SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Objective

We hypothesized that initiation of a new disease-modifying antirheumatic drug (DMARD) for treatment of rheumatoid arthritis (RA) would decrease the use of corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and narcotics.

Methods

Using administrative databases, we assembled 4 retrospective cohorts of RA patients (1998–2005) and identified 5 groups initiating DMARD regimens: methotrexate (MTX) with (new MTX) or without (first MTX) use of other nonbiologic DMARDs in the previous year; new hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ; new HCQ/SSZ) and new leflunomide (new LEF), both with previous use of MTX; and new tumor necrosis factor α (TNFα) antagonists (new anti-TNF). We compared within-person differences in any use of cotherapies (≥1 prescription) between the 6 months before and the 6–12 months after DMARD initiation.

Results

Among 32,476 DMARD initiators, the prevalence of corticosteroid, NSAID, and narcotic use increased by 15%, 5%, and 6%, respectively, in the 6 months before initiation compared to the previous 6 months, suggesting worsening of the disease. In the 6–12 months after initiation for most initiator groups, more patients stopped using corticosteroids and NSAIDs than started, with overall decreases of 8.9% (95% confidence interval [95% CI] 8.4–9.4%) for corticosteroids and 12.9% (95% CI 12.3–13.4%) for NSAIDs. The proportion of narcotic users changed little (overall decrease of 2.5%; 95% CI 1.9–3.0%).

Conclusion

Use of all 3 cotherapies increased in the 6 months before initiation of new DMARD regimens for RA. Use of corticosteroids and NSAIDs decreased modestly 6–12 months after initiation, but there was only a very small decrease in narcotic use. These differential changes require further study.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that can cause permanent joint damage and disability (1). Pain is common and caused by the inflammatory process and secondary osteoarthrosis (2). The goals of RA management are to prevent joint damage and loss of function, and to control pain. Early initiation of disease-modifying antirheumatic drugs (DMARDs) is aimed at controlling disease activity and preventing disease progression (3, 4). Effective treatment for RA might not only control disease activity but also reduce the need for cotherapies such as corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and narcotics that are mainly used to control symptoms.

Oral corticosteroids improve symptoms and may also reduce progression of RA (3, 5). However, another goal of therapy is to minimize long-term use of corticosteroids (6) because of their many side effects, including osteoporosis, fractures, hypertension, weight gain, peptic ulcer disease, osteonecrosis, risk of infection, and increased cardiovascular risk (7–9). In addition to corticosteroids, 2 other main groups of drugs are used in RA for symptom control: NSAIDs and narcotics (10–12). NSAIDs, including cyclooxygenase 2 inhibitors, increase the risk of peptic ulcers and gastrointestinal bleeding and also have adverse cardiovascular effects (13–15). Narcotic use, which is common among patients with RA (11, 16–19), carries the risks of drug abuse, addiction, withdrawal syndrome, respiratory depression, and fractures (20, 21). Reducing exposure to these cotherapies is desirable because it would decrease the incidence of therapy-related adverse outcomes in RA patients.

Although the efficacy of DMARDs in the treatment of RA is widely recognized (3), only a few small studies have addressed their effects on the use of corticosteroids and NSAIDs (12, 22–24). These studies were restricted to biologic drugs and showed that the use of both corticosteroids and NSAIDs decreased 3 to 6 months after a biologic was started (22, 23). For narcotics, one study addressed temporal trends in narcotic use among DMARD users (12), but the effect of DMARD initiation on narcotic use is not known. If DMARDs do improve pain and inflammation and allow reduction of these cotherapies, they could have ancillary benefits to patients beyond those documented in short-term clinical trials (25–28). Clinical trials generally do not allow for changes in these cotherapies during the controlled phase of the study (26, 28), but observational studies allow these changes in therapy to be examined.

Effective DMARD treatments could reduce the use of drugs needed to treat RA symptoms. We hypothesized that the initiation of DMARD therapy would reduce the use of corticosteroids, NSAIDs, and narcotics. To study the association between DMARD initiation and cotherapy use, we examined data from 4 major US administrative databases (frequently used for assessments of medication effects) that would allow broad extrapolation of our findings and also reflect clinical practice.

Significance & Innovations

  • Use of cotherapies increased in the 6 months before initiation of new disease-modifying antirheumatic drug (DMARD) regimens for rheumatoid arthritis.

  • In the 6–12 months after new DMARD initiation, the use of corticosteroids and nonsteroidal antiinflammatory drugs decreased modestly, but there was only a small decrease in narcotic use.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

This cohort study primarily assessed within-person differences in any use of oral corticosteroids, NSAIDs, and narcotics (≥1 prescription) in the 6 months before compared to the 6–12 months after initiating one of the study DMARD regimens.

Data source and study population.

We assembled 4 retrospective cohorts of patients ages ≥18 years with a diagnosis of RA (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 714.*, except for 714.3) from 1998 to 2005 enrolled in Tennessee's Medicaid program (TennCare), Kaiser Permanente Northern California (KPNC), Pennsylvania Pharmaceutical Assistance Contract for Elderly (PACE), and individuals from 49 US states who were dually eligible for Medicaid and Medicare or for Medicaid alone (MAX/MED; 2000–2005). We excluded Tennessee enrollees from the MAX/MED cohort to avoid duplication. Patients entered the RA cohort on the date the first prescription for a specific DMARD regimen was filled (initiation date) if they met the following criteria: continuous enrollment for at least 1 year before entering the cohort (≤30-day gaps were allowed) and no prescription for that DMARD during this time period. We also excluded records with missing sex information and those of patients with other diseases that might warrant DMARD treatment, including psoriasis or psoriatic arthritis (ICD-9-CM 696.0, 696.1, 696.2), juvenile rheumatoid arthritis (ICD-9-CM 714.3), systemic lupus erythematosus (ICD-9-CM 710.0), Crohn's disease (ICD-9-CM 555), ulcerative colitis (ICD-9-CM 556), and ankylosing spondylitis (ICD-9-CM 720). Patients who lacked 1-year followup after the initiation date were also excluded from the analysis.

Exposure groups.

The most common DMARDs used in RA are methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), leflunomide (LEF), etanercept, infliximab, and adalimumab (3, 29, 30). Five exposure groups were defined to examine whether initiation of common DMARD regimens is associated with change in the use of cotherapies. The selection of these groups was based on common patterns of use observed in the cohorts. We excluded any patient who filled a biologic DMARD different from an anti–tumor necrosis factor (anti-TNF) drug (e.g., anakinra, abatacept, rituximab).

Exposure groups (Table 1) were defined as patients who filled a first prescription for a specific DMARD, with no prescription filled for the same DMARD during the year before the initiation date: 1) first MTX: patients who filled a first prescription for MTX and did not have any previous DMARD prescription filled in the year before the initiation date and did not have LEF or a biologic DMARD filled on the same day; 2) new MTX: patients who filled a first prescription for MTX and had a previous nonbiologic DMARD filled but had no prescription for any biologic DMARD in the year before the initiation date; 3) new HCQ/SSZ: MTX failures (patients who filled a MTX prescription within the past 90 days) who filled a first prescription for either HCQ and/or SSZ and had no prescription filled for any biologic DMARD in the year before the initiation date; 4) new LEF: MTX failures (patients who filled a MTX prescription within the past 90 days) who filled a first prescription for LEF and had no prescription filled for any biologic DMARD in the year before the initiation date; and 5) new anti-TNF: patients who filled a prescription for infliximab, etanercept, or adalimumab with no anti-TNF use in the year before the initiation date. Previous and concurrent use of MTX or other DMARD was allowed, but filling 2 TNFα antagonists on the same date was not. This group mainly includes patients who previously failed other nonbiologic DMARDs. Any patient who filled a prescription for an anti-TNF drug different from infliximab, etanercept, or adalimumab was excluded from the study (e.g., golimumab, certolizumab pegol).

Table 1. Description of DMARD groups*
  • *

    DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; HCQ = hydroxychloroquine; SSZ = sulfasalazine; LEF = leflunomide; anti-TNF = anti–tumor necrosis factor.

First MTX
 New user of MTX
  No DMARD [RIGHTWARDS ARROW] MTX
New MTX
 Switch from any other nonbiologic DMARD to MTX
  HCQ [RIGHTWARDS ARROW] MTX
  SSZ [RIGHTWARDS ARROW] MTX
  Other synthetic DMARD [RIGHTWARDS ARROW] MTX
New HCQ/SSZ
 Switch or add HCQ and/or SSZ in a current MTX user
  MTX [RIGHTWARDS ARROW] HCQ
  MTX [RIGHTWARDS ARROW] SSZ
  MTX [RIGHTWARDS ARROW] HCQ + MTX
  MTX [RIGHTWARDS ARROW] SSZ + MTX
  MTX [RIGHTWARDS ARROW] HCQ + SSZ + MTX
New LEF
 Switch or add LEF in a current MTX user
  MTX [RIGHTWARDS ARROW] LEF
  MTX [RIGHTWARDS ARROW] LEF + MTX
  Other(s) synthetic DMARD + MTX [RIGHTWARDS ARROW] LEF
  Other(s) synthetic DMARD + MTX [RIGHTWARDS ARROW] LEF + MTX
  Other(s) synthetic DMARD + MTX [RIGHTWARDS ARROW] LEF + synthetic DMARD
New anti-TNF
 First prescription of infliximab, etanercept, or adalimumab with or without another nonbiologic DMARD
  Synthetic DMARD [RIGHTWARDS ARROW] TNFα antagonist
  Synthetic DMARD [RIGHTWARDS ARROW] TNFα antagonist + synthetic DMARD

Outcomes.

The primary outcome was the overall change in the proportion of users of oral corticosteroids, narcotics, and NSAIDs in the 6-month period before DMARD initiation (P0) compared to the 6–12-month period after initiation (P+12) for each DMARD group in the 4 cohorts. We measured the use of these cotherapies in the 6–12 months (P+12) after the new regimen was started to allow time for disease control to be achieved and titration or withdrawal of other medications. To better define patterns of change in cotherapies, we also explored the 6–12-month period before initiation (P−6) and the period from initiation to 6 months later (P+6). Cotherapy use during each period was measured as follows: 1) oral corticosteroid use measurements included the average daily dose for each 6-month period calculated as prednisone equivalents per day (mg/day), and the percentage of days with corticosteroid therapy (i.e., days of supply in each period/180 days × 100); 2) NSAID use was measured as the percentage of days with NSAID therapy; and 3) narcotic use was measured as the percentage of days with narcotic therapy. We defined narcotics as natural, semisynthetic, and synthetic opioids (and combinations) that required a prescription, but we did not include opioids that are used to modulate gastrointestinal motility (e.g., laudanum, loperamide, diphenoxylate, difenoxin, etc.).

These summary measurements included only patients that were taking the specific cotherapy at each time period, excluding nonusers from the calculations.

Patient characteristics.

Other variables measured to describe users of DMARDs were age, race, rural residence (yes/no), and comorbidity (modified Charlson score).

Statistical analysis.

Corticosteroid, NSAID, and narcotic users for each time period were described as percentages with 95% confidence intervals (95% CIs), while the daily dose of corticosteroids and percentage of days with a specific cotherapy were described as median values. Other continuous variables were represented as medians and interquartile ranges unless otherwise specified. We calculated the changes in the percentage of cotherapy users from P0 to P+12 taking into account the correlation due to the paired measurements per subject. McNemar's tests were used to assess within-person differences in any use of oral corticosteroids, NSAIDs, and narcotics (≥1 prescription) during 6 months before initiation (P0) versus 6–12 months after initiation (P+12) for the 5 DMARD regimens. Statistical analyses were performed using SAS, version 9.2, and Stata, version 11.0. The study protocol was reviewed by the Tennessee Bureau of TennCare and approved by the Institutional Review Boards at Vanderbilt University, University of Alabama at Birmingham, Partners Healthcare, and Kaiser Foundation Research Institution.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Patient characteristics.

We identified 32,476 RA patients who started a new DMARD regimen and had a full year of baseline and followup data available: 13% from TennCare, 18% from KPNC, 7% from PACE, and 62% from MAX/MED. Study patients were mostly women, white, and between ages 50 and 64 years, except for PACE cohort enrollees, who were all age ≥65 years. Most were urban residents, except for the TennCare cohort, where 53% lived in a rural area. Enrollment between 1998 and 2001 was consistent for most of the cohorts. The median Charlson score was 2 for PACE enrollees and 1 for the other cohorts (Table 2).

Table 2. Baseline characteristics of rheumatoid arthritis patients initiating new episodes of disease-modifying antirheumatic drug use (1998–2005)*
 TennCare (n = 4,383)KPNC (n = 5,695)PACE (n = 2,133)MAX/MED (n = 20,265)
  • *

    Values are the number (percentage) unless otherwise indicated. TennCare = Tennessee's Medicaid program; KPNC = Kaiser Permanente Northern California; PACE = Pennsylvania Pharmaceutical Assistance Contract for Elderly; MAX/MED = Medicaid and/or Medicare program from 49 US states; IQR = interquartile range.

Age, years    
 <501,461 (33.3)1,636 (28.7)6,060 (29.9)
 50–641,966 (44.9)2,281 (40.1)7,456 (36.8)
 ≥65956 (21.8)1,778 (31.2)2,133 (100)6,749 (33.3)
Women3,383 (77.2)4,396 (77.2)1,926 (90.3)17,688 (87.3)
Race    
 White3,242 (74.0)3,737 (65.6)1,911 (89.6)11,889 (58.7)
 African American607 (13.9)521 (9.2)178 (8.4)3,829 (18.9)
 Other/unknown534 (12.2)1,437 (25.2)44 (2.1)4,547 (22.4)
Rural residence2,334 (53.3)115 (2.0)232 (10.9)5,847 (28.9)
Enrollment year    
 1998416 (9.5)523 (9.2)307 (14.4)
 1999645 (14.7)805 (14.1)377 (17.7)
 2000565 (12.9)799 (14.0)312 (14.6)2 (0.0)
 2001527 (12.0)764 (13.4)232 (10.9)4,161 (20.5)
 2002608 (13.9)728 (12.8)284 (13.3)3,668 (18.1)
 2003796 (18.2)1,024 (18.0)309 (14.5)6,181 (30.5)
 2004818 (18.7)1,036 (18.2)300 (14.1)6,192 (30.6)
 20058 (0.2)16 (0.3)12 (0.6)61 (0.3)
Charlson score, median (IQR)1 (1–2)1 (1–1)2 (1–3)1 (1–2)

DMARD (biologic and nonbiologic) and cotherapy use.

The distribution of patients that initiated different DMARD regimens differed among cohorts (Table 3). Between 25% and 31% of patients initiated an anti-TNF agent. In all of the cohorts, etanercept was the most frequent biologic started, and accounted for 15–19% of all DMARD regimens initiated. The day before the initiation date, the point prevalence of patients using corticosteroids across the 4 cohorts ranged from 24–32%, NSAIDs from 32–39%, and narcotics from 15–33% (Table 3). KPNC (15.3%) and PACE (16.4%) had lower narcotic use than the other cohorts; the low narcotic use in PACE compared to TennCare and MAX/MED was not explained by age differences in these cohorts (data not shown).

Table 3. Patterns of new DMARD use and cotherapies in rheumatoid arthritis patients (1998–2005)*
 TennCare (n = 4,383)KPNC (n = 5,695)PACE (n = 2,133)MAX/MED (n = 20,265)
  • *

    Values are the number (percentage). DMARD = disease-modifying antirheumatic drug; TennCare = Tennessee's Medicaid program; KPNC = Kaiser Permanente Northern California; PACE = Pennsylvania Pharmaceutical Assistance Contract for Elderly; MAX/MED = Medicaid and/or Medicare program from 49 US states; MTX = methotrexate; HCQ = hydroxychloroquine; SSZ = sulfasalazine; LEF = leflunomide; anti-TNF = anti–tumor necrosis factor; NSAIDs = nonsteroidal antiinflammatory drugs.

DMARDs    
 First MTX1,668 (38.1)1,359 (23.9)885 (41.5)6,741 (33.3)
 New MTX660 (15.1)1,443 (25.3)298 (14.0)3,686 (18.2)
 New HCQ/SSZ492 (11.2)689 (12.1)112 (5.3)1,698 (8.4)
 New LEF407 (9.3)745 (13.1)176 (8.3)1,835 (9.1)
 New anti-TNF1,156 (26.4)1,459 (25.6)662 (31.0)6,305 (31.1)
Cotherapy use the day before  DMARD initiation    
 Corticosteroids1,373 (31.1)1,822 (32.0)521 (24.4)5,789 (28.6)
 NSAIDs1,670 (38.1)2,010 (35.3)675 (31.7)7,852 (38.8)
 Narcotics1,424 (32.5)872 (15.3)349 (16.4)6,048 (29.8)

The median dosage of corticosteroids (mg/day of prednisone equivalents), the median percentage of days of therapy, and the percentage of users for each cotherapy differed across cohorts for each period of time (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Changes in corticosteroid use by DMARD groups.

The overall percentage of patients with any use of corticosteroids increased from 43.7% (95% CI 43.2–44.2%) during P−6 (6–12 months before initiation) to 58.6% (95% CI 58.0–59.1%) during P0 (the 6-month period prior to initiation), and then decreased to 49.7% (95% CI 49.1–50.2%) during P+12 (6–12 months after initiation) (Figure 1A) (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

thumbnail image

Figure 1. Percentage of patients with rheumatoid arthritis initiating a disease-modifying antirheumatic drug (DMARD) regimen that used (any use) A, corticosteroids, B, nonsteroidal antiinflammatory drugs (NSAIDs), and C, narcotics. P−6 = 6–12-month period before DMARD initiation; P0 = 6-month period before DMARD initiation; P+6 = 6-month period after DMARD initiation; P+12 = 6–12-month period after DMARD initiation; MTX = methotrexate; HCQ = hydroxychloroquine; SSZ = sulfasalazine; LEF = leflunomide; anti-TNF = anti–tumor necrosis factor; TennCare = Tennessee's Medicaid program; KPNC = Kaiser Permanente Northern California program; PACE = Pennsylvania Pharmaceutical Assistance Contract for Elderly program; MAX/MED = Medicaid and/or Medicare program from 49 US states.

Download figure to PowerPoint

From P0 to P+12, approximately 10–20% of patients stopped corticosteroids, while 5–12% started (Figure 2A), with an overall reduction of 8.9% (95% CI 8.4–9.4%) in the prevalence of any corticosteroid use. Within each cohort, for most of the DMARD groups, the pairwise analyses showed that more patients stopped corticosteroids than started (P < 0.005 for all significant changes). In PACE, the pairwise comparisons were not significant for new HCQ/SSZ (P = 0.103), new LEF (P = 0.327), and new anti-TNF (P = 0.064), likely due to the small number of patients in this cohort (Figure 2A).

thumbnail image

Figure 2. Percentage of patients with rheumatoid arthritis that were using A, corticosteroids, B, nonsteroidal antiinflammatory drugs, or C, narcotics during P0 (6 months before disease-modifying antirheumatic drug [DMARD] initiation) and P12 (6–12 months after DMARD initiation). Solid bars show patients that switch user status (from nonusers to users or vice versa) during P12, and hatched bars show those patients that remained unchanged in their use of cotherapies during P12. * = pairwise analysis with P values <0.05; MTX = methotrexate; HCQ = hydroxychloroquine; SSZ = sulfasalazine; LEF = leflunomide; anti-TNF = anti–tumor necrosis factor; TennCare = Tennessee's Medicaid program; KPNC = Kaiser Permanente Northern California; PACE = Pennsylvania Pharmaceutical Assistance Contract for Elderly; MAX/MED = Medicaid and/or Medicare program from 49 US states.

Download figure to PowerPoint

During P0, the median dosage of corticosteroids among corticosteroid users ranged from 2.3–9.5 mg/day of prednisone equivalents, and the median percentage of days with corticosteroid therapy ranged from 13–63% in the different DMARD groups for the 4 cohorts. During P+12, the median dosage of corticosteroids remained stable (range 3.3–8.2 mg/day of prednisone equivalents), and the median percentage of days with corticosteroid therapy ranged from 42–62% in the different DMARD groups for the 4 cohorts (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Changes in NSAID use by DMARD groups.

During P−6, the overall percentage of any use of NSAIDs was 64.1% (95% CI 63.5–64.6%), and increased to 69.1% (95% CI 68.6–69.6%) during P0, but decreased to 56.2% (95% CI 55.6–56.7%) during P+12 (Figure 1B) (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Comparing P0 to P+12, between 13% and 30% of patients stopped NSAIDs and 5–15% started in the different DMARD groups in the 4 cohorts (Figure 2B), with an overall reduction in NSAID use of 12.9% (95% CI 12.3–13.4%) (Figure 1B). For most of the DMARD groups, the pairwise analyses showed that more patients stopped NSAIDs than started (P < 0.005 for all significant changes). In PACE, the pairwise comparisons were not significant for new HCQ/SSZ (P = 0.590) and new LEF (P = 0.650) groups (Figure 2B).

The median percentage of days with NSAID therapy among NSAID users ranged from 29–68% during P0, and from 47–69% during P+12 in the different DMARD groups for the 4 cohorts (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Changes in narcotic use by DMARD groups.

The percentage of patients with any use of narcotics during P−6 was 58.7% (95% CI 58.2–59.2%), increased to 64.8% (95% CI 64.3–65.4%) during P0, and then decreased to 62.7% (95% CI 62.1–63.2%) during P+12 (Figure 1C) (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

Comparing P0 to P+12, between 7% and 20% of patients stopped narcotics and 7–18% started narcotics in the 4 cohorts (Figure 2C); therefore, a very small overall decrease (2.5%; 95% CI 1.9–3.0%) in the proportion of patients using narcotics was observed. The pairwise analyses showed consistently that more patients stopped narcotics than started in the first MTX group in the 4 cohorts (P < 0.05 for all significant changes) (Figure 2C). Narcotic use also decreased among new MTX initiators from KPNC (P < 0.0001), new HCQ/SSZ from TennCare (P = 0.015), and new anti-TNF from MAX/MED (P = 0.01) (Figure 2C).

The median percentage of days with narcotic therapy among narcotic users in the 4 cohorts ranged from 10–49% during P0, and ranged from 16–62% during P+12 in the different DMARD groups for the 4 cohorts (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

During RA treatment, corticosteroids, NSAIDs, and narcotics are often prescribed to relieve symptoms until a DMARD exerts its therapeutic effect. Once this is achieved there should be less need for the use of these cotherapies and discontinuation should follow in some patients. We evaluated changes in the use of these cotherapies after initiation of different DMARD regimens.

Our major findings are that in patients with RA, 1) the use of medications to control symptoms increased in the 6 months immediately before a new DMARD regimen was initiated compared to the previous 6–12-month period, most likely representing worsening of the disease that led to the new DMARD regimen; 2) after a new DMARD regimen was started, more patients stopped the use of corticosteroids and NSAIDs than started, which resulted in an 8.9% (95% CI 8.4–9.4%) decrease in the overall use of corticosteroids and 12.9% (95% CI 12.3–13.4%) for NSAIDs; and 3) narcotics were a common cotherapy in RA, but unlike corticosteroids and NSAIDs, there was only a very small decrease in their overall use after DMARD initiation.

The point prevalence of narcotic use at the initiation date was lower in KPNC (15.3%) and PACE (16.4%) compared to TennCare (32.5%) and MAX/MED (29.8%). This difference may reflect disparities in clinical practice patterns or patient populations. Patients from TennCare and MAX/MED are Medicaid insured, whereas patients from KPNC receive integrated care with insurance through their employer, through self-insurance, or through Medicare or MediCal. Differences in socioeconomic status might also affect the availability of resources, the type of patients enrolled in each cohort, differences in patterns of care, or use of specific medications. TennCare and MAX/MED include many patients with disabilities who may have more severe or chronic disease requiring narcotics to control pain. The reasons for lower narcotic use in PACE (which insures elderly Medicare patients) compared to TennCare and MAX/MED should be further investigated since the relatively low use was not related to age or to the presence of other comorbidities.

Although the overall proportion of corticosteroid users did not decrease considerably, we found that more patients stopped corticosteroids than started, with an overall decrease of 9% in corticosteroid use. We also found that the average dose of corticosteroids among users decreased slightly. This apparent corticosteroid-sparing effect is consistent with previous reports from small clinical studies (22–24, 31) where anti-TNF therapy was associated with a reduction in corticosteroid use as early as 3 months after starting therapy and persisting after 5 years (22, 32).

The absolute decrease in the proportion of corticosteroid users and the decrease in the median dose of corticosteroids among users after DMARD initiation, although both small, raises the possibility that improvement in disease control led to a decreased need for corticosteroids. Neumann et al reported that corticosteroid use correlated with measures of disease activity during anti-TNF therapy, and that reduction in corticosteroid use occurred as disease activity improved (22). However, because we did not measure disease activity before and after treatment, it is important to consider other reasons for the decrease in corticosteroid use besides improvement of disease control, e.g., physician and patient desire to limit adverse effects associated with long-term use of corticosteroids.

The proportion of corticosteroid users among PACE patients in the new HCQ/SSZ, new LEF, and new anti-TNF groups did not decrease significantly. Possible explanations are a small sample size in these exposure groups. It is important to point out that in our study, the HCQ/SSZ cohort is not a homogeneous group (Table 1), and might contain patients with different disease activity. Consequently, the observed increase in corticosteroid use in this cohort during P−6 compared to P0 could represent disease worsening (for those patients who added HCQ/SSZ to previous MTX), disease improvement (patients who switched from MTX to HCQ), or medication toxicity (patients who switched from MTX to HCQ/SSZ).

Along with the decreased use of corticosteroids, we found a similar pattern for NSAID use. The overall proportion of NSAID users decreased modestly (13%) after a new DMARD was started and the median percentage of days with NSAID therapy among the users remained unchanged, but for most of the groups there were more patients that stopped NSAIDs than started.

Pain control is one of the main goals in RA management, and although NSAIDs not only control pain but also reduce inflammation, few studies have examined the effects of DMARD initiation on NSAID use. Neumann et al reported that the proportion of NSAID users decreased by 16% (from 75% to 59%) after a year of anti-TNF therapy (22) among anti-TNF–adherent patients. We found an overall reduction of NSAID use of almost 13% after the same period of time. The reasons for the lack of significance found in the new HCQ/SSZ and new LEF groups for the PACE cohort might be the same as those for corticosteroid use.

We found that the percentage of patients with any narcotic use decreased after a new DMARD was started, but the median percentage of days with narcotic therapy increased. If RA-associated pain was the reason for narcotic use, we would have expected use to decrease, as was observed with NSAIDs and corticosteroids. However, in patients that had failed a previous DMARD regimen, the percentage of patients with any narcotic use remained unchanged. Clinical experience and previous reports showed that patients who failed MTX have more structural damage than patients who respond to therapy (33); pain from advanced structural damage might be more difficult to control, potentially explaining the lack of a reduction in narcotic use.

Another explanation might be that after a DMARD regimen controls disease activity, physicians prefer to first taper medications with a higher risk of serious side effects (gastrointestinal bleeding with NSAIDs, osteoporosis with corticosteroids, etc.). Doses of narcotics used for pain control are considered relatively safe; therefore, tapering narcotics might be delayed (34, 35). Studies with longer followup will be needed to clarify this hypothesis. Also, prolonged use of narcotics can cause dependence and make discontinuation difficult (36, 37).

Patients with recent-onset RA with active disease are more likely to start with MTX (alone or in combination) as their first DMARD (3). Therefore, in our study, the first MTX group is likely to represent many patients with recently diagnosed RA. Notably, in this group, there was a decrease in cotherapy use with corticosteroids, NSAIDs, and also with narcotics. These results are consistent with a previous report in clinical practice, where first DMARD users experienced a greater reduction in levels of acute-phase reactants than those patients with previous DMARD courses (38). Patients in this group might have less joint and bone damage (33) and because their pain is related to inflammation rather than structural damage (2), it might be more likely to be controlled by a DMARD.

The results of our descriptive study must be interpreted in light of some caveats. First, we ascertained medication use using pharmacy fill data but actual adherence to therapies could not be measured. Nevertheless, pharmacy data are not subject to recall bias and have high concordance with patients' reports of medication (39, 40). Second, although the remarkable consistency in findings across diverse patient populations suggests that decreased corticosteroid and NSAID use may be due to improved disease control due to DMARD initiation, other reasons for decreased use cannot be excluded. For instance, information on alternate indications for cotherapies was not available (e.g., narcotics might be prescribed for other reasons such as chronic low back pain in some patients with RA). Third, use of over-the-counter NSAIDs was not measured; thus, we cannot conclude that in some patients the initiation of a new DMARD regimen reduced all NSAID use. Fourth, the strength and dose of narcotics were not analyzed; therefore, it is possible that some patients experienced disease improvement and reduced narcotic use (dose reduction or switch to less potent narcotic) without completely stopping narcotics. Finally, although we used 1 year of baseline information to define first MTX use, we cannot be certain that these patients had truly never taken MTX.

In summary, we found that the overall proportion of patients with RA prescribed corticosteroids and NSAIDs decreased by 9% and 13%, respectively, 6–12 months after starting a new DMARD regimen. However, there was only a very small decrease in the proportion of patients using narcotics (2.5%) after initiation of new DMARD regimens. New studies using large data registries or clinical practices that include information on disease severity, pain levels, cotherapy indications, use of nonprescribed NSAIDs, and adherence (including reason for nonadherence) would complement these data and help identify determinants of continued cotherapy use. Our study highlights the frequent use of cotherapies in RA patients despite the use of specific RA treatments. Better and perhaps earlier treatment may help reduce the use of these cotherapies and the adverse events associated with them.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

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 published. Dr. Griffin 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. Kawai, Grijalva, Curtis, Delzell, Chen, Ouellet-Hellstrom, Herrinton, Liu, Stein, Griffin.

Acquisition of data. Curtis, Solomon, Delzell, Liu, Mitchel, Griffin.

Analysis and interpretation of data. Kawai, Grijalva, Arbogast, Curtis, Solomon, Delzell, Chen, Ouellet-Hellstrom, Liu, Stein, Griffin.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

We are indebted to the Tennessee Bureau of TennCare of the Department of Finance and Administration, which provided the data on TennCare recipients.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information
  • 1
    Goldring SR. Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology (Oxford) 2003; 42 Suppl: ii116.
  • 2
    McDougall JJ. Arthritis and pain: neurogenic origin of joint pain. Arthritis Res Ther 2006; 8: 220.
  • 3
    American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002; 46: 32846.
  • 4
    Quinn MA, Conaghan PG, Emery P. The therapeutic approach of early intervention for rheumatoid arthritis: what is the evidence? Rheumatology (Oxford) 2001; 40: 121120.
  • 5
    Bijlsma JW, Boers M, Saag KG, Furst DE. Glucocorticoids in the treatment of early and late RA. Ann Rheum Dis 2003; 62: 10337.
  • 6
    Genovese MC. Treatment of rheumatoid arthritis. In: Firestein GS, Budd RC, Harris ED Jr, McInnes IB, Ruddy S, Sergent JS, editors. Kelley's textbook of rheumatology, vol II. 8th ed. Philadelphia: Saunders; 2008. p. 111968.
  • 7
    Christiansen CF, Christensen S, Mehnert F, Cummings SR, Chapurlat RD, Sorensen HT. Glucocorticoid use and risk of atrial fibrillation or flutter: a population-based, case-control study. Arch Intern Med 2009; 169: 167783.
  • 8
    Doan T, Massarotti E. Rheumatoid arthritis: an overview of new and emerging therapies. J Clin Pharmacol 2005; 45: 75162.
  • 9
    Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts AC, Leufkens HG, et al. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart 2004; 90: 85965.
  • 10
    Schmajuk G, Schneeweiss S, Katz JN, Weinblatt ME, Setoguchi S, Avorn J, et al. Treatment of older adult patients diagnosed with rheumatoid arthritis: improved but not optimal. Arthritis Rheum 2007; 57: 92834.
  • 11
    Treharne GJ, Douglas KM, Iwaszko J, Panoulas VF, Hale ED, Mitton DL, et al. Polypharmacy among people with rheumatoid arthritis: the role of age, disease duration and comorbidity. Musculoskeletal Care 2007; 5: 17590.
  • 12
    Grijalva CG, Chung CP, Stein CM, Mitchel EF Jr, Griffin MR. Changing patterns of medication use in patients with rheumatoid arthritis in a Medicaid population. Rheumatology (Oxford) 2008; 47: 10614.
  • 13
    Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol 2005; 3: 13341.
  • 14
    Roumie CL, Choma NN, Kaltenbach L, Mitchel EF Jr, Arbogast PG, Griffin MR. Non-aspirin NSAIDs, cyclooxygenase-2 inhibitors and risk for cardiovascular events-stroke, acute myocardial infarction, and death from coronary heart disease. Pharmacoepidemiol Drug Saf 2009; 18: 105363.
  • 15
    Roumie CL, Mitchel EF Jr, Kaltenbach L, Arbogast PG, Gideon P, Griffin MR. Nonaspirin NSAIDs, cyclooxygenase 2 inhibitors, and the risk for stroke. Stroke 2008; 39: 203745.
  • 16
    Grijalva CG, Chung CP, Arbogast PG, Stein CM, Mitchel EF Jr, Griffin MR. Assessment of adherence to and persistence on disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis. Med Care 2007; 45 Suppl: S6676.
  • 17
    Hudson TJ, Edlund MJ, Steffick DE, Tripathi SP, Sullivan MD. Epidemiology of regular prescribed opioid use: results from a national, population-based survey. J Pain Symptom Manage 2008; 36: 2808.
  • 18
    Khanna R, Smith MJ. Utilization and costs of medical services and prescription medications for rheumatoid arthritis among recipients covered by a state Medicaid program: a retrospective, cross-sectional, descriptive, database analysis. Clin Ther 2007; 29: 245667.
  • 19
    Ytterberg SR, Mahowald ML, Woods SR. Codeine and oxycodone use in patients with chronic rheumatic disease pain. Arthritis Rheum 1998; 41: 160312.
  • 20
    Ballantyne JC, LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. Pain 2007; 129: 23555.
  • 21
    Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with the use of morphine and opiates. J Intern Med 2006; 260: 7687.
  • 22
    Naumann L, Huscher D, Detert J, Spengler M, Burmester GR, Buttgereit F. Anti-tumour necrosis factor α therapy in patients with rheumatoid arthritis results in a significant and long-lasting decrease of concomitant glucocorticoid treatment. Ann Rheum Dis 2009; 68: 19346.
  • 23
    Seror R, Dougados M, Gossec L. Glucocorticoid sparing effect of tumour necrosis factor α inhibitors in rheumatoid arthritis in real life practice. Clin Exp Rheumatol 2009; 27: 80713.
  • 24
    Kievit W, Adang EM, Fransen J, Kuper HH, van de Laar MA, Jansen TL, et al. The effectiveness and medication costs of three anti-tumour necrosis factor α agents in the treatment of rheumatoid arthritis from prospective clinical practice data. Ann Rheum Dis 2008; 67: 122934.
  • 25
    The Hera Study Group. A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA study. Am J Med 1995; 98: 15668.
  • 26
    Lipsky PE, van der Heijde DM, St.Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343: 1594602.
  • 27
    Sharp JT, Strand V, Leung H, Hurley F, Loew-Friedrich I, on behalf of the Leflunomide Rheumatoid Arthritis Investigators Group. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 2000; 43: 495505.
  • 28
    Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 158693.
  • 29
    Sokka T, Envalds M, Pincus T. Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs. Mod Rheumatol 2008; 18: 22839.
  • 30
    Mikuls TR, O'Dell J. The changing face of rheumatoid arthritis therapy: results of serial surveys [letter]. Arthritis Rheum 2000; 43: 4645.
  • 31
    Kievit W, Fransen J, Oerlemans AJ, Kuper HH, van der Laar MA, de Rooij DJ, et al. The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice. Ann Rheum Dis 2007; 66: 14738.
  • 32
    Geborek P, Crnkic M, Petersson IF, Saxne T. Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden. Ann Rheum Dis 2002; 61: 7938.
  • 33
    Van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, van Zeben D, Kerstens PJ, Gerards AH, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis 2007; 66: 135662.
  • 34
    Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 2005; 293: 304352.
  • 35
    American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. Pain Med 2009; 10: 106283.
  • 36
    Reid MC, Engles-Horton LL, Weber MB, Kerns RD, Rogers EL, O'Connor PG. Use of opioid medications for chronic noncancer pain syndromes in primary care. J Gen Intern Med 2002; 17: 1739.
  • 37
    Cowan DT, Wilson-Barnett J, Griffiths P, Vaughan DJ, Gondhia A, Allan LG. A randomized, double-blind, placebo-controlled, cross-over pilot study to assess the effects of long-term opioid drug consumption and subsequent abstinence in chronic noncancer pain patients receiving controlled-release morphine. Pain Med 2005; 6: 11321.
  • 38
    Aletaha D, Smolen JS. The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses. Rheumatology (Oxford) 2002; 41: 136774.
  • 39
    Landry JA, Smyer MA, Tubman JG, Lago DJ, Roberts J, Simonson W. Validation of two methods of data collection of self-reported medicine use among the elderly. Gerontologist 1988; 28: 6726.
  • 40
    West SL, Savitz DA, Koch G, Strom BL, Guess HA, Hartzema A. Recall accuracy for prescription medications: self-report compared with database information. Am J Epidemiol 1995; 142: 110312.

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
ART_20550_sm_appendix.doc64KSupplementary Data

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.