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1 February Volume 14 Issue 2 Copyright 2015 ORIGINAL ARTICLES SPECIAL TOPIC No Association Between TNF Inhibitor and Methotrexate Therapy Versus Methotrexate in Changes in Hemoglobin A1C and Fasting Glucose Among Psoriasis, Psoriatic Arthritis, and Rheumatoid Arthritis Patients Jashin J. Wu MD, a Christopher G. Rowan PhD, b Judith D. Bebchuk ScD, c and Mary S. Anthony PhD d a Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA b American Medical Group Association, Alexandria, VA c Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA d Amgen Inc., Center for Observational Research, Thousand Oaks, CA ABSTRACT Background: The use of tumor necrosis factor inhibitors (TNFi) has been associated with a reduced incidence of type 2 diabetes mellitus. Objective: To compare changes in hemoglobin A1C and fasting glucose for patients exposed to TNFi. Methods: In this retrospective cohort study, patients with at least 3 recorded diagnosis codes for psoriasis, psoriatic arthritis, or rheumatoid arthritis between January 1, 2004 and July 31, Patients were Kaiser Permanente Southern California members for at least 1 year prior to the index date. Results: For hemoglobin A1C, there were 344 patients in the MTX cohort, and 118 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, the TNFi+MTX cohort had a lower mean change in hemoglobin A1C of -0.18mg/dL (95% CI: -0.35, -0.01) compared to the MTX cohort, although the difference is small and this model was not complete as there were significant interactions. For fasting glucose, there were 524 patients in the MTX cohort, and 121 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, change in fasting glucose was not significantly different between groups: mg/dl (95% CI: -5.05, 3.88) for the TNFi+MTX cohort compared to the MTX cohort, although this model was not complete as there was a significant interaction. Conclusions: The use of TNF inhibitors Do with MTX was Not not associated with Copy a significant difference in the change of hemoglobin A1C or fasting glucose compared to MTX alone. J Drugs Dermatol. 2015;14(2): INTRODUCTION Psoriasis is a chronic skin condition affecting approximately 2-3% of the population 1, 2 that is associated with an increased risk of cardiovascular diseases, including obesity, 3, 4 diabetes type 2, 5, 6 hypertension, 5, 7 dyslipidemia, 3, 7 metabolic syndrome, 2, 8 and other cardiovascular risk factors. Psoriatic arthritis is a seronegative inflammatory arthritis condition that can accompany psoriasis or present separately. The prevalence of psoriatic arthritis among psoriasis patients may be as low as 11% 9 or as high as 30%. 10 Rheumatoid arthritis is an inflammatory autoimmune disease of the joints affecting about 0.5-1% of the adult population worldwide 11 and is also associated with increased risk of cardiovascular diseases Several systemic therapeutic options are available for the treatment of these inflammatory conditions. Treatment effects on comorbidities such as cardiovascular disease have been described recently. The use of tumor necrosis factor (TNF) inhibitors for psoriasis is associated with a significant reduction in myocardial infarction (MI) incidence and risk, 15, 16 and the use of TNF inhibitors for psoriasis, psoriatic arthritis, and rheumatoid arthritis is associated with a lower risk of diabetes. 17 However, some reports show that use of TNF inhibitors is not associated with changes in individual markers (such as lipids) for cardiovascular diseases. 18 The primary objective of this study was to assess changes in metabolic factors for patients with psoriasis, psoriatic arthritis, or rheumatoid arthritis exposed to a TNFi plus methotrexate (TNFi+MTX) compared to patients exposed to methotrexate (MTX) therapy alone.

2 160 FIGURE 1. Flowchart of study design. PATIENTS AND METHODS Design Overview This retrospective cohort study was conducted within the Kaiser Permanente Southern California (KPSC) Health Plan. The study period was from January 1, 2002 to July 31, We evaluated the change in hemoglobin A1C (HbA1C) and fasting glucose for patients exposed to a TNFi and concomitant MTX (TNFi+MTX cohort) compared to patients exposed to MTX without a concomitant TNFi (MTX cohort). The index date for the TNFi+MTX cohort was the date of TNFi initiation (Figure 1). MTX matched risk-sets were developed for each TNFi+MTX cohort Penalties member. The MTX Apply matched risk-sets included up to six patients exposed to MTX but not TNFi during the study period. The contemporaneous MTX exposure was within (+/-) 30 days of the corresponding TNFi+MTX cohort member s TNFi initiation date. The index date for each MTX matched risk-set was set to the TNFi+MTX cohort member s index date. The aggregation of patients in all MTX matched risk-sets comprises the MTX cohort. Other than matching on TNFi initiation, no other matching factors were considered. Study Population and Data Source The study population includes KPSC members with a diagnosis of psoriasis (PsO), psoriatic arthritis (PsA), or rheumatoid arthritis (RA). KPSC is a large integrated health maintenance organization that has served approximately 3.2 million members during each of the past 10 years. KPSC comprises approximately 15% of the region s population. The membership in KPSC spans the geographic area from Bakersfield in the lower California Central Valley to San Diego on the Mexican border. Attrition averages about 10% per year. Membership demographics, socioeconomic status, and ethnicity composition are representative of California. Health plan members receive the majority of their health care at KPSC-owned facilities, including medical centers and offices. However, the health plan is also financially responsible for KPSC members emergency medical care received at non-plan facilities. More than 92% of members have prescription drug benefits and obtain their prescription medication from a KPSC pharmacy. All patients have blood chemistry and other laboratory test benefits. All the data were extracted from HealthConnect, the electronic databases of KPSC clinic and hospital systems. The study protocol was approved by the local Institutional Review Board at KPSC. Inclusion Criteria We included KPSC members with at least 3 recorded diagnosis codes (international Classification of Diseases, 9th Revision, Clinical Modification) of PsO (696.1), PsA (696.0), or RA (714, 714.0, 714.1, 714.2, 714.4, ) 19 during the study period but prior to the index date. All cohort members were KPSC members for at least 1 year prior to the index date to allow adequate time for co-morbidity ascertainment. We also required cohort members to have a baseline (within 12 months prior to the index date) and a follow-up (30 days to 12 months following the index date) measurement of HbA1C and fasting glucose. The hemoglobin A1C and fasting glucose analyses were conducted independently.

3 161 Exposure Windows Baseline and follow-up exposure windows were developed to determine exposure status to TNFi and MTX. The baseline exposure window corresponded to the last HbA1C measurement and fasting glucose measurement within 12 months prior to the index date. The follow-up exposure window corresponded to the first measurement in the period 30 days to 12 months following the index date. Baseline and follow-up exposure windows were set at (-15) to (-45) days prior to the date of the baseline and follow-up HbA1C and fasting glucose measurements. These exposure windows were selected to allow adequate time for a potential biologic effect of either therapy to impact the change in HbA1C or fasting glucose. Exposure Defined Patients in the TNFi+MTX cohort and the MTX cohort were exposed to MTX during the baseline and follow-up exposure windows. Patients in the TNFi+MTX cohort were exposed to a concomitant TNFi (etanercept, infliximab, adalimumab, or golimumab) during the follow-up exposure window. To evaluate the potential impact of TNFi exposure on changes in HbA1C and fasting glucose, TNFi+MTX cohort members were not exposed to TNFi any time prior to the index date including the baseline exposure window. Outcomes Defined Changes in HbA1C and fasting glucose were determined as the follow-up measurement value subtracted from the baseline measurement value. The baseline measurement occurred within twelve months prior to the index date. If there was more than one baseline measurement, we used the measurement closest to, but prior to, the index date. We used follow-up measurements between 30 and 365 days following the index date. If more than one follow-up measurement was available, we used the first measurement. Potential Confounding Variables We evaluated the potential confounding effects of patient level demographics, comorbidities, and concomitant medications. Potential confounding variables were collected within 12 months prior to the index date. We evaluated the following demographics and comorbidities: age, gender, year at the index date, inflammatory condition (ie, PsO, PsA, and RA), diabetes, hypothyroidism, hyperthyroidism, liver disease (including hepatitis B and C), hypertension, lupus, peripheral vascular disease, hyperlipidemia, connective tissue disease, MI, atherosclerosis, stroke, and obesity. We also evaluated the potential confounding effects of the following medications during the baseline exposure window: anti-diabetic drugs, cholesterol lowering drugs (eg, statins), antihypertensive medications, nonsteroidal anti-inflammatory drugs (NSAIDs), ustekinumab, acitretin, cyclosporine, and other non-biologic disease-modifying antirheumatic drugs (DMARDs) (leflunomide, sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, gold, auranofin, penicillamine, and cyclophosphamide). We also evaluated the number of days between the baseline and follow-up measurement and the proportion of days covered with MTX prescriptions between the index date and the follow-up measurement. Patients in both cohorts (TNFi+MTX and MTX) were required to be either exposed to or unexposed to anti-diabetic drugs during both the baseline and follow-up measurements exposure windows (ie, we restricted the analyses to patients with consistent exposure status to anti-diabetic drugs for the baseline and follow-up measurements). Patients were classified with the presence or absence of a type 2 diabetes diagnosis that occurred any time before or up to ninety days following the index date. The first identification of diabetes was used as the diabetes diagnosis date. The presence of diabetes was classified by the following algorithm: ICD-9 codes 250.X1, 250.X3, or use of a diabetic medication. Statistical Analysis Continuous baseline characteristics were summarized using mean, median, standard deviation, and interquartile range and categorical baseline characteristics were summarized using frequency and percent. Baseline characteristics were compared between the two cohorts. We assessed the effect of TNFi exposure on the change from baseline for each metabolic factor using an ANCOVA model. The treatment effect was determined from the TNFi+MTX vs. MTX (reference) contrast. We accounted for baseline covariates using multivariable adjustment. Except for age, gender, diabetes, PsA, PsO, and RA, which were forced into the adjusted ANCOVA models, comorbidities were evaluated for inclusion in the multivariable model using the method described by Greenland and Rothman. 20 In this method, each potential confounder was evaluated in a univariate ANCOVA model to assess the impact of the comorbidity on the exposure effect. Comorbidities that changed parameter estimate for the exposure variable by more than 15% were included in the final multivariable model. We also evaluated interaction terms between the comorbidities and the treatment variable. If the interaction was significant at the alpha<0.10 level, we included the interaction variable and the corresponding main effects in the final multivariable model. One crude analysis and three ANCOVA models were developed. The crude analysis shows the unadjusted change in HbA1C and fasting glucose change (follow-up measurement subtracted from baseline measurement). All ANCOVA models include the baseline measurement value and the treatment variable. The main effects ANCOVA model also includes covariates (restricted to main effects only) meeting the confounder inclusion criteria described above as well as the covariates forced into the model. The interaction ANCOVA model includes all covariates meeting the confounder inclusion criteria, the covariates forced into the model, and significant interaction variables and the corresponding main effects for the interaction variables.

4 162 TABLE 1. Baseline Characteristics Hemoglobin A1C Fasting Blood Glucose MTX TNFi + MTX MTX TNFi + MTX N=344 N=118 P value N=524 N=121 P value Pre-measurement demographics Age, years, mean (sd) 64.7 (10.36) 59.4 (9.43) < (11.16) 57.7 (9.78) <0.01 Men, n,(%) 113 (32.8%) 35 (29.7%) (26.1%) 35 (28.9%) 0.53 Pre-measurement medical history Psoriasis, n (%) 46 (13.4%) 26 (22%) (8%) 20 (16.5%) <0.01 Psoriatic arthritis, n (%) 76 (22.1%) 27 (22.9%) (14.5%) 24 (19.8%) 0.14 Rheumatoid arthritis, n (%) 302 (87.8%) 105 (89%) (92.9%) 114 (94.2%) 0.61 Dyslipidemia, n (%) 261 (75.9%) 83 (70.3%) (54.4%) 67 (55.4%) 0.84 Hypertension, n,(%) 271 (78.8%) 93 (78.8%) (68.9%) 76 (62.8%) 0.20 Diabetes type 2, n (%) 247 (71.8%) 99 (83.9%) (17.6%) 34 (28.1%) 0.01 Atherosclerosis, n (%) 69 (20.1%) 14 (11.9%) (16.2%) 10 (8.3%) 0.03 Hyperthyroidism, n (%) 11 (3.2%) 4 (3.4%) (3.2%) 2 (1.7%) 0.35 Hypothyroidism, n (%) 70 (20.3%) 21 (17.8%) (21%) 18 (14.9%) 0.13 Lupus, n (%) 27 (7.8%) 7 (5.9%) (10.5%) 10 (8.3%) 0.46 Obesity, n (%) 128 (37.2%) 49 (41.5%) (26.3%) 41 (33.9%) 0.09 History of MI, n (%) 40 (11.6%) 7 (5.9%) (10.1%) 3 (2.5%) 0.01 History of stroke, n (%) 10 (2.9%) 1 (0.8%) (3.2%) 0 (0%) 0.04 Pre-measurement drug use Diabetes drug use, n (%) 135 (39.2%) 52 (44.1%) (10.3%) 17 (14.0%) 0.09 Lipid drug use, n (%) 197 (57.3%) 57 (48.3%) (33.6%) 31 (25.6%) 0.09 Hypertension drug use, n (%) 260 (75.6%) 86 (72.9%) (59.2%) 69 (57.0%) 0.67 NSAID use, n (%) 94 (27.3%) 37 (31.4%) (28.2%) 53 (43.8%) <0.01 Non-biologic DMARD use, n (%) 75 (21.8%) 26 (22.0%) (27.5%) 51 (42.1%) <0.01 Duration of treatment Pre-post duration, mean in days (sd) (142.27) (124.68) (162.88) (135.41) 0.27 MTX days, mean (sd) (75.11) (75.17) (93.51) (84.53) 0.43 TNFi days, mean (sd) (82.41) (89.35) < While we adjusted for age in the multivariable models, a sensitivity analysis was performed including only patients under age 65 at the index date. Patients aged 65 years and older have Medicare and are less likely to receive TNFi due to restricted medication coverage. The purpose of this analysis was to evaluate changes in HbA1C and fasting glucose for patients with likely similar medication coverage status. RESULTS HbA1C There were 344 and 118 patients with a mean age of 64.7 and 59.4 years in the MTX and TNFi+MTX cohorts, respectively (Table 1). In the MTX cohort, 302 (87.8%) had rheumatoid arthritis, 76 (22.1%) had psoriatic arthritis, and 46 (13.4%) had psoriasis. In the TNFi+MTX cohort, 105 (89%) had rheumatoid arthritis, 27 (22.9%) had psoriatic arthritis, and 26 (22%) had psoriasis. The mean duration between the baseline and follow-up measurements was and days in the MTX and TNFi+MTX cohorts, repsectively. The average number of days on MTX following the index date was and days in the MTX and TNFi+MTX cohorts, repsectively. The average number of days on TNFi following the index date was days in the TNFi+MTX cohort. The baseline HbA1C values were 6.7 and 6.9 mg/dl for the MTX and TNFi+MTX cohorts, respectively. The mean crude change from baseline to follow-up was 0.0 mg/dl (SD=0.8) and -0.1 mg/dl (SD=1.0)

5 163 TABLE 2. Baseline Metabolic Factors and Mean Change MTX TNFi + MTX N Mean (sd) N Mean (sd) Hemoglobin A1C, mg/dl Pre-treatment value (1.2) (1.7) Change in HbA1c (post-pre) (0.8) (1.0) Fasting blood glucose, mg/dl Pre-treatment value (28.1) (22.1) Change in fasting glucose (post-pre) (24.5) (18.6) for the MTX and TNFi+MTX cohorts, respectively (Table 2). In the unadjusted ANCOVA model, the TNFi+MTX cohort had a lower mean change in HbA1C by -0.13mg/dL (95% CI: -0.31, 0.04) compared to the MTX cohort (Table 3). Covariates included in the main effects ANCOVA model were: baseline HbA1c value, treatment variable, age, gender, diabetes, RA, PSO, and PSA. In addition to these covariates, the interaction ANCOVA model also included the following variables that showed significant interactions with the treatment variable: baseline hyperlipidemia, anti-hypertensive therapy (during baseline exposure window), and non-biologic DMARD use (during baseline exposure window). The main effects for each interaction variable were included in the interaction ANCOVA model. In the main effects ANCOVA model (only pre-hba1c and treatment effect presented), the TNFi+MTX cohort had a lower mean change in HbA1C of -0.18mg/dL (95% CI: -0.35, -0.01) compared to the MTX cohort. As there are three significant interaction terms in the interaction ANCOVA model, it is not possible to state a single treatment effect (Table 3). The results from the age restricted (<65 years) sensitivity analysis were consistent with the analysis of the whole study group and are therefore not presented. Fasting Glucose There were 524 and 121 patients with a mean age of 64.7 and 57.7 years in the MTX and TNFi+MTX cohorts, respectively (Table 1). In the MTX and TNFi+MTX cohorts, respectively, 487 (92.9%) and 114 (94.2%) had rheumatoid arthritis, 76 (14.5%) and 24 (19.8%) had psoriatic arthritis, and 42 (8%) and 20 (16.5%) had psoriasis. The mean duration between baseline and follow-up measurements was and days for the MTX and TNFi+MTX cohorts, respectively. The average number of days on MTX was and131.8 days for the MTX and TNFi+MTX cohorts, respectively. The average number of days on TNFi following the index date was days in the TNFi+MTX cohort. The TABLE 3. Model Results for Change in HbA1C Effect Unadjusted ANCOVA model Pre-measurement HbA1c (continuous) Treatment effect on change in HbA1c (TNFi+MTX vs MTX) Estimate (95% CI) p value for estimate (-0.26, -0.15) < (-0.31, 0.04) 0.12 Main effects ANCOVA model (only pre-hba1c and treatment effect presented)* Pre-measurement HbA1c (continuous) (-0.30, -0.18) <0.001 Treatment effect on change in HbA1c (TNFi+MTX vs MTX) Interaction ANCOVA model Pre-measurement HbA1c (continuous) Treatment effect on change in HbA1c (TNFi + MTX vs MTX) (-0.35,-0.01) (-0.29,-0.17) (-0.51, 0.33) 0.67 Age (continuous) (-0.01, 0.01) 0.50 Male (-0.20, 0.12) 0.60 Diabetes type (-0.00, 0.38) 0.05 Rheumatoid arthritis 0.22 (-0.08, 0.52) 0.15 Psoriasis (-0.29, 0.28) 0.98 Psoriatic arthritis 0.04 (-0.25, 0.33) 0.79 Hyperlipidemia 0.24 ( 0.04, 0.44) 0.02 Do Not Hypertension Copy drug use (-0.28, 0.13) 0.46 Non-biologic DMARD drug use 0.29 ( 0.07, 0.50) 0.01 Interaction of treatment and (-0.76,-0.00) 0.05 hyperlipidemia Interaction of treatment and 0.45 ( 0.07, 0.82) 0.02 hypertension drug use Interaction of treatment and non-biologic DMARD drug use (-0.85,-0.10) 0.01 * The main effects ANCOVA model also included age, male, diabetes type 2, psoriasis, psoriatic arthritis, rheumatoid arthritis, and diabetes drug use. baseline fasting glucose values were 104.1and mg/dl for the MTX and TNFi+MTX cohorts, respectively. The mean crude change from baseline to follow-up was an increase of 1.3mg/dL (SD=24.52) and 3.7 mg/dl (SD=18.62) for the MTX and TNFi+MTX cohorts, respectively (Table 2). Covariates included in the main effects ANCOVA model were: baseline fasting glucose value, treatment variable, age, gender, diabetes, RA, PSO, PSA, atherosclerosis, obesity, anti-diabetic medication use, and NSAID use. In addition to these covariates, the interaction ANCOVA model also includes a significant interaction term between the treatment effect and obesity.

6 164 In the unadjusted ANCOVA model change in fasting glucose was higher by an average of 2.01 mg/dl (95% CI: -2.37, 6.39) for the TNFi+MTX cohort compared to the MTX cohort (Table 3). In the main effects ANCOVA model (only baseline fasting glucose and treatment effect presented), change in fasting glucose was lower by an average of mg/dl (95% CI: -5.05, 3.88) for the TNFi+MTX cohort compared to the MTX cohort. As there is a significant interaction term in the final model, it is not possible to state a single treatment effect (Table 4). The results from the age restricted (<65 years) sensitivity analysis were consistent with the analysis of the whole study group and are therefore not presented. DISCUSSION In this retrospective study, in the various analytic models that we developed, the overall theme was that there was no meaningful difference in the change in HbA1C or fasting glucose among PsA, PsO, and RA patients treated with TNFi+MTX compared to patients treated with MTX without a concomitant TNFi. Additionally, there were no remarkable crude changes in HbA1C or fasting glucose (follow-up-baseline measurements) between the two cohorts. In the main effects adjusted ANCO- VA model, patients treated with TNFi+MTX had a significantly lower mean change in HbA1C compared to patients in the MTX cohort. However, this model did not account for interactions; once interactions were accounted for, the significant treatment effect became insignificant. There were no significant differences in type 2 diabetes mellitus rates between the two cohorts, suggesting that patients in the two cohorts can be compared to each with less risk for bias. Age (continuous) 0.01 (-0.15, 0.17) 0.93 Male 3.41 (-0.44, 7.26) 0.08 Diabetes type ( 5.58,14.85) <0.001 Rheumatoid arthritis ( 4.93,21.70) <0.01 Psoriasis 3.92 (-3.18,11.01) 0.28 Psoriatic arthritis 4.81 (-2.62,12.23) 0.20 Do Not Atherosclerosis Copy 2.73 (-2.24, 7.69) 0.28 Solomon et al 17 reported that among patients with PsA, PsO, or RA treated with a TNF inhibitor with or without other DMARDs, Diabetes drug use 7.67 ( 1.15,14.19) 0.02 the adjusted risk of incident of diabetes mellitus was significantly NSAID drug use 2.47 (-1.25, 6.19) 0.19 lower compared to the reference Penalties group (those treated Obesity Apply (-6.19, 2.22) 0.36 with other non-biologic DMARDs without TNF inhibitors, methotrexate, or hydroxychloroquine). They found that those treated Interaction of treatment and ( 1.94,20.14) 0.02 obesity with methotrexate without TNF inhibitors or hydroxychloroquine had a non-significantly lower adjusted risk of incident of diabetes mellitus compared to the reference group. Some key *Adjusted ANCOVA model also included age, male, diabetes type 2, psoriasis, psoriatic arthritis, rheumatoid arthritis, diabetes drug use, atherosclerosis, NSAIDs drug use and obesity. differences with our study are that the study by Solomon and colleagues did not examine laboratory values (HbA1C and fasting glucose) and the TNF inhibitor group could have also been treated with or without other DMARDs including MTX. etanercept for 24 weeks, fasting glucose and HbA1C did not change. 23 In a study of 37 patients with rheumatoid arthritis treated with TNF inhibitors (mean 24.2 months), MTX (mean 34.7 months), or were treatment-naïve, there were no significant changes in fasting glucose. 24 The data we present are consistent with other reports. In a 6 month retrospective study comparing psoriasis patients newly treated with TNF inhibitor or methotrexate, there was no observed association of etanercept or infliximab with changes in fasting glucose. 21 In a 24 week retrospective study comparing TNF inhibitor, efalizumab, and MTX, there was no significant changes in fasting glucose in any of the groups. 22 In an open-label series of 9 psoriasis patients treated with TABLE 4. Model Results for Change in Fasting Glucose Unadjusted ANCOVA model Pre-measurement fasting glucose (continuous) Treatment effect on change in fasting glucose (TNFi + MTX vs. MTX) Estimate (95% CI) p value (-0.36, -0.23) < (-2.37, 6.39) 0.37 Adjusted ANCOVA model (only pre-fasting glucose and treatment effect presented)* Pre-measurement fasting glucose (continuous) (-0.47, -0.33) <0.001 Treatment effect on change in fasting glucose (TNFi + MTX vs. MTX) Full model with interaction Pre-measurement fasting glucose (continuous) Treatment effect on change in fasting glucose (TNFi + MTX vs. MTX) (-5.05, 3.88) (-0.47,-0.33) < (-9.42, 1.21) 0.13 This study has several strengths: KPSC has a stable membership with a large number of psoriasis, psoriatic arthritis, and rheumatoid arthritis patients, and there is accurate diagnosis coding of these diseases as well as other medical co-morbidities. This allowed a substantial collection of cumulative longitudinal follow-up, giving the study adequate

7 165 power to capture changes in these metabolic factors. Furthermore, prescription drug use among the study cohort was very well documented, since more than 90% of all prescriptions of KPSC members are filled in a health plan pharmacy (internal records). The study results may be generalizable to other patients who are from an insured and ethnicallydiverse population. Based on internal documentation for the KPSC database, the accuracy and completeness for all of the variables were in the mid-90% range and above. There are some limitations to this study. We were not able to determine which factors influenced the physician s decision to order various systemic treatments or to order laboratory tests. Varying co-payments and benefits for office visits or medical procedures such as laboratory tests may impact the likelihood of being diagnosed with some health conditions. However, high deductible plans with varying benefits and medication co-pays were not offered comprehensively at Kaiser Permanente Southern California until A potential confounder is the effect of the intensity of diabetes control, which may affect the HbA1C or fasting glucose values. When examining fasting blood glucose, the majority of patients did not have diabetes type 2, so we may not necessarily expect to see any change in fasting blood glucose. If a Kaiser Permanente patient had an elevated blood sugar at baseline, it is possible they would have been started on a medication to control the blood sugars, so both cohorts may have similar levels of improvement. However, both cohorts had similar percentages of diabetes drug use. In conclusion, the use of TNF inhibitors with concomitant MTX was not associated with a significant change in HbA1C or fasting glucose when compared to MTX use alone in patients with RA, PsO, or PsA. The lack of difference in changes in these metabolic factors among MTX and MTX+TNF inhibitor treated patients might suggest no difference in diabetes risk between these two therapies. DISCLOSURES Dr. Wu and Dr. Bebchuk had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Wu received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, and Sandoz; he is a consultant for AbbVie, Amgen, Celgene, DUSA Pharmaceuticals, Eli Lilly, and Pfizer. Dr. Anthony was employed by Amgen during the study, and she owns stock of Amgen. The other authors do not have any potential conflicts of interest. Funding Sources This study was sponsored by Immunex, a wholly owned subsidiary of Amgen Inc., and by Wyeth, which was acquired by Pfizer Inc. in October Amgen had a role in the following: design and conduct of the study; analysis, and interpretation of the data; and review or approval of the manuscript. Amgen did not have a role in the collection or management of the data. ACKNOWLEDGMENT We would like to acknowledge Anny H. Xiang, PhD, for her assistance in the early statistical design of this project; and Yi Luo for her work as programmer. Both are affiliated with the Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA; and this research grant funded the salaries of both. REFERENCES 1. Hinchman KF, Liao W, Koo J, Wu JJ. Current and potential applications of pharmacogenetics in the treatment of psoriasis. In: Koo JY, Lebwohl MG, Lee CS, Weinstein GD, Gottlieb A, editors. Moderate-To-Severe Psoriasis. 3rd ed. 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