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VBCR - December 2014, Volume 3, No 6 - Drug Update
Loretta Fala

Inflammatory autoimmune conditions can affect different body systems, resulting in a variety of diseases involving the joints, skin, brain, and other organs. Rheumatoid arthritis, gout, juvenile idiopathic arthritis, psoriasis, and psoriatic arthritis are among the common chronic inflammatory autoimmune diseases affecting millions of Americans annually.

Rheumatoid Arthritis
Rheumatoid arthritis, a chronic inflammatory, autoimmune disorder that affects the lining (synovium) of the joints, affects 1.3 million people in the United States.1 Aside from causing painful swelling that may eventually lead to bone erosion and joint deformity, rheumatoid arthritis can also affect other organs of the body, including the skin, eyes, lungs, and blood vessels.1,2

Patients with rheumatoid arthritis have a high risk for disability and mortality, and they are twice as likely to die as people of the same age without rheumatoid arthritis.3 Approximately 40% of all deaths associated with rheumatoid arthritis are attributed to cardiovascular causes, including ischemic heart disease and stroke.3

Rheumatoid arthritis has a substantial impact on a patient’s functional status and quality of life.3 In addition, this disease is associated with substantial direct and indirect costs. According to one study, rheumatoid arthritis accounted for $19.3 billion (2005 dollars) in societal costs, excluding intangible costs, which rose to $39.2 billion when intangible costs were added.4

The management goals for patients with rheumatoid arthritis include reducing joint pain and swelling, alleviating stiffness, and preventing joint damage.1 According to the 2012 American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) and biologic agents in the treatment of rheumatoid arthritis, “The goal for each rheumatoid arthritis patient should be low disease activity or remission. In ideal circumstances, rheumatoid arthritis remission should be the target of therapy, but in others, low disease activity may be an acceptable target.”5 The ACR recommendations also state that decisions about treating to target are left to the clinician caring for the individual patient, based on the patient’s preferences, comorbid conditions, and other relevant factors. Moreover, treatment plans involve patient-tailored risk–benefit analysis based on the clinician’s assessment and collaboration with the patient.5

The early diagnosis and treatment of rheumatoid arthritis are vital.1 More aggressive treatment in early rheumatoid arthritis may improve outcomes, prevent irreversible joint damage, and preserve physical function and health-related quality of life.5 Therapies for rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, DMARDs (ie, methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine), immunosuppressants, tumor necrosis factor (TNF)-alpha inhibitors, and other biologic anti-inflammatory agents.2

Polyarticular Juvenile Idiopathic Arthritis
Rheumatoid arthritis characteristically develops in adults, but it can affect people of all ages. When rheumatoid arthritis affects young individuals aged <16 years, the condition is called juvenile arthritis. Although juvenile arthritis generally develops in children before age 16 years, symptoms may start as early as 6 months of age.6 Approximately 300,000 children in the United States have been diagnosed with some form of juvenile arthritis.7 An estimated 40% of all cases of juvenile arthritis are polyarticular disease.8

Polyarticular juvenile idiopathic arthritis (pJIA) is characterized by the involvement of many joints (≥5), which may include the large and small joints of the legs and arms, as well as the jaw and neck. The polyarticular form of juvenile arthritis may eventually evolve into rheumatoid arthritis.

The symptoms of pJIA include swollen or warm joints, limping, rash, sudden high fever, joint stiffness or pain, and swollen glands.6 Other disease manifestations may include red eyes, eye pain, photophobia, or vision changes. The severity of disease cor­responds with the number of major joints affected.6

Complications of pJIA include erosion or destruction of the joints, a slow rate of growth, vision loss from chronic uveitis, anemia, and pericarditis.6 Moreover, children affected with pJIA may have poor school attendance as a result of chronic pain.6 In addition to its substantial health impact on young patients, juvenile arthritis diseases in the United States account for an estimated $285 million annually in direct costs, based on 1989 data from the Centers for Disease Control and Prevention.8

The treatment goal for patients with pJIA is to control symptoms, prevent joint damage, and help them maintain function.7 First-line therapy for pJIA includes NSAIDs, which are admin­istered in a dose appropriate for the child’s weight. If a response is not achieved with NSAIDs, DMARDs are used as second-line therapy. These DMARDs include methotrexate and biologic agents, which consist of several TNF-alpha inhibitors.7

Psoriasis
Psoriasis is a chronic, inflammatory autoimmune skin disease that is often accompanied by thick, itchy, red patches that can be painful.9 In some cases, the disease is disfiguring and disabling. The most prevalent autoimmune disease in the United States, psoriasis affects an estimated 7.5 million people.9 Severe psoriasis is characterized by involvement of more than 10% of the body.10

Individuals with psoriasis have an increased risk for developing psoriatic arthritis, eye disorders, obesity, type 2 diabetes, and hypertension.11 They also have an elevated risk for cardiovascular disease, Parkinson’s disease, kidney disease, and other autoimmune diseases.11 Moreover, psoriasis has a dramatic impact on a patient’s quality of life and self-esteem. It can lead to depression, social isolation, and problems at work.11 Psoriasis also imposes a substantial financial burden on affected individuals, as well as on the national healthcare costs. The annual US costs attributable to psoriasis totaled a staggering $11.25 billion in 2008.9

The treatment goals for patients with psoriasis include slowing the speed of skin growth to reduce inflammation and plaque formation, removing skin scales, and smoothing the skin.11 Topical treatments include topical corticosteroids, vitamin D analogs, anthralin, topical retinoids, calcineurin inhibitors, salicylic acid, and coal tar.12 Phototherapy (artificial ultraviolet A and ultraviolet B lights) is sometimes used alone or in combination with other medications. Oral or injectable therapies for psoriasis include methotrexate, retinoids, cyclosporine, and biologic immunomod­ulator agents, including several TNF-alpha inhibitors (ie, etanercept, infliximab, adalimumab) and the interleukin-12/interleukin-23 inhibitor, ustekinumab.12

Methotrexate Injection Approved in 10 Dosage Strengths for 3 Autoimmune Conditions
Oral methotrexate has been available for the treatment of inflammatory autoimmune disorders for many years. In fact, for more than 2 decades, methotrexate has been recognized as a cornerstone therapy for patients with rheumatoid arthritis and severe psoriasis. The first once-weekly subcutaneous formulation of methotrexate (Otrexup; Antares Pharma) was approved by the US Food and Drug Administration (FDA) in 2013 for adults with severe active rheumatoid arthritis who do not respond to or cannot tolerate first-line therapy, for children with active pJIA, and for adults with severe, refractory psoriasis.13

In July 2014, the FDA approved a new once-weekly subcutaneous injection of methotrexate (Rasuvo; Medac Pharma) for the treatment of patients with rheumatoid arthritis, pJIA, or psoriasis.14 The new methotrexate injection is administered once weekly subcutaneously via an autoinjector pen. Methotrexate injection is not indicated for the treatment of neoplastic diseases.15

Eric Ruderman, MD, Professor of Medicine, Northwestern University Feinberg School of Medicine, said in a press release from Medac Pharma, “As a rheumatologist, I believe Rasuvo will offer patients the opportunity to maximize the benefit they get from methotrexate. Rasuvo’s dosing flexibility, in particular, will be very helpful, as RA patients do not all respond equally to methotrexate, making it important to select a treatment regimen that is appropriate for the patient’s condition.”14

The subcutaneous delivery of methotrexate injection and its availability in 10 dosage strengths (ranging from 7.5 mg to 30 mg) was designed to improve its bioavailability, according to the manufacturer.14 Results of a clinical study showed that subcutaneous methotrexate administration with a prefilled autoinjector pen led to a higher relative bioavailability compared with oral administration of the drug.16 The use of oral methotrexate is associated with gastrointestinal side effects, including nausea and abdominal pain.17 Studies suggest that the subcutaneous pen administration of methotrexate is associated with fewer, less intense gastrointestinal adverse events than oral methotrexate.16,17

Mechanism of Action
Methotrexate works by inhibiting dihydrofolic acid reductase.15 Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of one-carbon groups in synthesizing purine nucleotides and thymidylate. Methotrexate interferes with the synthesis and repair of DNA, as well as cellular replication. In general, actively proliferating tissues (eg, malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder) are more sensitive to this effect of methotrexate.15

The mechanism of action of methotrexate in patients with rheumatoid arthritis is unknown, but it may affect immune function. The production rate of epithelial cells in the skin is greatly increased in patients with psoriasis versus patients with normal skin. This differential in proliferation rates serves as the basis for using methotrexate to control the process of psoriasis.15

Dosing and Administration
Methotrexate injection is administered once weekly subcutaneously in the abdomen or the thigh. A different formulation of methotrexate should be used instead of the subcutaneous form for patients requiring oral, intramuscular, intravenous, intra-arterial, or intrathecal dosing; doses of <7.5 mg weekly; doses >30 mg weekly; high-dose regimens; or dose adjustments of <2.5-mg increments.
The starting doses of methotrexate are listed in the Table. The dose should be adjusted gradually in the individual patient to achieve an optimal response.


Table

Methotrexate injection is available as a single dose from a manually triggered autoinjector pen that delivers the drug. It is available in 10 different dosage strengths, ranging from 7.5 mg to 30 mg, including 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg.14,15

Clinical Studies
In patients with rheumatoid arthritis, clinical trials were performed using other formulations of methotrexate. The effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks after the start of treatment in patients with rheumatoid arthritis. Most studies of methotrexate in patients with rheumatoid arthritis have been of relatively short duration (3-6 months). Based on limited data from long-term studies, an initial clinical improvement should be maintained for at least 2 years with continuous therapy with subcutaneous methotrexate.15

Clinical trials in patients with pJIA were performed using formulations other than subcutaneous methotrexate.15 Treatment with methotrexate was evaluated in a 6-month, double-blind, placebo-controlled study in 127 pediatric patients with pJIA (mean age, 10.1 years; mean duration of disease, 5.1 years).15,18 This study showed that in patients receiving background NSAIDs and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2 resulted in significant clinical improvement compared with placebo as measured by the physician’s global assessment or by a patient composite (ie, 25% reduction in the articular severity score plus improvement based on parent and physician global assessments of disease activity).15,18

More than 66% of the patients in this study had pJIA; the numerically greatest response was seen in this subgroup of patients who received 10 mg/m2 per week of methotrexate.15,18 The overwhelming majority of the remaining patients had systemic-course juvenile idiopathic arthritis. All patients were unresponsive to NSAIDs; approximately 33% were receiving low-dose corticosteroids.15,18 The 5-mg/m2 dose of weekly methotrexate was not significantly more effective than placebo.15,18

Safety
The most common adverse reactions associated with methotrexate injection are nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and burning of skin lesions.15

Contraindications
Methotrexate injection is contraindicated in pregnant women, nursing mothers, and in patients affected by alcoholism or those with liver disease, immunodeficiency syndromes, preexisting blood dyscrasias, or hypersensitivity to methotrexate.15

Drug Interactions

Aspirin, NSAIDs, and steroids. The concomitant use of methotrexate injection with aspirin, NSAIDs, and steroids may elevate and prolong serum methotrexate levels and may cause increased toxicity.15

Proton pump inhibitors. The concomitant use of methotrexate injection with proton pump inhibitors may prolong serum methotrexate levels and may cause increased toxicity.15

Hepatotoxins. Patients receiving concomitant treatment with methotrexate and potential hepatotoxins (eg, azathioprine, retinoids, and sulfasal­azine) should be monitored closely for the possible increased risk for hepatotoxicity.15

Theophylline. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when taken concurrently with methotrexate.15

Folic acid and antifolates.Vitamin preparations containing folic acid or its derivatives may decrease the response to systemically administered methotrexate.15

Mercaptopurine. Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.15

Other drugs. Methotrexate is partially bound to serum albumin, and its toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. The use of methotrexate with probenecid should be monitored carefully, because renal tubular transport is also diminished by probenecid.15

Warnings and Precautions

Boxed warnings. The prescribing information for methotrexate injection carries a boxed warning stating that serious toxic reactions and death have been reported with its use, and that patients should be monitored closely for bone marrow, liver, lung, skin, and kidney toxicities. Methotrexate has been reported to cause fetal death and/or congenital anomalies and is contraindicated in pregnancy. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) with some NSAIDs.15

The boxed warning also notes the risk for hepatotoxicity, fibrosis, and cirrhosis, which may occur after prolonged use of methotrexate. Methotrexate may cause interstitial pneumonitis at any time during therapy; this has been reported at low doses. Consequently, pulmonary symptoms—especially a dry, nonproductive cough—may require interruption of treatment and careful investigation.15

In addition, diarrhea, ulcerative stomatitis, hemorrhagic enteritis, and death from intestinal perforation may occur, as well as potentially fatal opportunistic infections. Severe, occasionally fatal, skin reactions have also been reported.15

Organ system toxicity. Serious toxic reactions are possible with this medication. Methotrexate should only be used by physicians who are experienced in antimetabolite therapy.15

Embryofetal toxicity. Methotrexate is not recommended for women of childbearing potential unless medical evidence shows that the benefits will outweigh the risks. Women of childbearing potential should not start taking methotrexate until pregnancy is excluded and should be counseled about the serious risk to the fetus if they become pregnant while undergoing treatment. Pregnancy should be avoided if the man or the woman is receiving methotrexate (a minimum of 3 months for men, and for at least 1 ovulatory cycle after therapy for women).15

Effects on reproduction. Methotrexate may cause infertility, oligospermia, and menstrual dysfunction; these effects should be discussed with all patients.15

Laboratory tests. Patients using subcutaneous methotrexate injection should be monitored closely to detect any toxic effects promptly. Complete blood counts, renal function, and liver function tests should be performed at the intervals recommended in the prescribing information.15

Risks from improper dosing. The physician and the pharmacist should emphasize to the patient that subcutaneous methotrexate is administered once weekly and that mistaken daily use has led to fatal toxicity.15

Patients with impaired renal function, ascites, or pleural effusions. Because methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions, such patients require especially careful monitoring for toxicity as well as dose reduction or, in some cases, the discontinuation of methotrexate.15

Dizziness and fatigue. Adverse reactions from methotrexate, such as dizziness and fatigue, may affect the ability to drive or operate machinery.15

Malignant lymphomas. Non-Hodg­kin’s lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate; however, some cases of malignant lymphoma related to low-dose oral methotrexate have regressed completely after the withdrawal of methotrexate, without requiring active antilymphoma treatment. Methotrexate should be discontinued, and if the lymphoma does not regress, ap­propriate treatment should be instituted.15

Tumor lysis syndrome. Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumors.15

Concomitant radiation therapy. Methotrexate given concomitantly with radiotherapy may increase the risk for soft-tissue necrosis and osteonecrosis.15

Use in Specific Populations

Pediatric use. The safety and efficacy of methotrexate injection have not been established in pediatric patients with psoriasis or in pediatric patients with malignancy.15

Geriatric use. Clinical studies of methotrexate did not include sufficient numbers of patients aged ≥65 years to determine whether they respond to it differently from younger patients. In general, dose selection for an elderly patient should be done cautiously, reflecting the greater frequency of decreased hepatic and renal functions, decreased folate stores, and concomitant disease or other drug therapy (ie, that interfere with renal function, methotrexate, or folate metabolism) in this population.15

Conclusion
The recent FDA approval of methotrexate subcutaneous injection marks the availability of a new once-weekly therapeutic option for patients with severe rheumatoid arthritis or pJIA who do not tolerate or respond to first-line treatment, and for patients with severe psoriasis who do not respond to other treatments.14 Methotrexate subcutaneous injection is available in 10 dosage strengths, providing a wide range of patient-tailored dosing options. In clinical studies, the subcutaneous delivery of once-weekly methotrexate via an autoinjector pen resulted in a higher relative bioavailability than oral methotrexate; furthermore, it is associated with fewer, less severe gastrointestinal adverse events than oral methotrexate.16,17

References
1. Ruderman E, Tambar S; for the American College of Rheumatology. Rheumatoid arthritis. Updated August 2012. www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/ra.asp. Accessed November 10, 2014.
2. Mayo Clinic. Rheumatoid arthritis. October 29, 2014. www.mayoclinic.org/diseases-conditions/rheu matoid-arthritis/basics/definition/con-20014868. Accessed November 10, 2014.
3. Centers for Disease Control and Prevention. Rheumatoid arthritis. Updated November 6, 2014. www.cdc.gov/arthritis/basics/rheumatoid.htm. Accessed November 10, 2014.
4. Birnbaum H, Pike C, Kaufman R, et al. Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin. 2010;26:77-90.
5. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625-639.
6. MedlinePlus. Juvenile rheumatoid arthritis. Updated April 20, 2013. www.nlm.nih.gov/medlineplus/ency/article/000451.htm. Accessed October 15, 2014.
7. Abramson LS; for the American College of Rheu-matology. Arthritis in children. Updated May 2013. www.rheumatology.org/practice/clinical/patients/diseases_and_conditions/juvenilearthritis.asp. Accessed October 15, 2014.
8. Centers for Disease Control and Prevention. Child-hood arthritis. Updated October 23, 2013. www.cdc.gov/arthritis/basics/childhood.htm. Accessed October 15, 2014.
9. National Psoriasis Foundation. Psoriasis and comorbid conditions issue brief. Executive summary. January 2012. www.psoriasis.org/document.doc?id=793. Accessed October 17, 2014.
10. National Psoriasis Foundation. Psoriasis severity. www.psoriasis.org/about-psoriasis/treatments/severity. Accessed October 17, 2014.
11. Mayo Clinic staff. Psoriasis. April 11, 2014. www.mayoclinic.org/diseases-conditions/psoriasis/basics/symptoms/con-20030838?p=1. Accessed October 17, 2014.
12. National Psoriasis Foundation. Moderate to severe psoriasis: biologic drugs. www.psoriasis.org/about-psoriasis/treatments/biologics. Accessed October 17, 2014.
13. Brooks M. FDA OKs methotrexate autoinjector (Otrexup). October 18, 2013. Medscape. www.medscape.com/viewarticle/812821. Accessed October 22, 2014.
14. Medac Pharma, Inc. Medac Pharma, Inc. secures FDA approval of Rasuvo (methotrexate) injection for rheumatoid arthritis, poly-articular-course juvenile idiopathic arthritis and psoriasis. Press release. July 14, 2014. www.medacpharma.com/u-s-district-court-for-the-district-of-delaware-concurrently-denies-motion-for-preliminary-injunction-filed-by-antares-pharma-inc/. Accessed November 10, 2014.
15. Rasuvo (methotrexate) injection [prescribing information]. Chicago, IL: Medac Pharma, Inc; July 2014.
16. Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol. 2014;32:563-571.
17. Rutkowska-Sak L, Rell-Bakalarska M, Lisowska B. Oral vs. subcutaneous low-dose methotrexate treatment in reducing gastrointestinal side effects. Reumatologia. 2009;47:207-211.
18. Giannini EH, Brewer EJ, Kuzmina N, et al; for the Pediatric Rheumatology Collaborative Study Group, and the Cooperative Children’s Study Group. Methotrexate in resistant juvenile rheumatoid arthritis: results of the U.S.A.–U.S.S.R. double-blind, placebo- controlled trial. N Engl J Med. 1992;326:1043-1049.

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