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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Objective

To estimate the incidence and risk factors for gastrointestinal (GI) perforation among patients with rheumatoid arthritis (RA).

Methods

Claims from employer health insurance plans were used to identify RA patients and those hospitalized for upper or lower GI perforation. GI perforation cases were identified using both a sensitive and a specific definition. A Cox model using fixed and time-varying covariates was used to evaluate the risk of GI perforation.

Results

Among 143,433 RA patients, and using a maximally sensitive GI perforation definition, 696 hospitalizations with perforation were identified. The rate of perforation was 1.70 per 1,000 person years (PYs; 95% confidence interval [95% CI] 1.58–1.83), and most perforations (83%) occurred in the lower GI tract. The rate of perforation was lower when a more specific GI perforation definition was used (0.87; 95% CI 0.78–0.96 per 1,000 PYs). Age and diverticulitis were among the strongest risk factors for perforation (diverticulitis hazard ratio [HR] 14.5 [95% CI 11.8–17.7] for the more sensitive definition, HR 3.9 [95% CI 2.5–5.9] for the more specific definition). Among various RA medication groups and compared to methotrexate, the risk of GI perforation was highest among patients with exposure to nonsteroidal antiinflammatory drugs (NSAIDs), concomitant nonbiologic disease-modifying antirheumatic drugs, and glucocorticoids. Biologic agents without glucocorticoid exposure were not a risk factor for perforation.

Conclusion

GI perforation is a rare but serious condition that affects patients with RA, most frequently in the lower GI tract. Clinicians should be aware of risk factors for GI perforation when managing RA patients, including age, history of diverticulitis, and use of glucocorticoids or NSAIDs.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Despite the gravity of gastrointestinal (GI) perforations, little is known about the incidence and prevalence of this condition, particularly in the lower GI tract, in clinical practice among patients with rheumatoid arthritis (RA). Medications used to treat RA include systemic nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologic response modifiers (biologic agents). While the expanding array of therapies has notably mitigated the disability associated with RA for many patients, all of these agents have the potential for side effects, including serious adverse events such as GI bleeding and perforation (1–4).

Likewise, glucocorticoid treatment has been associated with a broad array of adverse systemic events. Even at low doses, as commonly used in RA patients, long-term glucocorticoid therapy is associated with gastritis, pancreatitis, gastric ulcers, edema, and GI bleeding when concomitantly used with NSAIDs (1, 3). Additionally, oral glucocorticoid use is associated with a 3-fold increase in the risk of diverticular perforation (5).

Among various RA medications, aspirin and NSAIDs have been the best characterized with respect to serious GI events, including bleeding and perforation of colonic diverticula (6, 7). A prospective cohort study by Strate et al (2011) assessed the use of these medications and other risk factors biennially among 47,210 men in the US. During the 22-year followup period, 256 cases of diverticular bleeding were documented. After adjustment for risk factors, men who took aspirin and nonaspirin NSAIDs regularly (≥2 times/week) had multivariable-adjusted hazard ratios (HRs) of 1.70 (95% confidence interval [95% CI] 1.21–2.39) and 1.74 (95% CI 1.15–2.64), respectively, for diverticular bleeding compared with men who denied use of these medications. Use of aspirin at intermediate dosages (2–5.9 standard, 325 mg tablets/week) and frequency (4–6 days/week) were associated with the highest risk of bleeding (HR 2.32, 95% CI 1.34–4.02 and HR 3.13, 95% CI 1.82–5.38, respectively) (7).

The incidence of NSAID-associated upper GI tract complications is well recognized and described in the literature (8, 9). Although the incidence of lower GI tract complications is less well understood, an increasing body of evidence suggests that NSAID-induced GI toxicity extends into the lower GI tract (10). Given this finding, an increasing number of studies are evaluating complications of both the upper and lower GI tract together (11, 12).

Most studies evaluating GI events, such as ulcers, bleeding, and perforations, report data for these complications collectively, making it difficult to discern the incidence of and characterize risk factors for GI perforations alone (8, 13, 14). Few studies have evaluated either the frequency or risk of lower GI tract perforations, and fewer still have examined the impact of exposure to other medications used to treat RA, either alone or in combination, on the risk of perforation. To address these gaps in knowledge, the present study analyzed a large administrative database to estimate the incidence of GI perforation among patients with RA and to identify RA- and non–RA-related risk factors for both upper and lower GI perforations.

Significance & Innovations

  • Our retrospective analysis of a large US health plan database showed that the main risk factors for gastrointestinal (GI) perforation in patients with rheumatoid arthritis included age, history of diverticulitis, and use of glucocorticoids and prescription nonsteroidal antiinflammatory drugs.

  • Using a sensitive definition for GI perforation, the overall rate of perforation was 1.70 per 1,000 patient-years (PYs), and was 0.87 per 1,000 PYs when a more specific definition of perforation was used.

  • Biologic agent use (predominantly anti–tumor necrosis factor therapy) was not a significant risk factor for perforation.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Data sources.

This study analyzed data derived from the MarketScan Commercial Claims and Encounters database (Thomson Reuters; online at www.thomsonreuters.com) and the Medicare Supplemental and Coordination of Benefits database for the period January 1, 2001 to June 30, 2009. These databases provide information about inpatient, outpatient, and outpatient prescription drug experience of approximately 94.1 million people of all ages covered under a variety of fee-for-service, point-of-service, and capitated benefit plans. Approximately 7.7 million of those covered are from the Medicare database, which consists of persons with Medicare coverage with supplemental employer-funded coverage. These databases are derived from employer health insurance plans and have been widely used for diverse epidemiologic and health economic studies, including studies of RA (15–19).

Population selection.

Patients included in the analysis were ages ≥18 years and had ≥2 nondiagnostic inpatient or outpatient medical claims (e.g., claims from physician evaluation and management) with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for RA (714.0x or 714.3x). The RA claims had to occur between January 1, 2002 and December 31, 2008, and were required to be for services on different days, 30 to 365 days apart. In addition, patients had a minimum of 12 months of continuous eligibility prior to the “index date,” defined as the second date of RA diagnosis. If a patient did not have 12 months of continuous enrollment prior to their second eligible RA diagnosis, the index date was moved forward in time until the 12-month continuous enrollment requirement was met. Patients were also required to have continuous medical and pharmacy coverage for the duration of their study eligibility.

Exclusion criteria consisted of patients with malignant GI cancer or hospitalization for GI perforation in the 12 months preceding the index date. Patients were followed until death, occurrence of the first GI perforation, disenrollment from the study database, or study end.

Study outcome measures.

The outcome of interest was hospitalization with a nontraumatic upper or lower GI perforation. The number and proportion of patients with a GI perforation, the rate per unit of person-time observed, and time to the perforation were reported. We considered upper and lower GI perforations as a single entity for 2 reasons: 1) the larger number of events gave us greater statistical power to identify risk factors, and 2) based on current and available evidence, both upper and lower GI complications have been linked to use of NSAIDs, aspirin, and glucocorticoids, age, sex, etc., all of which were factors of interest.

Two definitions of GI perforation were evaluated. The first definition, intended to be more sensitive, included any inpatient admission with evidence of perforation based on 1) the presence of the word perforation in the following ICD-9-CM diagnosis descriptions: esophageal rupture; gastric, duodenal, peptic, or gastrojejunal ulcers; appendicitis; and GI perforation of an unspecific location in the large intestine, or 2) an ICD-9-CM diagnosis of diverticulitis, diverticulosis, or ischemic colitis plus a Current Procedural Terminology (CPT) code for suture or resection of the small or large intestine (Table 1). This sensitive GI perforation definition was our primary study outcome. A second, more specific definition was also used. This definition only included inpatient admissions with evidence of perforation based on the presence of the word perforation in ICD-9-CM diagnosis descriptions for esophageal rupture; gastric, duodenal, peptic, or gastrojejunal ulcers; and unspecified GI perforation. The specific GI perforation definition did not include cases of appendicitis, diverticulitis, diverticulosis, or ischemic colitis associated with surgical GI procedures. The definitions of GI perforation were based on a validated claims-based algorithm. The validation study for the algorithm evaluated the medical charts of 92 RA patients identified by the algorithm as having a GI perforation and showed the positive predictive value of the algorithm to be 94% (95% CI 86–98%) in identifying confirmed GI perforations (20). In the validation study, the study algorithm initially included 1) ICD-9-CM codes with perforation language and 2) ICD-9-CM codes without perforation language plus a CPT code for confirmatory surgery; however, no cases in the validation sample were identified by the latter method due to limitations in the data source. Given this result, the acknowledged constraint, and additional concerns about the inclusion of the perforated appendix, our study used the full study algorithm in order to provide the most sensitive perforation definition, but also evaluated the more specific definition that was better supported by the methodology of the published perforation validation study.

Table 1. Frequency of GI perforation during followup by location*
Perforation location and subtypeNTotal events, %ICD-9-CM diagnosis code
  • *

    Rows are not additive because patients may have multiple diagnoses on the same day (e.g., 1 patient with ICD-9-CM codes 530.4 and 531.1 classified as having a single upper GI tract perforation spanning both the esophageal and gastric locations). GI = gastrointestinal; ICD-9-CM = International Classification of Diseases, Ninth Edition, Clinical Modification.

  • Requires evidence of confirmatory surgery via a professional claim with Current Procedural Terminology (CPT) code 44602, 44603, 44120, 44121, 44125, 44130, 44202, or 44203.

  • Requires evidence of confirmatory surgery via a professional claim with CPT code 44604, 44605, 44140, 44145, 44204, or 44205. ICD-9-CM codes 557.0x, 557.1x, and 557.9x are not specific to ischemic colitis and may include other diagnoses.

Upper GI tract   
 Esophageal perforations111.6530.4
 Gastroduodenal perforations   
  Gastric ulcer557.8531.10, 531.11, 531.20, 531.21, 531.50, 531.51, 531.60, 531.61
  Duodenal ulcer547.8532.10, 532.11, 532.20, 532.21, 532.50, 532.51, 532.60, 532.61
  Peptic ulcer172.4533.10, 533.11, 533.20, 533.21, 533.50, 533.51, 533.60, 533.61
Lower GI tract   
 Perforations of the small intestine   
  Gastrojejunal ulcer60.9534.10, 534.11, 534.20, 534.21, 534.50, 534.51, 534.60, 534.61
  Diverticulosis30.5562.00, 562.02
  Diverticulitis20.3562.01, 562.03
 Perforations of the large intestine   
  Appendicitis14019.7540
  Ischemic colitis243.4557.0, 557.1, 557.9
  Diverticulosis9413.2562.10, 562.12
  Diverticulitis18025.4562.11, 562.13
 Unspecified perforations24434.4569.83

Baseline characteristics and exposures of interest.

Patient demographics and clinical characteristics were captured as of the study index date. Two measures of baseline comorbidity were calculated: the Deyo-adapted Charlson Comorbidity Index (CCI) and baseline medical and pharmaceutical expenditure.

Exposure to systemic medications used to treat RA was also evaluated. Medication classes analyzed include the following groups: methotrexate (MTX), anti–tumor necrosis factor (anti-TNF) biologics, other biologic agents (e.g., anakinra, abatacept, and rituximab), glucocorticoids, prescription NSAIDs, and other DMARDs (e.g., hydroxychloroquine, gold compounds, and sulfasalazine). Patients with multiple RA medication exposures were assigned a grouping based on the following mutually exclusive hierarchy: biologics (anti-TNF and other) [with or without nonbiologic DMARDs] → MTX [with or without other nonbiologic DMARDs] → all other DMARDs excluding MTX → none of these. Use of a medication hierarchy allowed us to explicitly evaluate the possible interactions between medications. The medication hierarchy was established based upon clinical relevance in RA treatment and informed by the degree of hypothesized immunosuppression. Use of the over-the-counter (OTC) medications, including NSAIDs, was not captured in this data source. Each of these 4 exposure groups was also analyzed with glucocorticoids, yielding a total of 8 mutually exclusive categories. Exposure to NSAIDs was measured independently of the hierarchical RA medication groups.

Several time-varying covariates were measured both during the baseline period and during followup (updated daily), including the occurrence of diverticulitis or diverticulosis, treatment with RA medications (biologic agents, MTX, and other DMARDs, with or without concurrent glucocorticoids), and exposure to NSAIDs. Time receiving a medication and the time-varying risk factors were computed for each day of the study. Patients with a history of diverticulitis or diverticulosis at baseline were flagged as having the condition on the first day of followup. Patients without a baseline history of these conditions but who developed them during followup were identified. For these individuals, the assigned date of the diagnosis of diverticulitis and diverticulosis was delayed by 90 days to avoid capturing these conditions only at or near the time of the perforation event.

Medication exposure was characterized as current versus noncurrent on each day of the study period and was determined by the prescription fill date plus the number of days' supply of medication. A fixed extension period of 60 days was applied to all pharmacy-based prescriptions. Exposure to facility-based injectable or infused medications was based on the administration date plus a clinically relevant exposure window specific to each medication (56 days for infliximab, 30 days for abatacept, and 180 days for rituximab).

Statistical analysis.

Baseline characteristics of the patients with and without GI perforation events during the followup period were compared for demographic and risk factors of clinical interest. Chi-square tests were used to assess the statistical significance of categorical variables; t-tests and analysis of variance were used for continuous variables.

A Cox model with time-varying covariates assessed the impact of fixed and time-varying characteristics on the risk of GI perforation. Fixed explanatory variables included age, sex, census region, population density, and the Deyo-adapted CCI score. Time-varying covariates included exposure to RA medications, diverticulitis, and diverticulosis without diverticulitis. Study RA medication categories in the model were biologic agents, MTX, and other DMARDs, each with and without glucocorticoids. NSAIDs were assessed independently.

Additional analyses evaluated a possible interaction between biologic agent use (in the absence of glucocorticoids) with both age (dichotomized as <65 and ≥65 years) and history of diverticulitis. This assessed whether the risk associated with biologic agents varied for these 2 patient subgroups. Conventional P values (less than 0.05) were used to evaluate the significance of the associated interaction terms.

Finally, we performed a sensitivity analysis in which we censored unspecified and upper GI events at the perforation event date. We then used the remainder of the lower GI perforations as the outcome to see if the risk factor HRs were comparable.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

A total of 143,433 RA patients were included in the analysis (Figure 1). The most common reasons for exclusion were inadequate continuous eligibility (19.9%) and lack of data availability (20.6%), either because of incomplete data or lack of a pharmacy benefit. Patients were followed for a mean ± SD of 34.8 ± 22.9 months, yielding 409,587 person-years (PYs) of followup.

thumbnail image

Figure 1. Study accrual and attrition. RA = rheumatoid arthritis; 1 = defined as the second date of RA diagnosis after 12 full months of continuous enrollment; GI = gastrointestinal.

Download figure to PowerPoint

Perforations in the lower GI tract were most frequent, representing 83% of all cases (Table 1). The unadjusted GI perforation rate per 1,000 PYs was 1.70 overall, 1.44 in the lower GI tract, and 0.30 in the upper GI tract. Upper GI tract events were largely associated with gastric and duodenal ulcers, whereas lower GI events were mostly unspecified location perforations and those associated with diverticulitis and appendicitis.

Demographic and clinical characteristics.

Approximately three-quarters of the sample population was female, with a mean ± SD age of 57.7 ± 14.1 years. Compared to US Census population estimates for the study period, the study population was notably concentrated in the Midwest (28.1% versus 22.1%) and underrepresented in the Northeast (9.8% versus 18.5%).

At baseline, 91% of patients received some form of pharmacotherapy for RA. The most commonly used medications for RA included prescription NSAIDs (56%), glucocorticoids (55%), MTX (43%), a DMARD other than MTX (34%), and biologic agents (18%). The study population had a median Deyo-adapted CCI score of 1.0 (interquartile range 1.0–2.0), consistent with modest levels of comorbidity.

Table 2 shows baseline demographic and clinical characteristics of patients by perforation status. Compared to patients not experiencing a GI perforation, patients with a GI perforation were older (mean age 62.0 versus 57.6 years; P < 0.0001), more likely to have Medicare as a primary payer (43.0% versus 30.4%; P < 0.0001), more likely to reside in a rural area (22.8% versus 18.3%; P = 0.002), and more likely to reside in the Midwest (33.3% versus 28.0%; P = 0.002). The mean length of followup for patients who had a perforation was also lower (24.2 versus 34.8 months; P < 0.0001). At baseline, patients who subsequently experienced a GI perforation had an increased likelihood of exposure to glucocorticoids (without NSAIDs: 25.3% versus 21.3%; P = 0.01 and with NSAIDs: 40.5% versus 34.1%; P < 0.01) and non-MTX DMARDs (38.5% versus 33.7%; P < 0.00001), higher levels of overall comorbidity (mean CCI score 1.7 versus 1.5; P < 0.001), an increased likelihood of GI conditions (diverticulitis, diverticulosis, esophageal or GI hemorrhage, and noninfectious gastroenteritis/colitis), and higher annual medical expenditures (mean $11,543 versus $9,031; P < 0.001) than patients not experiencing a GI perforation.

Table 2. Baseline demographic characteristics by GI perforation status at followup*
 Patients without perforation (n = 142,737)Patients with perforation (n = 696)P
  • *

    Values are the number (percentage) unless otherwise indicated. GI = gastrointestinal; CCI = Charlson Comorbidity Index; RA = rheumatoid arthritis; TNF = tumor necrosis factor; DMARDs = disease-modifying antirheumatic drugs; NSAID = nonsteroidal antiinflammatory drug; PPIs = proton-pump inhibitors.

  • Azathioprine, chloroquine, hydroxychloroquine, cyclosporine, D-penicillamine, leflunomide, sulfasalazine, and gold compounds.

  • Excludes perforation.

  • §

    Unspecified.

Female sex106,714 (74.80)506 (72.70)0.21
Age, mean ± SD years57.6 ± 14.162 ± 12.9< 0.01
Insurance plan type   
 Commercial99,364 (69.60)397 (57.00)< 0.01
 Medicare43,373 (30.40)299 (43.00)< 0.01
Geographic region   
 Northeast13,935 (9.80)60 (8.60)0.31
 Midwest40,013 (28.00)232 (33.30)< 0.01
 South56,305 (39.40)262 (37.60)0.33
 West31,532 (22.10)137 (19.70)0.13
 Unknown952 (0.70)5 (0.70)0.87
Population density   
 Rural26,111 (18.30)159 (22.80)< 0.01
 Urban115,792 (81.10)532 (76.40)< 0.01
 Unknown834 (0.60)5 (0.70)0.64
Length of followup, mean ± SD months34.8 ± 22.924.2 ± 19.2< 0.01
Deyo-adapted CCI score, mean ± SD1.5 ± 1.11.7 ± 1.2< 0.01
Baseline expenditure, mean ± SD dollars9,031 ± 19,85611,543 ± 22,212< 0.01
RA medication history   
 Methotrexate61,369 (43.00)285 (41.00)0.28
 Biologic, TNF24,350 (17.10)119 (17.10)0.98
 Biologic, other810 (0.60)3 (0.40)0.63
 All other DMARDs48,025 (33.70)268 (38.50)< 0.01
 NSAID without glucocorticoid31,581 (22.10)137 (19.70)0.12
 Glucocorticoid without NSAID30,413 (21.30)176 (25.30)0.01
 NSAID and glucocorticoid48,632 (34.10)282 (40.50)< 0.01
 No NSAID or glucocorticoid32,111 (22.50)101 (14.50)< 0.01
 No prescription RA medication13,084 (9.20)41 (5.90)< 0.01
Any H2 blockers, PPIs, or misoprostol42,115 (29.50)271 (38.90)< 0.01
Other GI disturbance8,026 (5.60)68 (9.80)< 0.01
 Diverticulitis401 (0.30)20 (2.90)< 0.01
 Diverticulosis without diverticulitis583 (0.40)10 (1.40)< 0.01
 Esophageal or GI hemorrhage1,253 (0.90)13 (1.90)< 0.01
 Noninfectious gastroenteritis/colitis§803 (0.60)10 (1.40)< 0.01

Perforation incidence rates.

During the followup period, 710 GI perforations occurred in 696 patients (14 patients had both upper and lower GI perforations). The overall incidence of GI perforation in this study was low, with 0.5% of patients hospitalized with a perforation during followup, yielding a rate of 1.70 events per 1,000 PYs (95% CI 1.58–1.83) (Table 3). This rate was 0.87 events per 1,000 PYs (95% CI 0.78–0.96) when the more specific definition of perforation was used.

Table 3. Incidence of GI perforation, by medication exposure, in the total study population (n = 143,433)*
Medication exposure groupSensitive GI perforation definitionSpecific GI perforation definition
IR/1,000 PYs95% CIIR/1,000 PYs95% CI
  • *

    GI = gastrointestinal; IR = incidence rate; PYs = person-years; 95% CI = 95% confidence interval; DMARDs = disease-modifying antirheumatic drugs.

  • Azathioprine, chloroquine, hydroxychloroquine, cyclosporine, D-penicillamine, leflunomide, sulfasalazine, and gold compounds.

Biologic agents with glucocorticoids1.871.46–2.350.910.63–1.26
Biologic agents without glucocorticoids1.020.80–1.290.470.32–0.66
Methotrexate with glucocorticoids2.241.82–2.741.250.94–1.63
Methotrexate without glucocorticoids1.080.86–1.350.470.33–0.66
All other DMARDs with glucocorticoids3.032.34–3.851.651.16–2.29
All other DMARDs without glucocorticoids1.711.34–2.160.660.44–0.96
Glucocorticoids without DMARDs or biologic agents2.862.27–3.562.151.64–2.76
No DMARDs, biologic agents, or glucocorticoids1.681.44–1.960.810.64–1.01
Overall1.701.58–1.830.870.78–0.96

The unadjusted rate of GI perforation per 1,000 PYs in patients with a history of diverticulitis was 22.98 (95% CI 19.16–27.35) compared to 1.41 (95% CI 1.29–1.53) in those without such a history (Table 4). Conversely, the unadjusted rate of GI perforation per 1,000 PYs in patients with diverticulosis was 1.30 (95% CI 0.65–2.33), which was not higher than the rate among patients without the disorder (data not shown). The highest rates of GI perforation (per 1,000 PYs) were observed in patients with a history of diverticulitis and exposure to DMARDs (other than MTX) and glucocorticoids (41.0; 95% CI 22.9–67.6), exposure to other DMARDs without glucocorticoids (33.1; 95% CI 18.5–54.6), and exposure to biologic agents with glucocorticoids (32.0; 95% CI 18.64–51.22). The addition of glucocorticoids to each RA medication combination, with the exception of MTX, was associated with a higher incidence of perforation, ranging from 24% (during exposure to other DMARDs) to 95% (during exposure to biologic agents) among patients with a history of diverticulitis.

Table 4. Incidence of GI perforation, by medication exposure, in patients with and without a history of diverticulitis and exposure to prescription NSAIDs*
Medication exposure groupPositive history of diverticulitis (n = 1,802)Negative history of diverticulitis (n = 141,631)Positive prescription NSAID exposure (n = 88,899)Negative prescription NSAID exposure (n = 54,534)
IR/1,000 PYs95% CIIR/1,000 PYs95% CIIR/1,000 PYs95% CIIR/1,000 PYs95% CI
  • *

    GI = gastrointestinal; NSAIDs = nonsteroidal antiinflammatory drugs; IR = incidence rate; PYs = person-years; 95% CI = 95% confidence interval; MTX = methotrexate; DMARDs = disease-modifying antirheumatic drugs.

  • Azathioprine, chloroquine, hydroxychloroquine, cyclosporine, D-penicillamine, leflunomide, sulfasalazine, and gold compounds.

Biologic agents with glucocorticoids31.9918.64–51.221.441.09–1.882.191.52–3.041.641.15–2.26
Biologic agents without glucocorticoids16.428.19–29.370.870.66–1.121.280.88–1.790.870.61–1.20
MTX with glucocorticoids21.7711.90–36.521.951.55–2.422.732.01–3.621.911.41–2.52
MTX without glucocorticoids23.9213.67–38.840.870.67–1.111.411.03–1.890.830.58–1.16
All other DMARDs with glucocorticoids40.9922.94–67.612.381.77–3.133.572.43–5.072.671.86–3.71
All other DMARDs without glucocorticoids33.1218.53–54.621.361.03–1.771.751.19–2.471.691.19–2.31
Glucocorticoids without DMARDs or biologic agents20.0410.67–34.272.451.90–3.123.372.25–4.832.641.96–3.47
No DMARDs, biologic agents, or glucocorticoids16.8311.00–24.671.441.21–1.701.561.09–2.151.731.44–2.05
Overall22.9819.16–27.351.411.29–1.531.931.71–2.161.571.42–1.73

The rate of GI perforation during exposure to NSAIDs, independent of exposure to other study RA medications, was 1.93 (95% CI 1.71–2.16) per 1,000 PYs. When NSAIDs were added to most other study RA medication groups, there was an increased rate of GI perforation of approximately 0.4–0.9 per 1,000 PYs (P = 0.007 comparing the overall rate with and without NSAID exposure) (Table 4).

Multivariate analysis results.

Results of the Cox model indicated that patients with a history of diverticulitis were at the greatest risk of GI perforation (HR 14.5, 95% CI 11.8–17.7; P < 0.0001) (Table 5). Although the magnitude of the risk decreased, diverticulitis remained a significant risk factor when the specific GI perforation definition was used (HR 3.9, 95% CI 2.5–5.9; P < 0.0001). Other clinically significant factors with both GI perforation definitions were use of glucocorticoids, use of NSAIDs, increasing age, and higher levels of comorbidity. The HR for diverticulosis without diverticulitis was not significant for either of the outcome definitions. There were no significant interactions between biologic agent use without steroids and age or a history of diverticulitis.

Table 5. Relative risk of GI perforation during followup*
Risk factorSensitive GI perforation definitionSpecific GI perforation definition
HR95% CIHR95% CI
  • *

    GI = gastrointestinal; HR = hazard ratio; 95% CI = 95% confidence interval; CCI = Charlson Comorbidity Index; RA = rheumatoid arthritis; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate; NSAID = nonsteroidal antiinflammatory drug.

  • With or without NSAIDs.

  • Azathioprine, chloroquine, hydroxychloroquine, cyclosporine, D-penicillamine, leflunomide, sulfasalazine, and gold compounds.

  • §

    With or without DMARDs, glucocorticoids, or biologic agents.

Age, years    
 18–39
 40–641.61.1–2.42.11.1–3.9
 ≥652.11.4–3.13.61.9–6.9
Sex    
 Male
 Female0.90.8–1.11.00.8–1.2
Population density    
 Rural or suburban
 Urban0.80.7–0.90.90.7–1.1
Census region    
 Northeast
 Midwest1.00.8–1.41.00.6–1.4
 South1.10.8–1.41.10.7–1.7
 West1.10.8–1.41.20.8–1.8
History of diverticulitis    
 No
 Yes14.511.8–17.73.92.5–5.9
History of diverticulosis    
 No
 Yes0.80.5–1.50.80.4–1.6
Deyo-adapted CCI score    
 0
 Score1.11.0–1.21.21.1–1.3
During RA medication exposure (time varying)    
 Methotrexate without glucocorticoids
 Glucocorticoids without DMARDs or biologic agents2.21.6–3.14.02.6–6.2
 Other DMARDs with glucocorticoids2.51.8–3.53.22.0–5.2
 MTX with glucocorticoids1.91.4–2.52.516–3.8
 Biologic agents with glucocorticoids1.81.3–2.42.11.3–3.3
 No DMARDs, glucocorticoids, or biologic agents1.51.2–2.01.81.2–2.7
 Other DMARDs without glucocorticoids1.61.1–2.21.40.8–2.3
 Biologic agents without glucocorticoids1.00.8–1.51.10.7–1.8
During NSAID exposure (time varying)§    
 No
 Yes1.41.2–1.61.81.4–2.2

Patients with no exposure to DMARDs, glucocorticoids, or biologic agents had a higher risk for GI perforation than patients with exposure to MTX alone. We conducted additional analysis on those patients (n = 8,032 [6%]) who had no medical or pharmacy claim evidence of any RA-specific prescription medication during followup and found that they were significantly older (P < 0.0001) and more likely to be age ≥75 years, to have higher CCI scores, to have each of the comorbid conditions evaluated during baseline, to have shorter followup windows, and to have higher baseline expenditures. These findings are consistent with channeling of older, higher-risk patients away from MTX and other commonly used RA therapies.

In the sensitivity analysis, the exclusion of upper GI perforations and perforations with an unspecified location decreased the number of GI perforation events from 696 to 374 and the rate of GI perforations from 1.70 to 0.91 (95% CI 0.82–1.01). Although the statistical significance of several variables was no longer present in this analysis, use of other DMARDs with glucocorticoids remained significant (HR 2.0, 95% CI 1.3–3.1) and the risk associated with a history of diverticulitis increased (HR 32.4, 95% CI 25.5–41.2). The HR for diverticulosis without diverticulitis was not significant.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Findings from this study suggest that the risk of GI perforation is low in patients with RA and that perforation occurs more frequently in the lower GI tract than in the upper GI tract. Results of the multivariate analysis showed that the most significant factors associated with an increased risk of GI perforation were a history of diverticulitis, use of glucocorticoids, exposure to NSAIDs, increasing age, and higher levels of comorbidity. Diverticulosis without diverticulitis was not a risk factor for perforation, nor was use of the biologic agents that were studied (predominantly anti-TNF therapy).

Our findings are consistent with results from other studies reporting perforation rates among RA patients. A similar but smaller administrative database analysis involving 40,841 RA patients found that among the 37 patients hospitalized for GI perforation, 19 (51.4%) were currently being treated with glucocorticoids at the time of the event (21). Similar to our findings, risk factors for GI perforation included diverticulitis and current treatment with glucocorticoids, with or without NSAIDs. The Multinational Etoricoxib and Diclofenac Arthritis Long-term program, comparing the use of etoricoxib or diclofenac in >34,000 patients with osteoarthritis or RA, reported upper GI perforation rates of 0.2–0.4 per 1,000 PYs, similar to our finding of 0.30 upper GI perforations per 1,000 PYs (22).

We tested the sensitivity of these results to our definition of GI perforation, acknowledging that some clinicians would exclude GI perforation events associated with appendicitis and those with diverticulitis/diverticulosis or ischemic colitis diagnoses and GI surgery but without explicit mention of perforation. Removal of these types of events resulted in a reduction of the unadjusted GI perforation rate (1.70 versus 0.87 per 1,000 PYs), a reduction in the number of GI perforation events (696 versus 356), and a lower HR for GI perforation associated with diverticulitis (14.5 versus 3.9).

Given that the majority of events were lower GI perforations, we believed that the addition of upper GI perforations and unspecified perforations should not change, but may dilute, our study findings. To test this, we performed a sensitivity analysis in which we censored unspecified and upper GI events as of the event dates. With this most stringent GI perforation definition, statistical significance was lost for many variables. This may have been a function of the decreasing number of events because this definition was restrictive (n = 374), or due to better precision in evaluating risk factors for lower GI perforations. Variables that remained significant included a history of diverticulitis, other DMARDs with glucocorticoids, biologic agents with glucocorticoids, MTX with glucocorticoids, and other DMARDs without glucocorticoids.

Among the key strengths of this study is the data source. Large claims databases provide insight into the routine practice of medical care and allow for the analysis of relatively uncommon adverse events in specific patient populations. Furthermore, this particular database had a relatively large proportion of older patients. Of the 696 RA patients who experienced a GI perforation, 294 (42.2%) were age >65 years. Finally, although we did not have access to medical records, our case definition for GI perforation was based on a validated and high-performing claims algorithm, shown to have a positive predictive value of 94% among RA patients (20).

In interpreting our findings, several factors should be considered. Although the present study was based on a large and diverse sample of patients with RA, it is not a random sample and medical records were not available to supplement or validate this information. The MarketScan databases comprise employer-sponsored coverage for active employees, dependents, and retirees, and therefore did not include patients with other forms of insurance (Medicaid, military, self-insured) or the uninsured. Therefore, the generalizability of these findings may be limited to relatively healthier patients, although this does not compromise the internal validity of our results.

Another limitation is that we did not conduct a new user design, and followup time began based upon the first date that patients were observable in the health plan and met the eligibility criteria. We used a validated algorithm to identify GI perforation cases, although it is possible that cases were misclassified, perhaps more likely for outcomes using our more sensitive definition that were associated with nonspecific ICD-9-CM diagnosis codes (e.g., diverticulitis) with a CPT code for suture or resection. In the construction of medication exposure windows, prescription medications were presumed to be taken based upon their pharmacy fill dates. We assigned clinically relevant exposure windows or a grace period to all medications. To the extent that this window could have been too short or long, we may have under- or overstated exposure. Also, information was not available for OTC medications such as OTC NSAIDs and OTC GI medications (e.g., histamine receptor blockers and proton-pump inhibitors). Furthermore, glucocorticoid use was characterized only as current or not current in this study, not by daily dose or cumulative exposure. Finally, we had an insufficient sample size to be able to compare the risks for perforation between anti-TNF biologics versus those biologics with different mechanisms of action.

GI perforation is a rare but serious condition that affects patients with RA, most frequently in the lower GI tract, and was observed among patients exposed to every combination of RA therapies. Our retrospective analysis of a large US database showed that the main risk factors for GI perforations in RA patients include age, history of diverticulitis, and use of glucocorticoids and prescription NSAIDs. Reassuringly, diverticulosis in the absence of diverticulitis and biologic agent use (predominantly anti-TNF therapy in this population) did not appear to be risk factors for GI perforation. Clinicians should be aware of risk factors for GI perforation when managing patients with RA, especially when prescribing medications such as systemic glucocorticoids or NSAIDs to older patients and those with a history of diverticulitis.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

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. Curtis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Curtis, Lanas, John, Johnson, Schulman.

Acquisition of data. Curtis, Lanas, John, Johnson, Schulman.

Analysis and interpretation of data. Curtis, Lanas, John, Johnson, Schulman.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Genentech had no role in the study design; in the collection, analysis, or interpretation of data; or in writing the report or deciding to submit the report for publication. Publication of this article was contingent on the approval of Genentech. No authors received funding for preparation of the article. United BioSource Corporation provided medical writing.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

The authors thank Kristin A. Hanson, PharmD, MS, and Jyoti S. Nandi, MD, PhD, who provided medical writing services on behalf of United BioSource Corporation, Bethesda, Maryland.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES
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