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19 Articles in Volume 20, Issue #4
20/20 with Dr. Nathaniel Katz: Pain Research and Future Therapeutics
A 20-Year Timeline: Pain Therapeutics and Regulations
A Comparison of the Alpha-2-Adrenergic Receptor Agonists for Managing Opioid Withdrawal
A Pain Assessment Primer
After the Task Force: A Conversation with Vanila A. Singh, MD
Ask the PharmD: Can opioids and benzodiazepines ever be used together?
Cognitive Strategies and Mindful Awareness for Integrative Pain Care
COVID: Clinical Considerations for Acute and Post-Infection Symptoms
Editorial: Fudin and Gudin Tackle Pain Care History – Asking, Have We Done a 180?
From Hands-On to Home-Based Care: Physical Therapy Undergoes a Paradigm Shift Due to Pandemic
MS-Related Pain and Spasticity: Are Cannabinoids an Option?
New Biological Agents for Psoriatic Arthritis: A Monoclonal Antibody Primer
Pandemic Presents Unexpected Opportunity to Embrace Multimodal Analgesia and the Integrative Care Team
Provider Perspective on Knee OA: Injections and RFA Options
Redefining the “Pain Specialist” of Today
Resident’s Corner: Climbing the Learning Curve in Pain Management
The Evolution of Pain Management: Experts Weigh In
Tips from the Field: How to Enhance Practice Efficiency
Tumor Necrosis Factor (TNF) Inhibitors: A Clinical Primer

Tumor Necrosis Factor (TNF) Inhibitors: A Clinical Primer

What practitioners need to know about how TNF biologics manage inflammation and painful autoimmune conditions, including RA, PsA, ankylosing spondylitis, and juvenile idiopathic arthritis.

Autoimmune disorders such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and juvenile idiopathic arthritis (JIA) are often associated with significant pain. Many patients with rheumatologic autoimmune disease suffer months to years without understanding the etiology of their pain and receive less than optimal effectiveness from commonplace pain medications such as non-steroidal anti-inflammatory drugs (NSAIDs).

When a patient does not respond to standard treatment, consideration should be given to an autoimmune disease process as causality.

TNF inhibitors are relative newcomers to pain management and include Remicade (infliximab) and Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol), and Simponi (golimumab). (Image: iStock)

Indications

Tumor necrosis factor (TNF) inhibitors are relative newcomers to the armamentarium of drugs used to manage autoimmune conditions, such as those listed above. Remicade (infliximab) and Enbrel (etanercept) received the first FDA approvals in 1998.1,2 In 2002 Humira (adalimumab) was approved, subsequently, Cimzia (certolizumab pegol) in 2008, and Simponi (golimumab) in 2009.3-5 Simponi Aria, the IV infusion formulation of golimumab, was approved in 2013. Approved indications are summarized in Table I.

The current body of literature does not provide evidence regarding comparative effectiveness among TNF inhibitors for indicated diseases. Therefore, the American College of Rheumatology (ACR) guidelines for the treatment of RA do not specify superiority or preference among these five TNF inhibitors.6

As Anti-Inflammatories

TNF binds to TNF-receptors on immune cells initiating a cascade of cellular events that culminates in the release of inflammatory cytokines. 8Under normal physiological conditions without autoimmune condition, this response is reserved for the situation when the body faces antigens, i.e., bacteria and viruses. Patients with an autoimmune condition, however, may have uncontrolled immune response associated with TNF without such antigen presence, triggered by ‘self’ protein.  In this setting, TNF inhibitors aim to reduce the presence and activity of inflammatory cytokines in the body, which lead to decreased symptoms of joint swelling and stiffness.7

Elevated levels of TNF have been identified in patients with various autoimmune conditions, thus inhibition of TNF is thought to reduce immunogenicity in these conditions.9 This mechanism is particularly important for autoimmune diseases such as RA, PsA, and AS, because increased cytokine activities in these conditions lead to irreversible joint narrowing and damage at affected locations. These changes at the cellular level become symptomatic can be relieved by anti-inflammatory agents such as NSAIDs or glucocorticoids, which cannot prevent or delay the joint damage. Therefore, long term use of those medications is not recommended, with the exception of NSAIDs.

Disease modifying anti-rheumatic drugs (DMARDs), which include TNF inhibitors, are the medication of choice for RA with documented efficacy with radiographical evidence of inflammatory changes.

As Disease-Modifiers

Current American College of Rheumatology (ACR) rheumatoid arthritis guidelines recommend DMARD use as soon as possible after disease diagnosis.6

DMARDs are categorized:

  • Conventional DMARDs such as methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide.
  • Biologic DMARDs (biologics), such as TNF inhibitors, B cell depleting agent, T cell modulator, IL6 inhibitors, and IL-17 inhibitors.
  • Targeted synthetic DMARDs; also known as Janus Kinase (JAK) inhibitors

 

Drug Delivery and Use

Among biologic DMARDs, TNF inhibitors have the longest experience with 20 years on the market. TNF inhibitors are administered via injection or infusion. Etanercept, adalimumab, certolizumab, and golimumab (Simponi formulation) are marketed with autoinjector or prefilled syringe formulation. These agents may be self-administered by patients or caregivers subcutaneously. Infliximab and golimumab (Simponi Aria) are given as infusions that patients are required to receive in a doctor’s office or designated infusion facility.

Each administration method has its own pros and cons. For example, self-injection with autoinjector may be more convenient to patients; however, for patients who have a higher risk of non-adherence, office-based administration may allow for better treatment outcome. Further, office-based administration reduces the financial burden of non-adherence on the healthcare system.  

Unlike other TNF inhibitors that are fully human or humanized monoclonal antibody (mAb), infliximab is a chimeric mAb that contains both human and murine proteins. Due to this murine component in the molecule, infliximab has been associated with a higher risk of allergic reaction than other TNF inhibitors.8 However, with treatment prior to infusion and careful monitoring, infliximab has been safely used in many patients. (Editor’s Note: See our new primer on mAb nomenclature)

Compared to prefilled fixed-dose autoinjector formulation, infliximab provides additional merits in terms of dose calibration and administration intervals based on treatment response. Risk and benefit should be assessed and discussed between patient and clinician based on disease characteristics and past treatment history of individual patient.  

 

Biosimilar TNF Inhibitors

In the years since the initial approval of TNF inhibitors, biosimilar products have become available in the market.9 Biosimilars are not “generic” products but are “highly similar” to the originator in terms of quality, safety, and efficacy in spite of minor differences in clinically inactive components in the molecular structure. Biosimilars should have the same mechanism(s) of action, indications in labeling, route of administration, dosage form, and strength to the originator.

The first biosimilar product, Inflectra (infliximab-dyyb) received FDA approval in the United States in 2016. Biosimilars for infliximab, etanercept, and adalimumab have gained FDA approvals but only infliximab biosimilars are available in the US market at the time of this writing (June 2020).9 See also Table II.

Questions remain regarding interchangeability between biosimilar compounds and their corresponding originators.9,11 Currently, no biosimilars have been granted interchangeability status in the US market.  

           

Risks, Side Effects, and Monitoring

TNF inhibitors carry a boxed warning for serious infection and malignancy risk.7,11,12 Patient counseling should include the importance of infection control, annual influenza vaccination, and self-hygiene such as hand washing.

Malignancy risk has been studied closely via post-marketing surveillance for the past two decades. As a result, we know now that solid tumor risk does not seem to increase, while skin cancer risk slightly increases. ACR guidelines reflect these findings in their most recent guidelines: a patient with a history of solid tumor who was treated and cured could use TNF inhibitors safely. Patients using TNF inhibitors should take measures to protect their skin from excessive sun exposure by wearing sunscreen, appropriate clothes, and hats.6

Minor side effects of TNF inhibitors include headache, rash, abdominal distress, and upper respiratory symptoms, and injection site reactions, which are generally transient and can be managed successfully. With rare incidence, demyelinating disorder, multiple sclerosis, optic neuritis, peripheral demyelinating disease, including Guillain-Barré syndrome, have been reported.

Patients receiving infliximab are at risk of infusion reactions such as fever, hypotension, shortness of breath, and urticaria. With standard infusion protocols using premedication (glucocorticoid, acetaminophen, and antihistamines), slow infusion and close monitoring, infliximab can be safely used.7

All TNF inhibitor patients should be monitored for latent tuberculosis, hepatitis B, hepatitis C, CBC, and LFTs. 7

Patient Non-Adherence

Medication non-adherence is well known as a major component of poor treatment outcomes, decreased quality of life, and increased healthcare costs. Suboptimal disease control can further lead to more costly healthcare utilization such as hospitalization and/or emergency department visits.10 More importantly, clinicians and patients need to be aware of the higher risk of antibody development in medication non-adherence, which may lead to loss of effectiveness and/or adverse reactions such as rash.

Once antibodies develop, the treatment should be discontinued and other treatment options should be sought. Considering that the biologic DMARD users are, in general, characterized with advanced diseases and history of failures of other DMARDs, losing therapeutic options due to non-adherence related antibody development must be maximally prevented via patient education and counseling.  

Patient Education

As illustrated in Table I, TNF inhibitors are indicated for the treatment of autoimmune conditions. Pain relief with TNF inhibitor use often requires weeks to months depending on the location of pain and severity of autoimmune diseases. This is a particularly important counseling point to communicate with patients at the initiation of therapy to prevent non-adherence or self-discontinuation. An additional pain management regimen is often required concomitantly with a TNF inhibitor initiation, especially for the first three months. Routine clinical practice includes follow up visit at or around 3 months to assess treatment effectiveness.  

Drug Interactions and Potential Liver Injury

Drug interaction is an important aspect to consider when recommending or prescribing concomitant therapies for pain management. Given that these biologic compounds are polypeptides rather than small molecules, they are not subject to metabolism through the CYP enzyme system of the liver as many drugs are. In fact, they are metabolized by proteases throughout the body and through intracellular degradation.13 This unique feature of biologic agents mitigates pharmacokinetic interactions making concomitant administration with traditional analgesics free of any significant drug-drug interaction concerns.

While not a direct drug-drug interaction, it is important to note that hepatic injury can occur with the use of TNF inhibitors. Hepatic injury is typically reversible with discontinuation of the agent, but liver function tests should be monitored closely and in the instance of acute injury, concomitant agents with hepatic toxicity profiles should also be avoided (such as acetaminophen).14

Patients with autoimmune conditions are often managed on glucocorticoids, oral DMARDs and/or NSAIDs prior to initiation of TNF therapy. As described above, there are no significant drug interactions, therefore continuation of NSAIDs, glucocorticoids, conventional DMARDs are generally accepted.15 In addition, short courses of NSAIDs or steroids are often employed to control acute exacerbations.15

However, if a patient continues to require pain medications, or experience frequent flares, ACR guidelines recommend switching to an alternative DMARD or combination DMARD use based on treat to target principle.

 

In Summary

The management of chronic pain associated with certain painful autoimmune conditions presents a unique challenge given the specific etiology of pain. Anti-tumor necrosis factor therapy provides a potential option for those patients with pain associated with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and juvenile idiopathic arthritis.

Adjuvant therapy with traditional analgesics is often required with TNF-inhibitors and given the fact that they are not subject to metabolism via the CYP system drug interactions are not of concern. These biologic therapies remain highly regulated with insurance’s step therapy principle and prior authorization process due to high drug cost. The advent of biosimilar products may improve accessibility in the future.

 

See also, TNF inhibitors for Axial Spondyloarthritis

Last updated on: August 3, 2020
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New Biological Agents for Psoriatic Arthritis: A Monoclonal Antibody Primer
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