Abbott Laboratories' Humira (adalimumab)

Rheumatoid arthritis (RA) is an autoimmunedisorder of unknown etiologycausing inflammation of the joints. Itaffects approximately 1% of the population,afflicting more women than men.¹RA usually presents with pain, stiffness,and swelling of the joints, although diseaseprogression is highly variable. It mayrange from mild arthritis to progressivejoint destruction and disability.¹ RA guidelines,developed in 1996, focused mainlyon disease management and drug therapy.Currently, the focus of treatment is onearly prevention of disease progression.²In October 2005, Abbott Laboratoriesreceived additional FDA approval forHumira (adalimumab) as a first-line treatmentfor recent-onset moderate-tosevereRA.³

Pharmacology

Adalimumab is a recombinant humanIgG1 monoclonal antibody that bindsspecifically to tumor necrosis factor(TNF)-alpha. Although TNF-alpha is a naturallyoccurring cytokine involved in normalinflammatory and immune responses,elevated levels are found in the synovialfluid of patients with RA. By binding toTNF-alpha, adalimumab blocks the interactionof cell surface TNF receptors,therefore inhibiting TNF activity.⁴

Clinical Trials

A subset analysis of the DE019 adalimumabstudy found that early treatmentmight be more efficacious than treatmentin later disease progression. TheDE019 study evaluated adalimumab 20mg weekly or 40 mg every other weeksubcutaneously in combination withmethotrexate (MTX) over a 52-week periodin a double-blind, randomized, placebo(MTX monotherapy)-controlled trial.The trial included 618 patients with RAwho had inadequate response to MTX. Asubset analysis of clinical and radiographicresponse was conducted inpatients with early disease (<2 yearsduration) versus late disease (>2 yearsduration). When comparing the 74patients with early disease with the 544patients with late disease, responseswere higher, and health-adjusted quality-of-life scores showed improvement inthe early-disease patients.⁵

Approval for the additional indicationfor early onset was based on the PREMIERtrial. The PREMIER trial comparedadalimumab monotherapy, MTX monotherapy,and the combination in a 2-yearstudy involving 799 patients with early-onsetmoderate-to-severe RA. The primaryend points were inhibition of jointdamage and improvement in signs andsymptoms at 1 year. Inhibition of jointdamage was measured using the modifiedtotal sharp score (mTSS), whichassesses bone erosion and joint spacenarrowing on x-rays. After 2 years,patients receiving MTX alone had a meanchange in mTSS of 10.4, compared withpatients receiving combination treatmentwith a mean change in mTSS of1.9. Improvement in signs and symptomswas measured using the AmericanCollege of Rheumatology (ACR)-50 score,which measures a 50% improvement.After 2 years, 59% of patients receivingcombination therapy achieved ACR50,compared with 43% receiving MTX aloneand 37% receiving adalimumab alone.³

Safety

The most serious adverse reactionsinclude serious infection, neurologicevents, and malignancies.⁴ A trial evaluatingthe safety of adalimumab in RA foundadverse events to include injection-sitereaction, rash, and back pain.⁶ Humirashould not be initiated in patients withactive infections, and administration withother immunosuppressants increasestheir risk of infection.⁴ Humira is in pregnancycategory B, has not been studiedin patients under 18, and should be usedwith caution in the elderly because ofincreased risk of infection.⁴

Outlook

Humira has been shown to be safe andeffective in delaying RA disease progression.Early prevention of RA disease progressionis of great importance as jointdestruction may occur rapidly. Patientsshould be closely monitored due to rarecases of severe infections, sepsis, tuberculosis,and hypersensitivity reactions.The recommended dose of Humira forpatients with RA is 40 mg subcutaneouslyevery other week. It may be used incombination with MTX, glucocorticoids,salicylates, nonsteroidal anti-inflammatorydrugs, analgesics, or other disease-modifyingantirheumatic drugs.⁴

Dr. Soo is a senior research pharmacistwith the Investigational DrugService at Brigham and Women'sHospital, Boston, Mass. Ms. Dascoli isa sixth-year PharmD candidate fromNortheastern University currently onclinical clerkship in the InvestigationalDrug Service at Brigham andWomen's Hospital.

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