Use of Oral and Subcutaneous Methotrexate in Rheumatoid Arthritis Patients in the United States

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1 Arthritis Care & Research Vol. 66, No. 11, November 2014, pp DOI /acr , American College of Rheumatology ORIGINAL ARTICLE Use of Oral and Subcutaneous Methotrexate in Rheumatoid Arthritis Patients in the United States JEFFREY R. CURTIS, 1 JIE ZHANG, 1 FENGLONG XIE, 1 TIM BEUKELMAN, 1 LANG CHEN, 1 JOAQUIM FERNANDES, 2 SETH GINSBERG, 3 CLAIRE SPETTELL, 2 HUIFENG YUN, 1 KENNETH G. SAAG, 1 AND MICHAEL SCHIFF 4 Objective. To examine the patterns of methotrexate (MTX) use among rheumatoid arthritis (RA) patients. Methods. Using data from RA patients enrolled in a US commercial health plan and the US Medicare program, we identified RA patients initiating oral MTX. Persistence with MTX (oral or subcutaneous [SC]) was defined as no gap for >90 days. Results. New oral MTX users in Medicare (n 20,431) were 76.9% women, had a mean SD age of years, and contributed a median followup of 2.6 years (interquartile range years). Only 38% received dosages >20 mg/week at any time. Approximately 50% of patients discontinued MTX at 1 year, although more than one-third of patients subsequently restarted. New commercially insured oral MTX users (n 4,048) were similar to Medicare patients, except for age. Among Medicare patients, 19% starting oral MTX subsequently initiated a biologic agent, mostly anti tumor necrosis factor (85%). Of these, only 50% received MTX at a dosage of >20 mg/week, and only 21% of individuals switched to SC MTX (4%) or received hydroxychloroquine (8%), sulfasalazine (5%), or leflunomide (8%) prior to biologic agents. In commercially insured patients, 35% initiated a biologic agent, mostly anti tumor necrosis factor therapies (90%). Of these, 43% never received MTX >20 mg/week. Conclusion. Titration to a higher-dose oral MTX and use of SC MTX among RA patients were infrequent and may have been underutilized. Further work to optimize MTX dosing before patients are switched to a biologic agent may be warranted. INTRODUCTION Methotrexate (MTX) is a folic acid antagonist and is the most commonly used medication for the treatment of rheumatoid arthritis (RA). It is also used to treat other inflammatory conditions, such as psoriasis, psoriatic arthritis, sarcoidosis, and inflammatory bowel disease. MTX is the first-line medication recommended to treat newly diagnosed RA patients (1). For patients who do not respond sufficiently, biologic agents and/or other nonbiologic disease-modifying antirheumatic drugs (DMARDs) may be added or substituted. MTX can be given orally, subcutaneously (SC), or via intramuscular injection. When taken orally, its bioavailability varies considerably (2). On average, two-thirds of MTX taken orally is bioavailable (3), although variability (21 96%) in the bioavailability of MTX can be even larger when higher dosages (between 25 and 40 mg/week) of oral MTX are used (2). Because parenteral MTX allows more complete absorption of MTX, the effect of switching from oral to parenteral MTX has been examined among RA patients with insufficient response to their initial oral MTX; in small studies, switching has been shown to be safe and effective (4 8). Some evidence suggests that Supported by the Agency for Healthcare Research and Quality (grant R01-HS ) and an unrestricted educational grant from Antares. 1 Jeffrey R. Curtis, MD, Jie Zhang, PhD, Fenglong Xie, MS, Tim Beukelman, MD, MSCE, Lang Chen, PhD, Huifeng Yun, PhD, Kenneth G. Saag, MD, MSc: University of Alabama, Birmingham; 2 Joaquim Fernandes, MS, Claire Spettell, PhD: Aetna Informatics, Blue Bell, Pennsylvania; 3 Seth Ginsberg, BS: CreakyJoints, New York, New York; 4 Michael Schiff, MD: University of Colorado, Denver. Dr. Curtis has received consultancy fees and/or research grants (less than $10,000 each) from Pfizer, BMS, Celgene, Crescendo Bioscience, and AbbVie, and (more than $10,000 each) from Roche/Genentech, UCB, Janssen, CORRONA, and Amgen. Dr. Beukelman has received consultancy fees, speaking fees, and/or honoraria (less than $10,000 each) from Genentech, UCB, and Crescendo Bioscience, and (more than $10,000) from Novartis. Dr. Schiff has received consultancy fees, speaking fees, and/or honoraria (less than $10,000 each) from BMS, AbbVie, Novartis, Johnson & Johnson, Amgen, Antares, Biotest, Eli Lilly, and UCB. Address correspondence to Jeffrey R. Curtis, MD, th Street South, FOT 802D, Birmingham, AL jcurtis@uab.edu. Submitted for publication February 4, 2014; accepted in revised form June 10,

2 Use of MTX in Daily Practice in the US 1605 Significance & Innovations Although methotrexate (MTX) is considered an anchor drug for rheumatoid arthritis (RA), its use, titration, and receipt of oral versus subcutaneous MTX has not been well-characterized in realworld settings. In this large cohort of nearly 25,000 RA patients initiating oral MTX, a large proportion of patients did not receive dosages of 20 mg/week or higher, even among the subgroup of patients who went on to initiate a biologic agent. Few patients ever used subcutaneous MTX. On the basis of patterns of use characterized in this analysis, further refinement of the optimal use of MTX appears warranted. MTX given SC can increase longer-chain MTX polyglutamates, which correlates with clinical efficacy (9,10). Among MTX-naive patients, the comparative effectiveness of oral versus SC MTX in RA patients was examined in a recent randomized trial starting with 15 mg/week of MTX. In this trial, a somewhat higher proportion of patients receiving SC MTX compared with oral MTX achieved the American College of Rheumatology (ACR) 20% improvement criteria (ACR20; 78% versus 70%) and ACR70 (41% versus 33%) responses, although the difference in the ACR50 response was negligible; the ACR20 difference (89% versus 63%) was more pronounced in patients who had a disease duration of 12 months (6,11). In addition to variable bioavailability, oral MTX sometimes is associated with gastrointestinal side effects, and patients who experience this condition may benefit from parenteral administration (12). A retrospective cohort study reported that switching from oral MTX to SC MTX improved clinical response, regardless of whether the switching reason was inefficacy or poor gastrointestinal tolerability (13). Switching to parenteral MTX has been advocated by some to be a cost-effective alternative prior to stepping up to biologic agents (5). However, there are little data examining the use of MTX in RA patients in routine practice in the US. In the present study, we aimed to examine the epidemiology of MTX use among RA patients initiating MTX, including dosing, method of administration (oral versus SC), and persistence, and compare the effectiveness of 2 strategies in regard to delaying or avoiding use of biologic agents: switching to SC MTX or adding another nonbiologic DMARD. PATIENTS AND METHODS Patient population. To examine a more diverse cohort, we studied RA patients enrolled in 2 different health insurance programs: commercial health plans offered by a national health insurer ( ) and Medicare with Part A and B, with a Part D drug plan, and no enrollment in Medicare Advantage ( ). We applied identical eligibility criteria with the intention to capture patients who initiated oral MTX monotherapy. Within each payment plan, we identified individuals who initiated oral MTX after a continuous 6-month period with medical and pharmacy benefits. Patients were required to have at least 2 RA diagnosis codes from a physician and could not have received any of the following RA medications during the 6-month baseline period or on the index date: MTX, hydroxychloroquine (HCQ), sulfasalazine (SSZ), leflunomide (LEF), or any biologic agent. The use of prior HCQ, SSZ, and LEF excluded 35% of the commercially insured patients and 33% of the Medicare-enrolled patients that would have otherwise been eligible for the analysis, and 3.6% of the commercially insured patients and 1.8% of the Medicare enrollees who started MTX and biologic agents on the same day. All pharmacy data in and prior to the 6-month baseline period were searched to exclude patients with any prior use of MTX. The median amount of preceding data used to exclude prior MTX exposure was 21.4 months (interquartile range [IQR] months) for commercially insured patients and 19.1 months (IQR months) for Medicare enrollees. Followup started at the time of oral MTX initiation, defined as the index date, and ended when the patient lost coverage or at the end of the study period. Ascertainment of RA medication use. Use of MTX, other nonbiologic DMARDs, and biologic agents was determined based on records of filled prescriptions identified using national drug codes for pharmacy-filled medications or Healthcare Common Procedure Coding System codes for infused medications received at physician offices or hospitals. For each day during followup, medication exposure to MTX and other nonbiologic DMARDs was determined based on the prescription date and days of supply. The weekly oral MTX dose was calculated based on the amount prescribed divided by the days of supply. Patterns of MTX use. We examined a number of descriptive outcomes to characterize the use of MTX. We examined the frequency of MTX used at various doses among all filled prescriptions of oral MTX, the proportion of patients who increased their oral MTX dose or switched to SC MTX, the peak (i.e., maximum) MTX dose and peak MTX dose among the subgroup of patients who later initiated a biologic agent, and the proportion of patients who added HCQ, SSZ, or LEF. Persistence with MTX was defined as remaining on MTX (in any formulation, oral or SC) without a gap in therapy of 90 days. The dose of SC MTX was not estimated, given the uncertainty in the data regarding the relationship between the volume of MTX dispensed, the dose prescribed by the provider, and the potential of some volume being wasted by the patient. Association between addition of a biologic agent and use of an increased dose of oral MTX, SC MTX, and nonbiologic DMARDs. We subsequently evaluated time to initiating a biologic agent conditional to patients following 1 of the following 3 treatment strategies, which were the

3 1606 Curtis et al main exposure variables of interest: increasing the oral MTX dose; adding HCQ, SSZ, or LEF to oral MTX; or switching from oral MTX to SC MTX. For this analysis, patients were censored if they discontinued all MTX use (oral or SC). Each of these 3 treatment strategies was considered as time varying, and patients who adopted 1 were considered exposed to both. For example, a patient who switched to SC MTX and then added HCQ was considered exposed and contributed person time to the 2 treatment changes. The start of followup for this analysis began at the first date that a patient adopted any of these 3 treatment strategies. Statistical analysis. We examined the distribution of patient demographics and MTX use during the entire followup period. We used Kaplan-Meier graphs to examine persistence on MTX and compared the commercially insured to the Medicare-enrolled RA patients using Wilcoxon s rank sum test. Finally, we used Cox proportional hazards regression to examine whether the 3 treatment strategies were different with regard to time to initiation of biologic agents, adjusting for potentially confounding variables that were selected based upon content expertise and hypothesized associations with initiation of biologic agents. These variables included age, sex, use of oral glucocorticoids, nonsteroidal antiinflammatory drugs (NSAIDs), narcotics, inpatient and outpatient visits during baseline, and dose of oral MTX; in the Medicare population, 2 additional covariates were included: the original reason for Medicare enrollment (e.g., disability) and receipt of state subsidy (as a proxy for low income). All analyses were done in SAS, version 9.2. The university Institutional Review Board approved the study, and use of the data was governed by data use agreements with the Centers for Medicare and Medicaid Services and the commercial health plan. RESULTS Among RA patients enrolled in the commercial health plan, we identified a total of 4,048 new MTX users who were eligible to be included in the analysis (Table 1). Among these patients, the mean SD age was years and 74% were women. The median followup was 2.4 years (IQR years). Patients enrolled in Medicare were considerably older (mean SD age years), but both the proportion of women (77%) and duration of followup (median 2.6 years [IQR years]) were similar. Steroid use was relatively comparable between cohorts. Medicare patients were less likely to take prescription NSAIDs and more likely to take narcotics. Table 1. Characteristics of RA patients initiating oral MTX by type of health insurance program (commercial insurance versus Medicare)* Patient characteristics Commercial data source (n 4,048) Medicare data source (n 20,431) Demographics Age, mean SD years Women, % Duration of followup, median (IQR) years 2.4 ( ) 2.6 ( ) Clinical characteristics COPD, % Diabetes mellitus, % Charlson Comorbidity Index, % Hospitalized during baseline period, % No. of physician visits during baseline, mean SD Oral glucocorticoid use (daily average dose in prednisone equivalents), % None mg mg Any use of NSAIDs, % Any use of narcotics, % Enrolled in Medicare for reasons other N/A 36.4 than age (e.g., disability), % Receipt of low income subsidy, % N/A 34.0 *RA rheumatoid arthritis; MTX methotrexate; IQR interquartile range; COPD chronic obstructive pulmonary disease; NSAIDs nonsteroidal antiinflammatory drugs; N/A not applicable. All factors measured in the 6-month baseline period prior to the start of followup, which began when patients initiated oral MTX.

4 Use of MTX in Daily Practice in the US 1607 Table 2. MTX use among commercially insured and Medicare-enrolled RA patients* Commercially insured (n 4,048) Medicare (n 20,431) Starting MTX dosage, mean SD mg/week All MTX prescriptions combined, % 10 mg/week and 15 mg/week and 20 mg/week mg/week Peak MTX dosage anytime during followup 10 mg/week and 15 mg/week and 20 mg/week mg/week Patients who initiated a biologic agent at any time * Values are the percentage unless indicated otherwise. MTX methotrexate; RA rheumatoid arthritis. MTX use during followup. Among patients enrolled in the commercial health plan, the most commonly taken MTX dosages were between 15 and 20 mg/week, accounting for approximately one-third of all MTX prescriptions (Table 2). When the peak MTX dose was examined, nearly half of the patients received dosages 20 mg/week. In contrast, among patients enrolled in Medicare, the most common dosage of MTX was between 10 and 15 mg/week. Almost 40% of the Medicare patients received a maximum dosage of MTX of 20 mg/week. However, in contrast to commercially insured patients, more than one-third of patients never received 15 mg/ week of MTX or higher. MTX use prior to initiating biologic agents. In commercially insured RA patients, 35% initiated a biologic agent, compared with 19% in the Medicare population (Table 3). Most of the initial biologic agents used were anti tumor necrosis factor (anti-tnf) therapy (84 90%). In this subgroup of patients, and prior to initiating biologic agents, more than one-third of the patients (43% and 50%, respectively) never received MTX at doses 20 mg. In both RA populations, 80% of patients were treated with only oral MTX and did not add or switch to other nonbiologic DMARDs; 5% of patients received SC MTX in either cohort. Persistence with MTX. Approximately 50% of patients discontinued MTX at one year, regardless of the route of administration (Figure 1). The proportion discontinuing was numerically similar between the Medicare and com- Table 3. MTX use among commercially insured and Medicare-enrolled RA patients who initiated a biologic agent during followup* Commercially insured (n 1,429) Medicare (n 3,922) Initiated an anti-tnf biologic agent (rather than a biologic agent with a different mechanism of action), % Months from initiation of MTX to 7.2 ( ) 7.1 ( ) initiation of biologic agent, median (IQR) Median oral MTX dose increase 2.5 ( ) 0.0 ( ) before initiating biologic agent, median (IQR) mg/week Peak MTX dose before initiating biologic agent, mean SD 10 mg/week, % and 15 mg/week, % and 20 mg/week, % mg/week, % Treatment change before initiating biologic agents, % Stayed only on oral MTX Switched to SC MTX Added HCQ Added SSZ Added LEF * MTX methotrexate; RA rheumatoid arthritis; anti-tnf anti tumor necrosis factor; IQR interquartile range; SC subcutaneous; HCQ hydroxychloroquine; SSZ sulfasalazine; LEF leflunomide. Except for staying only on oral MTX, categories are not mutually exclusive.

5 1608 Curtis et al mercially insured patients, although this was statistically significant (P ). Among the subgroup of patients discontinuing MTX who had at least one subsequent year of followup (n 2,419 commercially insured patients and n 15,216 patients enrolled in Medicare), the median followup time was 26.1 months (IQR months) for commercially insured patients, and 30.0 months (IQR months) for Medicare enrolled patients. Following MTX discontinuation in this subgroup, 37% of the commercially insured patients and 41% of the Medicare patients subsequently restarted MTX within the next 12 months. The changes in oral glucocorticoid use after starting MTX are shown in Figure 2. Among patients who previously received oral glucocorticoids in the 6 months prior to initiating MTX, 25 35% of patients were able to stop altogether, and even more patients were able to use glucocorticoids at lower doses. Effect of switching to SC MTX, adding other nonbiologic DMARDs, or increasing MTX dose on time to initiation of biologic agents. Comparing the treatment strategies of any dose increase of oral MTX, adding a nonbiologic DMARD, or switching to SC MTX, the adjusted Cox regression analysis in commercially insured RA patients showed no significant difference in the time to initiation of biologic agents between the 3 treatment strategies (Table 4). The corresponding analysis in the Medicare data found that those who added HCQ compared with those who increased oral SC MTX dose were less likely to initiate a biologic agent (hazard ratio 0.69 [95% confidence interval ]), but there were no other significant differences between the groups after multivariable adjustment. DISCUSSION MTX has been commonly described as the anchor drug in RA (14) and its use has increased appreciably over time (15 17). In this study of 25,000 RA patients initiating Figure 1. Persistence with methotrexate (oral or subcutaneous) among new users for rheumatoid arthritis patients enrolled in Medicare or a commercial health plan. The time since initiation was measured in days. The values listed above the x-axis represent the number of patients at risk, stratified by whether they were commercially insured or enrolled in the Medicare program. Persistence was significantly different at P Figure 2. Changes in oral glucocorticoid use after initiation of oral methotrexate among commercially insured rheumatoid arthritis patients (A) and Medicare enrollees (B). Period refers to 6-month intervals following the start of oral methotrexate. oral MTX, we found that the use of oral MTX at dosages of at least 20 mg/week and switching to SC MTX were somewhat uncommon, even for patients who went on to require a biologic agent. We found that, although 50% of patients discontinued MTX (either oral or SC) within 1 2 years after starting, between one-third and one-half of these patients subsequently restarted therapy, reinforcing MTX as a relatively well-tolerated anchor drug in RA. Prior studies have found that persistence with MTX was comparable to our observations (16) or even better (17 20). Some variability in the proportion of patients considered adherent exists because of differences in the definition of adherence, source of data about adherence (e.g., patient self-report, clinician report, pharmacy data, Medication Event Monitoring System cap devices), practice settings, and extent of followup. In general, studies that have shown better long-term persistence were generally derived from smaller single-center RA populations using methods that may be more subjective (e.g., patient self-report) or obtained in settings that may not be generalizable to the majority of typical RA patients. We recognize that pharmacy data, like those used in this ana-

6 Use of MTX in Daily Practice in the US 1609 Table 4. Multivariable-adjusted association between initiation of biologic agents and RA treatment changes* Commercially insured (n 2,672) Medicare (n 12,531) Treatment strategies Commercially insured/medicare, no. Crude HR (95% CI) Adjusted HR (95% CI) Crude HR (95% CI) Adjusted HR (95% CI) Switch to SC MTX 67/ ( ) 1.24 ( ) 1.60 ( ) 1.24 ( ) Increase oral MTX dose 2,187/9, (ref.) 1.00 (ref.) 1.00 (ref.) 1.00 (ref.) Additions to oral MTX Add LEF 206/1, ( ) 1.35 ( ) 1.29 ( ) 1.11 ( ) Add SSZ 133/ ( ) 1.18 ( ) 1.35 ( ) 1.14 ( ) Add HCQ 306/1, ( ) 0.89 ( ) 0.83 ( ) 0.69 ( ) * Adjusted for age; sex; Charlson Comorbidity Index (26); use of oral glucocorticoids, NSAIDs, and narcotics; inpatient and outpatient visits during baseline; and dose of oral MTX at the start of followup. In the Medicare population, 2 additional covariates were included: original reason for Medicare enrollment (e.g., disability) and receipt of state subsidy (as a proxy for low income). Analysis was limited to the subgroup of patients who increased their dose of oral methotrexate (MTX), switched to subcutaneous (SC) MTX, or added leflunomide (LEF), sulfasalazine (SSZ), or hydroxychloroquine (HCQ). RA rheumatoid arthritis; HR hazard ratio; 95% CI 95% confidence interval. Analyzed as a time-varying covariate. lysis, might be subject to uncertainty regarding whether patients are actually taking the medication as prescribed. However, given that the medications studied required outof-pocket costs to patients, it is unlikely that a continuous and ongoing pattern of refills (as was used to define persistence in our analysis) meaningfully misclassified persistence. In 2 large cohorts of RA patients, we observed that between 3% and 4% of RA patients switched from oral to SC MTX, and that fewer than 1 in 4 patients added HCQ, SSZ, or LEF. These low proportions suggest that optimizing nonbiologic DMARDs may be underutilized in the US. Another important observation of our study was that the most common dosages of MTX used were 10 mg/week and 15 mg/week, whereas titration to a dosage higher than 20 mg/week ever during followup occurred in only 38 48% of the patients. Even among those RA patients who later initiated biologic agents, titration of MTX to 20 mg/week occurred only slightly more frequently (50 57% of all patients) than in the overall analysis. While we were unable to assess the reason behind the clinical decisions to not switch to SC MTX or to add other nonbiologic DMARDs and not to titrate to higher MTX doses, these decisions may be clinically appropriate based upon intolerance, adverse events (e.g., hepatotoxicity), or other patient symptoms. However, our finding that 5% of patients ever switched to SC MTX and that about half of all patients never received 20 mg/week of MTX suggests that the use of MTX may not have been optimized to realize its full clinical potential. In a systemic review of the literature pertaining to the optimal dose and route of MTX for RA, based on clinical evidence, the authors recommended starting MTX 15 mg/week orally, escalating to mg/week, and then switching to SC administration as the optimal management (21). The ACR and the European League Against Rheumatism have recommended MTX, alone or with other medications, to be the first-line treatment for the management of active RA (1). Our analyses also addressed whether there is a difference in the timing and need for initiation of biologic agents related to switching to SC MTX or adding different nonbiologic DMARDs when oral MTX alone is unable to achieve the desired clinical benefit. We found that there was not a statistically significant difference in the time to initiation of biologic agents between patients treated with these approaches for commercially insured patients. Among Medicare enrollees, adding HCQ to oral MTX was associated with a reduced likelihood of subsequently receiving a biologic agent, and trends were similar numerically but not significant (although perhaps underpowered) in the younger, commercially insured patients. While this could represent a true benefit of treatment strategies that include HCQ (22), a cautious interpretation of this result is warranted because of the possibility of confounding by indication. In other words, less active RA patients might preferentially receive HCQ, a drug that could be perceived as less toxic, albeit somewhat less effective, and thus more suitable for patients who do not need more aggressive treatment. A major strength of our study is the consistency in our multiple analyses for 2 different RA patient populations. Other strengths include large numbers of patients and well-defined patient populations with high generalizability to RA patients enrolled in commercial health insurance plans in the US and the inclusion of all patients enrolled in fee-for-service Medicare with pharmacy benefits. Our results must be considered in light of some limitations. Despite use of at least a 6-month minimum baseline period during which patients were free of MTX and pharmacy data even prior to that baseline period, it is possible that some patients in these cohorts were not truly treatment naive, as was desired, despite our look back period in the data of almost 2 years. Additional supporting evidence that we had identified a new-onset RA population came from the fact that, among those who later initiated a biologic agent, most initiated anti-tnf therapy, the most common first-line choice for biologics-naive RA patients. By way of contrast, in a prior study, we examined RA patients enrolled in Medicare initiating a biologic agent with prior use of a different biologic agent in the preceding 12 months and found that only 43% of patients received etanercept, infliximab, or adalimumab among those who had prior exposure to a different biologic agent (23). The much higher proportion of anti-tnf use in our Medi-

7 1610 Curtis et al care population (85%) suggests that a majority of patients in this analysis were biologic naive, if not RA treatment naive. As an additional limitation, the health plan data used lacked information on clinical phenotype, including RA severity, disease activity, or reasons for medication discontinuation or switching. It is possible that the reason for switching could have an important impact on subsequent outcomes (24), but this was not captured within our data. Finally, we recognize the potential role for low-dose glucocorticoid therapy as adjunctive therapy to MTX, although we characterized steroid use only descriptively (25). In conclusion, our results provide further information regarding MTX as an anchor medication for the management of RA because of its demonstrated long-term effectiveness in large controlled trials. Persistence as shown in this analysis was reasonably good; even though 60% of patients stopped therapy at any time over 3 years, almost half of these patients subsequently restarted within the next year. However, use of higher dosages of MTX ( 20 mg/week) was suboptimal, as was use of SC MTX. Further data to inform how best to optimize the use of MTX appear warranted, given our findings that MTX treatment may not be maximized in real-world settings, even for people in whom biologic agents might be needed. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Curtis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Curtis, Zhang, Xie, Beukelman, Chen, Ginsberg, Saag, Schiff. Acquisition of data. Curtis, Xie, Fernandes, Ginsberg, Spettell, Saag. Analysis and interpretation of data. Curtis, Zhang, Xie, Beukelman, Chen, Ginsberg, Yun, Saag, Schiff. ROLE OF THE STUDY SPONSOR Antares had no role in the study design or in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Antares. ADDITIONAL DISCLOSURES Authors Fernandes and Spettell are employees of Aetna Informatics. REFERENCES 1. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al update of the 2008 American College of Rheumatology recommendations for the use of diseasemodifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64: Hamilton RA, Kremer JM. Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis. 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