Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects at least 1.3 million adults in the United States.1 Symptoms include pain, stiffness, swelling, and limited motion and function of many joints, particularly the small joints in the hands and feet.1 A diagnosis of RA is made on the basis of symptoms, physical examination results, and blood tests that are positive for anemia, rheumatoid factor, antibodies, and elevated erythrocyte sedimentation rate.1 Continued inflammation of the synovium can lead to cartilage and bone damage.1,2
Although the etiology of RA is unknown, there is an association with genetic factors and environmental exposures.2 Risk factors include smoking, reproductive hormone exposures, dietary factors, and microbial exposure, as well as having human leukocyte antigen class II genotypes (eg, DR4 and DRB1 molecules).2
In addition to affecting the functioning and quality of life of patients, RA exacts a heavy economic toll on patients, employers, and payers. A recent study highlights the significant cost borne by American workers who live with RA and their employers.3 The research was conducted using a database of US employees’ administrative healthcare and payroll data for individuals enrolled in an employer-sponsored insurance plan for at least 1 year.3
Compared with employees who do not have RA, an employee with RA incurs approximately $5200 more in annual healthcare costs.3 Workers with RA also pay an average of $1500 more per person for prescription medications annually, and are absent from work approximately 3.5 more days annually.3 On the whole, patients with RA cost their employers across the United States approximately $5.8 billion annually.3
Today’s treatment of RA is symptom-based and often requires a combination of agents.1 Typically, therapy begins with disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, hydroxychloroquine, or sulfasalazine.1 DMARDs are administered along with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or low-dose corticosteroids to reduce swelling, pain, and fever.1
The treatment course for more serious cases of RA includes biologic agents, which are also considered DMARDs, that target specific aspects of the immune system.1 These drugs include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), and tocilizumab (Actemra). The most recently approved agent for RA in adults, tofacitinib (Xeljanz), is an oral inhibitor of Janus kinase–mediated cell signaling.4
As unique biomarkers, genetic defects, and drug targets are identified, the development of novel RA agents continues. A recent genome-wide association study identified 42 new genes that confer the risk for RA at a genome-wide level of significance, bringing the total of known RA risk genes to 101.5 Although many current RA therapies target these genes, these findings suggest that drugs that are currently approved for other indications may be repurposed for use in patients with RA.5 Other novel targeting agents, including inhibitors of granulocyte-macrophage colony-stimulating factor receptors, have been shown to suppress cytokine responses in patients with RA.6
Otrexup: Novel Delivery of Methotrexate
In October 2013, the US Food and Drug Administration (FDA) approved the first methotrexate injection (MTXI) for subcutaneous (SC) use (Otrexup; Antares Pharma).7 This once-weekly self-administered injection is indicated for adults with severe active RA who have had inadequate response to or are intolerant of first-line therapy.7 MTXI was also approved for use in children with active polyarticular juvenile idiopathic arthritis.7
The approval of MTXI was based on the demonstration of bioavailability in a 12-week, open-label, crossover study comparing the relative bioavailability of MTXI with oral methotrexate.8 Data from this study were presented at the 2013 annual meeting of the American College of Rheumatology.
Originally developed as an oncology drug, methotrexate has become a cornerstone in the treatment of RA.9 In a recent interview regarding his experience in the study of MTXI, Michael Schiff, MD, Clinical Professor of Medicine in the Division of Rheumatology at the University of Colorado, stated, “This new delivery system for methotrexate provides a welcome option for physicians and their patients to continue effective use of methotrexate….The availability of an easy and safe way to administer subcutaneous methotrexate may…enable more patients to realize the possibility of continued disease control.”7
The use of parenteral methotrexate for the treatment of RA is less popular as a result of the challenges related to self-administration. Patients with RA may have compromised manual dexterity, needle phobia, and/or a lack of confidence in safely self-injecting with a vial, a needle, or a syringe, which can be barriers to use.7 Kevin Deane, MD, of the Division of Rheumatology at the University of Colorado stated, “Injectable [methotrexate] to date has come in a large vial, and [the] patient draws up medication and injects it....Drawing up and administering this medication may be somewhat difficult for some patients to do, especially with arthritic conditions.”10
Mechanism of Action
Methotrexate, an inhibitor of dihydrofolic acid reductase, interferes with DNA synthesis, repair, and cellular replication.11 Cells that are actively proliferating are particularly susceptible to these effects. The mechanism of action of methotrexate in RA is unknown. It may work by altering immune function.11
Dosing and Administration
MTXI is a single-dose, easy-to-use autoinjector for once-weekly SC use.11 It is available in doses ranging from 10 mg to 25 mg in 5-mg increments and is administered in the abdomen or thigh.11 The MTXI dose can be adjusted gradually for optimal outcomes.
Therapeutic response to methotrexate is usually seen within 3 to 6 weeks and continues for 12 weeks or more.11 The optimal duration of MTXI therapy is unknown.11
Healthcare professionals should ensure that patients understand that MTXI is administered once weekly. The daily use of methotrexate has resulted in fatal toxicity.11
The bioavailability of MTXI was assessed in an open-label, crossover study in which 49 adults with RA who had been receiving methotrexate for 3 months or more were given 10 mg, 15 mg, 20 mg, or 25 mg of methotrexate.8 They were randomized to receive either oral methotrexate, MTXI injected in the abdomen, or MTXI injected in the thigh.8 Blood samples were collected for analysis before the drug’s administration and at 13 time points of 15 minutes to 12 hours after drug administration.8 The average age of patients with RA who enrolled in the bioavailability study was 61 years and they had been diagnosed with RA for an average of 13 years.8 Their mean body mass index was 30.7 kg/m2.8
Pharmacokinetic parameters of interest included the area under the plasma concentration time curve (AUC), the maximum drug concentration, and the time of occurrence for maximum drug concentration. Safety was determined using the incidence of treatment-emergent adverse events (AEs), including injection-site reactions, as well as by monitoring laboratory parameters and vital signs.8
The analysis of pharmacokinetic parameters demonstrated that 4 hours after administration, the bioavailability of MTXI (administered in the thigh) was consistently greater than oral methotrexate at all dose levels (10-25 mg).8 At doses of 10 mg, 15 mg, 20 mg, and 25 mg, the relative bioavailability calculations (AUC of MTXI vs oral methotrexate) were 121%, 114%, 131%, and 141%, respectively, as summarized in Table 1.8 No bioavailability plateau was seen for MTXI, whereas the bioavailability of oral methotrexate plateaued at a dose of 15 mg.8
Phase 2 Clinical Trial
A phase 2, multicenter, open-label, single-dose, single-arm, in-clinic study enrolled 101 adults with RA to evaluate the ease of use of MTXI.12 The autoinjected product was tested with the intention of addressing the concerns of patients with RA regarding self-administering methotrexate using a conventional vial and syringe.12
The patients in the trial received MTXI at a dose of 10 mg, 15 mg, 20 mg, or 25 mg weekly.12 Dosing was determined by investigators based on each patient’s previous methotrexate regimen and disease status (ie, controlled or uncontrolled) at the time of study enrollment.
Of the 101 patients enrolled, 99 patients were evaluable.12 Most patients (79%) were female, with an average age of 61 years.12 These patients had been diagnosed with RA for an average of 13 years.12 All patients had received methotrexate for at least 3 months before enrolling in the study.12 Overall, 20% of patients had received SC methotrexate, and their functional status ranged from mild to severe; 89% were in American College of Rheumatology Functional Class II or III.12
The primary outcome measure in this phase 2 trial of MTXI was pain associated with SC administration as measured using a 100-mm visual analog scale (VAS).12 The administration sites were evaluated before administration and at 15 minutes, 1 hour, 6 hours, and 24 hours after self-administration.12 The mean administration-site pain ratings for all enrolled patients (N = 101) were 3.6 on day 1 and 1.4 on day 2 (standard deviations, ±9.1 and ±3.2, respectively).12
Of the 99 evaluable patients, 94% reported VAS scores of ≤10 on day 1, and 87% had scores of ≤5 on day 1.12 All 99 patients handled the autoinjector successfully.12
Of 404 skin sites that were evaluated after MTXI administration, 92% reported no erythema, with the balance showing “very slight, barely perceptible” erythema.12
Three patients experienced AEs while taking MTXI, including sick sinus syndrome, exostosis, and headache.12 None of these was considered to be related to the study drug.12
Methotrexate and MTXI were safe and well tolerated in the bioavailability study.8 The few AEs that were observed with MTXI were deemed transient and manageable. None required medical treatment.8 Two serious AEs were deemed unrelated to treatment, including 1 death from myocardial infarction in a 79-year-old man with a history of heart disease.8
MTXI is contraindicated in pregnant women, nursing mothers, patients with alcoholism or liver disease, patients with immunodeficiency syndromes, patients with preexisting blood dyscrasias, and patients with hypersensitivity to methotrexate.11
Warnings and Precautions
Boxed warning. Like the oral formulation of methotrexate, MTXI labeling includes a boxed warning for multiple safety risks, including embryo-fetal toxicity and death.11 These warnings include11:
- Serious toxic reactions and death; patients taking methotrexate should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities
- Fetal death and congenital anomalies; methotrexate is contraindicated in pregnancy
- Unexpectedly severe and sometimes fatal bone marrow suppression, aplastic anemia, and gastrointestinal toxicity; these events were reported when methotrexate and some NSAIDs were administered concurrently
- Hepatotoxicity, fibrosis, and cirrhosis after prolonged use
- Interstitial pneumonitis
- Diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation
- Severe and occasionally fatal skin reactions
- Potentially fatal opportunistic infections.
Laboratory tests needed. Patients who are candidates for MTXI should undergo a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest x-ray before initiating therapy.
During MTXI therapy, clinicians should monitor hematology parameters at least monthly, and monitor renal and liver function parameters every 1 to 2 months.
Embryo-fetal toxicity. Fetal death and congenital anomalies have been reported with methotrexate use. MTXI is not recommended for women of childbearing age unless its benefits outweigh risks. Steps to avoid conception should be taken if either partner is receiving MTXI therapy.
Malignant lymphomas. Non-Hodgkin lymphoma and other tumors have been observed in patients taking low-dose oral methotrexate. In some cases, however, malignancies that arose during treatment regressed completely after methotrexate withdrawal. Before initiating antilymphoma treatment, MTXI should be discontinued.
Additional warnings. Additional warnings and precautions related to MTXI include organ-system toxicity, infection, skin reactions, dizziness and fatigue, malignant lymphomas, as well as gastrointestinal, hematologic, hepatic, neurologic, pulmonary, and renal complications. Additional information regarding these warnings and precautions is listed in Table 2.
The FDA approval of a new delivery system for the administration of methotrexate adds a new and convenient treatment option for patients with RA. Although the literature documents the clinical utility of SC methotrexate in patients with active RA, this dosing alternative is often overlooked by clinicians. Methotrexate administered subcutaneously using an autoinjector is a well-tolerated, effective, and nearly pain-free alternative for patients with severe RA who have had inadequate response to or who are intolerant of first-line therapy. In addition to higher drug exposure levels with MTXI, easy self-administration of the medication with this first-in-class autoinjector may help to improve patient adherence and overall clinical outcomes.
- Ruderman E, Tambar S. Rheumatoid arthritis. Updated August 2012. www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/ra.asp. Accessed January 4, 2014.
- Centers for Disease Control and Prevention. Rheumatoid arthritis. Updated November 19, 2012. www.cdc.gov/arthritis/basics/rheumatoid.htm. Accessed January 4, 2014.
- Kleinman NL, Cifaldi MA, Smeeding JE, et al. Annual incremental health benefit costs and absenteeism among employees with and without rheumatoid arthritis. J Occup Environ Med. 2013;55:240-244.
- Xeljanz (tofacitinib) tablets [prescribing information]. New York, NY: Pfizer Inc; November 2013.
- Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2013 Dec 25 [Epub ahead of print].
- Burmester GR, Feist E, Sleeman MA, et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis. 2011;70:1542-1549.
- Antares Pharma, Inc. Otrexup (methotrexate) injection approved by FDA: a new treatment for adults with rheumatoid arthritis, children with polyarticular idiopathic arthritis, and adults with psoriasis. Press release. October 14, 2013. www.antarespharma. com/files/8613/8175/5363/OTREXUP_FDA_Approval.pdf. Accessed January 4, 2014.
- Schiff MH, Simon LS, Freundlich B, et al. Drug exposure limitations of oral methotrexate (MTX) at doses >15 mgs may be overcome by using a subcutaneous MTX auto-injector in patients with rheumatoid arthritis (RA). Arthritis Rheum. 2013;65 (10 suppl):S337-S338.
- Gower T. Understanding methotrexate, a cornerstone in RA treatment: how did a cancer drug become a staple in rheumatoid arthritis treatment? www.arthritistoday.org/about-arthritis/types-of-arthritis/rheumatoid-arthritis/treatment-plan/treatment- choices/understanding-methotrexate.php. Accessed January 5, 2014.
- Brooks M. FDA OKs Methotrexate Autoinjector (Otrexup). Medscape. October 18, 2013. www.medscape.com/viewarticle/812821. Accessed January 28, 2014.
- Otrexup (methotrexate) injection [prescribing information]. Ewing, NJ: Antares Pharma, Inc; October 2013.
- Kivitz AJ, McLain D, Hill J, et al. Nearly pain free self-administration of methotrexate using an investigational auto-injector: results of a phase-2 clinical trial in rheumatoid arthritis patients with mild-to-severe functional limitations. Arthritis Rheum. 2013;65(10 suppl):S565.