crucial regulatory functions that include cellular activation and apoptosis. TNFα is produced intracellularly primarily by monocytes and macrophages but also by B cells, T cells, mast cells and fibroblasts. The 26kD precursor transmembrane form is cleaved off by TNFα- converting enzyme (TACE) to produce soluble, biologically active TNF (sTNFα). This molecule can aggregate and exist as a heterotrimer. TNFα and the closely related TNFβ (also known as lymphotoxin) will equally bind to p55 (CD120a) and p75 (CD120b) receptors (also known as TNFR-I and TNFR-II, respectively) present on many cell types. The TNF receptor has an extracellular domain that can also be cleaved and released as a soluble TNF receptor (sTNFR) and function as a naturally occurring inhibitor.

TNFα modulates the growth, differentiation and trafficking of many cells and, therefore, plays a pivotal role in the pathogenesis of RA. The biologic effects of TNF inhibitors are listed in Table 14-2. Two different forms of TNFα—transmembrane (mTNFα) and sTNFα—are responsible for its biologic activities. Both forms can stimulate other cells by binding to two structurally distinct cell-associated receptors: TNFRI (55 kd receptor or CD120a) and TNFRII (75 kd receptor or CD120b). These receptors have different binding abilities, signaling properties and primary functions. The binding of TNFα to its receptors initiates several signaling pathways, including the activation of transcription factors (e.g., nuclear factor-kappa B [NF-kB]), protein kinases (e.g., c-Jun N-terminal kinase [JNK], p38 MAP kinase) and proteases (e.g., caspases). Soluble TNF-Rs can attenuate the biologic activity of TNFα.

TNFα may further contribute to the pathogenesis of RA by induction of proinflammatory cytokines (such as IL-1 and IL-6), enhancement of leukocyte migration by increasing endothelial layer permeability, expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophils and eosinophils, induction of the synthesis of acute-phase reactants and tissue-degrading enzymes (matrix metalloproteinase enzymes) produced by synoviocytes and/or chondrocytes.

Thus blockade of TNFα activity yields clinical benefit in RA patients through several coincident mechanisms, including downregulation of local and systemic proinflammatory cytokine production, reduction of lymphocyte migration into the joint and reduction of angiogenesis in the joints. The relevance of these has been demonstrated with posttreatment synovial biopsies showing reduced numbers of effector cells, changes in soluble E-selectin, soluble intercellular adhesion molecule (ICAM)-1, vascular endothelial growth factor (VEGF) expression and circulating lymphocytes and correlation of clinical outcomes with these biologic effects.

While all five of the currently approved TNF inhibitors share many effects, construct differences among them confer different binding properties and potential functional differences. While the monoclonal antibody constructs (infliximab, adalimumab, certolizumab, golimumab) are specific for TNFα, etanercept binds both TNFα as well as LTα. Nevertheless, all three agents bind to TNF with high affinity and all three are virtually the same in their ability to neutralize soluble and transmembrane TNF. Furthermore, induction of cell lysis has been demonstrated by in vitro studies with infliximab and adalimumab, and apoptosis was demonstrated by both in vitro and in vivo studies with all three agents. While monoclonal antibody-induced apoptosis was thought to explain the clinical differences between the p75 receptor agent (etanercept) and the monoclonal antibodies (adalimumab, infliximab), reports indicating the efficacy of certolizumab pegol (a pegylated Fab’ construct) in Crohn’s disease questions the mechanistic importance of antibody-mediated apoptosis. Reasons underlying the disparate results between anti-TNF agents in Crohn’s disease, granulomatous disease, uveitis and secondary opportunistic infections (e.g., tuberculosis (TB)) await further study.

Indications for and Use of TNF Inhibitors in RA

As noted, the current indications for the use of anti-TNF therapy includes RA, early RA, juvenile arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease (Table 14-1). In RA, juvenile arthritis and psoriatic arthritis, TNF blockers are indicated for moderate to severe disease, usually after an inadequate response to methotrexate (MTX) (or other disease-modifying antirheumatic drug (DMARDs)). In RA, TNF inhibitors are also indicated for the control of signs and symptoms, improvement in physical function and the prevention of radiographic deterioration.

Based on multiple randomized, controlled clinical trials, it appears prudent to consider TNF-inhibitor therapy when there is active synovitis in multiple joints with evidence of radiographic erosions and the presence of either functional impairment or elevated acute-phase reactants (erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)) or a disease activity score (DAS) >5.1 (high activity). The 2021 American College of Rheumatology (ACR) guidelines for the treatment of rheumatoid arthritis suggest that biologics be considered after an inadequate response to MTX, or in select patients with poor prognostic factors, in combination with MTX. In a 2005 survey of nearly 1,200 rheumatologists, the top five-ranked indications for TNF inhibitor use included:

• Failure of MTX
• Failure of multiple DMARDs
• Physician assessment of active disease
• Radiographic worsening or erosive disease
• Functional disability.

Thus, the prudent physician must assess the level of clinical activity or disability, response to prior therapy, and radiographic risk factors or prognostic risk factors when considering TNF-inhibitor therapy in RA. This same approach also applies to patients with early RA, as a minority of new-onset RA patients may also be candidates for TNF inhibitor or other biologic therapies at their initial presentation.

The pharmacology and clinical trial experience with the anti-TNFα and other biologic agents in RA are discussed in this and subsequent sections.

Safety Concerns With Anti-TNF Therapy

The decision to use a biologic therapy may be challenging in early disease when the risk of progression vs remission may be unclear. However, there may be instances when safety concerns more clearly define who should not receive TNF-inhibitor therapy (Table 14-3). Moreover, the tolerability of the TNF inhibitors may influence the durability and success of long-term therapy.

Extensive clinical trials, postmarketing observations and pharmacovigilance programs have defined the safety profile and monitoring needed to optimize the safety of TNF inhibitors.

Prior to Food and Drug Administration (FDA) approval, a large number of RA patients were studied in controlled clinical trials of etanercept (1,272 patients), infliximab (1,372 patients), adalimumab (2,468 patients) and anakinra (2,932 patients). While common adverse events were defined during the conduct of phase 2 and 3 clinical trials, the full spectrum of potential toxicities has evolved during the postmarketing era, which now spans 11 years and over 2 million patients treated with TNF inhibitors worldwide.

Real-world observational studies have shown that the durability of the TNF inhibitors comparable to MTX; namely, 80% of RA patients continue to take their TNF inhibitors 2 years after drug initiation (Figure 14-1). Observational studies lasting 3 to 5 years have consistently showed the dropout rate with these agents to be approximately 10% per year, with only 50% to 65% being due to toxicity or the loss of efficacy. Compared with current DMARDs, TNF blockers have exhibited a favorable safety profile with few nuisance side effects and a paucity of serious adverse events. For most patients with active RA, the clinical and radiographic benefits far outweigh the small risks associated with TNFα blockade. Nonetheless, patients and clinicians must carefully evaluate the potential benefits and hazards of choosing TNF inhibitor therapy. Drug safety can be enhanced by proper patient selection, heeding important precautions and discussing safety concerns with patients when initiating therapy and when monitoring patient progress.

See the following individual sections on infliximab, etanercept, adalimumab, golimumab and certolizumab for discussions of the specific safety concerns for each of the currently available TNFα-blockers.

Infusion Reactions/Injection Site Reactions

The most common side effects with these agents are infusion reactions and Injection Site Reactions (ISRs). For example, clinical trial data indicate that about 20% of infliximab-treated patients have experienced an infusion reaction. However, <1% of infliximab-treated patients develop serious infusion-related reactions and only 2.5% of such reactions result in discontinuation of therapy. Most reactions with infliximab occur during infusion or within 2 hours postinfusion. Common complaints include headache (20%), nausea (15%), urticaria, pruritus, rash, flushing, fever, chills, tachycardia and dyspnea.

In many patients, infusion reactions occur when the infusion is administered too quickly (i.e., <2 hours). Reactions are usually transient, rarely severe and typically can be controlled by slowing the rate of infusion or by treatment with acetaminophen, antihistamines, or short-acting corticosteroids. Premedication (with acetaminophen, nonsedating antihistamines, or short-acting corticosteroids) is usually not given but may be necessary in patients who exhibit infusion reactions. Rarely, severe or anaphylactic reactions may occur. The patient may complain of chest tightness, bronchospasm, hypotension, diaphoresis, anaphylaxis, or a feeling of impending doom. In such circumstances, infliximab therapy should be discontinued and supportive or emergent care administered until the patient is stabilized.

Since they are administered subcutaneously, cutaneous ISRs (Figure 14-2) are the most frequent side effect with etanercept and adalimumab, although these rarely require treatment or cause discontinuation of therapy (<2% and 0.3%, respectively). In pivotal clinical trials, ISRs occurred in approximately 37% of patients treated with etanercept and in 20% of those treated with adalimumab. In routine practice, however, the frequency appears to be less. ISRs are usually mild-moderate, occurring 1 to 2 days after injection and resolving within 7 days. Patients typically reported localized erythema, urticaria, pruritus, or dysesthesia. ISRs are most common during the first 4 to 8 weeks of use and uncommon thereafter.

Other cutaneous reactions have only rarely been associated with the TNF inhibitors. Such reactions include lupus-like rashes, hypersensitivity vasculitis, palpable purpura, folliculitis, pernio, granuloma annulare, lichenoid eruptions, new-onset psoriasis, bullous lesions, erythema multiforme, chilblain, opportunistic skin infections and cutaneous T-cell lymphoma.

Infections

RA patients have an inherently higher risk of infection compared with the normal population. In fact, infectious events are important contributors to the morbidity and mortality observed in RA. There are many factors that contribute to the increased infectious risk in RA. Factors most strongly linked to serious infections include severity of RA (both debility and inflammatory activity), corticosteroid use, comorbidities (e.g., diabetes mellitus, renal failure, heart disease), skin breakdown and joint replacement surgery. Less clear is whether there is a risk imposed by immunosuppressive medications (e.g., DMARDs, cytotoxic agents), as these are likely to be used in RA patients with active disease.

In pivotal drug-development RA trials, at least one third of patients developed upper respiratory infections. Usually the frequencies of these infections were comparable to those seen in the placebo group, or were slightly increased among patients receiving TNFα inhibitors. Importantly, patients with these nonserious infections fared well with just observation or symptomatic therapy and without cessation of the study drug or adverse consequences. Other common frequent infections included urinary tract infection, bronchitis and pharyngitis. Patients suspected of having non-serious or serious infections should be assessed and appropriately managed. TNF inhibitor therapy should be suspended if fever (>101ºF) or symptoms of serious infection (e.g., pneumonia, septic arthritis) are evident.

Serious Infections

Of greater concern is the risk of serious infectious events (SIEs), such as pneumonia, sepsis, septic arthritis, cellulitis, or infections requiring hospitalization or parenteral antibiotics. Experimental data indicate that anti-TNF therapy interferes with the ability to mount an inflammatory response against intracellular organisms. Historic data suggest the incidence of SIEs in RA patients before the anti-TNF era ranged from approximately 0.02 to 0.12 per patient-year. The incidence of SIEs during clinical trials of TNF antagonists in RA has been comparable to that seen in the placebo comparator groups. The SIE rates based on clinical trial data were 0.04 per patient-year in both the etanercept and placebo groups; 0.03 per patient-year in both the infliximab and placebo groups; and 0.04 and 0.02 per patient year in the adalimumab and placebo groups, respectively. Early RA patients appear to be at an even lower risk for SIEs, presumably because of less disease activity, less steroid use and fewer comorbidities. Thus while the overall rate of serious infections ranged from two to four SIEs per 100 patient-years with TNF inhibitors, a few clinical trials noted a small but significant increase in SIEs in patients treated with TNF blockade. It should be noted these trials were powered for efficacy outcomes and true incidence of rare serious infections may require larger controlled trials or observational studies.

Data from observational databases suggest either no or only a slight increase in the risk of serious infections in RA patients receiving TNF inhibitors. Data from the British Society of Rheumatology Biologics Register—a database of patients receiving TNF inhibitors—showed 52 to 62 SIEs per 1,000 patient-years for TNF inhibitors, with a similar infection rate observed in DMARD-treated patients. By contrast, the German Society of Rheumatology Biologics Registry found their patients to have a higher a priori risk of infection that was further increased by the use of etanercept or infliximab (i.e., relative risk of pneumonia was 2.4 and 4.7, respectively).

An analysis of a large US health care organization demonstrated that RA patients treated with TNF inhibitors had nearly a 2-fold risk of serious (hospitalized) bacterial infections compared with those treated with MTX. Moreover, it appears this risk may be greatest in the first 6 months of use. While there appears to be a small risk of SIEs when using TNF inhibitors, the clinician must also recognize that uncontrolled rheumatoid inflammation may also confer an increased risk for serious (e.g., bacterial) infections. Therefore, current prescribing guidelines mandate that these agents should not be administered to patients with acute serious infections or a history of chronic, recurrent infections. Moreover, TNF inhibitors are relatively contraindicated in those with skin breakdown, chronic open cutaneous ulcers, or multiple comorbidities that may predispose to infection.

While there is a small, but significant, increased risk of bacterial infections with TNF inhibitors, clinical trials and post marketing surveillance data indicate that the risk of mycobacterial and other opportunistic infections is increased in patients receiving TNF inhibitors. Awareness of this risk and employment of screening procedures and prescribing precautions plus heightened suspicion are necessary to prevent or minimize these serious opportunistic infections.

Tuberculosis (TB)

TNF plays an important role in the formation and maintenance of granulomas. Therefore, TNF-antagonism can interfere with an individual’s ability to fight or contain TB. TB cases, including some fatalities, have been observed and reported with all five currently marketed anti-TNF agents, with most cases appearing within 6 months of initiating treatment. Thus it is presumed that this represents reactivation of latent mycobacterial (or fungal) infection. Interestingly, patients treated with TNF inhibitors are more likely to have extrapulmonary, miliary/disseminated and nonpulmonary presentations of TB. Common sites of extrapulmonary infection include the joints, bone, vertebra, bladder, meninges, peritoneum, lymph nodes, etc. Additionally, the rates of TB associated with the use of TNF antagonists have been shown to be higher in geographic regions where TB is more prevalent in the general population.

Although no cases of TB occurred in etanercept-treated patients during clinical trials, postmarketing analyses have shown 38 confirmed cases of etanercept-associated TB worldwide in 150,000 patients treated through December 2002. For infliximab, 441 cases of infliximab-related TB were reported among 492,874 treated patients worldwide, while there were only six infliximab-related TB cases reported in the clinical trials. Ninety-seven percent of the infliximab-related cases occurred within 7 months, with a median time of onset of 12 weeks. The incidence of TB in clinical trials with adalimumab was higher in early clinical trials when the dose of adalimumab was higher and before screening procedures were recommended. However, the incidence decreased by 85% when the adalimumab dose was reduced and screening measures (purified protein derivative [PPD] test, chest x-ray) for latent TB infection were required prior to therapy. To date, a greater number of cases have been seen among patients receiving infliximab than the other TNF inhibitors, but this may in part relate to several issues, including greater worldwide use of infliximab (especially in endemic regions); an older patient population (influenced by Medicare reimbursement); different screening procedures between the United States and Europe; slow off-rate (sustained TNF binding); the induction of apoptosis or cell lysis; and the need for dose escalation over time in a minority of patients. Nonetheless, TB and opportunistic infections have been reported with TNF inhibitors to the extent that this should be considered a class-related risk.

The increased risk and unusual presentations of TB in patients receiving anti-TNF agents compared with the overall population mandates clinical suspicion and close follow-up. The risk of developing TB with TNF antagonists is significantly reduced with screening and appropriate clinical monitoring. The preventive value of tuberculin skin testing was best shown in the adalimumab trials, in which a TB infection rate of 1.3 per 100 patient-years was decreased to <0.11 per 100 patient-years by simply employing a screening strategy.

While the current (2021) ACR guidelines contain no TB-related recommendations, the previous 2015 ACR guidelines recommend screening to identify latent TB infection (LTBI) in all RA patients being considered for treatment with biologic agents, 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. 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 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. However, patients with RA may have false-negative TST or IGRA results due to immunosuppression, therefore a negative TST or IGRA should not be interpreted as excluding the possibility that a patient has LTBI. Accordingly, a repeat TST or IGRA could be considered 1 to 3 weeks after the initial negative screening in immunosuppressed RA patients with risk factors for LTBI. Appropriate antitubercular treatment should be initiated RA patients in whom test results indicate active or latent TB. Treatment with biologic agents can be initiated or resumed after 1 month of latent TB treatment and after completion of the treatment of active TB. Center for Disease Control (CDC) guidelines suggest that 9 months of INH therapy is optimal, although 6 months of INH or other alternative regimens (e.g., rifampin) also have proven efficacy. Annual TB testing is recommended for RA patients who live, travel, or work in situations where TB exposure is likely while they continue treatment with biologic agents. Patients who test positive for TST or IGRA at baseline can remain positive for these tests even after successful treatment of TB. These patients need monitoring for clinical signs and symptoms of recurrent TB, since repeating tests will not help in the diagnosis of recurrent TB.

Opportunistic Infections

Other opportunistic infections have also been reported in patients treated with TNF inhibitors. Atypical mycobacterial infections include Mycobacterium avium intracellulare, M kansasii and M marianum. Other fungal and opportunistic pathogens, including histoplasmosis, pneumocystis, aspergillosis, coccidioidomycosis, sporotrichosis, Nocardia, listeriosis and cytomegalovirus, also have been observed with TNF inhibitors. As no reliable skin or serologic tests exist for these infections, clinicians must closely monitor patients for symptoms or signs of opportunistic infections, especially in endemic areas (e.g., Europe, South America, Ohio River Valley, San Joaquin Valley). It should be noted that chronic prednisone therapy may also predispose to such infections. Last, there have been many reports of herpes zoster infection in patients receiving TNF inhibitors. It is unknown if this is related to the TNF inhibitor, the diagnosis, or other background therapies.

Neoplasia and Lymphoma

Numerous population-based studies have shown that RA patients generally are at increased risk for lymphoma but are not at risk for other malignancies (e.g., solid tumors). They may, in fact, be at lower risk for adenocarcinoma of the colon, presumably from the use of nonsteroidal anti-inflammatory drug (NSAIDs) or cyclooxygenase (COX)-2 inhibitors. An overall 2- to 3-fold increase in the incidence of lymphoma (primarily non-Hodgkin’s) has been shown in RA population studies. The lymphoma risk appears to be further increased with age and increasing inflammatory disease activity.

In an FDA analysis of this issue, six cases of lymphoma were found among 6,303 RA patients in controlled clinical trials but none were observed in placebo-treated patients. A total of 23 cases of lymphoma were observed (9 etanercept, 4 infliximab, 10 adalimumab) during drug development, with an increased standardized incidence ratio (relative risk) of 3.47, 6.35 and 5.42, respectively. Unfortunately, the 95% confidence intervals for these rates were particularly wide and overlapping (ranging, 1.59-16.3), thereby not permitting any separation of lymphoma risk due to drug or active RA alone. Thus, lymphoma rates in RA patients taking TNF inhibitors are elevated, but it is not yet known if this merely reflects an excess risk above that resulting from active rheumatoid inflammation. The lag time from TNF-inhibitor exposure to the onset of lymphoma varied but most occurred after 6 to 24 months of TNF therapy. Hodgkin’s lymphoma occurred in 15%, with the remaining majority being non-Hodgkin’s lymphoma, usually of the diffuse, large B-cell class. Follicular, mantle, mucosa-associated lymphoid tissue (MALT) and T-cell lymphomas were uncommonly observed. Longer-term follow-up of larger numbers of patients treated with TNF inhibitors is needed to provide a clear understanding of the risk for lymphoma.

A drug-related risk of solid tumor malignancies was not suggested by the FDA and other reviews but has been inferred by others. Bongartz and colleagues reviewed the rates of malignancies in the registration trials for infliximab and adalimumab and surmised a 3-fold increase in malignancies for those treated with these drugs (compared with placebo). While the product labeling also reveals more malignancies in anti–TNF-treated patients compared with placebo, the FDA prefers comparisons with age-matched population controls because the placebo populations were fewer in number and observed for a much shorter period (due to withdrawals, early planned study exits). Thus when malignancy rates in TNF-inhibitor–treated patients were compared with the general population (Surveillance, Epidemiology, and End Results (SEER) database), no increase in solid tumors was observed with the available TNF inhibitors.

Autoimmune Responses

The development of antibodies against these agents, which are large foreign proteins, is inevitable. Although the clinical relevance of such antibodies is presently unclear, it is nonetheless possible that they may lead to immune-complex formation, hypersensitivity reactions, or even impaired drug efficacy. Approximately 3% of the etanercept-treated patients developed antibodies to etanercept.

In one study, antibodies to infliximab developed in 53%, 21% and 7% of patients receiving 10, 3, or 1 mg/kg of drug, respectively. RA trials of infliximab, with or without concomitant MTX treatment, revealed that immunogenicity was decreased by concomitant MTX, due perhaps in part to the increase in the half-life of infliximab associated with MTX use. A multicenter trial of infliximab therapy in Crohn’s disease revealed that the induction of these anti-infliximab antibodies might have contributed to hypersensitivity reaction in some patients who had been treated with this drug. Although antibodies to adalimumab developed in about 12% of patients during clinical trials, the rate is reduced to 1% with concurrent MTX treatment. However, routine testing for antibodies to these anti-TNF constructs is not currently recommended as the assays have not been standardized and the results would be of questionable clinical value.

Although nearly 40% of RA patients have serum antinuclear antibody (ANAs), the prevalence of ANA positivity increases with the use of anti-TNF agents. The mechanism(s) underlying autoantibody induction is uncertain but may relate to a compensatory increase in IL-10 or interferon-α, both of which are inhibited by TNFα, resulting in an increased B-cell activity, which is increased in patients treated with anti-TNF therapy. Antibodies to double-stranded DNA (dsDNA) have also been reported to develop in about 5% to 10% of RA patients treated with all anti-TNF therapies. However, very few (0.2% to 0.4%) develop symptoms consistent with drug-induced lupus. A finding of ANA or dsDNA seropositivity is poorly predictive of subsequent toxicity and thus pretreatment or routine monitoring of autoantibodies is not recommended.

The occurrence of drug-induced lupus has been ascribed to TNF inhibitors. Such patients need not meet criteria for lupus but must manifest a lupus-specific feature with evidence of ANA or dsDNA positivity and resolution with drug cessation. During drug development, there were very few reports of TNF-inhibitor related rashes (e.g., discoid lupus, subacute cutaneous lupus, hypersensitivity, vasculitis), serositis, cytopenias or polyarthritis.

In a study of 22 French patients who developed drug-induced lupus on either etanercept (n = 7) or infliximab (n = 15), 12 patients had four or more of the ACR criteria for lupus, while 10 patients demonstrated more limited lupus symptoms. All patients were ANA-positive and 11 were dsDNA-positive. Many exhibited constitutional (n = 9; fever, weight loss, asthenia), skin (n = 11), articular (polyarthritis in 6), serosal (2 with serositis or pneumonitis), or hematologic (n = 6) features. Skin findings included maculopapular rash (6), butterfly rash (5), alopecia (1), photosensitivity (5) and purpura (2). Myalgia and myositis were seen in three patients. This syndrome usually emerged within 4 months for etanercept and within 9 months for infliximab. All improved with drug cessation. Only six patients required limited treatment with systemic corticosteroids. The estimated frequency of drug-induced lupus was 0.18% to 0.19% in this French cohort. Review of the literature reveals over 100 cases of drug-induced lupus. Table 14-4 lists the spectrum of findings seen in these cases of drug-induced lupus. Several points about drug-induced lupus related to the TNF inhibitors are worth summarizing:

• Common skin findings include malar rash, palpable purpura, or a “sunburnt” rash
• The new onset of an acute large- and small-joint polyarthritis in a previously stable RA patient treated with a TNF inhibitor may indicate drug-induced lupus
• Fever, serositis, and cytopenia are common
• ANA or dsDNA positivity is required to consider the diagnosis
• Diagnostic confirmation rests with resolution of symptoms upon drug cessation.

Demyelinating Syndromes

Multiple sclerosis (MS), optic neuritis and other forms of demyelinating neurologic dysfunction have been described in patients using etanercept, infliximab and adalimumab. This includes reports of new-onset optic neuritis, de novo MS, recurrence or flare of MS, encephalitis, myelitis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, neuropathy, transverse myelitis, seizures and leukoencephalopathy. Nearly all of these cases improved or resolved with discontinuation of TNF-inhibitor therapy. Although clinical data suggest that TNF antagonists may exacerbate existing demyelinating disease, it is unclear if these rare events exceed those seen in the general or rheumatoid populations and the frequency of demyelinating disorders in RA is also unknown. It is recommended that the clinician should exercise caution when considering a TNF antagonist for a patient with a preexisting or recent-onset optic neuritis, MS, or other demyelinating disorder.

Congestive Heart Failure

TNF has been implicated in the pathogenesis of heart failure and cardiac cachexia. TNFα levels are consistently elevated in patients with congestive heart failure (CHF) and TNF has been shown to have negative inotropic effects on the myocardium and to cause myocyte dysfunction. Furthermore, RA patients are known to be at increased risk for CHF, presumably reflecting the hazardous effect of systemic TNF and inflammation on the heart. For these reasons, it was anticipated that TNF inhibition might improve cardiac outcomes in patients with CHF. However, clinical trials with high-dose infliximab (10 mg/kg) in patients with CHF were discontinued early because of an increase in mortality and a worsening of CHF in patients with New York Heart Association (NYHA) class III and IV disease. Two large etanercept trials in CHF were also terminated due to lack of efficacy and the observation that high-dose etanercept (25 mg three times weekly) was associated with worse cardiac outcomes.

Despite the negative reported outcomes in CHF patients, TNF antagonists in RA clinical trials were not associated with an increase in new-onset CHF but instead may actually reduce risk. Nevertheless, increased caution is recommended when using anti-TNF agents in patients with CHF, especially with NYHA class III and IV disease.

Cytopenias

There have been rare reports of pancytopenia and aplastic anemia in patients treated with etanercept, infliximab and adalimumab, and a small minority of cases resulted in death. Leukopenia, neutropenia and thrombocytopenia have also been reported. Cytopenias developed in the first few weeks (median, 4 weeks) after initiating TNF inhibitors. Reasons for this sporadic association are unclear but may be attributed to comorbidities or other myelosuppressive drugs in use. Periodic monitoring (every 3 to 6 months) of blood cell counts should be done. Patients with features of blood dyscrasias (fever, pallor, bleeding, sore throat) should be evaluated for this complication.

Hepatotoxicity

Elevations in aminotransferases and reports of hepatic failure have been reported with anti-TNF treatment. A 2003 FDA review of TNF-inhibitor safety revealed an unexpected 134 spontaneous reports of TNF-inhibitor–related liver failure. When 50 cases (31 infliximab, 19 etanercept) were reviewed, there were confounding diagnoses or hepatotoxin exposure in 43 cases (e.g., sepsis, TB, INH use, alcohol, viral hepatitis, graft-versus-host disease, hepatotoxic drugs). However, in seven cases (14%), no other cause could be identified, suggesting that TNF-inhibitor use may have led to hepatic failure. In the clinical trials with infliximab and adalimumab, sporadic 2- to 3-fold liver function test (LFT) elevations may have been attributable to the TNF inhibitor. There have also been rare reports of serious or fatal reactivation of hepatitis B infection in patients receiving TNF inhibitors. Hence clinicians should be aware of these rare events, screen for hepatitis prior to TNF-inhibitor use, and monitor hepatic enzymes every 3 to 6 months.

Pregnancy and Lactation

There have been no controlled trials of TNF inhibitors in pregnant women, and there is little information on the use of TNF inhibitors in women who are or may become pregnant. TNF inhibitors are a category B pregnancy risk because of this lack of controlled studies in pregnant women. Nevertheless, there are several databases and registries that are beginning to accumulate data on this issue. Patients who become pregnant while on TNF inhibitors should be reported to http://www.otispregnancy.org. A small number of premature or low–birth-weight deliveries have been reported, and only one case of tetralogy of Fallot that was successfully repaired. Katz and associates reviewed the pregnancy outcomes (e.g., normal deliveries, miscarriages, etc.) in infliximab-treated women with RA or Crohn’s disease who became pregnant while being treated with infliximab. When compared with outcomes in age-matched populations, there were no differences in terms of rates of normal deliveries and miscarriages. We surveyed 1,021 US rheumatologists and found that collectively, they have observed 454 pregnancies that were conceived while the patients were taking a TNF inhibitor. Moreover, nearly 30% (n = 131) of these patients continued to take the drug throughout their pregnancies. Outcomes were quite favorable: there were 366 full-term live births, nine premature births, 21 miscarriages, five therapeutic/elective abortions, and no reports of birth defects or neonatal death. Nevertheless, when these respondents were again queried, a subsurvey disclosed similar results but instead identified two offspring with birth defects (2%).

Despite these survey results, there are insufficient data to routinely advise continuation or initiation of anti-TNF therapy if a patient becomes pregnant. Furthermore, it is not known if TNF-blocking agents are secreted in human milk, and the safety of these agents during lactation has not been established. Overall, it appears that the risk to the fetus and the mother is negligible, but further research in this area is sorely needed as there are many young women with RA who will face this issue.

Monitoring

Before initiating anti-TNF therapy, the clinician must weigh the potential clinical benefits against potential adverse effects. Although specific laboratory monitoring is not mandated by current package labeling, physicians are strongly advised to obtain complete blood counts, and liver function test (LFTs) every 3 months (for the first 6 to 12 months), in patients treated with anti-TNF agents. While autoimmune disorders (e.g., drug-induced lupus, MS) have occurred in TNF-inhibitor–treated patients, pretreatment or periodic serologic testing has no predictive value. In contrast, patients exhibiting signs of autoimmune disease should undergo serologic testing to help establish a diagnosis.

Patients should be evaluated carefully for the risk or presence of infection, malignancy, demyelinating disorders, or any other comorbidities that may alter the patient’s risk:benefit ratio. Physicians should suspend anti-TNF therapy and exercise caution when patients develop a serious infection. Tuberculin skin testing (TST) using TST or  interferon-gamma release assays (IGRAs) is recommended before starting treatment with all TNF inhibitors. If the TST is positive, chest radiography is recommended to establish latent vs active disease. Appropriate anti-TB treatment should be started if latent or active TB is discovered. Periodic, assiduous monitoring for signs or symptoms of cytopenia, infection, demyelinating disease, or neoplasia is needed for those on anti-TNF treatment.

While currently available TNF blockers have undoubtedly constituted a considerable advance in the management of RA, future challenges remain. For example, further research is needed to identify the ideal patient to receive TNF inhibition and the patient in whom TNF inhibition should be avoided. Moreover, the identification of demographic, clinical, laboratory, or genetic factors that would predict clinical response or toxicity to these agents is highly desirable.

Infliximab (Remicade)

Infliximab was first approved for use in moderate to severe Crohn’s disease in 1998 and became commercially available for use in RA in 1999. Because of its dual indications and time on the market, infliximab has had more worldwide use than the other TNF inhibitors. As of 2023, over 2.8 million patients have been treated with infliximab. Infliximab has also been approved for use in early RA, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, ulcerative colitis and pediatric Crohn’s disease and ulcerative colitis.

Indications and Dosing

Infliximab, in combination with MTX, is indicated for reducing the signs and symptoms of RA, inhibiting progression of structural damage and improving physical function in patients with moderate to severe RA. Infliximab is primarily used in combination with optimal doses of MTX to limit the immunogenic response to the construct and possibly for additional clinical benefit. The usual recommended dose in RA patients is 3 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter. It is packaged as a lyophilized powder in 100-mg vials (10 mL reconstituted) and is given as an IV infusion over 2 hours.

With time, a minority of patients will require shorter dosing intervals (e.g., every 6 or 4 weeks) or larger doses to maintain an effect. This “dose-creep” phenomenon is most likely to occur in the second year of therapy and either represents a true loss of efficacy or may be due to physician and patient efforts to reduce other adjunctive therapies (e.g., MTX, NSAIDs, prednisone). Studies have shown that 8 weeks after a 3-mg/kg infusion, 25% of patients have undetectable infliximab levels. This is compared with 15% for patients on 3 mg/kg every 4 weeks and 0% for patients who received 10 mg/kg every 4 or 8 weeks. These data suggest that higher doses rather than shorter dosing intervals may be more effective in some patients. For patients in whom the drug appears to lose efficacy over time, many clinicians will first increase the dose by 100 mg (1 vial), but if this is unsuccessful, shorter dosing intervals and higher doses (up to 10 mg/kg) may be needed.

Infliximab is contraindicated in patients with moderate to severe CHF, active MS, untreated TB or PPD positivity, or chronic recurrent infections.

Pharmacology

Infliximab is a chimeric anti-TNF monoclonal antibody consisting of human IgG1k engrafted to the murine FV region (initially designated cA2). The antibody is produced in a murine myeloma cell line transfected with cloned DNA coding for cA2 and subsequently purified. The cA2 antibody has been shown to bind with high affinity to both soluble and membrane-bound TNF and is capable of neutralizing TNF in vitro and in vivo. Infliximab can mediate cytotoxicity of TNF-expressing cells in vitro and is capable of inducing cell lysis of TNF-expressing cells via antibody-dependent cellular cytotoxicity in vitro. Infliximab binds TNFα but not lymphotoxin (TNFβ). The terminal half-life of infliximab in RA patients is 8 to 9.5 days (mean, 210 hours) and it has a dose-dependent pharmacokinetic profile with infusions of 3-20 mg/kg. When used with MTX (7.5 mg once a week), serum infliximab concentrations tend to be slightly higher than when administered alone. The pharmacokinetic profile is the same in adolescents, but studies in the elderly and in those with renal insufficiency or hepatic dysfunction have not been done.

Clinical Efficacy in RA

The initial trials of infliximab in RA assessed the efficacy of monotherapy after DMARD washout. Elliott and colleagues treated 20 RA patients in an 8-week open-label trial in which infliximab was administered as infusions of 10 mg/kg on days 0 and 14, or as infusions of 5 mg/kg at days 0, 4, 8 and 12. There were no differences in outcomes between the two groups. Clinical benefit was noted after week 3 and was maximal by week 6. There were significant improvements in all clinical measures (e.g., pain, stiffness, global assessments, HAQ scores) and the Ritchie Articular Index decreased by 79% at week 6. CRP levels were normalized in 89.5% of patients. Clinical responses lasted a median of 14 weeks (range, 8 to 25 weeks) after their last infusion of infliximab.

Another placebo-controlled, monotherapy, single-infusion trial in 73 patients showed significant improvement by week 4, with Paulus 20% responses of 79% and 44% in those receiving 10 mg/kg and 1 mg/kg, respectively (compared with an 8% placebo response). Eight responders went on to receive repeated infusions when clinical relapse became evident. In the subgroup treated with infliximab alone, a trend toward shorter response intervals showed some correlation with the presence of human antichimeric antibodies (HACAs). Four patients were withdrawn from the study because of a vasovagal episode, urticaria, chronic sinusitis, or autoantibodies without clinical evidence of lupus. These early monotherapy trials with infliximab were important in establishing effective dosing, magnitude of efficacy, and that major or significant toxicities were lacking.

Subsequent multicenter trials with infliximab evaluated the effects of chronic infliximab dosing when given with background MTX in patients with RA. ATTRACT was a 428-patient, randomized, placebo-controlled trial of infliximab (3 mg/kg or 10 mg/kg) given every 4 or 8 weeks in patients with active RA who had an inadequate response to weekly MTX monotherapy. Patients enrolled in this trial had a mean age of 54 years, disease duration of 8.4 years, and, despite a median MTX dose of 15 mg/week, had active disease with a mean of 31 tender and 20 swollen joints. The addition of infliximab (either 3 mg/kg or 10 mg/kg) to background MTX therapy showed significantly superior ACR20 responses (50% to 58%) compared with MTX alone (20%) at 30 weeks. At week 54, the ACR20 response rates were 59% in the 10-mg/kg group, 42% to 48% in the 3-mg/kg group and 17% in those who received placebo (Table 14-5). In addition, there were significantly greater ACR50 and ACR70 response rates in patients who received infliximab plus MTX compared with those receiving only MTX.

During a 2-year extension of this trial, infliximab also demonstrated significant improvement in functional status and quality of life of RA patients. Radiographic outcomes also were assessed, using the modified total Sharp score (mTSS), at weeks 30, 54 and 102. Radiographic damage was progressive in the MTX/placebo group, increasing by a mean of 12.6 Sharp units over 2 years. By contrast, both of the infliximab-treated groups (3 or 10 mg/kg) showed almost no change (≤1 unit) in this 2-year period (Figure 14-3). During this 2-year extension, 43% to 47% of the infliximab 3-mg/kg group and 64% of the 10-mg/kg/week group showed no evidence of radiographic change, while only 22% of the placebo group showed no evidence of radiographic progression.

ATTRACT was instrumental in demonstrating that TNF inhibition is critical to halting radiographic damage, especially in patients with active disease and risk factors for radiographic progression (e.g., many swollen joints, elevated acute-phase reactants, serum rheumatoid factor (RF), erosions). In fact, infliximab-treated patients demonstrated radiographic benefits, irrespective of clinical efficacy.

Use in Early RA

Infliximab is approved for use in early RA based on several trials. Emery and colleagues performed a subanalysis of patients in ATTRACT to examine the efficacy of combined infliximab and MTX in patients with early RA. When defined with a disease duration of <3 years, data from 82 patients with early RA were analyzed and showed similar clinical responses to all ATTRACT patients. By 2 years, the mean total Sharp score (TSS) increased by 25 units in the MTX/placebo group and remained unchanged (mean, -0.5 units) in the infliximab-treated patients. This small subanalysis suggested there may be even greater benefits in those with early aggressive RA.

Quinn and coworkers studied the clinical and magnetic resonance imagine (MRI) effects of MTX and infliximab in 20 early RA (≤1-year duration) patients. All patients received MTX and half also received infliximab for 12 months. During the first 12 months, the infliximab-plus-MTX–treated patients had significantly greater clinical responses, better MRI scores and no new erosions. Patients were observed during the second year and of those treated with infliximab induction, 70% maintained their clinical responses on MTX alone with a mean disease activity score (DAS) of 2.05.

ASPIRE examined the effects of infliximab with or without MTX in 1049 MTX-naïve patients with early RA (<3-years’ duration) with a mean disease duration of 7 months and a mean of 30 tender and 19 swollen joints at entry. Enrolled patients were required to have one of the following radiographic risk factors: a positive serum RF, CRP ≥2.0 mg/dL, or radiographic erosions. All patients received weekly MTX (20 mg/week) and were randomized to also receive placebo, 3 mg/kg infliximab, or 6 mg/kg infliximab every 8 weeks. At 54 weeks, the percentage of patients achieving an ACR20 response was significantly higher in the infliximab group (Table 14-6 and Figure 14-4). In addition, a significant increase in radiologic destruction was observed in patients treated only with MTX, whereas a 90% reduction in the radiographic progression was observed in infliximab-plus-MTX groups.

The primary end points for this trial were the ACR-N (mean response over time) and radiographic outcomes. Significantly greater responses were seen in those treated with MTX plus infliximab (39% to 47%) compared with MTX alone (26%). Radiographic progression was primarily observed in patients treated only with MTX alone. Although 45% of the MTX-only group showed no progression, those on infliximab demonstrated greater protection as evidenced by no progression in x-ray scores in 58% to 59% of patients.

The 2-year BeSt study was designed to assess four different regimens in 508 patients with newly diagnosed (<2 years) active RA who had not been previously treated with DMARDS. The patients were randomized to one of four treatment groups:

• Sequential DMARD monotherapy
• MTX with step up to combination DMARD therapy
• Initial combination therapy with MTX, sulfasalazine (SSZ) and a high dose of prednisone (tapered over 6 weeks)
• Initial combination therapy with MTX and infliximab.

Therapy adjustments at each 3-month blinded evaluation were dictated by calculation of the DAS. If the DAS was >2.4 at any of the 3-month evaluations, the treatment was changed according to a prescribed protocol for each group; if the DAS was <2.4 for at least 6 months, the medication could be tapered to monotherapy at a maintenance dose. Radiographs of hands and feet were assessed yearly, blinded for patient identity and treatment and in random order, to measure joint damage progression.

After 2 years of treatment, 80% of all patients achieved the goal of DAS ≤2.4 and 42% reached clinical remission (DAS <1.6) (Figure 14-5). Initial combination therapy, either with prednisone (group 3) or with infliximab (group 4), resulted in earlier improvement in functional ability, more continuous clinical remission (DAS <1.6) and less joint damage progression than initial monotherapy. Patients in the initial monotherapy groups needed more therapy adjustments, including introduction of combination therapy with prednisone or infliximab, to achieve a DAS ≤2.4, whereas more than half of the initial combination therapy patients (groups 3 and 4) were able to taper to monotherapy with either SSZ or MTX. While all of these early RA patients demonstrated impressive efficacy regardless of the treatment strategy, this outcome was mandated by protocol-driven, goal-oriented treatment. Such findings are a strong endorsement for using objective metrics to guide treatment, especially in early RA. Another important point was that the most aggressive regimens (groups 3 and 4) yielded less joint damage progression, better ability to wean DMARD or biologic therapy, and greater numbers of actual drug-free remissions (data not shown).

Safety in RA

The scope of safety concerns seen with infliximab is identical to that with other TNF inhibitors since nearly all of these can be ascribed to the biologic consequences of TNF inhibition (Table 14-7). Patient selection plays a critical role in limiting the frequency of undesirable or serious adverse events. Thus patients with multiple comorbidities, prior or recurrent infections, lymphoma, demyelinating disease, or hypersensitivity to infliximab or mouse proteins may not be appropriate candidates for infliximab therapy.

While infusion reactions may be seen in up to 20% of patients receiving infliximab, <2% of patients will have to suspend therapy because of serious infusion reactions. These reactions are most commonly observed when the infusion is given too quickly (<2 hours). Patients may complain of headache, nausea, rash, urticaria, pruritus, flushing, fever, chills, tachycardia, or dyspnea. Such reactions are best managed by assessing the patient and slowing the rate of infusion. Some may benefit from treatment with acetaminophen, antihistamines, or short-acting corticosteroids. There have been rare reports of anaphylactic reactions or serious complaints of chest tightness, bronchospasm, hypotension, diaphoresis, or a feeling of impending doom. In case of such effects, therapy should be halted and supportive or emergent care administered until the patient is stabilized.

Infliximab infusions should only be administered in the clinic or hospital, with appropriate medical personnel in attendance and with ready access to parenteral corticosteroids, diphenhydramine and epinephrine. It is unclear if such reactions are related to the development of HACAs since these events have been correlated with human antichimeric antibody (HACAs) in Crohn’s disease patients but not in RA. Low-titer HACAs are seen in 10% of RA patients. However, the immunogenicity of infliximab is abrogated by concomitant MTX use (<5%) or higher doses (e.g., 10 mg/kg has 0% HACA).

Serious infections were reported in 6.1% of patients in ATTRACT. Pneumonia was reported in 2% to 3% of patients in ASPIRE and product labeling reports a 1.7% frequency of pneumonia overall. Mycobacterial and other opportunistic infections have been well described in patients receiving infliximab. Somewhat higher rates of infection may be ascribed to several factors, including greater worldwide use in endemic areas, longer drug half-life, slower off-rates when binding TNFα, induction of apoptosis and cytotoxicity and the approved use in an older Medicare population. Nonetheless, the risk of mycobacterial infections can be minimized by proper patient selection and prescreening patients with tuberculin skin testing. Chest radiographs are indicated in those with a positive PPD, suspicious symptoms of pulmonary or extrapulmonary infection, travel from endemic areas, or recent contact with someone infected with TB.

During a 2003 FDA review of TNF-inhibitor safety, infliximab-associated lymphoma was reported to be increased with a standardized incidence rate (SIR) of 6.35. However, this frequency is not significantly different from other TNF inhibitors or active-RA patients not treated with TNF inhibitors. While no increase in other neoplasms or solid tumors was seen with infliximab, a 157-patient trial of infliximab in chronic obstructive pulmonary disease revealed nine neoplasms in the infliximab group (7.67/100 patient-years) and one in the control group (1.63/100 patient-years). Most of these were malignancies of the lung, head, or neck and 80% had a >50 pack-year history of smoking and 60% were current smokers.

Serious hepatotoxicity is rare with infliximab. While sporadic modest elevations of transaminases occur in up to one third of patients, these seldom persist or progress to liver failure or jaundice. Postmarketing analyses have revealed 34 cases (0.006%) of severe hepatotoxicity (defined as >5-fold ALT increases, jaundice, symptoms of hepatitis), with most of these occurring during the first year of therapy. Many of these cases are confounded by other comorbidities or the use of hepatotoxic agents.

Reactivation of hepatitis B virus (HBV) infection may occur in patients receiving TNF inhibitors, including infliximab. In some instances, these events have been fatal. Patients at risk for HBV infection should be screened for HBV prior to initiating TNF inhibition. Those found to be carriers or actively infected should either avoid TNF blockade, or receive chronic anti-viral therapy and be monitored closely should TNF inhibition be necessary.

Etanercept (Enbrel)

Etanercept was approved for use in RA in 1999. Since that time, it has been widely used worldwide and has also been approved by the FDA for use in other inflammatory disorders (e.g., juvenile arthritis, psoriatic arthritis, psoriasis, ankylosing spondylitis).

Indications and Dosing

Etanercept is specifically indicated for reducing the signs and symptoms of RA, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA. It can used alone or in conjunction with MTX. Etanercept is also approved for use in ankylosing spondylitis, psoriatic arthritis, psoriasis and moderately to severely active, polyarticular-course and juvenile RA. Etanercept is not recommended for persons with active serious infections, sepsis, MS, myelitis, or optic neuritis.

In adult RA patients, etanercept is given by self-administered subcutaneous injection at 25 mg weekly or 50 mg once a week. In a controlled clinical trial, higher doses (e.g., 50 mg subcutaneously twice a week) were not associated with increased efficacy but were associated with more adverse events.

Pharmacology

Etanercept is a dimeric fusion construct that links two p75 (type II) TNF receptors to the Fc portion of human IgG1. The latter is responsible for the drug’s long half-life. Etanercept is produced by recombinant DNA technology in Chinese hamster ovary cells and has a molecular weight of 150 kd. Etanercept will inhibit the binding of TNFα and lymphotoxin-α to TNF receptors. In contrast to the monoclonal antibodies, etanercept does not induce cell lysis or apoptosis of TNF-expressing cells. The half-life of etanercept in adult RA patients is 102 hours (±30 hours) with a range of 4.1 to 12.5 days. The pharmacokinetic (PK) profile is assumed to be similar in children, although drug clearance may be reduced in children between the ages of 4 and 8 years. The PK profile has not been well studied in children <4 years old. Serum concentration profiles at steady state were comparable among patients with RA treated with 50 mg once weekly or 25 mg twice weekly. The route of clearance from the circulation is unclear, although it is believed to be via Fc binding in the reticuloendothelial system. MTX has no effect on the pharmacokinetics of etanercept. Etanercept is supplied in a 50-mg/mL prefilled syringe or as 25-mg lyophilized powder that is reconstituted with 1 mL of sterile bacteriostatic water.

Clinical Efficacy in RA

The pivotal clinical trials (discussed below) that led to approval included over 1,700 RA patients. Adult RA patients were enrolled if they had ≥12 tender or 10 swollen joints and had failed one to four DMARDs prior to entry. Collectively, these trials consistently demonstrated impressive clinical outcomes, namely ACR20 responses ranging from 59% to 75% and ACR70 response rates as high as 25% after 6 to 12 months of therapy. Several groups analyzed these data to determine if these results persisted with continued treatment. For example, Klareskog and colleagues reviewed the data from nearly 2,000 etanercept-treated RA patients with >3 years of drug exposure. After 2 years of treatment, nearly 80% of patients remained on etanercept and at 3 years, the dropout rate was 29% (8% for lack of efficacy and 9% for adverse events) (Figure 14-1).

In a 6-month, randomized, double-blind, placebo-controlled monotherapy trial in patients with active and long-standing RA, etanercept doses of 10 mg and 25 mg twice weekly were found to be effective in rapidly reducing disease activity. The efficacy and safety of etanercept together with MTX were demonstrated in an 89-patient pilot trial in which etanercept or placebo was given to those with an inadequate response to MTX (mean weekly dose of 19 mg). Rapid and sustained improvement was seen and a 75% to 78% improvement in tender and swollen joints was noted after 6 months. An ACR20 response was achieved by 27% of patients in the placebo-plus-MTX group and by 71% of those receiving etanercept plus MTX (Figure 14-6). During the first 6 months, only 2% of combination-therapy patients withdrew from the trial compared with 9% of placebo-treated patients. Seventy-nine patients entered the open-label long-term observational study and continued to receive MTX plus etanercept for up to 36 months. In the third year, 65 patients remained on combination therapy with persistence of their ACR20, ACR50 and ACR70 responses over the 3 years (Figure 14-7). After 3 years, 68% to 85% of these patients were able to decrease or discontinue MTX or prednisone, and 39% to 59% were able to discontinue MTX or prednisone.

TEMPO compared the effects of etanercept alone, MTX alone and etanercept plus MTX in patients with established disease. The 682 enrolled patients had a mean disease duration of 6 years and experienced failure of a mean of 2.3 DMARDs. Although this was originally an MTX-naïve trial, nearly 42% had previously received MTX. However, this subset had been off MTX for >2 years, previously took lower doses of MTX (11-13 mg/week) and showed the same outcomes as MTX-naïve patients. Active disease was present as evidenced by a mean of 34 tender and 22 swollen joints at entry. Results at 12 and 24 months showed that the combination of etanercept and MTX was significantly more effective than either monotherapy (Table 14-8). At 12 months, the combination group had more ACR20 (85%) and ACR70 (43%) responders and DAS remissions (37%) than did MTX (75%, 19%, 14%, respectively) or etanercept (76%, 24%, 18%, respectively) monotherapy groups. The mean TSS decreased by 0.5 units with etanercept plus MTX, which was significantly better than the increase of 0.5 units observed in patients treated with etanercept alone and the increase of 2.8 units in those treated with MTX alone. Impressively, 80% of those on combination therapy had no radiographic worsening. This compares favorably to 57% to 68% of those on MTX or etanercept who showed no radiographic worsening. This study underscores that radiographic protection may be the primary benefit of TNF therapy, especially when combined with MTX.

Use in Early RA

Etanercept was the first cytokine-targeted therapy tested in early RA and later approved for the same. The 12-month, double-blind, Early Rheumatoid Arthritis (ERA) trial was a head-to-head comparison of etanercept vs MTX, performed in 632 MTX-naïve patients with early RA. The patients had a disease duration of <3 years (mean of 11 months) and had to be either RF-positive or have radiographic erosions at entry. Over 87% had erosive disease at baseline and nearly 40% had previously received a DMARD (other than MTX). Patients were randomized to receive MTX 20 mg/week or etanercept 10 or 25 mg twice weekly. After 12 months, both the MTX- and the 25-mg etanercept-treated groups fared equally well with an ACR20 response of 65% and 72%, respectively (Figure 14-8). The only significant group difference was the more rapid onset of improvement noted in patients treated with etanercept in the first 4 months. Both drugs were well tolerated, but etanercept-treated patients had fewer adverse events and nonrespiratory infections and more ISRs compared with MTX patients. Serious infectious events were infrequent in both groups (<3%).

Radiographic assessments at 0, 6, 12 and 24 months showed that the rate of x-ray progression appeared to be slowed by both agents, the effect of 25-mg etanercept being greater than that of MTX (Figure 14-9). In the first year, mTSS showed little change in the MTX (1.3 units) and etanercept (0.8 units) groups, yet both were significantly better than their projected rates of x-ray deterioration (estimated to be ~9 Sharp units per year). In the second year of the trial, significant differences were seen, with etanercept patients increasing only 1.3 Sharp units (no progression in 63%) and MTX patients increasing 3.2 Sharp units (no progression in 51%). In addition, in the second year, significantly greater ACR20 response rates were seen in the etanercept group (72%) compared with the MTX group (59%).

The ERA trial was pivotal in demonstrating the potency of either MTX or etanercept in patients with early, aggressive RA. The added radiographic advantage of TNF inhibition in early disease was largely seen in those with erosions at entry. Etanercept was significantly superior to MTX in protecting against new erosions in patients with baseline erosive disease. However, when no erosions were present at baseline, MTX and etanercept were equipotent (86% and 96%, respectively) in protecting against new erosions (data not shown).

The subsequent COMET trial is a 24-month, double-blind, randomized, parallel-group study with two periods. In the first 52-week period, 542 MTX-naïve patients with early moderate-to-severe RA were randomly assigned to receive etanercept 50 mg once weekly plus MTX or MTX monotherapy. In both groups, MTX was titrated up from 7.5 mg/week to a maximum of 20 mg/week by week 8. Stable doses of oral corticosteroids (≤10 mg/ day prednisone or an equivalent agent) or a single NSAID was permitted if started at least 4 weeks before baseline and kept constant throughout the first 24 weeks of the study. After completion of 24 weeks of treatment, corticosteroids and NSAIDS were tapered or discontinued according to pre-established schedules. The coprimary end points were the proportion of patients who achieved remission (DAS28 <2.6) at week 52 and the change in the mTSS (joint erosion score plus joint space narrowing score) from baseline to week 52.

At 52 weeks, the proportion of participants who achieved DAS28 remission was significantly greater in the etanercept plus MTX group than the MTX monotherapy group (50% vs 28%, respectively; effect difference, P <00001). As early as week 2, and at all subsequent time points, the proportion of patients who achieved DAS28 remission was significantly greater in the etanercept plus MTX group than in the MTX monotherapy group (Figure 14-10). Analysis of radiographic non-progression, defined as mTSS of ≤0.5, revealed that 59% of patients in the MTX monotherapy group achieved radiographic non-progression while 80% of those in the etanercept plus MTX group achieved that outcome (effect difference, P <0.0001) (Figure 14-11). Analysis that used the more stringent definition of non-progression as mTSS ≤0 produced similar results (Figure 14-11).

Patient-reported outcomes (PROs) were secondary outcomes in the COMET study. Kekow and associates performed a subsequent analysis of the results of this trial to assess the relationship between improvements in PROs and changes in clinical status defined as three mutually exclusive disease activity categories: “achieved remission” (DAS28 <2.6), “achieved low disease activity (LDA) but not remission” (DAS28 ≥2.6 but ≤3.2) and “did not achieve LDA” (DAS28 >3.2).

Analyses performed to examine the relationship between 52-week PROs and remission or LDA were adjusted for age, sex and baseline score. Overall, for all PROs, differences between patients who “achieved remission,” “achieved LDA but not remission,” and “did not achieve LDA” were statistically significant (P <0.0001) (Table 14-9). Patients who achieved remission showed greatest improvement in PROs, followed by patients who achieved LDA but not remission. Pairwise comparisons of changes in PROs between disease activity categories also showed statistically significant differences, favoring groups who achieved better disease control with one exception (Table 14-9).

The results from the second year of the COMET trial have now been reported, specifically how the long-term clinical and radiographic outcomes were affected by continuation of, and alterations to the initial combination and monotherapy regimens. Patients were randomized at baseline for the entire 2-year period; those who completed 1 year of treatment with combination or MTX monotherapy entered year 2. The original combination group either continued combination therapy (the EM/EM group) or were switched to etanercept monotherapy (the EM/E group). The original MTX monotherapy group was switched to combination therapy (the M/EM group) or continued monotherapy (the M/M group).

The efficacy end points were remission (DAS28 <2.6) and radiographic nonprogression (change in the modified Sharp/van der Heijde score <0.5) at year 2. After 2 years of treatment (LOCF method), the proportions of patients achieving DAS28 remission in the EM/EM and M/EM groups (57%) and (58%), respectively, were significantly greater than that in the M/M group (35%) but not significantly greater than that in the EM/E group (50%) (Figure 14-12). Based on these results, 4.5 patients would have to be treated with the EM/EM regimen rather than the M/M regimen to achieve 1 DAS28 remission during a period of 2 years. During year 2, the proportion of patients in whom radiographic nonprogression was demonstrated (LOCF method) was significantly higher in the EM/EM group than in the EM/E, M/EM and M/M groups (Figure 14-13). An estimated 4.5 patients would need to be treated with the EM/EM regimen rather than the M/M regimen for 2 years to achieve radiographic nonprogression.

These results indicate that in patients with early, active RA, sustained combination therapy was consistently more effective than continuous MTX monotherapy in improving clinical and radiographic outcomes after 2 years. The second year of this study also found that the effect of switching to a combination M/EM regimen after 1 year of MTX monotherapy was significantly more effective than continuing MTX monotherapy (the M/M regimen) in providing DAS28 remission. Furthermore, delaying combination therapy until year 2 of the study resulted in a significantly lower percentage of patients attaining radiographic nonprogression compared with early and sustained combination therapy (75% vs 90%; P = 0.009). It is also interesting to note that a “step down” from the combination regimen in year 1 to etanercept monotherapy in year 2 was numerically less effective than continuous combination therapy in providing DAS28 remission (50% vs 57%; P = NS) and significantly less effective in producing nonprogression (75% vs 90%; P = 0.008), demonstrating the importance of MTX as an adjunct to etanercept for optimizing clinical and radiographic outcomes in early RA.

Safety in RA

Etanercept, like adalimumab, is administered subcutaneously; therefore, ISRs are relatively common. Although clinical trial data showed an ISR frequency of nearly 37%, post marketing experience suggests that the frequency is less. As with the other TNF inhibitors, common infections (e.g., upper respiratory infection and sinusitis) are common, serious infections (e.g., pneumonia) are uncommon and opportunistic infections are rare. Serious infections occurred in <3% of ERA trial patients and <4.5% of patients in the TEMPO study with no difference between MTX- and TNF-treated patients (Table 14-10). The combined use of etanercept and anakinra should be discouraged since both an open-label trial and a randomized controlled trial failed to show clinical benefit, an increased risk of serious infections (7%) and neutropenia (2%). Mild neutropenia has also been rarely noted when etanercept is combined with SSZ.

Although ANA or dsDNA antibodies (11% to 15%) may arise during therapy, there is no value in prescreening or monitoring autoantibodies, as these are poorly predictive of actual autoimmune manifestations. There appears to be no difference in the safety concerns of etanercept compared with infliximab or adalimumab, since all three agents have been implicated in the rare occurrence of drug-induced lupus, demyelinating disorders (MS, optic neuritis), cytopenias, TB and other mycobacterial infection, opportunistic infections, lymphoma and CHF.

TB and atypical mycobacterial infections have been described in patients receiving etanercept, but tuberculin skin testing is not suggested by current product labeling. Reasons for this include lower rates of TB infection (compared with infliximab) and a longer latency period from initiation to infection (mean, 11 months). Lower rates may relate to a substantial number of patients getting by on less-frequent dosing, a fast off-rate and shorter half-life. Nonetheless, most rheumatologists advise PPD prescreening all patients being considered for TNF-inhibitor therapy as the risk of TB appears to be a class effect.

Lymphoma rates with etanercept (SIR = 3.47) are equivalent to those with the other TNF inhibitors and to the risk incurred by those with very active RA. While there has been no increase in the incidence of other neoplasms in RA patients, a 180-patient randomized placebo-controlled trial of etanercept in Wegener’s granulomatosis showed an increase in solid tumors (six tumors vs 1.92 expected = SIR 3.12) that was unexpected. However, those developing these tumors had previously received treatment with cyclophosphamide. Etanercept has been given to patients with NYHA class II-IV CHF in two different studies. Both were halted prematurely at 12 months for “futility,” as they did not meet expected efficacy outcomes. While one study showed no benefit, the other did show a dose-related increase in CHF hospitalizations. Reasons for this are unclear as analysis of clinical trial data in RA patients failed to disclose any increase in CHF or cardiac events for those taking etanercept.

Adalimumab (Humira)

Adalimumab became commercially available in December 2002. At the time of FDA approval, nearly 2,500 RA patients in 17 different clinical trials had received this drug. As of January 2021, more than 1.4 million patients have been prescribed adalimumab worldwide.

Indications and Dosing

Adalimumab is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active RA. It can be used alone or in combination with MTX or other DMARDs. Adalimumab is also approved for use in juvenile RA, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis and plaque psoriasis.

The usual recommended dose is 40 mg administered subcutaneously every other week (EOW). Some RA patients not taking concomitant MTX may derive additional benefit from increasing the dosing frequency of adalimumab to 40 mg every week.

Pharmacology

Adalimumab is a fully human IgG1 anti-TNFα monoclonal antibody that was initially called D2E7 during early development. This recombinant human monoclonal antibody is produced by phage display and holds the potential advantages of being less immunogenic, having a long half-life and requiring less-frequent dosing. The antibody binds circulating and cell-bound TNFα and blocks its interaction with p55 and p75 receptors. Adalimumab does not interact with lymphotoxin (TNFβ). The drug induces cell lysis of TNF-expressing cells (in the presence of complement). The terminal half-life of adalimumab is 10 to 20 days (approximately 14 days). After a single 40-mg subcutaneous dose, the maximum serum concentration is achieved within 131 hours. Adalimumab appears to have a low clearance and distributes mainly in the vascular compartment. It is unknown if pharmacokinetics are altered in the setting of renal or hepatic impairment. It should be noted that coadministration of adalimumab and MTX may result in increased adalimumab blood levels as a result of decreased excretion of adalimumab.

Clinical Efficacy in RA

Early clinical trials showed that single doses of adalimumab produced significant and rapid clinical improvement, reduced acute-phase reactants, increased circulating lymphocyte counts and significantly reduced systemic IL-6 and IL-1Ra levels that lasted for at least 14 days. In controlled, dose-ranging monotherapy studies, ACR20 response rates ranged from 56% to 80%. In a large, placebo-controlled monotherapy trial in 544 RA patients, a dose-dependent rise in ACR response rates was observed; 46% of patients receiving 40 mg EOW achieved an ACR20 response.

ARMADA evaluated the efficacy of adalimumab in 271 RA patients with an inadequate response to MTX. In this multicenter, randomized controlled trial, patients remained on stable doses (mean of 16-17 mg/week) of MTX and received either placebo or adalimumab 20 mg, 40 mg, or 80 mg EOW. These patients had a mean disease duration of 11 to 13 years and had received an average of three prior DMARDs. ACR20 response rates were 13%, 48%, 67% and 66% for those taking placebo, 20 mg, 40 mg, or 80 mg, respectively (Figure 14-14). Similarly, the ACR70 responses were 3%, 11%, 24% and 19% for those taking placebo, 20 mg, 40 mg, or 80 mg, respectively. ISRs occurred in 15% of patients, but no other unusual or serious adverse events were noted.

Another pivotal trial (DEO19), reported by Keystone and colleagues, assessed the efficacy and radiographic outcomes in a 618-patient, 52-week trial in which adalimumab or placebo was given to MTX partial responders. Patients continued their usual MTX dose and were randomized to receive either placebo or adalimumab 20 mg/week or adalimumab 40 mg every other week (EOW). Their mean age was 56 years, mean disease duration was 11 years and they had experienced failure of an average of 1.9 DMARDs at study enrollment. Their disease activity was demonstrated by a mean of 28 tender joints, 19 swollen joints, CRP of 1.8 mg/dL and TSS of 66 to 72 (range, 0–380). After 52 weeks, the ACR20 response rates were 24%, 55% and 59% in the placebo, adalimumab 20-mg and adalimumab 40-mg groups, respectively. As shown in Figure 14-15, the ACR20, ACR50 and ACR70 response rates were sustained in the 457 patients who went on to receive open-label adalimumab 40 mg EOW plus MTX for a second year. While 77% of adalimumab 40-mg patients completed the 12-month trial, only 70% of placebo patients did so. Radiographic deterioration, as measured by mTSS, was significantly worse in the placebo group (+2.7 Sharp units) compared with the 20-mg/week (+0.8 Sharp units) or 40-mg EOW (+0.1 Sharp units) groups (Figure 14-16). In the second year, open-label adalimumab showed the same lack of x-ray progression. In both the ARMADA and DE019 studies, substantial improvements were noted in those taking 40 mg EOW as measured by ACR50 (42% to 54%) and ACR70 (23% to 27%) responses, and functional surveys (HAQ, SF-36). Moreover, the significant retardation of radiographic progression evident at the end of the 12-month DE019 trial has been shown to persist for up to 3 years in open-label extension studies.

A large, ongoing postmarketing (“real-world”) trial of adalimumab is studying the outcomes of 6610 patients from 450 sites in Europe and Australia. So far, this trial has revealed clinical efficacy and safety outcomes that echo the randomized, comparative clinical trial results. Moreover, this trial has shown impressive clinical responses when adalimumab was given to patients who had previously received either etanercept or infliximab.

Use in Early RA

Adalimumab has been approved for use in early RA. Initial data on the use of adalimumab in patients with early RA came from a subset analysis of the DE019 trial (adalimumab 40 mg EOW) that compared the results in 78 patients with early disease (≤3 years, mean of 1.8 years) to the results in 329 patients with long-standing RA (>3 years, mean disease duration 13.1 years). Although patients in both the early and established-disease groups exhibited statistically significant clinical improvement with adalimumab compared with placebo, the ACR20, ACR50 and ACR70 responses of 61.0%, 46.3% and 24.4%, respectively, at 52 weeks for adalimumab-treated patients with early disease were not statistically significantly different than the ACR20, ACR50 and ACR70 responses of 56.0%, 37.3% and 19.9%, respectively, for patients with established disease. However, radiographic progression in the placebo groups was greater in the early disease group, as indicated by a mean change in TSS of 5.71 compared with 2.11 in the established-disease group (Figure 14-17). In both adalimumab-treated groups, radiographic progression was substantially inhibited with a mean change of 0.39 TSS units in the early disease group and 0.05 TSS units in the established-disease group (P <0.05).

These results suggest that adalimumab treatment of patients with early RA reduces radiographic progression compared with placebo to a greater degree than progression in patients with established disease.

These preliminary findings led to the subsequent 2-year, multinational, PREMIER trial that compared the efficacy and safety of adalimumab plus MTX, adalimumab alone and MTX alone in 799 DMARD/MTX-naïve early RA patients. Patients were included if they had a disease duration <3 years, with active disease defined as at least eight swollen joints (of a potential 66 joint count), an elevated ESR (≥28 mm/hour) or CRP (≥1.5 mg/dL) and either have a positive serum RF or one radiographic erosion. Patients were excluded if they were pregnant, had previously received MTX, azathioprine, cyclosporine, cyclophosphamide, or more than two DMARDs (HCQ and SSZ were permitted), or if there was a history of hepatic or renal dysfunction, recurrent serious infections, TB, or untreated tuberculin skin test positivity. The coprimary outcomes were the ACR50 response rate and change in TSS at 12 months. Other radiographic, functional and clinical efficacy outcomes were collected at 12 and 24 months.

The results showed that in MTX-naïve patients with recent-onset RA, adalimumab plus MTX was statistically significantly better than either MTX alone or adalimumab alone in alleviating the signs and symptoms of RA (Figure 14-18) and in inhibiting radiographic progression (Figure 14-19 and Figure 14-20). Remission at 2 years, as measured by DAS28 and major clinical response, was achieved by approximately half of patients receiving combination therapy. A total of 539 patients (68%) completed 2 years of therapy, including 66% of those in the MTX arm, 61% in the adalimumab arm and 76% in the combination arm. The frequencies of adverse events were comparable among the three arms.

The results of PREMIER did not indicate whether the superior radiographic efficacy of adalimumab plus MTX was entirely attributable to its efficacy or involved an additional, independent effect. Therefore, a subsequent analysis of the radiographic outcomes in PREMIER was performed using cumulative probability plots and other measures of clinical status to assess radiographic progression in patients grouped according to their clinical outcomes, both early and late in the trial. The analysis used mean changes in TSS (∆TSS), percentages of progressors (∆TSS >0.5) and cumulative probability plots. When patients were grouped by ACR response (<ACR20, ACR20, ACR50, ACR70) the mean ∆TSS values were significantly smaller for MTX monotherapy than with adalimumab plus MTX for each level of ACR response at week 26 (except ACR70) and week 104 (Figure 14-21).

For adalimumab monotherapy, mean ∆TSS values were intermediate to those for the other two treatments, with a statistically significant difference from MTX monotherapy observed only for the <ACR20 responders. For each category of ACR response, the percentages of patients with radiographic progression from baseline (∆TSS >0.5) were significantly smaller (by approximately 50% at week 104) for patients who achieved the response with adalimumab plus MTX compared with MTX monotherapy. Analyses based on cumulative probability plots and other measures of clinical status (e.g., DAS28) supported the general conclusion that, across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, treatment of patients with early RA with adalimumab plus MTX resulted in less radiographic progression at weeks 26 and 104 than MTX alone.

Use in the Elderly

Adalimumab has been studied in the elderly. In the pivotal clinical trials, 519 RA patients were ≥65 years of age, including 107 who were ≥75 years of age. While efficacy and most safety concerns were similar to those in younger patients, not surprisingly, there was an increased rate of serious infections and malignancies in this elderly group compared with patients <65 years of age. Hence, caution and/or close observation is required if TNF inhibition is to be considered in the elderly. Other rare, unusual and unexplained adverse events have been reported, including accidental injury, back pain, cutaneous vasculitis, liver failure and anaphylaxis.

Safety in RA

The adverse events seen with adalimumab have also been seen with other anti-TNF preparations. The frequencies of potentially serious adverse events are listed in Table 14-11.

ISRs are the most common adverse reaction with adalimumab therapy. In placebo-controlled trials, 20% of adalimumab-treated patients developed ISRs manifested as erythema and/itching, hemorrhage, pain or swelling, compared with 14% of patients who received placebo. Most ISRs were mild and generally did not result in discontinuation of treatment. The occurrence of ISRs has not been correlated with dose, frequency, or the presence of neutralizing human anti-human antibodies. Other common (>10%) adverse events seen in clinical trials were upper respiratory infections and seen in up to 17% and 11%, respectively, in patients treated with adalimumab. In the clinical trials, patients did not suspend or stop anti-TNF therapy for these nuisance infections and most responded very well to either observation or symptomatic therapy.

Although antibodies against adalimumab are seen in up to 12% of patients, concurrent use of MTX reduces this finding to only 1%. These antibodies have not been shown to alter drug efficacy or safety. Adalimumab use may also give rise to ANAs (12%) or antibodies to native DNA (5%). While such findings are rarely (<0.1%) associated with drug-induced lupus, routine monitoring of antibody titers is not suggested since such findings have a low predictive value.

Serious infections and mycobacterial infections have been remarkably infrequent as a result of following prescribing guidelines and screening procedures. In placebo-controlled and ongoing global clinical studies that include over 13,000 patients, the overall rate of TB is approximately 0.26 per 100 patient-years. In the United States and Canada, the rate is approximately 0.07 per 100 patient-years. The requirement of tuberculin skin testing has resulted in an 85% reduction in TB risk. Risk may be further limited by avoiding these agents in patients with a past history of TB or opportunistic infection and in those with a positive PPD test in whom the condition has not been treated. Like the other TNF-targeting agents, opportunistic infections have been rarely described, including infection with Histoplasma, Candida, Pneumocystis, Cryptococcus, Nocardia, Listeria, Toxoplasma and herpes zoster. Coccidiomycosis has not been reported. In clinical studies, the overall rate of opportunistic infections are approximately 0.075 per 100 patient-years.

The rates of serious bacterial infections have remained stable over many clinical trials and long-term follow-up. In placebo-controlled trials, the incidence of serious infections was 0.04 per patient-year with adalimumab and 0,02 per patient-year in those treated with placebo. Uncommon serious infections have included pneumonia, cellulitis, septic arthritis, wound infection, postsurgical infections, diverticulitis, pyelonephritis, abscess and sepsis. While most of the trials failed to demonstrate a difference in serious infection rates between adalimumab- and placebo-treated patients, the DE019 did show more serious infections in the MTX/adalimumab group (3.8%) compared with the MTX/placebo group (0.5%). Reasons for this increase may be related to the longer disease duration or disease severity in the patients enrolled in this trial. Regardless, the uncommon risk of serious bacterial infections may be minimized by proper patient selection and caution when using TNF inhibitors in patients with numerous risk factors, such as advanced age, debility, extreme inflammatory activity, corticosteroid use, other comorbidities, skin breakdown and planned major surgery (e.g., joint replacement).

Reactivation of HBV infection may occur in patients receiving TNF inhibitors, including adalimumab. In some instances, these events have been fatal. Patients at risk for HBV infection should be screened for HBV prior to initiating TNF inhibition. Those found to be carriers or actively infected should either avoid TNF blockade or receive chronic anti-viral therapy and be monitored closely should TNF inhibition be necessary.

Adalimumab therapy does not affect the immune responses of vaccination, allowing pneumococcal and influenza vaccination. However, since vaccination with live viruses have not been studied, they should be avoided. Studies have shown that adalimumab treatment does not cause anergy, alter delayed-type hypersensitivity reactions, or change cellular subsets or immunoglobulin levels.

Last, while lymphoma has rarely been reported in patients taking adalimumab, this rate does not appear to be higher than that observed for RA in general or RA patients with active disease. The cumulative clinical trial experience with this drug shows a 3.5-fold lymphoma risk compared with a limited number of controls.

Certolizumab Pegol (Cimzia)

Certolizumab pegol (previously identified as CDP870) became commercially available in the United States in May 2009. Approval of certolizumab was based on data from multicenter, placebo-controlled, phase 3 trials that involved >2300 adult patients with moderate to severe RA diagnosed according to the ACR criteria.

Indications and Dosing

Certolizumab pegol is indicated for treatment of adults with moderately to severely active RA. The recommended initial dose of certolizumab in patients with RA is 400 mg (given as two subcutaneous injections of 200 mg) initially and at weeks 2 and 4, followed by 200 mg EOW. For maintenance dosing, 400 mg every 4 weeks can be considered. Certolizumab is supplied as a powder for reconstitution for subcutaneous administration. It is also available in an exclusively designed, patient-friendly, prefilled syringe. Certolizumab is also approved for use in Crohn’s disease, ankylosing spondylitis and psoriatic arthritis.

Pharmacology

Certolizumab is a Fab’ fragment of a humanized anti-TNFα antibody conjugated to polyethylene glycol in order to extend the terminal plasma elimination half-life of the Fab’ fragment. Certolizumab pegol selectively neutralizes membrane-associated and soluble human TNFα in a dose-dependent manner but does not neutralize lymphotoxin (TNFβ). In pharmacokinetic studies in healthy volunteers and patients with RA, certolizumab pegol plasma concentrations were broadly dose-proportional and its pharmacokinetics in patients with RA were consistent with those seen in healthy subjects. The terminal elimination phase half-life was approximately 14 days for all doses tested. MTX pharmacokinetics are not altered by concomitant administration with certolizumab in patients with RA. The effect of MTX on certolizumab pharmacokinetics was not studied. However, MTX-treated patients have a lower incidence of antibodies to certolizumab.

Clinical Efficacy in RA

The approval of certolizumab pegol for RA was based on data from four multicenter, placebo-controlled, phase 3 trials involving >2,300 patients with RA. It was studied at dosing intervals of 2 or 4 weeks and administered subcutaneously together with MTX or as monotherapy.

In the 52-week, double-blind, placebo-controlled, RAPID-1 trial, 982 adults with active RA were randomized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0, 2 and 4, with subsequent administration of 200 mg or 400 mg given every 2 weeks, plus MTX, or placebo plus MTX. The primary end points were the ACR20 response rate at week 24 and the mean change from baseline in the mTSS at week 52. Patients had to have received MTX for at least 6 months, with a stable dosage of ≥10 mg/week for at least 2 months prior to baselìne. Patients who had received any biologic therapy within 6 months of baseline were excluded from participation.

At week 24, ACR20 response rates for the groups treated with 200 mg and 400 mg of certolizumab pegol plus MTX were 58.8% and 60.8%, respectively, compared with 13.6% in those who received placebo plus MTX (Figure 14-22). These differences in ACR20 responses were statistically significant (P <0.001 for each vs placebo) and remained significant through week 52 (P <0.001 for each comparison) (Figure 14-23). In addition, ACR50 and ACR70 responder rates with certolizumab plus MTX were also superior (P <0.001) to placebo plus MTX. At week 1, significantly more patients in the certolizumab 200-mg and 400-mg groups achieved an ACR20 response than did those in the placebo group (P <0.001). The proportion of ACR20 responders peaked at week 12 and was sustained to week 52.

The mean change from baseline in the mTSS at week 52 was significantly (P <0.001) smaller in patients treated with certolizumab 200 mg (0.4 Sharp units) or 400 mg (0.2 Sharp units) than in placebo-treated patients (2.8 Sharp units). Significant differences between the certolizumab and placebo groups were also observed at 24 weeks (P <0.001).

The RAPID-1 study also included a 52-week open-label extension with the objective of determining whether dose escalation of certolizumab from 200 mg to 400 mg every other week would benefit some patients with RA. The open-label study included those who had completed the RAPID 1 study (to week 52) and also those who had been withdrawn from the study (at week 16, due to inadequate response). At the end of the 52-week trial, 243 patients who completed the study began receiving an escalated dosage of certolizumab, from 200 mg every other week in the RAPID 1 study to 400 mg every other week in the open-label study and 265 patients who completed the study maintained a stable dosage, receiving certolizumab 400 mg every other week in both the RAPID 1 study and the open-label study. The median DAS28 at the time of enrollment in the open label study was similar for these dose-escalation and stable-dose patients (3.5 vs 3.4, respectively). At 12 weeks and 48 weeks after enrollment in the open-label study, changes in the DAS28 were compared in dose-escalation patients vs stable-dosage, using cumulative probability plots of individual patient-level data.

In the group of patients who had completed the RAPID 1 study and had moderate or severe disease activity at entry into the open-label study and in those who had been withdrawn early from the RAPID 1 study, the median DAS28 improvements 12 weeks after enrollment into the open-label study were similar in the dose-escalation and stable-dose groups. Individual patient-level data revealed no greater likelihood of response in the group of patients who received an increased dosage of certolizumab vs those in whom a stable dosage was maintained, whether they had completed the RAPID 1 study or had been withdrawn early. At 12 weeks after enrollment in the open-label study, the median change in the DAS28 was -0.34 in the dose-escalation group and -0.28 in the stable-dose group. At this time point among patients who had moderate or severe disease activity at the time of enrollment in the open-label study, 16.1% of the dose-escalation patients (19 of 118) and 19.7% of the stable-dose patients (24 of 122) exhibited improvement in the DAS28 (>1.2 units). Based on these results, the authors acknowledge that increasing the dose of certolizumab from 200 mg to 400 mg offers little additional benefit in RA, even for selected patients.

The RAPID 2 study was a 24-week, phase 3, double-blind, randomized, placebo-controlled study similar in design to the RAPID 1 study. A total of 619 adult patients with active RA despite prior treatment with MTX were randomized to one of two certolizumab regimens (400 mg at weeks 0, 2 and 4, followed by 200 or 400 mg every 2 weeks) plus MTX, or placebo plus MTX. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in mTSS, ACR core set variables and physical function. As shown in Figure 14-24, the ACR20 responder rates at week 24 with both certolizumab plus MTX regimens were significantly (P <0.001) greater than with placebo plus MTX, as were the ACR50 and ACR70 responder rates (P <0.01).

Significantly higher ACR20 responses were observed with certolizumab as early as week 1, then increased over the first 12 weeks and were maintained through week 24. A similar pattern was noted for ACR50 and ACR70 responder rates. Treatment with both regimens of certolizumab resulted in significant improvements in mTSS as well as improvements in all ACR core components vs placebo, including significant reductions in number of swollen joint counts by week 1, with continued improvement to week 24 (Figure 14-25). In addition, significantly more certolizumab-treated patients reported significant improvements in physical function vs placebo from week 1 to week 24 (P <0.001) and clinically meaningful improvements in physical function from weeks 2 to 24.

The FAST4WARD study assessed the efficacy of certolizumab monotherapy in patients with RA who had failed treatment with one or more DMARDS. In this 24-week, double-blind, placebo-controlled study, 220 patients were randomized in a 1:1 ratio to receive certolizumab 400 mg or placebo every 4 weeks after discontinuation and washout of previous DMARD therapy. At week 24, the ACR20, ACR50, and ACR70 responder rates were significantly higher with certolizumab 400 mg compared with placebo (Figure 14-26). The ACR20, ACR50 and ACR70 responses with certolizumab were statistically significant vs placebo over time (P ≤0.05) at all time points, with the exceptions of ACR70 at weeks 1, 2 and 4. The difference for certolizumab vs placebo in the ACR20 response was statistically significant as early as week 1.

Patients treated with certolizumab experienced statistically significant improvements (P ≤0.05) in all ACR components, including tender and swollen joint counts at weeks 1 and 24 vs placebo (Figure 14-27). In addition, significant improvements in the disease disability scores, which were all patient-reported outcomes, were also observed early in patients treated with certolizumab and were sustained throughout the study.

Comparison of Certolizumab Pegol vs Adalimumab

Although TNF inhibitors are often the first biologic DMARDs to be prescribed in clinical practice, there are limited data directly comparing their safety and efficacy. The EXXELERATE study was the first prospective clinical trial to compare two TNF inhibitors—certolizumab pegol and adalimumab—in a head-to-head setting, both in combination with MTX. The study also assessed the safety and efficacy of directly switching from one TNF inhibitor to the other without a washout period, following insufficient response to the first.

The 104-week study enrolled patients 18 years of age and older with active RA who had prognostic factors for severe disease progression (positive rheumatoid factor and/or anti-cyclic citrullinated peptide antibody). All patients were biologic DMARD-naïve with active disease despite at least 12 weeks of MTX therapy prior to baseline. Eligible patients were randomized 1:1 to either certolizumab pegol (400 mg weeks 0, 2 and 4, then 200 mg Q2W) plus MTX or adalimumab (40 mg Q2W) plus MTX. At week 12, patients were classified as either responders (DAS28-ESR ≤3.2 or a DAS28-ESR reduction from baseline of ≥1.2) or nonresponders. All responders continued their initial treatment until week 104. Nonresponders in each treatment group were switched to the other treatment group at week 12. Patients who switched yet remained nonresponders at week 24 were withdrawn from the study. The primary endpoints were the superiority of certolizumab pegol plus MTX vs adalimumab plus MTX, according to ACR20 response rate at week 12 and the proportion of patients achieving DAS28-ESR ≤3.2 at week 104.

Primary analysis demonstrated that certolizumab pegol plus MTX was not superior to adalimumab plus MTX, with no significant differences observed between treatment groups for ACR20 response at week 12 (P = 0.467) or the proportion of patients reaching DAS28-ESR ≤3.2 at week 104 (P = 0.532) (Figure 14-28). In primary nonresponders (patients who switched treatments at week 12), 58% switching to certolizumab pegol and 62% switching to adalimumab responded to treatment at week 24. All clinical variables improved substantially following treatment switch.

The safety profiles of the two treatments over the 104-week trial were comparable, including serious and opportunistic infections. Treatment emergent adverse events following treatment switch were similar between treatment groups. After switching, no serious infection events were reported in either population within 70 days following the final dose of the initial study drug.

Overall, EXXELERATE demonstrated no significant differences in efficacy between certolizumab pegol and adalimumab in the treatment of RA, with safety profiles remaining similar. The trial supports the use of a second TNF inhibitor when the first fails to give an adequate response after a predetermined time interval and the option to directly switch between certolizumab pegol and adalimumab without a washout period.

Safety in RA

The safety concerns and types of adverse events seen with certolizumab treatment are largely typical of those reported with other anti-TNF blockers. The following discussion is based primarily on the safety information from placebo-controlled trials and long-term follow-up studies. These data reflect certolizumab exposure in 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 exposed for at least 1 year and 282 for at least 2 years and 1,774 in adequate and well-controlled studies.

Upper respiratory infections, rash and urinary tract infections were the most common adverse reactions associated with certolizumab treatment in these clinical trials. The incidence of new infections was 0.91 per patient-year for all certolizumab-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections and lower respiratory tract infections.

There were more new cases of serious infections, including TB, pneumonia, cellulitis and pyelonephritis, in the certolizumab treatment groups compared with the placebo groups (0.06 per patient-year for all certolizumab doses vs 0.02 per patient-year for placebo). There was no evidence of increased risk of infections with continued exposure over time. The proportion of patients with RA who discontinued treatment due to an adverse event was 5% with certolizumab and 2.5% with placebo. The most common adverse reactions leading to discontinuation of certolizumab were TB infections (0.5%) and pyrexia, urticaria, pneumonia, and rash (0.3% each). In the RA studies with certolizumab, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases.

The overall incidence of malignancies was similar in certolizumab-treated and control patients across all clinical studies. In the RA trials, a total of three cases of lymphoma were observed among 2,367 patients. However, this was approximately 2-fold higher than expected in the general population. There were rare reports of symptoms that could be compatible with hypersensitivity reactions and hematologic abnormalities, although any causal relationship to certolizumab is unclear.

In controlled RA trials, 7% patients had detectable antibodies to certolizumab and in approximately one third, the antibodies exhibited neutralizing activity in vitro. The rate of antibody development was lower among patients treated with concomitant immunosuppressants (MTX). In neutralizing antibody-positive patients, the ACR20 response rate was reduced compared with antibody-negative patients. However, there was no association between antibody development and the development of adverse events.

Certolizumab therapy does not affect the immune responses of vaccination, allowing pneumococcal and influenza vaccination. However, vaccination with live viruses has not been studied and should be avoided.

Golimumab (Simponi)

Golimumab (previously identified as CNTO 148) became commercially available in April 2009. At the time of FDA approval, the efficacy of golimumab for RA had been evaluated in randomized, placebo-controlled studies in 1,714 patients ≥18 years of age with moderately to severely active RA, diagnosed according to the ACR criteria.

Indications and Dosing

Golimumab, in combination with MTX, is indicated for the treatment of adult patients with moderate to severe active RA. Golimumab has also been approved for ulcerative colitis, psoriatic arthritis and ankylosing spondylitis. For patients with RA, golimumab can be administered subcutaneously or intravenously. The subcutaneous dose regimen is 50 mg golimumab administered by subcutaneous injection once a month in conjunction with MTX. The intravenous dose regimen is 2 mg/kg golimumab administered by intravenous infusion over 30 minutes at weeks 0, 4 and every 8 weeks thereafter, in conjunction with MTX. Golimumab is available in a prefilled, single-dose syringe and also in the specially designed Smartject Autojector for patient subcutaneous self-injection. Corticosteroids, nonbiologic DMARDs and/or NSAIDs may be continued during treatment with golimumab.

Pharmacology

Golimumab is a human IgG1қ monoclonal antibody produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses. Golimumab binds to both the soluble and transmembrane bioactive forms of human TNFα. There was no evidence of the golimumab antibody binds to other TNF superfamily ligands; in particular, the golimumab antibody does not bind or neutralize human lymphotoxin. Golimumab does not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells. In preclinical studies, golimumab was shown to have a high affinity for human TNFα and to effectively neutralize TNFα.

When golimumab 50 mg is administered every 4 weeks in patients with RA, serum concentrations reach steady-state by week 12. With concomitant use of MTX, treatment with 50 mg golimumab every 4 weeks results in a mean steady-state trough serum concentration of approximately 0.4-0.6 mcg/mL. In patients with RA treated with golimumab 50 mg and MTX, the mean steady-state trough concentrations of golimumab are approximately 52% higher than in those treated with golimumab 50 mg alone. The presence of MTX also decreases the incidence of anti-golimumab antibody from 7% to 2%.

Clinical Efficacy in RA

The efficacy of golimumab in RA was demonstrated in a 52-week, phase 2, dose-ranging study in 172 patients with active RA despite MTX therapy. Patients were randomly assigned to one of five treatment groups in approximately equal proportions: placebo, 50-mg golimumab every 4 weeks, 50-mg golimumab every 2 weeks, 100-mg golimumab every 4 weeks, or 100-mg golimumab every 2 weeks. All patients continued to receive their assigned dosage of MTX. Patients initially assigned to receive golimumab injections every 2 weeks had the interval increased to every 4 weeks starting at week 20.

The primary end point was the proportion of patients meeting the ACR20 improvement criteria at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least one of the individual dose groups were compared with placebo. A significantly greater proportion of patients in the combined golimumab plus MTX groups (61.3%; P = 0.010) and in the group receiving 100 mg golimumab every 2 weeks (79.4%; P <0.001) had an ACR20 response at week 16 compared with patients in the placebo plus MTX group (37.1%). When compared individually with the placebo group, the other three golimumab treatment groups did not show a statistically significant difference in the proportions of patients achieving an ACR20 response. However, each individual golimumab dose regimen had statistically significantly greater proportions of ACR50 responders compared with placebo. In addition, significantly greater proportions of patients in the combined golimumab plus MTX groups also achieved ACR50 (P = 0.003) and ACR70 (P = 0.028) responses at week 16 compared with the placebo plus MTX group. ACR20, ACR50, and ACR70 responses were observed as early as week 2 and were maintained through week 52, but there was no clear dose-response relationship (Figure 14-29). At week 20, patients who had been receiving golimumab injections every 2 weeks switched to injections every 4 weeks without an appreciable decrease in the proportion of ACR20 responders.

In the phase 3 GO-FORWARD study, 444 patients who had not previously received treatment with any other TNFα blocker and had moderate to severe RA despite MTX therapy were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). All patients continued to receive their background MTX therapy. Injections were administered subcutaneously every 4 weeks. The co-primary end points were the proportion of patients with 20% or greater improvement in the ACR20 criteria at week 14 and the change from baseline in the HAQ-DI score at week 24. This study was designed to include a double-blind controlled phase to week 52 and an open-label extension up to 5 years. The results through week 24 have been reported. The proportion of ACR20 responders at week 14 was 33.1% in the placebo/MTX group, 44.4% (P = 0.059) in the golimumab 100 mg/placebo group, 55.1% (P <0.001) in the golimumab 50 mg/MTX group, and 56.2% (P <0.001) in the golimumab 100 mg/MTX group (Figure 14-30). In addition, the proportions of ACR50 and ACR70 responders were significantly greater in the golimumab 50 mg/MTX and golimumab 100 mg/MTX groups compared with the placebo/MTX group (Figure 14-30). There was no clear evidence of improvement in the proportion of ACR responders with the golimumab 100-mg dose compared with the 50-mg dose. Also, in terms of ACR20 responders, golimumab 100-mg monotherapy was not statistically different from MTX monotherapy. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (P = 0.240), 0.38 (P <0.001) and 0.50 (P <0.001) in the placebo/MTX, golimumab 100-mg monotherapy, golimumab 50 mg/MTX, and golimumab 100 mg/MTX groups, respectively.

The randomized, double-blind, placebo-controlled GO-AFTER study evaluated golimumab 50 mg or 100 mg every 4 weeks in 461 patients with active RA who had been previously treated with ≥1 anti-TNFα agent which had been discontinued for any reason (58.4% lack of efficacy, 16.5% for intolerance, 39.7% other reason. Patients continued to receive stable doses of MTX, SSZ, and/or HCQ if they were receiving them at baseline. The primary end point was the proportion of patients achieving ACR20 response criteria. In addition, improvement from baseline in HAQ at week 24 was assessed. Treatment with golimumab 50 mg or 100 mg every 4 weeks resulted in significantly greater proportions of patients who achieved ACR20 and ACR50 response criteria (Table 14-12). In addition, there were significant improvements in physical function with both doses of golimumab compared with placebo.

Golimumab was also studied in 637 patients with active RA who were MTX-naïve and had not previously been treated with a biologic TNF-blocker (GO-BEFORE study). Patients were randomized to receive MTX/placebo, golimumab 100 mg/placebo, golimumab 50 mg/MTX, or golimumab 100 mg/MTX. For patients receiving MTX, MTX was administered at a dose of 10 mg/week beginning at week 0 and increased to 20 mg/week by week 8. The use of other DMARDs or other biologics was prohibited. The primary end point in this study was the percentage of patients achieving an ACR50 response at week 24. Secondary end points included ACR20 responders at week 24. The proportion of ACR50 responders was significantly (P = 0.42) greater in patients who received golimumab 50 mg plus MTX compared with those who received MTX alone (Table 14-13).

A post-hoc modified ITT analysis performed to compensate for patients who were randomized but did not receive study drug also showed that golimumab 50 mg plus MTX was significantly better that MTX alone. The number of patients with missed injections was higher in the golimumab monotherapy group (n = 14) and golimumab 100 mg/MTX group (n = 6) than in the other 2 (n = 3 in each). Despite this, a prespecified noninferiority comparison between the MTX monotherapy and golimumab monotherapy groups showed that golimumab 100-mg monotherapy was similar to MTX alone.

Emery and associates recently evaluated the effect of golimumab on radiographic progression in patients with RA who participated in the GO-BEFORE and GO-FORWARD trials (discussed above). Radiographic progression was a coprimary end point in the GO-BEFORE study and a secondary end point in the GO-FORWARD study. Radiographs of the hands and feet were taken at baseline, week 28 and week 52 in the GO-BEFORE study and at baseline, week 24 (week 16 for patients who entered early escape) and week 52 in the GO-FORWARD study. Radiographs were scored by two independent readers in each study using modified Sharp scores.

In the GO-BEFORE study, golimumab in combination with MTX inhibited radiographic progression significantly better than MTX therapy alone (Figure 14-31). The difference in radiographic progression between the golimumab and MTX monotherapy groups, however, was not statistically significant. In the GO-FORWARD study, the comparator phase continued through week 24 and in patients who entered early escape, their modified Sharp score at week 24 was extrapolated linearly from the baseline and week 16 values. Overall, minimal progression was observed in all treatment groups during this phase (Figure 14-32), and the differences in the changes in modified Sharp scores from baseline between the golimumab and placebo groups were not statistically significant.

The benefits of the combination of golimumab plus MTX were comparable for the 50-mg and 100-mg dosage groups. The authors note that these findings may have been attributable to the limitations of the study design and the inclusion/exclusion criteria. First, since radiographic outcomes were only secondary end points in this study, they were not considered in the power calculation assumptions. Second, an elevated CRP level was not required for study entry, and only one third of patients in this study had CRP levels that were ≥1.5 mg/dL. Patients with low CRP levels are known to have less radiographic progression over time than those with high CRP levels. Given the low overall progression rate and the short 16-week time period in patients who entered early escape, linear extrapolation from week 16 to week 24 may have underestimated the true progression that these patients would have shown without adjustment in the medication regimen.

The efficacy and safety of intravenous golimumab were assessed in a 48-week, randomized, double-blind, phase 3 trial in 643 patients in whom RA remained active despite MTX treatment. Nearly half of the study participants (49%) had been receiving MTX therapy for RA for 3 years, and the overall median MTX dosage among patients assigned to treatment with golimumab plus MTX was 15 mg/week. Eighty percent of the patients were female, the average disease duration was >8 years and the median age was 51 years. Approximately 5% of the randomized patients had received infliximab (n = 36), etanercept (n = 9) and/or adalimumab (n = 36) prior to study participation. Patients were randomized to receive IV infusions of placebo plus MTX or IV infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. The primary end point was the proportion of patients achieving an ACR50 response at week 14. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24).

Similar proportions of patients across the treatment groups (80% to 90%) completed the study through week 48. At week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX (P = 0.051). Thus, the primary efficacy end point was not met. By week 24, significantly more patients treated with golimumab plus MTX achieved an ACR50 response compared with patients treated with placebo plus MTX (22% vs 9%; P = 0.002). Treatment with golimumab at a dose of 4 mg/kg plus MTX resulted in an increased proportion of patients achieving an ACR50 response at week 24 compared with week 14.

The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). Among the patients for whom appropriate samples were available, antibodies to golimumab were detected in 27 of 529 golimumab-treated patients (5%) through week 24 with higher proportions in patients receiving golimumab monotherapy compared with those who received golimumab plus MTX. The incidence of infusion reactions among all golimumab-treated patients through week 48 was 4, compared with 5% in patients treated with placebo plus MTX. None of the antibody-positive patients had an infusion reaction through week 24.

The efficacy and safety of intravenous golimumab was also evaluated in a 52-week, double-blind, placebo-controlled, phase 3 study in patients with active RA despite MTX therapy (GO-FURTHER study). 592 patients were randomized to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and every 8 weeks. All patients continued to receive their stable MTX regimen. Patients initially receiving placebo who had a <10% improvement in combined swollen/tender joint counts at week 16 could switch to intravenous golimumab 2 mg/kg (early escape), while the rest of the patients crossed over at week 24. The primary endpoint was the proportion of patients meeting the ACR20 improvement criteria at week 14, which was seen in a significantly greater proportion of patients in the combined golimumab plus MTX group compared with the placebo plus MTX group (59% vs 25%; P <0.001).

Improvements in the golimumab plus MTX group over the placebo plus MTX group were observed as early as week 2 (Figure 14-33). Importantly, approximately 80% of patients receiving golimumab plus MTX who achieved ACR20 responses by week 24 maintained these responses at week 52. Similar proportions of patients receiving golimumab plus MTX and placebo plus MTX reported adverse events through week 16. Serious adverse events were reported by more golimumab plus MTX patients than placebo plus MTX patients (4.1% vs 2.0%) at week 24. This study showed that the addition of intravenous golimumab rapidly and significantly improved signs and symptoms in patients with active RA, despite ongoing MTX, as early as week 2, and were sustained up to 1 year.

The GO-FURTHER study also assessed radiographic outcomes up to 1 year in patients receiving intravenous golimumab who had active RA despite MTX therapy. Radiographs of the hands and feet were measured at weeks 0, 24 and 52, using van der Heijde-Sharp (vdH-S) scoring. Significant and rapid clinical improvement was observed up to week 24 of intravenous golimumab therapy. Patients in the golimumab plus MTX group demonstrated less radiographic progression than placebo-treated patients at week 24 (vdH-S mean change 0.03 vs 1.09; P <0.001) and week 52 (0.13 vs 1.22; P = 0.001). Between week 24 and week 52, patients initially assigned to receive golimumab plus MTX generally demonstrated minimal change in total vdH-S score, indicating little radiographic progression. The GO-FURTHER trial showed that in addition to sustained clinical outcomes, intravenously administered golimumab appears to significantly inhibit radiographic progression up to 1 year of treatment.

Safety in RA

The adverse events seen with golimumab treatment also have been observed with other anti-TNF agents. Since golimumab was approved and released commercially just months before this was written, the following discussion is based primarily on the safety information from five pooled, randomized, double-blind, controlled phase 3 trials in patients with RA, psoriatic arthritis and ankylosing spondylitis that included 639 control-treated patients and 1659 golimumab-treated patients (1,089 with RA).

The most common adverse events reported in these controlled trials were upper respiratory tract infections (7% of golimumab-treated patients vs 6% of control-treated patients) and nasopharyngitis (6% of golimumab-treated patients vs 5% of control-treated patients). Serious infections, including sepsis, pneumonia, cellulitis, abscess, TB, invasive fungal infections and hepatitis B infection) occurred in 1.4% of golimumab-treated patients and 1.3% of control-treated patients. The incidences of such serious infections were 5.4 per 100 patient-years of follow-up with golimumab and 5.3 per 100 patient-years with control treatment. A total of 2% of patients in the golimumab groups and 3% of those in the control groups discontinued treatment due to an adverse event. The most common adverse reactions leading to discontinuation of golimumab were sepsis (0.2%), increased alanine aminotransferase (0.2%) and increased aspartate aminotransferase (0.2%).

Since golimumab is administered subcutaneously, as are several other anti-TNF agents, ISRs would be expected. In these controlled trials, 6% of golimumab-treated patients experienced ISRs compared with 2% of control-treated patients. The majority of the ISRs (most frequently injection site erythema) were mild and did not result in discontinuation of therapy.

Among the 2,347 golimumab-treated patients and 674 placebo-treated patients who participated in all controlled and uncontrolled clinical trials, the incidences of active TB were 0.23 and 0 per 100 patient-years, respectively. The overwhelming majority of these TB cases occurred in countries with a high incidence rate of TB. The risk of TB may be reduced by avoiding anti-TNF agents, including golimumab, in patients with a history of TB or opportunistic infection and in those with a positive PPD test in whom the condition has not been treated.

There have been reports of severe hepatic reactions, including acute liver failure, in patients receiving TNF-blockers. In controlled phase 3 trials with golimumab, ALT elevations ≥5 times the upper limits of normal occurred in 0.2% of control-treated patients and 0.7% of golimumab-treated patients and ALT elevations ≥3 times the upper limits of normal occurred in 2% of control-treated patients and 2% of golimumab-treated patients. Since many of the patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between golimumab and liver enzyme elevation is not clear.

As noted previously, there have been reports of a higher incidence of lymphomas among patients treated with anti-TNF agents compared to those treated with placebo. During the controlled portions of trials with golimumab, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 among patients treated with golimumab compared with an incidence of 0 in the placebo groups. Among the total of 2347 golimumab-treated patients with a median follow-up of 1.4 years in the controlled and uncontrolled portions of these clinical trials, the incidence of lymphoma was 3.8-fold higher than expected in the general US population, according to the SEER database.

The incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not higher among all golimumab-treated patients compared with those who received placebo. The incidence of malignancies other than lymphoma among golimumab-treated patients was similar to that expected in the general US population, according to the SEER database.

Antibodies to golimumab were detected in 57 (4%) of golimumab-treated patients and included all phase 3 trials. The incidence of such antibodies was lower in patients who received concomitant MTX compared with those who received golimumab without MTX (approximately 2% vs 7%, respectively). The use of TNF-blockers has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In these trials, there was no association of golimumab treatment and the development of newly positive anti-dsDNA antibodies.

Golimumab therapy does not affect the immune responses of vaccination, allowing pneumococcal and influenza vaccination. However, since vaccination with live viruses has not been studied, it should be avoided.

Biosimilars Approved for RA

Biologic medicines account for a significant share of the pharmaceutical market and by 2020 were projected to comprise up to 28% of the global market. Once patent protections expire for the currently marketed biologics, competing manufacturers gain the right to develop their own versions of these medicines. These biosimilar products—also known as follow-on-biologics or subsequent entry biologics—are similar, but not identical, to their originator products.

As per the FDA definition, a biosimilar product is a biological product approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable. A biosimilar product will only be approved by the FDA if it has the same mechanism(s) of action (if known), route(s) of administration, dosage form(s) and strength(s) as the reference product and only for the indication(s) and condition(s) of use that have been approved for the reference product.

As of June 2023, 41 biosimilar medicines have been approved in the United States, of which 15 are indicated for the treatment of patients with RA: the Remicade (infliximab) biosimilars Inflectra, Renflexis, Ixifi and Avsola; the Enbrel (etanercept) biosimilars Erelzi and Eticovo; and the Humira (adalimumab) biosimilars Amjevita, Cyltezo, Hyrimoz, Hadlima, Abrilada, Hulio, Yusimry, Idacio, and Yuflyma.

Inflectra (Remicade Biosimilar)

In April 2016, the FDA approved Inflectra (infliximab-dyyb) across all eligible indications of Remicade, making it the second biosimilar to be approved in the United States, following Zarxio. The approval was based on a comprehensive package of analytical, nonclinical and clinical data confirming that Inflectra is highly similar to the US-licensed reference product.

Among the supporting evidence was data from PLANETRA, a 54-week clinical trial that evaluated the similarity of infliximab-dyyb compared to infliximab in adult patients with active RA and an inadequate response to methotrexate. Patients were randomized 1:1 to receive either 3 mg/kg of infliximab-dyyb or infliximab via intravenous infusion at weeks 0, 2 and 6, followed by an additional six infusions every 8 weeks until week 54. The primary endpoint was ACR20 (≥20% improvement in the American College of Rheumatology Criteria assessment) response rate at week 30. Treatments were concluded to have equivalent efficacy if the 95% CI for the treatment difference was within ±15%. The trial also assessed ACR50, ACR70, DAS28, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and EULAR response rates, patient-reported outcomes and joint damage progression (JDP).

PLANETRA demonstrated comparable efficacy results for infliximab-dyyb and infliximab up to week 54, with no statistical differences observed for any efficacy endpoint. For the primary endpoint, 74.7% of infliximab-dyyb-treated patients met the ACR20 endpoint at week 30 compared to 71.3% of infliximab-treated patients. JDP was assessed in the 336 patients that had radiographs at both baseline and at week 54. The mean change from baseline to week 54 in JDP was comparable between treatment groups, in terms of total Sharp score, joint space narrowing score and erosion score. Immunogenicity, safety and pharmacokinetic/dynamic findings were also comparable between treatments. Overall, PLANETRA demonstrated that infliximab and its biosimilar, infliximab-dyyb, are comparable in all assessed safety and efficacy parameters for up to 54 weeks.

Patients who completed the 54-week study were invited to enter the extension study for an additional 1 year of treatment. Of the 455 patients who completed PLANETRA, 301 were treated in the extension. Patients who previously received infliximab-dyyb continued with this treatment (the maintenance group). To assess the safety and efficacy of switching to the biosimilar, all patients previously treated with infliximab were switched to infliximab-dyyb (the switch group). ACR20, ACR50 and ACR70 response rates were maintained throughout the extension period, with no differences between switch and maintenance groups at week 78 or 102. Additionally, switching was not associated with detrimental effects on safety, immunogenicity, or any other efficacy endpoint. In the maintenance group, treatment with infliximab-dyyb remained efficacious and well tolerated.

Overall, PLANETRA and its extension study demonstrated that infliximab-dyyb was efficacious and well tolerated over a 2-year treatment period in patients with RA and an inadequate response to methotrexate and that switching from infliximab to infliximab-dyyb was not associated with detrimental effects.

Renflexis (Remicade Biosimilar)

The second infliximab biosimilar, Renflexis (infliximab-abda), was approved by the FDA in April 2017 across the same indications as the originator, including Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, RA in combination with MTX, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. Infliximab-abda has the same dosing, boxed warnings and warnings and precautions as infliximab and infliximab-dyyb.

The clinical equivalence between infliximab-abda and infliximab was assessed in a phase III study (CT01936181) that enrolled patients with moderate to severe RA despite MTX treatment. Eligible patients were 18-75 years of age and had RA for at least 6 months, with at least six tender joints and swollen joints and an ESR rate of ≥28 mm/h or a CRP of ≥1.0 mg/dL. Patients were required to have taken MTX for at least 6 months, with stable doses for at least 4 weeks prior to randomization. Patients were randomized 1:1 to receive either infliximab-abda (n = 291) or infliximab (n = 293) 3 mg/kg intravenously, with dosing at weeks 0, 2, 6, 14, 22, 30, 38 and 46. Dose increases were permitted from week 30 by 1.5 mg/kg per visit, up to a total of 7.5 mg/kg. During the trial, MTX was given weekly with folic acid; other DMARDS were prohibited. The primary endpoint was ACR20 response at week 30. Secondary efficacy endpoints included ACR50, ACR70, DAS28-ESR and EULAR response.

At week 30, ACR20 response was 64.1% for infliximab-abda and 66.0% for infliximab, with a 95% CI for the rate difference of -10.26% to 6.51%, which was within the prespecified equivalence margin of ±15%. Comparable results were also observed for ACR50 and ACR70 response. Improvement in DAS28 at each visit was similar between groups; at week 30, the proportion of patients with low disease activity was 11.1% for infliximab-abda and 9.8% for infliximab and for remission it was 14.6% vs 15.9%. Safety, immunogenicity and PK profiles were also comparable between treatments.

Overall, this phase III trial demonstrated clinical equivalence between infliximab-abda and infliximab at week 30, with results comparable to those from the PLANETRA study for infliximab-dyyb.

Ixifi (Remicade Biosimilar)

The third infliximab biosimilar to receive FDA approval was Ixifi (infliximab-qbtx), approved in December 2017 for the treatment of RA, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. Infliximab-qbtx, in combination with MTX, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA.

The approval of infliximab-qbtx was based on comprehensive data package demonstrating similarity to the reference infliximab. In the REFLECTIONS B537-02 trial, a total of 650 patients with active RA were randomized (1:1) to receive either infliximab-qbtx or the reference infliximab. The primary endpoint was the ACR20 response at week 14. The primary endpoint (with nonresponder imputation) was achieved by 61.1% of patients in the infliximab-qbtx group and 63.5% of patients in the reference infliximab group (treatment difference -2.39%; 95% CI -9.92% to 5.11%), which fell within the statistical equivalence margin (95% CI for treatment difference of ±13.5%). Secondary efficacy endpoint results and safety and immunogenicity profiles were all comparable between the two groups. At week 30, patients in the reference infliximab group were re-randomized (1:1) to continue reference infliximab or switch to infliximab-qbtx. The results remained comparable through week 54, with similar rates of ACR20 (71.1% in the infliximab-qbtx group, 64.3% in the reference infliximab group, and 70.6% in the reference infliximab to infliximab-qbtx switch group) and secondary endpoints, as well as a comparable safety profile.

Avsola (Remicade Biosimilar)

In December 2019, the FDA approved another infliximab biosimilar, Avsola (infliximab-axxq), for use in patients with RA, Crohn’s Disease, ulcerative colitis, plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. Infliximab-axxq is indicated, in combination with MTX, for reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active RA.

The FDA approved infliximab-axxq based on the totality of data demonstrating pharmacokinetic similarity in healthy subjects and efficacy and safety equivalence to the reference infliximab. The efficacy and safety comparison trial randomized (1:1) 558 patients with active RA to either infliximab-axxq or the reference infliximab.The primary endpoint was the ACR20 response difference at week 22. In the infliximab-axxq group, 68.1% of patients achieved the primary endpoint, compared to 59.1% of patients in the reference infliximab group, for a treatment difference of 9.37% (90% CI, 2.67% to 15.96%). The lower 90% CI bound fell within the pre-specific equivalence criteria of 90% CI of ±15%, demonstrating noninferiority. The two groups were also comparable with respect to secondary efficacy endpoint achievement rates and safety and immunogenicity profiles.

Erelzi (Enbrel Biosimilar)

In August 2016, Erelzi (etanercept-szzs) was approved across all indications of Enbrel based on a comprehensive package of data confirming similarity to its reference product. Support for its approval included data from the EGALITY clinical trial.

EGALITY was a 52-week trial that enrolled 531 adult patients with active, but clinically stable, chronic 5plaque psoriasis. The trial consisted of three treatment periods. In treatment period 1 (weeks 0 to 12), patients were randomized 1:1 to self-administer 50 mg of etanercept or etanercept-szzs subcutaneously, twice weekly. In treatment period 2 (weeks 13 to 30), patients who achieved ≥50% improvement in the Psoriasis Area and Severity Index (PASI 50) at week 12 were re-randomized to either continue with their same treatment on a once-weekly dosing schedule, or undergo treatment switches between etanercept and etanercept-szzs every 6 weeks until week 30. During treatment period 3 (extension phase, weeks 31 to 52), patients continued with the last treatment they received during the final 6 weeks of treatment period 2.

The primary endpoint of the trial was the proportion of patients showing ≥75% improvement in PASI score from their baseline visit (PASI 75 response rate) at week 12. The main secondary endpoint was the percentage change in PASI score from baseline to week 12. Other efficacy, pharmacokinetic, safety and immunogenicity assessments were also performed.

At week 12, 73.4% of etanercept-szzs–treated patients and 75.7% of etanercept-treated patients met the PASI 75 endpoint (treatment difference, -2.3%; 95% CI, -9.85 to 5.30). Since the 95% CI fell within the prespecified interval of ±18%, this demonstrated therapeutic equivalence between treatments. The mean change in PASI score from baseline to week 12 was also comparable between treatments. Similarly, no clinically meaningful differences in other efficacy measures, safety, or immunogenicity were observed between etanercept and etanercept-szzs for up to 52 weeks of treatment.

Overall, the EGALITY study demonstrated the biosimilarity of etanercept-szzs to its reference product in patients with moderate to severe chronic plaque psoriasis. These results were extrapolated to support the approval of Erelzi across all indications of Enbrel, including the treatment of patients with RA.

The EQUIRA trial tested the effects of switching from reference etanercept to etanercept-szzs after 24 weeks of treatment. After another 24 weeks (at trial week 48), no significant differences in efficacy, safety, or immunogenicity were found between the switch group (24 weeks of reference etanercept followed by 24 weeks of etanercept-szzs) and the non-switch group (48 weeks of etanercept-szzs).

Eticovo (Enbrel Biosimilar)

The second etanercept biosimilar, Eticovo (etanercept-ykro) received FDA approval in April 2019 for the treatment of RA, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis and polyarticular juvenile idiopathic arthritis. Etanercept-ykro is indicated, alone or in combination with MTX, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA.

The safety and efficacy of etanercept-ykro was established in a phase 3 trial which randomized (1:1) 596 patients with active RA to either etanercept-ykro or the reference etanercept. The primary endpoint was the ACR20 response at week 24. Etanercept-ykro demonstrated therapeutic equivalence to the reference etanercept, with ACR20 rates of 78.1% and 80.3%, respectively (adjusted treatment difference -2.2%; 95% CI, -9.41% to 4.98%; pre-specified equivalence margin, 95% CI of ±15%). The secondary efficacy endpoint rates and the safety profile were similar, while immunogenicity was numerically lower with etanercept-ykro (0.7%) compared to the reference etanercept (13.1%). Efficacy remained comparable at week 52, with ACR20 rates of 80.8% and 81.5% in the etanercept-ykro and the reference etanercept group, respectively.⁸⁹ The safety profile was also similar at week 52 and immunogenicity rates remained numerically lower in the with etanercept-ykro group (1.0%) than in the reference etanercept group (13.2%).

Amjevita (Humira Biosimilar)

Following the approval of Inflectra and Erelzi, Amjevita (adalimumab-atto) was approved across all eligible indications of Humira in September 2016. Its approval was based on a comprehensive data package, including results from two phase 3 studies conducted in patients with moderate-to-severe plaque psoriasis or moderate-to-severe RA.

The phase 3 study that enrolled patients with moderate-to-severe RA was a head-to-head study evaluating the safety, efficacy and immunogenicity of adalimumab-atto with adalimumab in adult patients with an inadequate response to methotrexate. Patients were randomized 1:1 to receive either 40 mg of adalimumab-atto or adalimumab every 2 weeks until week 22, followed by a safety follow-up period until week 26. The primary endpoint of the trial was the risk ratio of ACR20 at week 24. Key secondary endpoints included ACR50, ACR70, safety and immunogenicity.

At week 24, 74.6% of adalimumab-atto-treated patients and 72.4% of adalimumab-treated patients met the ACR20 response criteria. The risk ratio of ACR20 was 1.039, with a two-sided 90% CI of 0.954-1.133, falling within the predefined equivalence margin of 0.738-1.355. At week 24, a similar proportion of patients also achieved ACR50 (49.2% vs 52% for adalimumab) and ACR70 (26% vs 22.9% for adalimumab). Overall safety, including incidence of treatment-emergent adverse events and immunogenicity were also similar between treatment groups, thus successfully demonstrating the equivalence between adalimumab-atto and its reference product.

Cyltezo (Humira Biosimilar)

The second adalimumab biosimilar to receive FDA approval was Cyltezo (adalimumab-adbm), initially approved in August 2017 for RA, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis and plaque psoriasis. In October 2021, the FDA classified adalimumab-adbm as the first (and to date, the only) adalimumab biosimilar interchangeable with the reference product. Interchangeability means that patients may switch from the reference product to the biosimilar without an intervention from the prescribing healthcare provider. Adalimumab-adbm is indicated, alone or in combination with MTX or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active RA.

The clinical equivalence of adalimumab-adbm to the reference adalimumab was established in VOLTAIRE-RA, a phase 3 trial which randomized (1:1) 645 patients with active RA to these two products. The co-primary endpoints were the ACR20 responses at week 12 and week 24. At week 12, ACR20 was achieved by 67.0% of patients in the adalimumab-adbm group and 61.1% of patients in the reference adalimumab group (treatment difference, 5.9%; 90% CI, -0.9% to 12.7%; pre-specified equivalence margin 90% CI -12% to 15%). At week 24, 69.0% of patients in the adalimumab-adbm group and 64.5% in the reference adalimumab group achieved ACR20 (treatment difference, 4.5%; 95% CI, -3.4% to 12.5%; pre-specified equivalence margin 95% CI ±15%). Secondary efficacy endpoints, safety and immunogenicity were similar across treatment groups.

Adalimumab-adbm received the FDA designation of interchangeable biosimilar on the basis of results from VOLTAIRE-X, a trial in patients with plaque psoriasis that assessed the impact of multiple switches between adalimumab-adbm and the reference adalimumab on pharmacokinetics, safety and immunogenicity. After a 14-week run-in period in which all patients received the reference adalimumab (last dose at week 12), a total of 238 patients were randomized (1:1) to either continuous reference adalimumab or the switching arm (adalimumab-adbm on weeks 14 and 16, reference adalimumab on weeks 18 and 20 and adalimumab-adbm every other week from week 22 to 48). The area under the plasma concentration–time curve (AUCτ) and maximum observed drug plasma concentration (Cmax) at weeks 30-32 were the primary endpoints. The point estimate for the adjusted mean ratio of switching and continuous treatment was 105.2% for AUCτ was (90.2% CI, 96.6% to 114.6%) and 101.1% for Cmax (90.2% CI, 93.3% to 109.7%), which fell within the predefined 90.2% CI bioequivalence range of 80.0-125.0%. Safety and immunogenicity were similar across the two groups.

Hyrimoz (Humira Biosimilar)

The adalimumab biosimilar Hyrimoz (adalimumab-adaz) received FDA approval in October 2018 for the treatment of RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis and plaque psoriasis. Adalimumab-adaz is indicated, alone or in combination with MTX or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.

Adalimumab-adaz was approved on the basis of a comprehensive data package demonstrating similarity to the reference product. This data package included the ADACCESS study, which showed equivalent efficacy in the treatment of plaque psoriasis and comparable safety and immunogenicity between adalimumab-adaz and the reference adalimumab. Efficacy equivalence for the treatment of RA was demonstrated in the ADMYRA trial, in which 353 patients with active RA were randomized to adalimumab-adaz or the reference adalimumab, and the primary endpoint (change from baseline in DAS28-CRP) assessed at week 12. Patients in the adalimumab-adaz group showed a DAS28-CRP score change of -2.16 compared to -2.18 in the reference adalimumab group (treatment difference, 0.02%; 95% CI, -0.24 to 0.27), which was within the pre-specified equivalence margin (95% CI ±0.6).).

Hadlima (Humira Biosimilar)

In July 2019, the FDA approved the adalimumab biosimilar Hadlima (adalimumab-bwwd) for the treatment of RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis and plaque psoriasis. Adalimumab-bwwd, used alone or in combination with MTX or other non-biologic DMARDs, is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.

The approval of adalimumab-bwwd was based on data from a phase 3 trial in which 544 patients with active RA were randomized (1:1) to adalimumab-bwwd or the reference adalimumab. The primary endpoint was the ACR20 rate at week 24. In the adalimumab-bwwd group, 72.4% of patients achieved ACR20 at week 24, compared to 72.2% in the reference adalimumab group. The 95% confidence interval (-7.83% to 8.13%) for the treatment difference (0.1%) was within the pre-specified equivalence margin (±15%). Adalimumab-bwwd was also comparable to the reference product with respect to secondary efficacy endpoints, safety, pharmacokinetic data and immunogenicity.

Abrilada (Humira Biosimilar)

Abrilada (adalimumab-afzb) is another adalimumab biosimilar. It received FDA approval in November 2019 for the treatment of RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis and plaque psoriasis. Adalimumab-afzb is indicated, alone or in combination with MTX or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active RA.

The comprehensive data package that served as a basis for FDA approval of adalimumab-afzb included data from the REFLECTIONS B538-02 trial. This clinical comparative study randomized (1:1) 597 patients with active RA to adalimumab-afzb or the reference adalimumab and assessed the ACR20 response at week 12 as the primary endpoint. The ACR20 rates were 68.7% and 72.7% in the adalimumab-afzb and the reference adalimumab group, respectively. The non-responder imputation adjusted treatment difference was -2.98%, with a 95% CI of -10.38% to 4.44%, within the pre-specified equivalence margin of ±14%. Secondary efficacy endpoints were similar in the two groups, as were the safety and immunogenicity profiles.

Hulio (Humira Biosimilar)

The sixth adalimumab biosimilar to receive FDA approval, Hulio (adalimumab-fkjp) was approved in July 2020 for RA, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, ulcerative colitis and plaque psoriasis. Adalimumab-fkjp is indicated, alone or in combination with MTX or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA.

Approval of adalimumab-fkjp was based on results from the comparative efficacy study ARABESC. In this trial, a total of 730 patients with active RA were randomized (1:1) to adalimumab-fkjp or the reference adalimumab and the primary endpoint was the ACR20 response at week 24. In the adalimumab-fkjp group, 74.1% of patients achieved ACR20, compared to 75.7% in the reference product group. The 95% CI for the treatment difference was -7.9 to 4.7%, within the pre-specified symmetric equivalence margin of ±13%, while the 90% CI was -7.3 to 3.6%, also falling within the pre-specified asymmetric equivalence margin of -12% to 15%. Other efficacy endpoints were similar between the two groups, as were the safety and immunogenicity profiles. Efficacy was maintained in the open-label period from week 24 to week 54.

Yusimry (Humira Biosimilar)

Yusimry (adalimumab-aqvh) is an adalimumab biosimilar which was approved by the FDA in December 2021 for the treatment of RA, plaque psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Crohn disease and ulcerative colitis. Adalimumab-aqvh, as monotherapy or in combination with MTX and other non-biologic DMARDs, is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA.

Adalimumab-aqvh received approval on the basis of pharmacokinetic data from a study in healthy subjects and PsOsim, a safety and efficacy comparative trial of adalimumab-aqvh and the reference adalimumab in patients with plaque psoriasis.

Idacio (Humira Biosimilar)

In December 2022, the FDA granted approval to Idacio (adalimumab-aacf) for the treatment of RA, plaque psoriasis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, ankylosing spondylitis and juvenile idiopathic arthritis. Adalimumab-aacf is indicated, alone or in combination with MTX or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA.

The approval of adalimumab-aacf was based on a comprehensive data package comparing its pharmacokinetic, efficacy, safety and immunogenicity properties to the reference adalimumab.

Yuflyma (Humira Biosimilar)

Yuflyma (adalimumab-aaty) received FDA approval for the treatment of RA and other inflammatory diseases including juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis and hidradenitis suppurativa, in May 2023, becoming the ninth and most recent adalimumab biosimilar to be approved. Adalimumab-aaty is indicated, alone or in combination with MTX or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA.

Adalimumab-aaty was approved on the basis of a comprehensive data package, which included results from a phase 3 comparative efficacy and safety trial. A total of 648 patients with active RA were randomized (1:1) to either adalimumab-aaty or the reference adalimumab. The primary endpoint was the ACR20 response at week 24. The same percentage (82.7%) of patients achieved ACR20 at week 24 in both groups. The 95% CI (-5.94% to 5.94%) and the 20% CI (-4.98% to 4.98%) were within the pre-specified equivalence margins of ±15% and -12% to 15%, respectively. Other efficacy and safety endpoints were comparable between the two groups, while immunogenicity was slightly numerically lower in the adalimumab-aaty group.

Discontinuation of TNF Blockers

Treatment with TNF blockers is expensive and has a possible risk of adverse events. Therefore, discontinuation of TNF blockers once the treatment goal has been achieved could be beneficial for both society and individual patients. However, there are no guidelines regarding cessation of therapy. Therefore, there is a need for markers predictive of sustained remission following cessation of TNF blocker therapy. Several studies have assessed the outcomes of discontinuation of TNF blocker treatment, as well as identifying factors predictive of successfully sustaining low disease activity after the cessation.

Brocq and associates assessed the time to relapse after discontinuation of TNF blocker treatment in 21 patients in remission (DAS28 <2.6) for at least 6 months. The mean age was 61 years, mean disease duration of 11.3 years and mean remission duration of 19.2 months. The TNF antagonist was infliximab in two patients, adalimumab in five and etanercept in 14; and 14 patients were taking a concomitant DMARD. Nine patients were still in remission after 6 months and five patients still in remission after 12 months. Compared with the patients who relapsed, the relapse-free patients had a longer time on TNF antagonist therapy (56 months vs 35 months, P = 0.012) and a longer time in remission on TNF antagonist therapy (35 months vs 14.5 months, P = 0.04). The patients who relapsed consistently achieved a remission after resuming the same TNF antagonist therapy.

Saleem and coworkers analyzed the clinical course of 47 patients in whom anti-TNF therapy was discontinued. Of these patients, 27 had received initial treatment and 20 delayed treatment with TNF-blocking drugs. Two years after stopping TNF blocker therapy, the main predictor of successful cessation was timing of treatment initiation; 59% of patients in the initial treatment group sustained remission compared with 15% in the delayed treatment group (P = 0.003). Within the initial treatment group, secondary analysis showed that the only clinical predictor of successful cessation of treatment was shorter symptom duration before receiving treatment (median 5.5 months vs 9 months; P = 0.008). No other clinical features were associated with successful cessation of therapy. Several immunological parameters were significantly associated with sustained remission, including abnormal differentiation subset of T cells and regulatory T cells. Similar nonsignificant trends were observed in the delayed treatment group

Tanaka and coworkers assessed the effects of discontinuation of infliximab in 114 patients with early or long-established RA who had maintained LDA (DAS28 <3.2) for >24 weeks. The mean disease duration was 5.9 years, mean DAS28 = 5.5 and mean mTSS = 63.3. After maintaining LDA for >24 weeks, infliximab was discontinued and concomitant use of MTX was started in all patients (dose determined by each attending physician). Of the 102 patients evaluable at 1 year, 56 (55%) maintained at least LDA, while disease activity flared in 46 (45%) patients. Considering only the 83 (81.4%) patients who had been in clinical remission (DAS28 <2.6) prior to discontinuation of infliximab, 39 (47%) remained in remission after 1 year. The estimated yearly progression of mTSS (ΔTSS) was lower among patients who maintained their initial clinical response compared with those who experienced a worsening (0.3 vs 1.6, respectively).

A post-hoc analysis of the BeSt study (discussed previously) examined changes in disease activity and joint damage progression in the subgroup of 104 patients in whom infliximab was discontinued. Of these patients, 77 were from the initial infliximab monotherapy group and 27 received infliximab plus MTX as initial treatment. Infliximab was discontinued after achieving low disease activity (DAS ≤2.4) for 6 months. Mean DAS at the time of infliximab cessation was 1.3, median symptom duration was 23 months, and median mTSS was 5.5. The median infliximab treatment duration was 11 months. These patients were followed for a median of 7.2 years. Of these 104 patients treated with infliximab in the BeSt study, 45% able to discontinue infliximab; the majority (80%) of these patients could stop for at least 1 year and 52% did not restart during a median follow-up of 7.2 years. Infliximab was restarted after loss of low disease activity in 48% patients after a median of 17 months. After reintroduction of infliximab, 84% of these patients again achieved a DAS ≤2.4. During the year after infliximab cessation, significant joint damage progression was rare, regardless of disease flare.