By: Erica Dimitropoulos, Senior Staff Editor

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Rheumatoid arthritis is a painful and often debilitating autoimmune disease characterized by symmetric polyarthritis, most commonly of the proximal interphalangeal and metacarpophalangeal joints, elbows, knees, ankles, and spine.¹ Its clinical manifestations vary, from a slowly progressing onset of fatigue and musculoskeletal discomfort to a sudden and worsening destruction of joints and periarticular structures. Furthermore, as an autoimmune disease, rheumatoid arthritis carries an increased risk of mortality from infection, vasculitis, gastrointestinal hemorrhage, and heart complications.¹ Although the cause of rheumatoid arthritis is unknown and the cure is unfound, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, and biologic response modifiers have been shown to control the pain and flares of this disease for most patients. However, other patients who are either nonresponsive or have developed tolerance to these drugs are turning to new options to manage their disease.

On November 7, 2012 the FDA approved Pfizer’s tofacitinib (Xeljanz®), an oral drug that targets patients with rheumatoid arthritis who are intolerant to or have failed therapy with methotrexate.² As a Janus kinase (JAK) 1 and 3 inhibitor, Tofacitinib interferes in the pathway involved with the inflammation and damage associated with rheumatoid arthritis. To elaborate, once a cytokine receptor associates with its respective cytokine, it undergoes a conformational change that causes JAKs to bind to it and phosphorylate its tyrosine residues. This triggers STATs, or signal transducers and activators of transcription, to bind to the newly phosphorylated domain. The JAKs can now phosphorylate and therefore activate the STATs, which then dissociate from the receptor complex and form an active dimer that is capable of entering the nucleus and regulating gene transcription processes. Blocking this pathway therefore blocks the activity of the inflammatory cytokine.³

STATs in particular have recently been proven to play an important role in rheumatoid arthritis and other inflammatory diseases. Individuals with the highest levels of inflammation have overly activated STAT1 pathways with an increased expression of STAT1 and the genes it regulates. Thus, since STAT activity may be modulated through JAK, particularly JAK3, the pathology of disease clearly demonstrates the potential of inhibitors of the Janus kinase pathway in treating rheumatoid arthritis.³

Tofacitinib has been approved at 5 mg twice daily as a second-line agent for rheumatoid arthritis, either as monotherapy or in conjunction with methotrexate or other DMARDs. The most common side effects include headache, diarrhea, and nasopharyngeal inflammation. Tofacitinib has also been associated with an increase in cholesterol and liver enzyme levels and a decrease in blood counts.⁴ Patients should be informed of the increased risk of infection, and all patients should be tested for tuberculosis before initiating therapy.²Lastly, the FDA has required Pfizer to conduct a postmarketing study to determine if this drug is associated with heart disease, cancer, or serious infections.⁴

An important yet incomplete 24-month research initiative called the ORAL Start study compares the effectiveness of tofactinib with methotrexate in methotrexate-naïve patients who have active rheumatoid arthritis.² The study included 952 patients who were split into three groups and given tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily (dose not yet approved), or methotrexate up to 20 mg weekly. After one year, the ACR70 response has been 36% to 38% in patients receiving tofacitinib, compared to only 12% for patients treated with methotrexate. The incidence of serious adverse events was the same for all groups (7%), although infections were slightly more common in patients treated with tofacitinib (32% to 39% compared with 27%). Thus, tofacitinib monotherapy was proven to be superior to methotrexate in improving the symptoms of rheumatoid arthritis and inhibiting the worsening of structural joint damage associated with this disease.²

In closing, despite the promising outlook and numbers this new drug has to offer, the true test of efficacy will come only when Tofacitinib enters the market and begins to be used in all patient populations and situations. Unfortunately, as its price is said to be comparable to that of biologic agents, its high cost may both deter prescribers and patients .⁵

SOURCES:

1. Rubin R, Strayer D. Pathology: Clinicopathologic Foundations of Medicine. 6^th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012: 1250-1259
2. Kay J. Tolfactinib Approved: Now How Do We Use It? Medscape. Nov 28,2012. http://www.medscape.org/viewarticle/775107. Accessed Dec 23, 2012.
3. Smith M, Walker JG. The Jak-STAT Pathway in Rheumatoid Arthritis. J. Rheumatol. 2005;32(9):1650-1653
4. Brooks M. FDA Approvals: Tofacitinib for Rheumatoid Arthritis. Medscape. Nov 29, 2012. http://www.medscape.org/viewarticle/775016. Accessed Dec 26, 2012.
5. Kyttaris VC. Kinase Inhibitors: A New Class of Antirheumatic Drugs. Drug Des Devel Ther. 2012;6(1):245-250.

Published by Rho Chi Post