Arthritis Care & Research
`Vol. 66, No. 11, November 2014, pp 1604 –1611
`DOI 10.1002/acr.22383
`© 2014, 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 SCHIFF4
`
`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 ⴝ 20,431) were 76.9% women, had a mean ⴞ SD age of 69.7 ⴞ 11.7 years,
`and contributed a median followup of 2.6 years (interquartile range 1.7–3.5 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 ⴝ 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 ar-
`thritis, sarcoidosis, and inflammatory bowel disease. MTX
`is the first-line medication recommended to treat newly
`diagnosed RA patients (1). For patients who do not re-
`spond sufficiently, biologic agents and/or other nonbio-
`logic 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 bioavail-
`ability 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-018517) and an unrestricted educa-
`tional grant from Antares.
`1Jeffrey 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; 2Joaquim Fernandes, MS, Claire Spettell, PhD:
`Aetna Informatics, Blue Bell, Pennsylvania; 3Seth Ginsberg,
`BS: CreakyJoints, New York, New York; 4Michael 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 con-
`sultancy 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, 510 20th
`Street South, FOT 802D, Birmingham, AL 35294. E-mail:
`jcurtis@uab.edu.
`Submitted for publication February 4, 2014; accepted in
`revised form June 10, 2014.
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`Use of MTX in Daily Practice in the US
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`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 real-
`world 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 polygluta-
`mates, which correlates with clinical efficacy (9,10).
`Among MTX-naive patients, the comparative effective-
`ness 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 pa-
`tients 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 differ-
`ence in the ACR50 response was negligible; the ACR20
`difference (89% versus 63%) was more pronounced in
`patients who had a disease duration of ⱖ12 months (6,11).
`In addition to variable bioavailability, oral MTX some-
`times 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 exam-
`ining 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 in-
`surance programs: commercial health plans offered by a
`national health insurer (2005–2012) and Medicare with
`Part A and B, with a Part D drug plan, and no enrollment
`in Medicare Advantage (2006 –2011). We applied identical
`
`eligibility criteria with the intention to capture patients
`who initiated oral MTX monotherapy. Within each pay-
`ment 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, hy-
`droxychloroquine (HCQ), sulfasalazine (SSZ), leflunomide
`(LEF), or any biologic agent. The use of prior HCQ, SSZ,
`and LEF excluded 35% of the commercially insured pa-
`tients 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 pre-
`ceding data used to exclude prior MTX exposure was 21.4
`months (interquartile range [IQR] 12.4 –32.8 months) for
`commercially insured patients and 19.1 months (IQR
`11.3–30.1 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 de-
`termined based on records of filled prescriptions iden-
`tified using national drug codes for pharmacy-filled
`medications or Healthcare Common Procedure Coding
`System codes for infused medications received at physi-
`cian 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 cal-
`culated based on the amount prescribed divided by the
`days of supply.
`
`Patterns of MTX use. We examined a number of de-
`scriptive 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 propor-
`tion 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 formula-
`tion, oral or SC) without a gap in therapy of ⱖ90 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
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`Curtis et al
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`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 con-
`sidered 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 con-
`sidered 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 exam-
`ine persistence on MTX and compared the commercially
`insured to the Medicare-enrolled RA patients using Wil-
`coxon’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 exper-
`tise 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 popula-
`tion, 2 additional covariates were included: the original
`reason for Medicare enrollment (e.g., disability) and re-
`ceipt 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 com-
`mercial 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 51 ⫾ 12
`years and 74% were women. The median followup was 2.4
`years (IQR 1.6 –3.6 years). Patients enrolled in Medicare
`were considerably older (mean ⫾ SD age 70 ⫾ 12 years),
`but both the proportion of women (77%) and duration of
`followup (median 2.6 years [IQR 1.7–3.5 years]) were sim-
`ilar. Steroid use was relatively comparable between co-
`horts. Medicare patients were less likely to take prescrip-
`tion 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†
`
`Demographics
`Age, mean ⫾ SD years
`Women, %
`Duration of followup, median (IQR) years
`Clinical characteristics
`COPD, %
`Diabetes mellitus, %
`Charlson Comorbidity Index, %
`0
`1–2
`ⱖ3
`Hospitalized during baseline period, %
`No. of physician visits during baseline,
`mean ⫾ SD
`Oral glucocorticoid use (daily average
`dose in prednisone equivalents), %
`None
`ⱕ7.5 mg
`⬎7.5 mg
`Any use of NSAIDs, %
`Any use of narcotics, %
`Enrolled in Medicare for reasons other
`than age (e.g., disability), %
`Receipt of low income subsidy, %
`
`Commercial
`data source
`(n ⴝ 4,048)
`
`51.1 ⫾ 11.9
`74.2
`2.4 (1.6–3.6)
`
`10.5
`12.4
`
`64.6
`30.1
`5.3
`8.0
`12.9 ⫾ 10.0
`
`42.0
`38.3
`19.8
`41.7
`46.9
`N/A
`
`N/A
`
`Medicare
`data source
`(n ⴝ 20,431)
`
`69.7 ⫾ 11.7
`76.9
`2.6 (1.7–3.5)
`
`14.9
`18.4
`
`51.3
`39.4
`9.3
`18.5
`10.7 ⫾ 8.4
`
`38.5
`50.0
`11.5
`34.0
`60.8
`36.4
`
`34.0
`
`* RA ⫽ rheumatoid arthritis; MTX ⫽ methotrexate; IQR ⫽ interquartile range; COPD ⫽ chronic obstruc-
`tive 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.
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`Use of MTX in Daily Practice in the US
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`
`Table 2. MTX use among commercially insured and
`Medicare-enrolled RA patients*
`
`Commercially
`insured
`(n ⴝ 4,048)
`
`Medicare
`(n ⴝ 20,431)
`
`13.6 ⫾ 8.7
`
`13.1 ⫾ 8.7
`
`8.7
`30.0
`34.4
`26.9
`
`5.7
`18.6
`28.0
`47.8
`35.3
`
`17.5
`33.5
`28.0
`21.0
`
`11.2
`25.1
`25.5
`38.3
`19.1
`
`Starting MTX dosage,
`mean ⫾ SD mg/week
`All MTX prescriptions
`combined, %
`⬍10 mg/week
`ⱖ10 and ⬍15 mg/week
`ⱖ15 and ⬍20 mg/week
`ⱖ20 mg/week
`Peak MTX dosage anytime
`during followup
`⬍10 mg/week
`ⱖ10 and ⬍15 mg/week
`ⱖ15 and ⬍20 mg/week
`ⱖ20 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 pre-
`scriptions (Table 2). When the peak MTX dose was exam-
`ined, nearly half of the patients received dosages ⱖ20
`mg/week. In contrast, among patients enrolled in Medi-
`care, 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 ⱖ20 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 commer-
`cially 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 sub-
`group of patients, and prior to initiating biologic agents,
`more than one-third of the patients (43% and 50%, respec-
`tively) never received MTX at doses ⱖ20 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*
`
`Initiated an anti-TNF biologic
`agent (rather than a biologic
`agent with a different
`mechanism of action), %
`Months from initiation of MTX to
`initiation of biologic agent,
`median (IQR)
`Median oral MTX dose increase
`before initiating biologic
`agent, median (IQR) mg/week
`Peak MTX dose before initiating
`biologic agent, mean ⫾ SD
`⬍10 mg/week, %
`ⱖ10 and ⬍15 mg/week, %
`ⱖ15 and ⬍20 mg/week, %
`ⱖ20 mg/week, %
`Treatment change before
`initiating biologic agents, %†
`Stayed only on oral MTX
`Switched to SC MTX
`Added HCQ
`Added SSZ
`Added LEF
`
`Commercially insured
`(n ⴝ 1,429)
`
`90.3
`
`Medicare
`(n ⴝ 3,922)
`
`84.3
`
`7.2 (3.5–14.8)
`
`7.1 (3.2–14.6)
`
`2.5 (0.0–7.5)
`
`0.0 (0.0–5.0)
`
`19.3 ⫾ 6.6
`
`18.0 ⫾ 6.6
`
`3.0
`12.7
`26.9
`57.4
`
`81.1
`2.1
`8.8
`4.6
`7.9
`
`6.5
`17.6
`26.3
`49.6
`
`79.0
`3.9
`8.3
`4.5
`8.4
`
`* 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.
`
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`mercially insured patients, although this was statistically
`significant (P ⫽ 0.0003). 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 17.9 –38.7 months)
`for commercially insured patients, and 30.0 months (IQR
`21.1– 40.8 months) for Medicare enrolled patients. Follow-
`ing 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 start-
`ing 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 nonbio-
`logic DMARDs, or increasing MTX dose on time to initi-
`ation of biologic agents. Comparing the treatment strate-
`gies of any dose increase of oral MTX, adding a nonbio-
`logic DMARD, or switching to SC MTX, the adjusted
`Cox regression analysis in commercially insured RA pa-
`tients showed no significant difference in the time to ini-
`tiation of biologic agents between the 3 treatment strate-
`gies (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% confi-
`dence interval 0.53– 0.90]), but there were no other sig-
`nificant 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 repre-
`sent the number of patients at risk, stratified by whether they were
`commercially insured or enrolled in the Medicare program. Per-
`sistence was significantly different at P ⫽ 0.0003.
`
`Figure 2. Changes in oral glucocorticoid use after initiation of
`oral methotrexate among commercially insured rheumatoid ar-
`thritis 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 some-
`what 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 subse-
`quently 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 obser-
`vations (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 gen-
`eral, studies that have shown better long-term persistence
`were generally derived from smaller single-center RA pop-
`ulations 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-
`
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`Use of MTX in Daily Practice in the US
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`Table 4. Multivariable-adjusted association between initiation of biologic agents and RA treatment changes*
`
`Treatment strategies†
`
`Switch to SC MTX
`Increase oral MTX dose
`Additions to oral MTX
`Add LEF
`Add SSZ
`Add HCQ
`
`Commercially insured (n ⴝ 2,672)
`
`Medicare (n ⴝ 12,531)
`
`Commercially
`insured/Medicare, no.
`
`Crude HR
`(95% CI)
`
`Adjusted HR
`(95% CI)
`
`Crude HR
`(95% CI)
`
`Adjusted HR
`(95% CI)
`
`67/574
`2,187/9,509
`
`206/1,030
`133/542
`306/1,421
`
`1.41 (0.70–2.84)
`1.00 (ref.)
`
`1.24 (0.61–2.52)
`1.00 (ref.)
`
`1.60 (1.21–2.11)
`1.00 (ref.)
`
`1.24 (0.93–1.64)
`1.00 (ref.)
`
`1.40 (0.91–2.16)
`1.31 (0.80–2.17)
`1.04 (0.70–1.55)
`
`1.35 (0.86–2.11)
`1.18 (0.71–1.96)
`0.89 (0.59–1.33)
`
`1.29 (0.98–1.69)
`1.35 (1.00–1.83)
`0.83 (0.64–1.07)
`
`1.11 (0.85–1.46)
`1.14 (0.84–1.55)
`0.69 (0.53–0.90)
`
`* 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 out-
`of-pocket costs to patients, it is unlikely that a continuous
`and ongoing pattern of refills (as was used to define per-
`sistence in our analysis) meaningfully misclassified per-
`sistence.
`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 optimiz-
`ing 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 un-
`able 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 intol-
`erance, adverse events (e.g., hepatotoxicity), or other pa-
`tient symptoms. However, our finding that ⬍5% of pa-
`tients ever switched to SC MTX and that about half of all
`patients never received ⱖ20 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 rec-
`ommended starting MTX 15 mg/week orally, escalating to
`25–30 mg/week, and then switching to SC administration
`as the optimal management (21). The ACR and the Euro-
`pean 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 differ-
`ence in the timing and need for initiation of biologic agents
`related to switching to SC MTX or adding different non-
`biologic 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 re-
`ceiving a biologic agent, and trends were similar numeri-
`cally 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 generalizabil-
`ity 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 limita-
`tions. Despite use of at least a 6-month minimum baseline
`period during which patients were free of MTX and phar-
`macy data even prior to that baseline period, it is possible
`that some patients in these cohorts were not truly treat-
`ment naive, as was desired, despite our look back period in
`the data of almost 2 years. Additional supporting evi-
`dence 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-
`
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`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 subse-
`quent 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 descrip-
`tively (25).
`In conclusion, our results provide further information
`regarding MTX as an anchor medication for the manage-
`ment of RA because of its demonstrated long-term effec-
`tiveness 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, al-
`most half of these patients subsequently restarted within
`the next year. However, use of higher dosages of MTX
`(ⱖ20 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 treat-
`ment 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 ap-
`proved the final version to be submitted for publication. Dr. Curtis
`had full access to all of the data in the study and takes responsi-
`bility 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 manu-
`script, 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 Infor-
`matics.
`
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