Review of the Tumor Necrosis Factor Blocker Adalimumab (HUMIRA)

First approved by the Food and Drug Administration (FDA) in 2002 for the treatment of rheumatoid arthritis, adalimumab (HUMIRA and biosimilars) is a human-derived, genetically engineered monoclonal antibody. The antibody blocks the activity of tumor necrosis factor (TNF), which plays an important role in many rheumatologic and inflammatory diseases.[1] TNF itself is a cytokine, a class of proteins that contribute to both beneficial (physiological) and harmful (pathologic) processes in the body.

Adalimumab belongs to a class of drugs known as disease-modifying antirheumatic drugs (DMARDs). Its initial approval was for the treatment of rheumatoid arthritis in patients who had an inadequate response to one or more older, synthetic DMARDs (such as methotrexate [JYLAMVO, OTREXUP, RASUVO, TREXALL, XATMEP and generics]), a requirement that is no longer listed in the label. Subsequently, adalimumab has been approved to treat various autoimmune diseases, including psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and ulcerative colitis. In total, the prescribing information lists nine different conditions. Adalimumab is injected subcutaneously (under the skin) once a week or every other week, depending on the indication.

Humira is also one of the best-selling drugs in the United States. In 2022, with $3.7 billion in gross Medicare Part D spending, Humira ranked fourth among all Part D drugs for Medicare expenditures.[2] At present, however, less expensive biosimilars are available. The biosimilars have similar but not identical efficacy and safety and disease indications.[3] Humira also has been heavily promoted to physicians.[4] From August 2013 to December 2022, Humira ranked third among the top 25 drugs related to industry payments to U.S. physicians, with total payments of about $100 million.[5]

DMARDs reduce pain and inflammation and can help to prevent damage to joints and skin. Methotrexate is still the recommended first-choice treatment for patients with rheumatoid arthritis because it is among the safest DMARDs.[6] If symptoms do not improve with a synthetic DMARD (such as methotrexate) alone, a biologic DMARD (such as a TNF blocker) can be added to or replace treatment with methotrexate.[7] Other TNF blockers include certolizumab pegol (CIMZIA), etanercept (ENBREL and biosimilars), golimumab (SIMPONI) and infliximab (REMICADE, ZYMFENTRA and biosimilars).

Public Citizen’s Health Research Group has previously designated adalimumab and all TNF blockers as Limited Use drugs. The exception is certolizumab pegol, which we designated as a Do Not Use drug because it is associated with unique, serious risks, such as increased risks of complete hair loss, kidney failure and cardiovascular diseases, and there is no evidence it is more effective than other biologic DMARDs.

Efficacy of adalimumab

Almost all the trials of adalimumab have been industry-funded. The approval of adalimumab for rheumatoid arthritis was based on five short-term, randomized, placebo-controlled, double-blind trials that included 2,869 adults with rheumatoid arthritis whose symptoms mostly did not improve with methotrexate.[8] All trials showed that treatment with adalimumab or a combination of methotrexate and adalimumab led to significantly greater improvements compared with placebo. Subsequently, additional studies have generally found that patients who do not improve with methotrexate alone have improved symptom relief and remission rates when adalimumab is added to their treatment.[9],[10] The most common reasons for discontinuing adalimumab are failure to maintain initial treatment response or inadequate response (43% for either reason).[11] Moreover, research suggests that across other indications, such as plaque psoriasis, there are only minor efficacy differences between treatment with adalimumab and the other TNF blockers alone or combined with methotrexate.[12],[13]

A complicating factor is the difficulty of assessing the efficacy of biologic drugs for rheumatoid arthritis.[14] Most clinical trials have been placebo-controlled and have not compared different drugs. Moreover, many trials have limited follow-up periods and enroll subjects who are not representative of all patients with rheumatoid arthritis. Many of the studies are industry-sponsored, and drug manufacturers are involved in the collection and analysis of data.

Serious adverse effects of adalimumab

TNF blockers, including adalimumab, are associated with serious, life-threatening adverse effects. Treatment requires close monitoring and sometimes must be discontinued. The prescribing information includes a boxed warning, the FDA’s most prominent warning, for serious infections and malignancy.

Infections

Because treatment with TNF blockers can lower the immune system’s ability to fight infections, the boxed warning states that adalimumab increases the “risk of serious infections leading to hospitalization or death.”[15] These infections include tuberculosis, invasive fungal infections (such as histoplasmosis), bacterial sepsis and infections with other opportunistic pathogens.

Across several studies, the incidence rate of serious infections was about four events per 100 person-years of treatment with adalimumab compared with three events per 100 person-years with placebo.[16],[17] For this reason, adalimumab should not be started during active infections, and live vaccines should be avoided during treatment. Patients also need to be tested for tuberculosis and monitored throughout treatment even if the initial tuberculosis test was negative. In rare cases, treatment with adalimumab can lead to a life-threatening reactivation of hepatitis B infection in chronic carriers of this virus.

Malignancies

An analysis of the long-term safety of adalimumab across several indications and including nearly 30,000 subjects across 77 clinical trials found that malignancies (excluding lymphoma, melanoma, nonmelanoma skin cancer and others) occurred at a rate of 0.6 events per 100 patient-years.[18] The manufacturer of Humira funded the study and contributed to the design of the study and the collection and interpretation of the data. A similar incidence rate (again excluding some types of cancer) was reported in an observational study of the long-term safety of adalimumab; this study was also funded by the manufacturer of Humira.[19] According to the prescribing information, among adults receiving adalimumab for different indications, the rate of lymphomas was about 0.11 per 100 patient-years, about three times higher than would be expected in the general U.S. population.[20] The boxed warning highlights the risk of lymphoma and other malignancies in children and adolescent patients, as well as cases of a rare type of T-cell lymphoma.

Congestive heart failure

Treatment with adalimumab may also lead to new or worsening congestive heart failure.[21] In the industry-funded observational study, the incidence rate for hospitalization for congestive heart failure was 0.15 per 100 patient-years.[22]

Other adverse events

Other adverse events for adalimumab include injection-site reactions, hypersensitivity reactions (including anaphylaxis), liver damage (including liver failure) and, in rare instances, lupus-like syndrome and new cases or exacerbation of certain central nervous system conditions (such as multiple sclerosis).[23]

What You Can Do

If your clinician prescribes adalimumab, fully discuss the benefits and risks with them. Discuss which vaccines are recommended before or during treatment, which should be avoided and which screening tests (for example, for latent tuberculosis) are needed. Seek immediate medical care if you think you have an infection, an allergic reaction (symptoms such as dizziness, hives and difficulty breathing or swallowing) or heart failure (symptoms including fatigue, difficulty breathing, rapid heartbeat and swelling around the legs and ankles).
 

References

[1] AbbVie Inc. Label: adalimumab (HUMIRA). November 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125057s423lbl.pdf. Accessed May 31, 2024.

[2] Medicare spending on Ozempic and other GLP-1s is skyrocketing. KFF Health News. March 22, 2024. https://www.kff.org/policy-watch/medicare-spending-on-ozempic-and-other-glp-1s-is-skyrocketing/. Accessed May 30, 2024.

[3] Lu X, Hu R, Peng L, et al. Efficacy and safety of adalimumab biosimilars: current critical clinical data in rheumatoid arthritis. Front Immunol. 2021;12(April 6):638444.

[4] Ioannidis JP, Karassa FB, Druyts E, et al. Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales. Nat Rev Rheumatol. 2013;9(11):665-673.

[5] Sayed A, Ross JS, Mandrola J, et al. Industry payments to US physicians by specialty and product type. JAMA. 2024;331(15):1325-1327.

[6] New biologic drugs for rheumatoid arthritis: Which are safe? Worst Pills, Best Pills News. March 2016. https://www.worstpills.org/newsletters/view/1024. Accessed May 31, 2024.

[7] Brown P, Pratt AG, Hyrich KL. Therapeutic advances in rheumatoid arthritis. BMJ. 2024;384(January 17):e070856.

[8] AbbVie Inc. Label: adalimumab (HUMIRA). November 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125057s423lbl.pdf. Accessed May 31, 2024.

[9] Brown P, Pratt AG, Hyrich KL. Therapeutic advances in rheumatoid arthritis. BMJ. 2024;384(January 17):e070856.

[10] Janke K, Biester K, Krause D, et al. Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. BMJ. 2020;370(June 7):m2288.

[11] Harrold LR, Griffith J, Zueger P, et al. Longterm, real-world safety of adalimumab in rheumatoid arthritis: analysis of a prospective US-based registry. J Rheumatol. 2020;47(7):959-967.

[12] Adalimumab: A last resort for treating plaque psoriasis: just another TNF alpha antagonist. Prescrire Int. 2017;17(98):240.

[13] Adalimumab: ankylosing spondylitis: just another TNF alpha antagonist. Prescrire Int. 2007;16(91):193.

[14] Ioannidis JP, Karassa FB, Druyts E, et al. Biologic agents in rheumatology: unmet issues after 200 trials and $200 billion sales. Nat Rev Rheumatol. 2013;9(11):665-673.

[15] AbbVie Inc. Label: adalimumab (HUMIRA). November 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125057s423lbl.pdf. Accessed May 31, 2024.

[16] Ibid.

[17] Brown P, Pratt AG, Hyrich KL. Therapeutic advances in rheumatoid arthritis. BMJ. 2024;384(January 17):e070856.

[18] Burmester GR, Gordon KB, Rosenbaum JT, et al. Long-term safety of adalimumab in 29,967 adult patients from global clinical trials across multiple indications: an updated analysis. Adv Ther. 2020;37(1):364-380.

[19] Harrold LR, Griffith J, Zueger P, et al. Longterm, real-world safety of adalimumab in rheumatoid arthritis: analysis of a prospective US-based registry. J Rheumatol. 2020;47(7):959-967.

[20] AbbVie Inc. Label: adalimumab (HUMIRA). November 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125057s423lbl.pdf. Accessed May 31, 2024.

[21] Ibid.

[22] Harrold LR, Griffith J, Zueger P, et al. Longterm, real-world safety of adalimumab in rheumatoid arthritis: analysis of a prospective US-based registry. J Rheumatol. 2020;47(7):959-967.

[23] AbbVie Inc. Label: adalimumab (HUMIRA). November 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125057s423lbl.pdf. Accessed May 31, 2024.