David J. Harrison, PhD

: To compare estimated actual dosing of etanercept and ustekinumab in patients with psoriasis and/or psoriatic arthritis with recommended dosing, and to estimate annual cost of these psoriasis treatments.

: Retrospective, observational cohort study.

: Administrative claims data from a commercial claims database from January 1, 2010, through December 31, 2013, were analyzed. Patients had a diagnosis of psoriasis and/or psoriatic arthritis, and continuous enrollment with medical and pharmacy benefits for the 12-month preindex period and the 12-month post index follow-up period. Dosing was determined with actual-to-expected dose ratios computed while patients were persistent to therapy. Expected dose was calculated according to US Package Inserts; expected weight-based dosing of ustekinumab was estimated using random weight assignment based on starting dose. Annual psoriasis-related costs consisting of biologics, nonbiologic psoriasis therapies, and psoriasis-related healthcare utilization were calculated.

: Data from 2997 patients (2128 etanercept, 869 ustekinumab) were analyzed. Actual-to-expected dose ratios (SD) for etanercept and ustekinumab were 0.939 (0.304) and 1.169 (0.687), respectively, for all patients; 1.012 (0.295) and 1.164 (0.666) for patients with psoriasis but without psoriatic arthritis; and 0.783 (0.261) and 1.203 (0.813) for patients with psoriatic arthritis. Annual costs (SD) for all patients were $28,291 ($13,296) and $37,537 ($17,209) for etanercept and ustekinumab, respectively; for psoriasis patients without psoriatic arthritis, they were $29,712 ($13,988) and $36,976 ($16,817), respectively; and for patients with psoriatic arthritis, they were $25,246 ($11,084) and $41,068 ($19,199), respectively.

Conclusions: Actual-to-expected dosing ratios and annual costs were lower for etanercept than for ustekinumab in patients with psoriasis and/or psoriatic arthritis.

Actual use of medications is important for payers to predict the cost of a treatment. Low variation between actual versus expected dosing can reduce the uncertainty of drug expenses, which can be beneficial from the payer’s budgeting perspective. There is a lack of evidence on actual dosing versus expected dosing patterns and costs of biologic therapies used for psoriasis and/or psoriatic arthritis. Drugs that possess the combined characteristics of low expected cost and minimal uncertainty of such cost would be optimal to payers.

Etanercept (a tumor necrosis factor inhibitor) and ustekinumab (an interleukin [IL]-12 and IL-23 blocker) are commonly used biologic therapies for the treatment of moderate to severe plaque psoriasis, with both drugs being efficacious in treating psoriatic arthritis. Etanercept for psoriasis is administered subcutaneously (SC) at a starting dose of 100 mg/week for 12 weeks followed by a maintenance dose of 50 mg/week.

 Ustekinumab is administered SC based on weight: 45 mg for patients weighing ≤100 kg (220 lbs) and 90 mg for patients >100 kg, with the first 2 doses 4 weeks apart followed by a dose every 12 weeks.

 These biologics are expected to be generally representative of biologics used to treat plaque psoriasis that use standard dosing and weight-based dosing.

A study by Thayer et al that examined actual versus expected dosing with etanercept showed that patients with psoriasis and/or psoriatic arthritis used 89% to 107% of the expected dose based on claims data from 2003 to 2008.

 This wide range was dependent on whether dosing was based on the psoriasis or psoriatic arthritis indication. Actual versus expected dosing patterns and costs for ustekinumab or other biologics used to treat moderate to severe plaque psoriasis have not been reported to date. The objective of this study was to estimate current actual dosing of etanercept and ustekinumab in patients with psoriasis and/or psoriatic arthritis and compare it with the recommended dosing in the US Package Inserts (USPIs), and to estimate annual psoriasis-related costs.

Data for this analysis were obtained from the Truven Health MarketScan Commercial Claims and Encounters Database. This database contains the annual inpatient, outpatient, and outpatient prescription drug experience of 30 million commercially insured US patients. Enrollees are covered under a variety of fee-for-service and managed care health plans, including exclusive provider organizations, preferred provider organizations, point-of-service health insurance plans, indemnity plans, and health maintenance organizations.

This was a retrospective, observational cohort study based on US administrative claims data from the Truven Health MarketScan® Commercial Database. Data were collected from January 1, 2010, through December 31, 2013 (Figure 1). The first new claim for etanercept or ustekinumab (index agent) between January 1, 2011, and December 31, 2012, was the index event/date. The baseline period comprised the 12 months prior to the index date, and the follow-up period was the 12 months after the index date. Patients were new to any biologic and had no outpatient medical claim or prescription claim for any biologic approved prior to initiation of the index agent.

Inclusion criteria were: an outpatient medical or prescription claim for etanercept or ustekinumab between January 1, 2011, and December 31, 2012; continuous enrollment with medical and pharmacy benefits for the 12-month baseline period and the 12-month follow-up period; aged 18 to 63 years on index date; and a diagnosis of psoriasis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 696.1x) and/or a diagnosis of psoriatic arthritis (ICD-9-CM code 696.0x) during the baseline period. Exclusion criteria included a diagnosis for any other indication for etanercept, including rheumatoid arthritis (ICD-9-CM code 714.0x), juvenile idiopathic arthritis (ICD-9-CM code 714.3x), or ankylosing spondylitis (ICD-9-CM code 720.0x); evidence of index biologic medication use during the baseline period; evidence of ≥2 claims for a different biologic on the index date; or evidence of receiving an outlier dose during the follow-up period. Outlier doses for etanercept were <12.25 mg (half the minimum label dose) or >200 mg (double the maximum label dose) per week, and for ustekinumab were <11.25 mg or >180 mg per claim.

Outcomes included the estimate of the ratio of actual dosing to expected dosing as defined by the USPI while persistent on index medication (no gap ≥45 days and no switching) during the follow-up period. For patients on ustekinumab, patient weight was inferred because weight data are not included in the database. Individual patient weight was assigned based on starting dose such that patients who initiated ustekinumab with an initial dose >67.5 mg were assumed to be high-weight patients (>100 kg) who required a dose of 90 mg; the remaining patients who initiated at a dose ≤67.5 mg were considered low-weight (≤100 kg), requiring a dose of 45 mg (weight based on starting dose). A preliminary query of the data indicated that 47.4% of patients initiated a dose closer to 90 mg per claim, while 52.6% of patients initiated with a dose closer to 45 mg per claim. As a sensitivity analysis, weight distributions from similar age and gender groups were derived from clinical trial data,

 where ~69% of psoriasis patients weighed ≤100 kg and 31% weighed >100 kg. Patient weight was assigned as a dichotomous variable so that the distribution of the study sample matched the weight distribution reported by Lebwohl et al (midpoint weight assignment).

These weight distributions were used to inform the expected dose for ustekinumab in this study population, and results for patients on ustekinumab represent the average for the entire cohort.

Annual treatment costs during the follow-up period were calculated. Costs included index biologic costs, total biologic therapy costs (for patients who switched biologics), and total psoriasis-related costs. Psoriasis-related costs included the cost of inpatient, outpatient, emergency department claims with a diagnosis of psoriasis in the primary diagnosis position, and costs of all nonbiologic and biologic agents approved for psoriasis treatment, including topical prescription therapy, phototherapy, and oral or intravenous corticosteroids. Healthcare costs were adjusted to 2013 US dollars using the Medical Care component of the Consumer Price Index.

This study was descriptive only, and no formal hypothesis was tested. Actual dosing data were calculated during the time period when patients were persistent (no gap ≥45 days and no switching). Descriptive results were stratified by diagnosis (all psoriasis patients with or without psoriatic arthritis, psoriasis patients without psoriatic arthritis, and patients with psoriatic arthritis). Chi-square and t tests were used to compare categorical and continuous variables, respectively, between etanercept and ustekinumab.

A total of 2997 eligible patients (2128 etanercept, 869 ustekinumab) were identified in the database. The mean age was 45 years, and slightly more than half of patients were male (Table 1). Patients on etanercept and those on ustekinumab had similar baseline Deyo Charlson Comorbidity Index scores. More patients on etanercept had psoriatic arthritis (n = 677; 31.8%) compared with patients on ustekinumab (n = 119; 13.7%).

For psoriasis patients with or without psoriatic arthritis, the actual mean (SD) dose for etanercept was 2176 (1255) mg and was 195 (130) mg for ustekinumab during the 12-month follow-up. Ratios of actual doses to expected doses were slightly higher for patients on ustekinumab based on random weight assignment than for patients on etanercept (Figure 2). In the sensitivity analysis, ratios were lower for ustekinumab based on midpoint weight assignment compared with weight based on starting dose.

Total psoriasis-related costs were lower for etanercept than for ustekinumab during the 12-month follow-up period (P <.001), including index biologic costs (P <.001) and other psoriasis- or psoriatic arthritis—related costs (P = .034) (Table 2). Annual costs (SD) for all patients were $28,291 ($13,296) and $37,537 ($17,209) for etanercept and ustekinumab, respectively; for psoriasis patients without psoriatic arthritis, they were $29,712 ($13,988) and $36,976 ($16,817); and for patients with psoriatic arthritis, they were $25,246 ($11,084) and $41,068 ($19,199). Across all patients, the annual cost for biologic therapy (SD) was $26,784 ($13,072) for etanercept and $35,686 ($16,897) for ustekinumab.

In this study of real-world etanercept and ustekinumab dosing patterns for moderate to severe plaque psoriasis and/or psoriatic arthritis, we found higher than expected rates of high-dose ustekinumab use. In contrast, actual doses of etanercept were lower than expected across all patients and for those patients with psoriatic arthritis, and were slightly above expected doses among patients with psoriasis only. Managers of healthcare plans that attempt to predict costs of ustekinumab should consider these findings and should not make assumptions on weight-based dosing based on patient populations enrolled in clinical trials.

Trends observed in this study are consistent with an analysis of administrative claims data by Thayer et al

 that evaluated etanercept treatment patterns in psoriasis patients with and without psoriatic arthritis. In the Thayer study, patients with only psoriasis received 107% of the expected dose (compared with 100% in our analysis), and patients with psoriatic arthritis received 89% of the expected dose (compared with 78% in our analysis).

A possible reason for the differences in etanercept and ustekinumab actual-to-expected dosing ratios observed in our study may be due to dose escalations and reductions. An analysis based on administrative claims data showed that patients on etanercept had a higher rate of dose escalation at 12 months of treatment (41.0%) compared with those on ustekinumab (35.9%), but the etanercept cohort also had higher rates of dose reductions (48.7%) compared with the ustekinumab cohort (37.4%).

 A cross-sectional study of a clinical practice in Spain reported dose escalation in 17.9% and 4.2% of patients on ustekinumab and etanercept, respectively, and dose reductions in 46.4% and 41.6%.

 The overall annual mean reduction in dose per patient was 0.9% for ustekinumab and 13.8% for etanercept.

 In a phase 3 trial of ustekinumab, 51% of patients had an increase in dose based on an efficacy algorithm.

 In a randomized controlled trial of etanercept, dose reductions were not associated with a decrease in efficacy.

Limitations of the study were inherent to the use of claims data for retrospective analyses. The results are limited to individuals with commercial health coverage and may not be generalizable to uninsured or underinsured patients, or those on Medicare. Claims could be misclassified and could be subject to data coding and entry errors. Cost data were associated with outpatient medical procedures, and line items could not be identified separately, which may have affected cost estimations. Administrative claims data do not contain information on disease severity or effects of treatment. It is not possible to determine whether patients had only psoriatic arthritis, which may warrant a different dosing regimen. Also, dose and weight distributions were not comparable with the results from the study used to estimate weight distributions.

 In this analysis, a higher proportion of patients (~50%) initiated at 90 mg, resulting in higher than expected doses using the random weight assignment for ustekinumab. It is possible that some patients received ustekinumab at an incorrect weight-based dose (eg, a 45-mg dose for a patient who weighed more than 100 kg).

Patients initiating psoriasis and/or psoriatic arthritis treatment with etanercept had a 20% lower actual-versus-expected dosing ratio while persistent on therapy and 25% lower total annual psoriasis-related costs than did patients initiating ustekinumab. These results suggest that products with variable dosing, such as ustekinumab, can introduce cost-related uncertainties for payers.

Dikran Toroser (Amgen Inc) and Julia R. Gage (on behalf of Amgen Inc) provided medical writing support.

: Truven Health Analytics (MB, KW, AH), Cambridge, MA; Amgen Inc (DHT, DJH, BSS), Thousand Oaks, CA.

: This study was sponsored by Immunex, a wholly owned subsidiary of Amgen Inc, and by Wyeth, which was acquired by Pfizer in October 2009.

: Dr Bonafede, Ms Wilson, and Ms Huang are employees of Truven Health Analytics, which received funding from Amgen Inc, for this study. Dr Tang is a former employee and current shareholder of Amgen Inc.

Drs Harrison and Stolshek are employees and shareholders of Amgen Inc.

: Concept and design (MB, DHT, KW, AH, DJH); acquisition of data (MB, KW, AH); analysis and interpretation of data (MB, DHT, KW, AH, DJH, BSS); drafting of the manuscript (MB); critical revision of the manuscript for important intellectual content (MB, DHT, KW, AH, DJH, BSS); statistical analysis (MB, KW, AH); provision of patients or study materials (MB); administrative, technical, or logistic support (DHT, KW, AH); and supervision (DHT, BSS).

 Machaon Bonafede, PhD, MPH, Truven Health Analytics, 150 Cambridge Park Dr, Cambridge, MA 02140. E-mail: 

1. Enbrel (etanercept) [prescribing information]. Thousand Oaks, CA: Immunex Corp; 2015.

2. Stelara (ustekinumab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; 2012.

3. Thayer S, Watson C, Song R, Globe DR, Harrison DJ. Etanercept treatment patterns in managed-care patients with psoriasis or psoriatic arthritis. J Med Econ. 2010;13(2):228-235. doi: 10.3111/13696998.2010.487469.

4. Lebwohl M, Yeilding N, Szapary P, et al. Impact of weight on the efficacy and safety of ustekinumab in patients with moderate to severe psoriasis: rationale for dosing recommendations. J Am Acad Dermatol. 2010;63(4):571-579. doi: 10.1016/j.jaad.2009.11.012.

5. Feldman SR, Zhao Y, Navaratnam P, Friedman HS, Lu J, Tran MH. Patterns of medication utilization and costs associated with the use of etanercept, adalimumab, and ustekinumab in the management of moderate-to-severe psoriasis. J Manag Care Spec Pharm. 2015;21(3):201-209.

6. Baniandrés O, Rodríguez-Soria VJ, Romero-Jiménez RM, Suárez R. Dose modification in biologic therapy for moderate to severe psoriasis: a descriptive analysis in a clinical practice setting. Actas Dermosifiliogr. 2015;106(7):569-577. doi: 10.1016/j.ad.2015.02.003.

7. Langley RG, Lebwohl M, Krueger GG, et al; PHOENIX 2 Investigators. Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up. Br J Dermatol. 2015;172(5):1371-1383. doi: 10.1111/bjd.13469. 

8. Papp KA, Tyring S, Lahfa M, et al; Etanercept Psoriasis Study Group. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152(6):1304-1312.

Articles

For patients with psoriasis and/or psoriatic arthritis, actual-to-expected dosing ratios and costs were lower for etanercept than for ustekinumab.

Etanercept and Ustekinumab Dosing for Psoriasis and Psoriatic Arthritis

: To examine the association between treatment compliance with biologics approved for rheumatoid arthritis (RA) and 1-year total and RA-specific nonbiologic healthcare costs.

: Retrospective analysis of MarketScan Commercial Database claims data from July 1, 2009, to December 31, 2013.

: Non-elderly adults (aged 18-63 years) with RA initiating treatment (index date) with a first-line biologic, with continuous plan enrollment for 6 months preindex and 12 months post index, were eligible. Outcomes included compliance (using proportion of days covered [PDC]) and persistence. Associations between compliance and total and RA-specific nonbiologic costs were assessed.

: Data from 14,696 patients were analyzed. Mean PDC (SD) was 0.65 (0.31); 46.8% of patients were persistent on index biologic. Mean total healthcare costs were $44,387 for intravenous abatacept, $40,434 for subcutaneous abatacept, $33,422 for adalimumab, $36,599 for certolizumab pegol, $33,214 for etanercept, $34,381 for golimumab, and $40,188 for infliximab. Compared with poorly compliant patients (PDC <0.2), total nonbiologic incremental costs for more compliant patients with PDC 0.2 to <0.4, 0.4 to <0.6, 0.6 to <0.8, and ≥0.8, respectively, were lower at —$1678 (cost ratio [CR] = 0.91; 95% CI, 0.86-0.97; P = .0025), –$4158 (CR = 0.78; 95% CI, 0.74-0.83; P <.0001), –$5127 (CR = 0.73; 95% CI, 0.69-0.78; P <.0001), and –$7961 (CR = 0.58; 95% CI, 0.56-0.62; P <.0001). The respective RA-related incremental nonbiologic costs, compared to poorly compliant patients, were $186 (CR = 1.08; 95% CI, 1.02-1.15; P = .0067), –$168 (CR = 0.92; 95% CI, 0.87-0.98; P = .0126), –$225 (CR = 0.90; 95% CI, 0.85-0.95; P = .0002), and –$560 (CR = 0.75; 95% CI, 0.71-0.79; P <.0001).

: Better compliance was associated with lower overall and RA-related nonbiologic costs.

Rheumatoid arthritis (RA) is a systemic, inflammatory, autoimmune disease that primarily affects the linings (synovial membranes) of the joints. Approximately 1.3 million adults in the United States are estimated to have RA.

 A recent study of the total societal burden of RA estimates an annual healthcare cost of $8.4 billion and total societal cost of $19.3 billion per year.

 Left untreated, 20% to 30% of people diagnosed with RA become work-disabled within 3 years.

 Patients with RA suffer significant impairments in health-related quality of life, which can be alleviated by effective treatment.

The American College of Rheumatology (ACR) recommends treatment with nonbiologic disease-modifying antirheumatic drugs (DMARDs) for early RA patients with low disease activity and an absence of poor prognostic features, and for early RA patients with moderate disease activity with poor prognostic features.

 ACR recommendations also suggest a more aggressive approach to inhibit the progression of joint damage and other complications from RA that may develop soon after diagnosis. These recommendations include the use of a biologic tumor necrosis factor (TNF) blocker with or without methotrexate in patients who have high disease activity with poor prognostic features. For patients with established RA (disease duration ≥6 months), biologic DMARDs are recommended if they have had an inadequate response to combination therapy with nonbiologic DMARDs. Biologic DMARDs approved by the FDA for first-line treatment of RA include the TNF blockers adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab, and a T-cell co-stimulation blocker, abatacept.

Medication compliance/adherence is an important aspect of any treatment. An analysis of pharmacy claims data across 6 chronic conditions reported adherence rates ranging from 28% to 66%.

 Noncompliance can lead to increased healthcare use, including hospitalizations, fractures, cardiovascular events, and emergency department visits.

 Notably, increased healthcare use due to medication noncompliance is associated with increased costs.

 In patients using antihypertensive medications, for instance, the cost of using more drugs by compliant patients was less than spending on acute cardiovascular events in noncompliant patients.

The objective of the current study was to examine and quantify the association between treatment compliance with first-line RA biologics and total and RA-specific nonbiologic healthcare costs over 1 year. Medication cost is a dominant component of healthcare cost among RA patients. Although increasing compliance to RA therapies would increase RA medication costs, some other components of healthcare costs may be reduced, because patients’ improved outcomes may result in lower likelihood of future hospitalizations, physician visits, or disease-related complications.

Data for this analysis were obtained from the Truven Health Analytics MarketScan® Claims and Encounters Database (Commercial). The Commercial Database contains inpatient medical, outpatient medical, and outpatient prescription drug information of employees and their dependents covered under a variety of fee-for-service and managed care health plans, including exclusive provider organizations, preferred provider organizations, point-of-service plans, indemnity plans, and health maintenance organizations. It provides detailed cost, use, and outcomes data for healthcare services performed in both inpatient and outpatient settings, including outpatient prescription drug claims and person-level enrollment data through the use of unique enrollee identifiers.

The study used data from July 1, 2009, to December 31, 2013, spanning the pre-index and postindex period for all eligible patients. The index date was the date of the first claim for abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab between January 1, 2010, and January 1, 2013. The baseline period included the 6 months prior to the index date (pre-index period). The follow-up period encompassed the 12 months following and including the index date (postindex period).

To be eligible for inclusion in the analysis, patients had ≥1 claim for first-line biologic therapy for RA between January 1, 2010, and January 1, 2013; were aged 18 to 63 years; had continuous enrollment in the claims database with medical and pharmacy benefits during the pre-index and postindex periods; and had ≥1 nondiagnostic medical claim with a primary or secondary diagnosis of RA (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnosis code 714.0x) during the pre-index period or on the index date. Patients were excluded from the analysis if they had ≥1 nondiagnostic medical claim with a diagnosis for other biologic indications at any time during the pre-index period (including the index date), including plaque psoriasis (ICD-9-CM code 696.1x), psoriatic arthritis (696.0x), ankylosing spondylitis (720.0x), juvenile idiopathic arthritis (714.3x), Crohn’s disease (555.xx), ulcerative colitis (556.xx), non-Hodgkin lymphoma (200.xx, 202.xx), or chronic lymphocytic leukemia (204.1x); ≥1 claim for any of the index drugs during the pre-index period (not including the index date); ≥1 claim for any biologic agent indicated for second-line treatment of RA (or not indicated for RA) or tofacitinib during the pre-index period (including the index date); ≥1 claim for ustekinumab during the study; claims for ≥2 different first-line RA biologics on the index date; any claim for tocilizumab prior to the FDA approval date (January 11, 2010); any claim for a first-line RA treatment administered only through subcutaneous (SC) injection with a Healthcare Common Procedure Coding System (HCPCS) code of that treatment (non-standard administration) during the study; or any claim for a first-line RA treatment administered only through intravenous (IV) infusion with a National Drug Code (NDC) of that treatment (non-standard administration) during the study.

Outcomes included rates of compliance, rates of persistence, and the total nonbiologic healthcare and RA-related nonbiologic healthcare cost over 1 year.

Compliance was determined by the proportion of days covered (PDC) for the index biologic during the 12-month follow-up period. Low compliance of self-administered biologics (abatacept, adalimumab, certolizumab pegol, etanercept, golimumab) was defined as proportion of days covered <80% during the post index period. Low compliance of infused biologics (abatacept, infliximab) was defined as insufficient infusions corresponding to the lower end of the permissible dosing schedules (14-18 infusions per year for abatacept or 7-10 infusions per year for infliximab) over the postindex period. Persistence was measured based on days on index therapy. Patients were considered persistent on index therapy until a 45-day gap was observed in claims for the index biologic or a switch to another biologic.

Total net healthcare cost was defined as all-cause healthcare cost (including both medical and pharmacy cost), excluding RA-related biologic cost, over 12 months of follow-up. RA-related net healthcare cost was defined as RA-related healthcare cost (medical and pharmacy cost), excluding RA-related biologic cost. Inpatient medical claims with a primary diagnosis of RA (ICD-9-CM: 714.0x) and outpatient medical claims with a primary or secondary diagnosis of RA constituted RA-related medical cost. Medical costs included all services rendered during a hospital stay, emergency department visits, physician visits, laboratory tests, medical procedures, and radiological examinations. RA-related pharmacy cost included both drug and administration costs using NDC or HCPCS codes that were indicative of oral- or joint-administered glucocorticoids, conventional DMARDs, biologic DMARDs, and tofacitinib. Total healthcare costs were the sum of patient and health plan costs.

Descriptive analyses were conducted for categorical variables (number, percentage) and continuous variables (mean, SD, range, and 95% CIs). Treatment exposure (dose and number of administrations) was accounted for using a validated effectiveness algorithm

 that has been applied to this database in previous analyses.

 Generalized linear models with a gamma distribution and a log link were specified to assess the association between compliance and the various cost variables. Additionally, treatment-specific comparisons in cost were explored within these models. Models were adjusted for patient demographics (age, gender, health plan type, index year), baseline clinical characteristics and indices of health status (pre-index medications including antibiotics, oral corticosteroids and joint injections, selected comorbid conditions, number of ICD-9-CM codes, number of prescriptions, number of unique medications), baseline treatments (index biologic), and pre-index costs. Adjusted incremental costs for each level of compliance were estimated using recycled predictions.

 The incremental analysis was conducted by comparing each subsequent PDC cohort with patients with PDC <0.2. Costs were adjusted to the most recent year of data available for the study (2013).

A total of 14,696 patients were eligible to be included in the study (eAppendix Table 1; [eAppendices available at ajpb.com]). The mean age (SD) was 49.3 (10.0) years, most patients were female (78.3%), and most patients were in a managed care plan (87.1%) (Table 1). During the pre-index period, the mean number (SD) of unique ICD-9-CM codes was 10.0 (6.7), the mean number (SD) of prescription claims with a unique NDC code was 21.2 (15.9), and the mean number (SD) of unique drug claims was 8.4 (5.3).

Across all RA biologic treatments, the mean (SD) PDC was 0.65 (0.31) for the index medication. Compliance based on PDC >0.8 was achieved by 44.4% of patients during the 12-month postindex period (eAppendix Table 2). Overall persistence on index medication during the 12-month post index period was 46.8%.

The mean net healthcare cost (SD) for all patients was $34,863 ($29,221), and mean RA-related healthcare cost (SD) was $22,665 ($11,571) during the postindex period (eAppendix Table 3).

Across all index medication cohorts, compliant patients had consistently lower total net healthcare costs compared with noncompliant patients (Figure). In general, increasing PDC led to lower all-cause and RA-related nonbiologic costs (Table 2). Decreases in incremental total net healthcare costs and RA-related nonbiologic costs were observed with increasing compliance (Table 3).

Based on generalized linear models, compliance was a significant predictor of all-cause nonbiologic costs and RA-related nonbiologic costs (Table 4). Compared with patients with poor compliance (PDC <0.20), the all-cause nonbiologic cost ratio for compliant patients (PDC ≥0.80) was 0.58 (95% confidence limits [CL], 0.56, 0.62; P <.0001) and RA-related nonbiologic cost ratio for compliant patients was 0.75 (95% CL, 0.71, 0.79; P <.0001). Compared with etanercept, cost ratios were significantly higher for abatacept (IV or SC), certolizumab pegol, golimumab, and infliximab (Table 4). Regression models for total healthcare costs, nonbiologic costs, RA-related costs, RA-related nonbiologic costs, and biologic costs are provided in eAppendix Tables 4 to 8.

The results of this study showed that across all index medication cohorts, compliant patients had consistently lower all-cause nonbiologic healthcare costs compared with those of noncompliant patients. Medication cost represents a large component of healthcare cost among RA patients. Intuitively, increasing compliance would increase RA medication costs, but understanding whether there may be a reduction in other healthcare costs due to improved outcomes is important in the overall care of the patient. Showing that increasing compliance with biologics for RA reduces other healthcare costs can help a health plan justify new programs to improve compliance and patient outcomes.

Studies have shown that nonadherence to medication can lead to accelerated progression of some diseases, increasing the need for more aggressive treatment and associated complications, and therefore increasing healthcare utilization and cost.

 Compliance with nonbiologic and biologic DMARDs for the treatment of RA is notoriously suboptimal.

 A prior study comparing medication adherence and cost of adalimumab and etanercept using a claims database showed that greater adherence to medication led to significantly fewer inpatient visits for etanercept (P = .0005) and a trend toward fewer inpatient visits for adalimumab (P = .0536).

 Similar to the results of our study, adherence to both medications led to significantly lower total costs (P ≤.0001). Compliance with RA medications over many years has the potential to lead to substantial savings in long-term nonbiologic costs for RA by further reducing disease progression and disability. Comparisons of compliance with oral DMARDs (eg, tofacitinib) versus compliance with injectable DMARDS (eg, biologics) are warranted.

This analysis was limited in that it evaluated only the impact of treatment compliance on direct medical costs; future research should include productivity costs, as these may also be impacted by biologic treatment compliance. Limitations that are commonly identified with the use of administrative claims databases for clinical research also apply. The database used in this study consists of adjudicated claims that are used to facilitate payment; while it is likely that coding errors are rare, claims that facilitate payment are more likely to be present and complete in the data. Patients were required to meet pre-index enrollment criteria; results from this study may not be generalizable to patients with shorter or intermittent insurance coverage. Some bias arising from dropping patients without complete data may have occurred. Reasons for discontinuing or changing therapy are not available in the databases. Clinical information about disease severity is not available in claims databases. Furthermore, other unmeasured confounders (demographic and clinical characteristics, physician preferences/education, etc) could have affected the association between compliance and total cost. These findings may not be generalizable to uninsured individuals, non-US patients, and pediatric patients with RA.

Patient compliance was associated with lower overall and RA-related nonbiologic costs. In addition to the clinical benefits of biologic therapies for RA (including improvement in symptoms to achieve low disease activity or remission and associated improvements in quality of life4), payers and patients who are highly compliant with their biologic therapies can realize economic benefits compared with patients who are poorly compliant. Efforts to encourage medication compliance in this patient population should always be included in a treatment plan.

 Truven Health Analytics, Cambridge, MA (MB, BHJ); Amgen Inc, Thousand Oaks, CA (DHT, DJH, BSS).

 This study was sponsored by Immunex, a wholly owned subsidiary of Amgen Inc, and by Wyeth, which was acquired by Pfizer in October 2009.

 MB and BHJ are employees of Truven Health Analytics, which received funding from Amgen Inc for this study. DHH and BSS are employees and shareholders of Amgen Inc. DT is a former employee and current shareholder of Amgen Inc.

Authorship Information: Concept and design (MB, BHJ, DHT, DJH); acquisition of data (MB, BHJ); analysis and interpretation of data (MB, BHJ, DHT, DJH, BSS); drafting of the manuscript (MB); critical revision of the manuscript for important intellectual content (MB, BHJ, DHT, DJH, BSS); statistical analysis (MB, BHJ); provision of patients or study materials (MB, BHJ); and supervision (DHT, BSS).

 Machaon Bonafede, Truven Health Analytics, 150 Cambridge Park Dr, Cambridge, MA 02140. E-mail: machaon.bonafede@truvenhealth.com.

1. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. doi: 10.1002/art.23177.

2. Birnbaum H, Pike C, Kaufman R, Marynchenko M, Kidolezi Y, Cifaldi M. Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin. 2010;26(1):77-90. doi: 10.1185/03007990903422307.

3. Sokka T. Work disability in early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21(5 Suppl 31):S71-S74.

4. Strand V, Sharp V, Koenig AS, et al. Comparison of health-related quality of life in rheumatoid arthritis, psoriatic arthritis and psoriasis and effects of etanercept treatment. Ann Rheum Dis. 2012;71(7):1143-1150. doi: 10.1136/annrheumdis-2011-200387. 

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 (Hoboken). 2012;64(5):625-639. doi: 10.1002/acr.21641.

6. Yeaw J, Benner JS, Walt JG, Sian S, Smith DB. Comparing adherence and persistence across 6 chronic medication classes. J Manag Care Pharm. 2009;15(9):728-740.

7. Sun P, Lian J. Treatment adherence in newly diagnosed type 2 diabetes: patient characteristics and long-term impact of adherence on inpatient care utilization. Postgrad Med. 2016;128(4):338-45. doi: 10.1080/00325481.2016.1151326.

8. Ho SC, Chong HY, Chaiyakunapruk N, Tangiisuran B, Jacob SA. Clinical and economic impact of non-adherence to antidepressants in major depressive disorder: a systematic review. J Affect Disord. 2016;193:1-10. doi: 10.1016/j.jad.2015.12.029.

9. Chodick G, Moser SS, Goldshtein I. Non-adherence with bisphosphonates among patients with osteoporosis: impact on fracture risk and healthcare cost. Expert Rev Pharmacoecon Outcomes Res. 2016;16(3):359-70. doi: 10.1586/14737167.2016.1171145.

10. Thomas NP, Curkendall S, Farr AM, Yu E, Hurley D. The impact of persistence with therapy on inpatient admissions and emergency room visits in the US among patients with multiple sclerosis. J Med Econ. 2016;19(5):497-505. doi: 10.3111/13696998.2015.1134546. 

11. Vekeman F, Sasane M, Cheng WY, et al. Adherence to iron chelation therapy and associated healthcare resource utilization and costs in Medicaid patients with sickle cell disease and thalassemia. J Med Econ. 2016;19(3):292-303.  doi: 10.3111/13696998.2015.1117979.

12. Dilokthornsakul P, Thoopputra T, Patanaprateep O, Kongsakon R, Chaiyakunapruk N. Effects of medication adherence on hospitalizations and healthcare costs in patients with schizophrenia in Thailand. SAGE Open Med. 2016;4:2050312116637026. doi: 10.1177/2050312116637026.

Medication compliance is associated with lower overall and disease-related healthcare costs in patients with moderate to severe rheumatoid arthritis receiving biologic therapies.

Compliance and Cost of Biologic Therapies for Rheumatoid Arthritis

: An effectiveness algorithm that was validated with the Veterans Affairs Rheumatoid Arthritis Registry was used to compare effectiveness of different biologic disease-modifying antirheumatic drugs (DMARDs) and cost per effectively treated patient in the Veterans Health Administration (VHA). 

: Effectiveness was estimated with the algorithm using VHA claims data for biologics (abatacept, adalimumab, etanercept, infliximab, or rituximab) newly initiated from 2008 to 2011. 

: Patients were considered effectively treated if they did not fail any of 6 algorithm criteria during 1 year of follow-up: 1) low treatment adherence; 2) biologic dose escalation; 3) biologic switch; 4) addition of nonbiologic DMARD; 5) new or increased oral glucocorticoid; and 6) more than 1 intra-articular glucocorticoid injection. Index biologic costs included medication and administration costs. Subgroup analyses were conducted by gender, smoking status, serologic status, and body mass index.

: The analysis included 4696 patients (mean age = 61 years; 87% male). The proportion of patients categorized as effectively treated was higher for subcutaneous biologics (adalimumab, 33.4%; etanercept, 32.3%) than for intravenous biologics (rituximab, 27%; infliximab, 26.4%; abatacept, 24.8%). Index biologic cost per effectively treated patient was lower for etanercept ($39,432) and adalimumab ($41,519) than for infliximab ($54,524), abatacept ($55,776), and rituximab ($58,260). Men had lower cost per effectively treated patient than did women ($40,745 vs $57,450). Outcomes were comparable within other subgroups.

: In veterans with rheumatoid arthritis, the subcutaneous biologics adalimumab and etanercept had the highest proportions of patients categorized as effectively treated and the lowest costs per effectively treated patient.

This study applied a validated algorithm to estimate effectiveness and costs of the index biologic used by 4696 US veterans with rheumatoid arthritis.

Compared with intravenous biologics (abatacept, infliximab, and rituximab), subcutaneous biologics (etanercept and adalimumab) had lower 1-year biologic costs, higher rates of effectiveness according to the algorithm, and lower costs per effectively treated patient.

Men had lower costs per effectively treated patient than women; outcomes were similar within other subgroups.

Previous studies in managed care settings used similar methods, but this was the first study to report comparable results in the unique setting of the Veterans Health Administration.

Approximately 1.3 million adults in the United States have rheumatoid arthritis (RA), an inflammatory autoimmune condition that primarily affects the synovial membrane in the joints of the body,

 causing inflammation in the joints and destruction of bone and cartilage.

 Biologics including abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, and anakinra play an important role in the treatment of RA by helping to regulate the body’s inflammatory process and inhibiting joint damage.

 The biologics differ in their method of administration, dosing level, dosing schedule, and whether they are approved for first-line use after treatment failure with a nonbiologic disease-modifying antirheumatic drug (DMARD).

Comparisons of effectiveness of different biologics and their costs in RA are critical for formulary decision makers to develop evidence-based formularies. Economic comparisons of biologics in RA have been published using managed care data,

 but only limited work has focused on the Veterans Health Administration (VHA).

 The VHA has a number of characteristics that make it difficult to generalize from managed care data, including a unique set of demographic characteristics (members are predominantly older men), physicians who are salaried rather than reimbursed on a fee-for-service basis, medication prices that are governed by the Federal Supply Schedule (FSS) and BIG 4 (Veterans Affairs [VA], Department of Defense, Coast Guard, and Public Health Service) pharmaceutical pricing rather than wholesale acquisition costs, and small or no patient co-payments.

 For these reasons, a detailed analysis of this population was expected to be informative for VHA decision makers, with potential application to other health systems.

Previous cost analyses for biologics in RA have been limited by the lack of information about effectiveness. Lower effectiveness leading to worse long-term outcomes with a biologic could offset any cost savings associated with that biologic. Curtis et al

 developed and validated a claims-based effectiveness algorithm using clinical outcomes in patients in the Veterans Administration Rheumatoid Arthritis (VARA) registry receiving biologic and nonbiologic DMARD therapy.

The algorithm uses data commonly available in claims data sets to estimate the effectiveness of biologics. The algorithm evaluates 6 criteria: adherence to the biologic, increases in biologic doses, switching biologics, adding a new nonbiologic DMARD, starting or increasing the dose of oral glucocorticoids, and the use of multiple intra-articular glucocorticoid joint injections. In the validation, the gold standard for effectiveness was a disease activity score using 28 joint counts (DAS28) of ≤3.2 units (the threshold for low disease activity) or improvement in DAS28 >1.2 units after 1 year of DMARD therapy. The DAS28 is a widely accepted metric of disease activity in RA that is commonly used both in clinical trials and in routine real-world settings. The sensitivity of the effectiveness algorithm was 75% and its specificity was 90%.

The positive predictive value and negative predictive value of the effectiveness algorithm were 76% and 90%, respectively. Recent studies applied the algorithm to commercial claims databases to estimate effectiveness and biologic cost per effectively treated patient,

 but this approach has not been applied to the VHA, which is a large purchaser of biologic agents.

The objectives of this study were to compare the estimated effectiveness of different biologics in veterans with RA by using a published algorithm based on administrative data

 to assess the reasons for treatment failure and estimate biologic costs per effectively treated patient.

This study was approved by the University of Utah Institutional Review Board and the VA Research Service. All data were from the VA Medical System. Patient data, procedures, and text notes were obtained from the Corporate Data Warehouse (CDW) and accessed through the Veterans Informatics and Computing Infrastructure.

Pharmacy dispensing data were obtained from CDW, Decision Support Services (DSS), and VA Pharmacy Benefits Management (PBM) Services. Because discrepancies were found in DMARD dispensing across the VHA data marts, a harmonization algorithm was developed to resolve such discrepancies that prioritized dispensing data found in multiple data sources based on source, with CDW first, PBM second, and DSS third. Priority was given to CDW because it is now considered production data; PBM now acquires their data from CDW and then applies data-cleaning algorithms; and DSS because it is now considered legacy data.

Since this study required careful tracking of average weekly dose to determine if a dose escalation occurred, accurate estimates of dosing were needed. In typical pharmacoepidemiological research, the dispensed quantity, unit strength, and days’ supply are used to estimate the prescribed average weekly dose. This approach, however, is unreliable for biologic DMARDs dispensed by the VHA system that are subcutaneously administered at home and for medications with complex weekly dosing schedules, such as methotrexate, because of known inconsistencies in pharmacy dispensing data.

The primary problem in the VHA setting is that the quantity dispensed is not well standardized; for example, the quantity dispensed for etanercept is at times listed differently at various VHA medical centers—dispensing of a box of 4 syringes of etanercept 50 mg may be listed as a quantity of 4 (meaning 4 syringes), or 1 (meaning 1 box of 4 syringes), or 200 (meaning 200 mg total per box). Fortunately, the VA CDW and PBM data contain some information on dispensed units in addition to the narrative medication schedules from prescriptions (sigs).

Determining dispensed quantity from sigs on a large scale is labor- and time-intensive, so an automated Natural Language Processing (NLP) tool was developed to extract and standardize the prescribed average weekly dose from the medication sig.

 This information was used with pharmacy dispensing data on days’ supply, unit dose, and quantity to generate the best estimate of average weekly dose. The process was validated by medical record review and comparison with the VARA registry.

Similar to the limitations in the VHA discussed above for subcutaneous biologics, outpatient infusions of medications such as intravenous biologics are not consistently documented in structured VHA pharmacy dispensing or nurse Barcode Medication Administration data.

 Healthcare Common Procedure Coding System procedure codes intended for administrative billing provide information on outpatient infusions but they are not used consistently, which makes it difficult to compute the total infused dose.

 An NLP tool was developed to search for outpatient infusion notes and extract total infused dose of biologic DMARDs.

 The process was validated by chart review and comparison with the VARA registry.

US veterans receiving care within the VHA were included in the analysis if they had at least one claim between January 1, 2008, and December 31, 2011, for abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, or tocilizumab. Patients with a claim for subcutaneous abatacept were removed from the analysis because abatacept was approved only for intravenous use before the start of the study period. Subcutaneous tocilizumab and intravenous golimumab were not included in the analysis because they were not approved at any time during the study period.

The first claim for one of these biologics provided the definition for the patient’s index date and the index biologic. Patients were included only if they were enrolled in the VHA for at least 365 days before their index date. Patients were required to be aged at least 18 years on the index date and to have a diagnosis of RA (

International Classification of Diseases, Ninth Revision, Clinical Modification

]: 714.0x) on at least 1 claim in the 365 days prior to or 30 days after the index date.

Patients were excluded from the analysis if they had psoriasis (

: 556.xx), juvenile idiopathic arthritis (

: 200.xx, 202.xx), or chronic lymphocytic leukemia (

: 204.1x) on any claim in the 365 days prior to or 30 days after the index date. To limit the analysis to patients who newly initiated biologic therapy, established users of biologics (patients with any other biologic claim in the 180 days before the index date) were excluded from the analysis.

Other exclusion criteria were an index claim for a biologic before it received FDA approval for treatment of RA, claims for more than 1 biologic on the index date, and sparse use of VHA services (no claim within 180 days before the index date and between 10 and 24 months from index date, as a proxy for leaving VHA care). Biologic agents with a sample size <100 patients were not evaluated since the sample size was deemed too small to provide reliable estimates.

 the following 6 criteria were applied to each patient’s claims for the 1-year follow-up period (365 days) after the index date:

Low adherence to the index drug: a) for subcutaneous biologics (adalimumab and etanercept): medication possession ratio <80%, defined as the total days’ supply in the follow-up period divided by 365 days; and b) for intravenous biologics: fewer infusions than recommended in the FDA-approved dosing schedules (ie, <12 abatacept infusions, <7 infliximab infusions, or <4 rituximab infusions).

Increase in biologic dose during the follow-up period compared with the beginning dose: a) abatacept: >100 mg dose increase or >18 infusions total; b) adalimumab: frequency increase to 40 mg once weekly; c) etanercept: frequency increase to 50 mg twice weekly; d) infliximab: >100 mg dose increase (with each dose rounded up to the nearest 100 mg) or >10 infusions total; and e) rituximab: no escalation rule was applied.

Switch to a new biologic agent during the follow-up period.

Addition of a new nonbiologic DMARD during the follow-up period.

Oral glucocorticoids: a) initiation of chronic glucocorticoids for those with no oral glucocorticoid prescriptions during the 180 days pre-index; and b) increase by >20% in oral glucocorticoid dose (based on prednisone equivalent dose

) between months 7 and 12 post index for those who received any oral glucocorticoid prescription during the 180 days pre-index.

More than 1 parenteral or intra-articular glucocorticoid joint injection on unique days between 90 days and 1 year post index.

According to the algorithm, the index biologic was considered “effective” and the patient was considered to be “effectively treated” if none of the 6 criteria were met. The index biologic was considered “not effective” if at least 1 of the 6 criteria was met. The proportion of patients (95% CI) that failed each of the criteria was analyzed. Proportions (95% CI) were also calculated for effective and not effective index biologics.

Total costs of the index biologic in the first year (ie, between the index date and 365 days after the index date, inclusive) were calculated by summing the lowest contracted amount using VHA prices from the 2013 fiscal year based on the FSS and BIG 4 (eAppendix 1 [eAppendices available at

 These were the most recent costs available at the time of the study. Intravenous abatacept was $1.58 per mg, adalimumab was $16.77 per mg, etanercept was $6.61 per mg, infliximab was $4.85 per mg, and rituximab was $4.70 per mg. The cost for each outpatient pharmacy dispensing episode for subcutaneously injected medication was $25 and the infusion costs were $169.09 per administration. Costs of other medications used in the first year, such as DMARDs or other biologics, were not included in the cost calculations.

One-year biologic cost per patient was calculated for each biologic as the total cost for the index biologic divided by the number of patients who received that index biologic. The 1-year cost per effectively treated RA patient (ie, a patient who met the algorithm effectiveness rule) was estimated for each index biologic. The metric reflected total expenditures by the VHA for the index biologic divided by the number of patients effectively treated by that biologic. It was calculated as follows:

Cost per effectively treated patient =  Total cost of index agent for all patients who index on it / Number of effectively treated patients on index agent

Subgroup analyses of effectiveness, biologic costs, and costs per effectively treated patient were stratified by the following baseline characteristics: gender (male or female), smoking status (current smoker or current nonsmoker), cyclic citrullinated peptide (CCP) (positive [>20 IU/mL] or negative), rheumatoid factor (positive [>20 IU/mL or >1:40 titer] or negative), and body mass index (≥30 kg/m

Continuous data are presented as means and 95% CIs, and categorical variables are presented as proportions and 95% CIs. The focus on 95% CIs instead of 

 values provides evidence for the stability of estimates along with statistical significance. In general, when the 95% CIs do not overlap between 2 groups 

 <.05 and the 2 groups are considered significantly different.

A total of 4696 patients met all inclusion and exclusion criteria (

), of whom 2069 (44.1%) started etanercept, 1989 (42.4%) started adalimumab, 267 (5.7%) started rituximab, 254 (5.4%) started infliximab, and 117 (2.5%) started abatacept. Eight patients who received subcutaneous abatacept in the first year were not analyzed. Fifty-seven patients who started anakinra, certolizumab, golimumab, and tocilizumab were not analyzed because of the small sample size (n <100 patients) for each of those agents.

This study applied a validated algorithm to estimate the effectiveness and costs of the index biologic used by 4696 US veterans with rheumatoid arthritis.

Effectiveness and Costs of Biologics in Veterans With Rheumatoid Arthritis

This study supports earlier research on the comparative effectiveness of tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients, but is unique in utilizing both clinical outcomes data from US clinical practices and actual drug utilization data from claims. 

Increased costs resulting from TNF blocker dose escalation may not always be accompanied by an improvement in clinical benefit. 

In the current comparative effectiveness research paradigm, understanding the clinical benefit gained from additional cost is critical to payers.

Among RA patients newly treated with adalimumab, etanercept, or infliximab, lower dose escalation rates and costs were seen with etanercept.

Among rheumatoid arthritis patients newly treated with adalimumab, etanercept, or infliximab, lower dose escalation rates and costs were seen with etanercept.