Biologic response modifiers

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The introduction of biologics is the latest advance in the treatment of RA, and one that has significantly broadened and improved the drug treatment options for patients. These treatments also fall under the category of disease-modifying anti-rheumatic drugs (DMARDs) because they can change or modify the disease course in RA and slow or prevent damage to joints and related structures. However, unlike conventional DMARDs, newer biologics specifically target certain key immune system cells and chemicals (specifically cytokines) that play an important role in the autoimmune response involved in RA.1,2

Biologics used in RA are proteins that come from human genes. In contrast to conventional DMARD treatments, which act on the immune system as a whole, biologics are engineered to target specific molecules on immune system cells, such as receptors on T- or B-cells, to block the actions of these cells and, thereby, dampen the out-of-control inflammatory process that characterizes an autoimmune disease like RA.2

There are several types of biologics currently available to treat RA. They are classified according to which molecules they target and include2-4:

  • Tumor Necrosis factor (TNF)-inhibitors (also called anti-TNF agents)
  • B-cell inhibitors
  • T-cell inhibitors
  • Interleukin-6 (IL-6) inhibitors
  • Interleukin-1 (IL-1) inhibitors
  • Janus kinase (JAK) inhibitors

 

TNF-inhibitors are the largest groups of biologics now available to treat RA and include etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), certolizumab (Cimzia), and golimumab (Simpon). Toclizumab (Actemra) is an IL-6 inhibitor, rituximab (Rituxan) is a B-cell inhibitor, abatacept (Orencia) is a T-cell inhibitor, anakinra (Kineret) is a IL-1 inhibitor, and, the newest biologic in RA tofacitinib (Xeljanz) is a JAK inhibitor.2,5

 

Biologics used in RA

Type
Agent
How it works
TNF-inhibitors
Recombinant human IgG1 monoclonal antibody
Soluble TNF-receptor fusion protein
Chimeric IgG1 anti-TNF-α antibody
Recombinant humanized fragment of TNF-antibody coupled with polyethylene glycol
Recombinant human IgG1 monoclonal antibody specific for TNF-α
Interleukin-6 inhibitor
Recombinant humanized IL-6 receptor monoclonal antibody
B-cell inhibitor
Monoclonal antibody targeting cells bearing CD20 surface marker
T-cell costimulation inhibitor
Immunoglobulin fused to the extracellular domain of cytoxic T-cell antigen
Interleukin-1 inhibitor
Recombinant human IL-1 receptor antagonist
JAK inhibitor
Janus kinase inhibitor

 

To learn more about any of the biologics included in this table, click on the name of the agent.

 

How are biologics used in RA?

Evidence from clinical trials supports the use of biologics in four scenarios2:

  • For prevention of RA
  • As first-line treatment in early active RA
  • After failure of methotrexate or other conventional DMARDs
  • After failure of one type of biologic (typically TNF-inhibitors are used first)

 

Several guidelines have been published in North America and Europe to ensure the most effective and cost effective use of biologics in RA. These guidelines, published by groups including the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), are based on careful systematic reviews of existing studies and share some common conclusions about the use of biologic treatments in RA. These state that treatment with biologics2:

  • Should be reserved for patients with active disease who do not respond to methotrexate and other conventional DMARDs
  • Should preferably be given in combination with methotrexate and, potentially, other conventional DMARDs
  • Should start with the most established agents, which are TNF-inhibitors, and, if these agents fail, other biologics should be used with the goal of achieving disease control

 

When should I start on a biologic treatment?

As stated above, the decision of whether to use a biologic to treat RA is a complex one that depends on several factors, including how active your disease is, whether you have already tried other conventional treatments that are considered the first option in RA treatment, and cost considerations. You and your doctor will work together to determine when and if a biologic treatment is appropriate for you. Given the high cost of biologic treatments, at present these drugs typically make sense in early RA only if other treatments fail to control the disease. As RA becomes established and disease control becomes more difficult to achieve, the case for using biologics becomes stronger on both a clinical and economic basis.2

 

How do different biologics compare?

There have been no head-to-head trials of biologic treatment in RA and it is difficult to compare results from different trials due to differences in patient groups involved (patients vary from trial to trial in severity and duration of disease). However, there have been some systematic comparisons of results from existing randomized, controlled clinical trials of different biologics. One review considered five different biologics, infliximab, rituximab, etanercept, adalimumab, and abatacept.6 All of these agents were significantly more effective than placebo in achieving disease control, defined as the rate of ACR50 response (the percentage of patients who improved by 50% in ACR disease activity criteria). There were no significant differences between individual biologics in terms of rates of ACR50 response. However, when individual agents were compared, some were more likely than others to result in this level of disease control.2

The table below also reflects results from another analysis conducted by the Agency for Healthcare Research and Quality (AHRQ), an agency within the US Department of Health and Human Services, comparing the relative effectiveness of different biologics in RA on the basis of existing data. Although not all available biologics were included and the results do not reflect head-to-head comparative trials, these results do give us a sense of the relative efficacy of these agents.3

 

Biologic treatments for RA: dosing, comparative efficacy, and safety

Drug (brand names)
Dosing and admin
Comparison with other biologics (AHRQ analysis)
Side effects and safety issues

TNF-inhibitor

Adalimumab (Humira)
  • Injection
  • 40 mg every 2 weeks
  • Disease control (ACR20): less effective than etanercept
  • Disease control (ACR50) in methotrexate resistant patients: better than Anakinra, equal to most other biologics
  • Response in early RA: equal to methotrexate
  • Early radiologic response: better than methotrexate
  • Injection site reactions
  • Infections
Certolizumab pegol (Cimzia)
  • Injection
  • 200 mg every 2 weeks or 400 mg monthly
  • Early radiologic response: better than methotrexate
  • Injection site reactions
  • Infections
  • Discontinued due to adverse effects: equal of infliximab, better than etanercept, rituximab
Etanercept (Enbrel)
  • Injection
  • 50 mg weekly or 25 mg twice weekly
  • Disease control (ACR50): better than most other biologics
  • Disease control in methotrexate resistant patients: better than anakinra
  • Early radiologic response: better than methotrexate
  • Injection site reactions
  • Infections
  • Discontinued due to adverse effects: better than infliximab, certolizumab
Golimumab (Simponi)
  • Injection
  • 50 mg or 100 mg every 4 weeks
  • Disease control (ACR50) in methotrexate resistant patients: equal to most other biologics
  • Injection site reactions
  • Infections
Infliximab (Remicade)
  • IV
  • 3 mg/kg, weeks 0,2, and 6, then 3-10 mg/kg every 4-8 weeks
  • Disease control (ACR50): less effective than etanercept
  • Disease control (ACR50) in methotrexate resistant patients: equal to most other biologics
  • Early radiologic response: better than methotrexate
  • Infusion reactions
  • Infections
  • Discontinued due to adverse effects: equal to certolizumab and more frequent than etanercept and rituximab

IL-6 inhibitor

Tocilizumab (Actemra)
  • IV
  • 8 mg/kg every 4 weeks
  • Disease control (ACR50): less than etanercept
  • Disease control (ACR50) in methotrexate resistant patients: equal to most other biologics
  • Infusion reactions
  • Infections
  • Elevated cholesterol

B-cell inhibitor

Rituximab (Rituxan)
  • IV
  • 1000 mg in 2 infusions 2 weeks apart, repeated every 4 to 8 months
  • Disease control (ACR50): less than etanercept
  • Disease control (ACR50) in methotrexate resistant patients: equal to most other biologics
  • Infusion reactions
  • Infections

T-cell costimulation inhibitor

Abatacept (Orencia)
  • IV: 8-10 mg/kg (500-1000 mg) at weeks 0,2, and 4, then monthly
  • Injection: (with or without IV loading dose above) 125 mg subcutaneous (within 1 day of loading dose), then weekly
  • Disease control (ACR50): less effective than etanercept
  • Disease control in methotrexate resistant patients equal to most other biologics
  • Improved disease activity: more effective than Infliximab
  • Infusion reactions
  • Infections
  • Rates of discontinuation and serious adverse effects less than Infliximab

JAK inhibitor

Tofacitinib (Xeljanz)
  • Oral
  • 5 mg twice daily
  • Not included in AHRQ analysis
  • Not included in AHRQ analysis

IL-1 inhibitor

Anakinra (Kineret)
  • Injection
  • 100 mg daily
  • Disease control (ACR50): less than etanercept
  • Disease control in methotrexate resistant patients: less than etanercept and adalimumab
  • Injection site reactions (highest among biologics)
  • Infections
  • Neutropenia

 
To learn more about any of the biologics included in this table, click on the name of the agent.

 

How long does a biologic take to achieve full effect?

Biologics take somewhat less time to achieve full effect than traditional DMARDs, with time to effect ranging from 2 to 6 weeks, depending on the specific drug. Most biologics must be taken by injection or intravenous (IV) infusion. Some are available for injection through the skin and may be taken at home. Others must be infused at your doctor’s office, with an infusion taking anywhere from 1 to 6 hours. The only agent that is available for oral administration is the newest FDA-approved biologic, tofacitinib (Xeljanz).1,4

 

How effective are biologic treatments?

Although individual biologics act differently and one may be more useful in an individual patient than another, we can make some generalizations about their effectiveness in RA. Based on results from existing randomized, controlled trials, biologic treatment were significantly more likely to result in control of disease activity, defined as either ACR20, 50, or 70 response, than placebo. They were also significantly more likely to result in responses and remission, defined as improved disease activity score (DAS).2

Another key outcome from clinical trials of biologics is radiographic progression. Clinical trials have shown strong evidence that biologics reduce the progression of joint erosion. One systematic review compared the effect on radiographic progression of biologics combined with methotrexate alone and found that biologics resulted in a significant decrease in the rate of progression and joint damage above and beyond methotrexate.7

 

Does the combination of a biologic with methotrexate increase efficacy?

A key systematic review of results from existing randomized, controlled trials in which a biologic was combined with methotrexate found that there was no evidence that the combination resulted in a greater likelihood of achieving an ACR50 response. The analysis considered 20 trials in which a biologic and methotrexate were given and 7 trials in which a single biologic treatment was used. Patients in the studies who received the combination were 3 times more likely than placebo to achieve an ACR50 response, while those who received a single biologic treatment were 4 times more likely than placebo to achieve an ACR50 response.6

 

What are the side effects and safety issues with biologic treatments?

While individual biologics have distinct safety profiles and the risk for specific side effects varies by agent, there are some common safety concerns with these drugs. Remember, biologics by design are intended to dampen the immune response. Therefore, these drugs may increase the risk of infections and cancers, the very health problems that the immune system defends against. This increased risk may be small for most patients, with the benefits of biologic treatments far outweighing the risks.2

The most common safety concerns with biologics include increased risk of infection, infusion or injection reactions (for those drugs that are taken by IV or injection), increased risk for certain types of cancer, the development of antibodies that neutralize the effect of the drug, and other autoimmune disorders (eg. lupus-like syndromes). It is useful to check the safety profile of individual biologic treatments to determine the risk for these safety problems.2

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