Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: J Invest Dermatol. 2017 Nov 2;138(4):760–767. doi: 10.1016/j.jid.2017.10.024

Risk of incident liver disease in patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis: a population-based study.

Alexis Ogdie 1, Sungat K Grewal 2, Megan H Noe 3, Daniel Shin 4, Junko Takeshita 5, Zelma C Chiesa Fuxench 6, Rotonya M Carr 7, Joel M Gelfand 8
PMCID: PMC6287638  NIHMSID: NIHMS981624  PMID: 29104161

Abstract

Relatively little is known about the risk for incident liver disease in psoriasis (PsO), psoriatic arthritis (PsA), and rheumatoid arthritis (RA). We performed a cohort study among patients with PsO, PsA, or RA and matched controls in The Health Improvement Network from 1994-2014. Outcomes of interest were any liver disease, non-alcoholic fatty liver disease (NAFLD), and cirrhosis (any etiology). Among patients with psoriasis (N=197,130), PsA (N=12,308), RA (N=54,251), and matched controls (N=1,279,754), the adjusted hazard ratios for any liver disease were elevated among patients with PsO (without systemic therapy HR 1.37; with systemic therapy/ST 1.97), PsA (without ST 1.38; with ST 1.67) and RA without a ST (1.49) but not elevated in RA patients prescribed a ST (0.96). Incident NAFLD was highest in patients with PsO prescribed a ST (2.23) and PsA with a ST (2.11). Risk of cirrhosis was highest among patients with PsO with an ST (2.62) and PsA without a ST (3.15). Additionally, the prevalence of liver disease and cirrhosis increased in a stepwise fashion with increasing body surface area affected by PsO (p for trend <0.001). More so than RA, PsO and PsA are associated with liver disease, particularly NAFLD and cirrhosis, and this was true even among patients without systemic therapy exposure.

Keywords: cirrhosis, non-alcoholic fatty liver disease, epidemiology, psoriasis, rheumatoid arthritis, psoriatic arthritis

INTRODUCTION

Psoriasis and psoriatic arthritis (PsA) have been associated with a number of metabolic comorbidities, in particular an increased incidence of diabetes and cardiovascular events. Furthermore, these diseases are associated with a high prevalence of obesity.(Dubreuil et al., 2014, Ogdie et al., 2015a, Ogdie et al., 2015c) Similarly, psoriasis has been associated with a high prevalence of liver function test abnormalities and liver disease.(Maybury et al., 2014, Ogdie et al., 2015a) Prior studies have reported an increased prevalence of liver disease, in particular fatty liver disease in patients with psoriasis (Abedini et al., 2015, Gisondi et al., 2016, Gisondi et al., 2009, Humphreys et al., 2017, Madanagobalane and Anandan, 2012, Miele et al., 2009, Tsai et al., 2011, van der Voort et al., 2014, van der Voort et al., 2016, Yang et al., 2011, Yeung et al., 2013). Among the factors associated with liver disease in patients with psoriasis, PsA had the strongest association.(Miele et al., 2009) However, most of these studies have been mainly clinic-based, focused on liver disease related to methotrexate use and have not adjusted for other risk factors for liver disease including obesity and alcohol intake. Furthermore, few longitudinal studies have addressed the incidence and risk for liver disease in a broadly representative population of patients with psoriasis and PsA. In other words, does having psoriasis or PsA predispose a patient to developing new liver disease? The incidence of liver disease among patients with PsO and PsA compared to the general population is unknown. Relatively little is known about how the liver responds to chronic inflammation and how this may differ by the type or severity of inflammation. Furthermore, little is known about how skin disease severity, obesity, diabetes, and medication use play a role in development of liver disease in patients with these diseases.

Liver injury in psoriasis has been postulated to result in part from cytokine release from skin-derived cells. This so-called hepato-dermal axis (Mantovani et al., 2016) postulates that psoriatic skin-derived lymphocytes and keratinocytes produce inflammatory cytokines such as II-6, II-17, and TNF-alpha which circulate systemically to the liver and induce an array of metabolic derangements that promote insulin resistance, a hallmark feature of non-alcoholic fatty liver disease pathogenesis. (Carr et al., 2016) The converse may also be true in that the ensuing hepatic inflammation promotes keratinocyte proliferation and cutaneous inflammation.(Mantovani et al., 2016) If such an axis exists, it is conceivable that patients with either longer duration of inflammation or increased psoriasis severity would have an increased risk of developing liver disease and propensity for developing cirrhosis, the most advanced form of liver disease.

In this longitudinal cohort study, we aimed to better understand the epidemiology of liver disease in patients with psoriasis and PsA. We used the The Health Improvement Network (THIN), a population-based electronic medical records database and the Incident Health Outcomes and Psoriasis Events (iHOPE) cohort (a nested study of psoriasis patients in the THIN database with additional data regarding affected body surface area) to compare psoriatic patients with the general UK population. We, additionally, compared patients with psoriatic disease to those with rheumatoid arthritis (RA), as RA is another Th1 and Th17 immune-mediated systemic inflammatory disorder that has a spectrum of skin and joint manifestations as in PsO. The three disorders share many treatment approaches (e.g., methotrexate is a first line therapy for all three diseases) and represent a spectrum of joint and skin inflammation (from skin only in psoriasis, joint only in RA and both in PsA).(Coates et al., 2016) The objectives of this study were to 1) determine whether PsO, PsA, or RA are independently associated with an increased risk of developing liver disease compared to general population controls after accounting for medications, alcohol intake, and co-morbidities such as obesity and metabolic syndrome and 2) determine whether psoriasis severity measured by body surface area, as a surrogate for inflammatory burden, is positively associated with liver disease.(Dey et al., 2017, Rocha-Pereira et al., 2004) We hypothesized that psoriasis and PsA would be associated with an increased risk for liver disease compared to patients in the general population, and more specifically that these disorders would be associated with an increased risk for fatty liver disease and cirrhosis (Supplemental Figure 1).

RESULTS

Baseline Characteristics

Baseline characteristics of the full THIN cohort are summarized in Table 1 (additional details in Supplemental Table 1). Patients with PsO (N=197,130), PsA (N=12,308), and RA (N=54,251) were identified and matched to unexposed controls (N=1,279,754). Patients with RA were more likely to be older, female, and suffer from more medical comorbidities. Compared with other groups, patients with PsA and PsO with a ST had higher BMIs. Among patients with PsO, PsA, and RA, 6%, 53%, and 61%, respectively were prescribed an ST. Methotrexate was the most commonly prescribed ST. STs used are reported in Supplemental Table 2.

Table 1.

Characteristics of the study population at study entry

Controls (N= 1,279,754) Psoriasis No ST (N= 186,006) Psoriasis ST (N= 11,124) PsA No ST (N= 5,786) PsA ST (N= 6,522) RA No ST (N= 21,396) RA ST (N= 32,855)
Age (Mean(SD)) 50.84 (17.98) 46.93 (17.76) 49.82 (15.60) 50.94 (14.96) 49.24 (13.69) 63.08 (16.46) 58.91 (14.58)
Female (N(%)) 715,274 (55.9%) 96,030 (51.6%) 5,687 (51.1%) 2,886 (49.9%) 3,227 (49.5%) 15,070 (70.4%) 22,908 (69.7%)
Diabetes mellitus (N(%)) 78,828 (6.16) 10,091 (5.43) 963 (8.66) 426 (7.36) 502 (7.70) 1,875 (8.76) 2,748 (8.36)
Hyperlipidemia (N(%)) 117,205 (9.16) 14,678 (7.89) 1,216 (10.93) 561 (9.70) 644 (9.87) 2,240 (10.47) 3,563 (10.84)
Smoking
Never (N(%)) 616,327 (48.16) 72,717 (39.09) 4,202 (37.77) 2,528 (43.69) 3,067 (47.03) 9,637 (45.04) 14,006 (42.63)
Past(N(%)) 270,148 (21.11) 52,995 (28.49) 3,027 (27.21) 1,308 (22.61) 1,231 (18.87) 4,291 (20.06) 7,256 (22.08)
Current(N(%)) 259,985 (20.32) 40,652 (21.86) 3,233 (29.06) 1,394 (24.09) 1,802 (27.63) 4,543 (21.23) 8,986 (27.35)
Missing (N(%)) 133,294 (10.42) 19,642 (10.56) 662 (5.95) 556 (9.61) 422 (6.47) 2,925 (13.67) 2,607 (7.93)
Alcohol Consumption
None (N(%)) 145,932 (11.40) 19,386 (10.42) 1,227 (11.03) 675 (11.67) 715 (10.96) 3,735 (17.46) 5,355 (16.30)
Some (N(%)) 812,057 (63.45) 120,659 (64.87) 7,407 (66.59) 3,838 (66.33) 4,367 (66.96) 11,768 (55.00) 19,737 (60.07)
A lot (N(%)) 52,982 (4.14) 6,917 (3.72) 731 (6.57) 214 (3.70) 394 (6.04) 1,075 (5.02) 2,158 (6.57)
Missing (N(%)) 268,783 (21.00) 39,044 (20.99) 1,759 (15.81) 1,059 (18.30) 1,046 (16.04) 4,818 (22.52) 5,605 (17.06)
BMI1 (Mean(SD)) 26.38 (5.45) 26.64 (5.58) 28.06 (6.08) 27.61 (5.62) 28.29 (5.99) 26.55 (5.53) 26.76 (5.53)
Oral steroids (N(%)) 135,057 (10.55) 17,225 (9.26) 2,701 (24.28) 758 (13.10) 1,510 (23.15) 5,018 (23.45) 14,376 (43.76)
NSAIDS2 (N(%)) 666,693 (52.10) 80,159 (43.09) 7,650 (68.77) 4,055 (70.08) 5,752 (88.19) 14,298 (66.83) 28,716 (87.40)
Cohort time in years (Mean(SD)) 6.50 (4.78) 6.21 (4.75) 5.31 (4.13) 6.12 (4.77) 5.83 (4.45) 5.71 (4.64) 6.13 (4.48)
Open in a new tab

Abbreviations: BMI, body mass index; NSAID, nonsteroidal anti-inflammatory drug; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SD, standard deviation; ST, systemic therapy

New diagnosis of any liver disease

The average follow-up time was approximately six years. The follow-up times, unadjusted incidence rates, and hazard ratios for liver disease, cirrhosis, and NAFLD are shown in Table 2. The hazard ratios and confidence intervals are also shown in Figure 1. In age and sex adjusted cox proportional hazard models, the risk of incident liver disease was higher for all disease categories compared to controls. Similarly, in the fully adjusted models, the risk of incident liver disease was significantly elevated compared to controls in all disease categories except the RA/ST group (aHR 0.96, 95% CI 0.83-1.12). Patients with PsO with an ST were associated with the highest risk (aHR 1.97, 95% CI 1.63-2.38) followed by patients with PsA prescribed an ST (aHR 1.67, 95% CI 1.29-2.15), RA patients without an ST (aHR 1.49, 95% CI 1.26-1.76), PsA without an ST (aHR 1.38, 95% CI 1.02-1.86), and PsO without an ST (aHR 1.37, 95% CI 1.29-1.45). NAFLD was the most common subtype (37.85%) followed by alcoholic liver disease (18.53%), unknown causes (10.35%), viral etiologies (7.76%), biliary disease (4.33%), and autoimmune liver disease (0.60%). Ten percent of patients with liver disease were diagnosed with cirrhosis during the observational period. Sub-classifications of new liver disease diagnoses are shown in Supplemental Table 3. We performed a series of sensitivity analyses to test the assumptions of the analyses performed (Supplemental Table 4). The sensitivity analyses did not substantially change the results of the primary models.

Table 2.

Incidence and risk of liver disease among patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis

Controls Psoriasis No ST Psoriasis ST PsA No ST PsA ST RA No ST RA ST
N 1,279,754 186,006 11,124 5,786 6,522 21,396 32,855
Mean cohort time(SD) 6.50 (4.78) 6.21 (4.75) 5.31 (4.13) 6.12 (4.77) 5.83 (4.45) 5.71 (4.64) 6.13 (4.48)
Person Years (PY) 831959.4 1155764.6 59017.8 35389.9 38017.6 122204.5 201351.3
 ANY LIVER DISEASE
Liver Disease cases (N(%)) 8,140 (0.64) 1,593 (0.86) 132 (1.19) 64 (1.11) 70 (1.07) 189 (0.88) 227 (0.69)
Incidence Per 10,000 PY 9.78 13.78 22.37 18.08 18.41 15.47 11.27
Unadjusted HR (95% CI) Ref 1.41 (1.34-1.49) 2.35 (1.98-2.79) 1.85 (1.45-2.37) 1.91 (1.51-2.41) 1.60 (1.38-1.84) 1.17 (1.02-1.33)
Age/sex HR (95% CI) Ref 1.40 (1.33-1.48) 2.32 (1.95-2.75) 1.80 (1.40-2.30) 1.87 (1.48-2.37) 1.60 (1.39-1.85) 1.19 (1.04-1.36)
Final Model HR (95% CI)* 1.37 (1.29-1.45) 1.97 (1.63-2.38) 1.38 (1.02-1.86) 1.67 (1.29-2.15) 1.49 (1.26-1.76) 0.96 (0.83-1.12)
NAFLD
NAFLD cases (N(%)) 3,654 (0.28) 592 (0.32) 75 (0.67) 22 (0.38) 47 (0.72) 66 (0.31) 105 (0.32)
Incidence Per 10,000 PY 4.37 5.11 12.67 6.20 12.34 5.38 5.20
Unadjusted HR (95% CI) Ref 1.18 (1.08-1.28) 3.09 (2.46-3.88) 1.43 (0.94-2.17) 2.91 (2.19-3.89) 1.26 (0.99-1.60) 1.22 (1.01-1.49)
Age/sex HR (95% CI) Ref 1.17 (1.07-1.27) 3.06 (2.44-3.85) 1.41 (0.93-2.14) 2.88 (2.16-3.84) 1.28 (1.00-1.63) 1.24 (1.02-1.51)
Final Model HR (95% CI)* Ref 1.18 (1.07-1.30) 2.23 (1.73-2.87) 1.02 (0.63-1.68) 2.11 (1.55-2.87) 1.20 (0.91-1.57) 0.92 (0.74-1.15)
CIRRHOSIS (any etiology)
Cirrhosis Cases (N(%)) 1,364 (0.11) 293 (0.16) 25 (0.22) 18 (0.31) 9 (0.14) 55 (0.26) 52 (0.16)
Incidence Per 10,000 py 1.63 2.52 4.21 5.07 2.35 4.48 2.57
Unadjusted HR (95% CI) Ref 1.55 (1.37-1.76) 2.66 (1.79-3.95) 3.11 (1.96-4.96) 1.46 (0.76-2.82) 2.77 (2.12-3.63) 1.60 (1.21-2.11)
Age/sex HR (95% CI) Ref 1.64 (1.45-1.86) 2.76 (1.85-4.09) 3.06 (1.92-4.87) 1.54 (0.80-2.96) 2.22 (1.70-2.92) 1.42 (1.08-1.87)
Final Model HR (95% CI)* Ref 1.63 (1.41-1.88) 2.62 (1.72-4.01) 3.15 (1.89-5.24) 1.78 (0.92-3.45) 2.07 (1.50-2.86) 1.37 (1.02-1.86)
Open in a new tab
*

Final models adjusted for included age at start date, sex, smoking status, alcohol intake, body mass index category, and use of oral glucocorticoids and NSAID in the baseline period. Diabetes was not statistically significant in the final model and did not change the HR when removed.

Figure 1. Risk of liver disease, cirrhosis, and NAFLD among patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis (fully adjusted models).

Figure 1.

Open in a new tab

Hazard ratios (HR) and 95% confidence intervals are shown for any incident liver disease (blue), incident cirrhosis (red), and incident NAFLD (green) respectively for each disease category. Models are adjusted for age, sex, smoking status, drinking, body mass index, oral glucocorticoid use and non-steroidal anti-inflammatory drug use in the baseline period.

New diagnoses of NAFLD

Overall, there were relatively few new diagnoses of NAFLD (Table 2). However, these cases were disproportionately identified in patients with PsO with an ST and patients with PsA prescribed an ST. After adjusting for age, sex, BMI, smoking, and alcohol intake, oral glucocorticoids, and NSAID use, patients with PsO with an ST and patients with PsA prescribed an ST had a substantially elevated risk of being diagnosed with NAFLD (Table 2, Figure 1).

New diagnoses of cirrhosis

In the unadjusted, age/sex adjusted, and fully adjusted models (Table 2), all disease categories were associated with an increased risk of being diagnosed with cirrhosis. This risk was statistically significant for all disease categories except among patients with PsA who were prescribed an ST. In the fully adjusted model, patients with PsA not prescribed a ST had the highest risk of cirrhosis relative to population controls (aHR 3.15, 95% CI 1.89-5.24) but this risk was also substantially elevated in patients with psoriasis with an ST (aHR 2.62 95% CI 1.72-4.01) and RA patients not prescribed an ST (aHR 2.07 95% CI: 1.50-2.86).

Prevalence of Liver Disease by Objective Measures of Psoriasis Severity

Demographics in the iHOPE cohort were similar to those for the full THIN cohort psoriasis population (Supplemental Table 5). Patients with mild (BSA ≤2%, N=4,539), moderate (BSA 3-10%, N=3,133), and severe (BSA >10%, N=1,088) psoriasis were matched to unexposed controls (N=87,596). Among the psoriasis patients, 268 cases of liver disease were identified (including 74 cases of NAFLD and 36 cases of cirrhosis). There was a higher prevalence of liver disease, cirrhosis, and NAFLD among all psoriasis patients compared to controls (Table 3). There was a step-wise increase in the prevalence of any liver disease by psoriasis severity after adjusting for age, sex and BMI: for mild, moderate, and severe psoriasis, OR (95% CI): 1.13 (95% CI 0.94-1.36), 1.19 (95% CI 0.96-1.48), and 1.67, 95% CI 1.22-2.30), respectively (p for trend <0.001). Patients with moderate or severe psoriasis had a substantially elevated prevalence of cirrhosis (moderate PsO: OR 1.82, 95% CI 1.01-3.28; severe PsO OR 4.21, 95% CI 2.14-8.27). The p-value for the trend was <0.001 for both liver disease and cirrhosis by psoriasis severity. The prevalence of NAFLD was elevated in patients with psoriasis but was not statistically significant in this smaller cohort.

Table 3.

Prevalence of liver disease among patients with psoriasis by body surface area in the iHOPE cohort

ANY LIVER DISEASE NAFLD CIRRHOSIS (any etiology)
Total (N) N (%) Age/sex Adj OR (95% CI) Age/sex/BMI Adj OR (95% CI) N (%) Age/sex Adj OR (95% CI) Age/sex/BMI Adj OR (95% CI) N (%) Age/sex Adj OR (95% CI) Age/sex/BMI Adj OR (95% CI)
Controls 87,596 2,145 (2.4%) Ref Ref 535 (0.6%) Ref Ref 198 (0.2%) Ref Ref
Mild PsO (≤2% BSA) 4,539 132 (2.9%) 1.18 (0.98-1.41) 1.13 (0.94-1.36) 37 (0.8%) 1.32 (0.94-1.84) 1.29 (0.92-1.81) 14 (0.3%) 1.33 (0.77-2.28) 1.31 (0.75-2.30)
Moderate PsO (3-10% BSA) 3,133 94 (3.0%) 1.22 (0.99-1.51) 1.19 (0.96-1.48) 28 (0.9%) 1.45 (0.99-2.13) 1.32 (0.89-1.97) 13 (0.4%) 1.83 (1.04-3.21) 1.82 (1.01-3.28)
Severe PsO (>10% BSA) 1,088 42 (3.9%) 1.62 (1.19-2.22) 1.67 (1.22-2.30) 9 (0.8%) 1.36 (0.70-2.64) 1.28 (0.66-2.48) 9 (0.8%) 3.83 (1.96-7.51) 4.21 (2.14-8.27)
Open in a new tab

The p-value for the trend for any liver disease and cirrhosis was <0.001.

DISCUSSION

In this population-based study, patients with inflammatory skin and/or joint disease had an elevated risk for new liver disease diagnoses, although patients with psoriasis with an ST had the highest risk and patients with RA who were prescribed an ST had the lowest risk. This increased incidence was independent of risk factors for liver diseases routinely captured in medical encounters. Overall, the lifetime prevalence of a diagnosis of liver disease in patients with psoriasis was 3-4% and, among patients without liver disease at baseline, the incidence over 5-6 years of follow up was approximately 1%. NAFLD was the most common cause of incident liver disease. Both NAFLD and cirrhosis were substantially elevated in psoriasis and PsA. To our knowledge, this is the first population-based study to simultaneously address the risk for incident liver disease in patients with these inflammatory diseases. Previous studies have also found an increased prevalence for NAFLD and liver disease but none have examined incident disease or more serious outcomes such as cirrhosis, and most have not adjusted for other risk factors for liver disease (e.g., gender, BMI, alcohol intake, smoking status). (Abedini et al., 2015, Gisondi et al., 2016, Gisondi et al., 2009, Madanagobalane and Anandan, 2012, Miele et al., 2009, Rosenberg et al., 2007, van der Voort et al., 2014, van der Voort et al., 2016, Yang et al., 2011)

The results of this study support a particularly strong association between psoriasis and incident liver disease. This may thus support the presence of the hepato-dermal axis. Our findings also suggest an important role for systemic inflammation, which is known to be present in these three related but unique skin and joint diseases in the development of liver disease. While systemic inflammation may play an important role in development of liver disease, medications used to treat these inflammatory diseases can also cause liver toxicity. Methotrexate is the most commonly used ST for all three diseases. Previous publications have suggested that patients with psoriasis are more susceptible to methotrexate toxicity than patients with RA but empiric data to support this hypothesis are scant.(Kalb et al., 2009, Saporito and Menter, 2004, Walker et al., 1993, Whiting-O’Keefe et al., 1991, Yazici, 2010) Our results suggest that patients with psoriasis prescribed an ST are at increased risk for liver disease, in particular NAFLD and cirrhosis, to a greater degree than patients with RA. After excluding patients prescribed methotrexate in a sensitivity analysis, the risk for liver disease remained increased in this psoriasis group but similar to the unexposed controls among patients with RA. Conversely, it may be that adequate control of inflammation reduces the risk of liver disease. We are unable to address this question in the current study as separating the effects of a medication from the reason for receiving a medication can be challenging (i.e. confounding by indication).

Strengths of this study include use of a population-based approach and cohort study design, the large sample size, validated exposure definitions, examination of the outcome by levels of disease severity, and stable results across numerous sensitivity analyses. Because THIN is broadly representative of the United Kingdom, our results should be generalizable to the larger UK population and populations of similar developed nations. Furthermore, use of the iHOPE sub-cohort, a population-based cohort with information on clinician-assessed BSA involvement by PsO, allowed for examination of the outcomes by objectively measured PsO severity. Likewise, the study should be interpreted in light of some limitations. First, the outcome definitions have not been formally validated against imaging diagnosis in THIN, although they tracked closely with another medical records database and have been used in several studies including studies in the Clinical Practice Research Datalink.(Loomis et al., 2016, Ratib et al., 2014a, Ratib et al., 2015, Ratib et al., 2014b) We did not examine death from liver disease as an outcome, perhaps the most consequential outcome, though very rare and challenging to measure.(Ogdie et al., 2017b) Due to the lack of reliable biomarkers for NAFLD diagnosis and staging, (Carr et al., 2016) NAFLD may be inconsistently captured in clinical practice. While there is potential for misclassification, it would likely affect all exposure groups to the same extent. However, patients with inflammatory diseases, particularly those who will receive or have received STs, may be more likely to have LFTs evaluated and consequently receive a diagnosis for liver disease when compared to their healthy counterparts. Nevertheless, stronger associations were seen with psoriatic disease and this is unlikely to be explained by observation bias alone; however, psoriasis, PsA, and RA patients may be screened with LFTs differentially given previous reports of the higher incidence of liver disease in patients with psoriasis using methotrexate.(Maybury et al., 2014) Our results were robust to several sensitivity analyses that addressed LFT testing. These included restriction to patients with liver function tests in the baseline period, in the follow up period, and requiring patients to have at least annual visits with their GP, regardless of blood testing. Next, as the data used was derived from a medical record database, information on alcohol use may be incomplete and disease activity in patients with RA or PsA was not available. Thus, we were unable to directly draw conclusions between the degree of systemic inflammation and the risk of liver disease in these two groups. Furthermore, while we were able to directly address disease severity in psoriasis patients within the iHOPE cohort, we did not have sufficient power to conduct longitudinal studies in this subgroup. In addition, we did not have sufficient knowledge of active and previous psoriasis therapies, in particular the biologics, to identify the impact of these therapies on the development of liver disease. Finally, we are unable to address whether patients who are likely to develop liver disease are “channeled” away from receiving a ST, thus making it appear as though the risk of liver disease is lower among RA patients receiving a therapy (i.e. channeling bias). However, at baseline, patients with previous liver disease were excluded; furthermore, it’s unclear why “channeling” may be different between those with RA and those with psoriasis or PsA, suggesting a true interaction with therapy (or disease severity) and liver disease in psoriasis and PsA.

In conclusion, this population-based cohort study demonstrates that patients with inflammatory disorders, in particular patients with more severe psoriasis have an elevated risk for serious liver disease. The findings also provide empirical support for the long held expert opinion that patients with psoriasis may be more predisposed to liver disease than patients with RA. Elucidating the role of inflammation in liver disease, and conversely, the role the liver plays in perpetuating inflammation in PsO, PsA and RA, may significantly advance our understanding of these inflammatory disorders. Risk factors for severe liver disease such as obesity, alcohol use, and hepatotoxic medications should be carefully considered in patients with psoriatic disease, particularly when systemic medications are indicated for more extensive skin or joint disease. Furthermore, physicians should counsel patients on the increased risk for liver disease and recommend weight loss and moderation of alcohol use, and possibly minimize use of NSAIDs in combination with other hepatotoxic medications.

METHODS

Study Design and Data Sources

A population-based cohort study was performed in The Health Improvement Network (THIN) using data from 1994 to 2014. We additionally performed a nested cross-sectional study to assess the prevalence of liver disease in the Incident Health Outcomes and Psoriasis Events (iHOPE) database, a nested sub-cohort of patients in THIN who have objective, general practitioner (GP)-assessed psoriasis severity data expressed as percentage of body surface area (BSA) affected by psoriasis.(Yeung et al., 2013). The two study cohorts are described below and in Supplemental Figure 2. THIN is an electronic medical records database in the United Kingdom (UK) that includes patients from 562 general practices and contains data for over eleven million individuals(Gladman et al., 2009). THIN database is broadly representative of the general UK population in terms of age, sex, geography, and medical diagnoses and has been used extensively in epidemiologic studies.(Blak et al., 2011, Desai et al., 2012, Haynes et al., 2011, Lewis JD, 2007)

Study Population

All patients in THIN between the ages of 18 and 89 at the start date who had a diagnosis of psoriasis, PsA, or RA were included. Patients were required to have observation time in THIN after implementation of Vision software (software needed to extract data from the medical record into THIN). Patients with prior liver disease at baseline were excluded from the full cohort. Up to five unexposed controls were selected for each patient with PsO, PsA, and RA. Controls were matched on clinical practice and start date within the practice. Match date was either diagnosis date or 180 days after registration date, whichever was later. The “diagnosis” date for unexposed controls was defined as the first GP visit within six months of the date on which the matched exposed patient was diagnosed with their PsO, PsA or RA. Ensuring that exposed and unexposed patients were followed by similar doctors during similar time periods minimizes bias. We have used this matching strategy in previous studies.(Ogdie et al., 2014b, Ogdie et al., 2017a, Ogdie et al., 2017b, Ogdie et al., 2015b)

The iHOPE nested cohort included patients with PsO aged 25 to 64 who were randomly sampled from THIN. Questionnaires were sent to the GP to ascertain the severity of PsO by BSA involvement, which was categorized as mild disease (≤ 2% BSA), moderate disease (3-10% BSA), or severe disease (>10% BSA). The start date for follow-up was defined by the GP survey sampling date (November 2008 to September 2010). Each patient in the cohort was assigned to up to ten randomly selected living, age category-matched non-psoriatic controls from the same practice with a visit to the GP within two years of sampling. Patients were then followed prospectively for the development of incident health outcomes (e.g., cardiovascular disease, incident PsA, etc). This cohort has been previously described by Seminara et al.(Seminara et al., 2011) and Yeung et al.(Yeung et al., 2013) More information on the study populations and the cohort time are provided in Supplemental Table 6.

Exposure definitions

Diagnoses in THIN are recorded using the READ diagnostic code scheme (J., 1990) and prescriptions are recorded using codes from the UK Prescription Pricing Authority.(Garcia Rodriguez and Perez Gutthann, 1998) Patients were identified as having PsO, PsA, or RA if they had at least one read code for their respective disease. Read codes for these diagnoses have been previously validated within the same or analogous databases.(Garcia Rodriguez and Perez Gutthann, 1998, Ogdie et al., 2014a, Rodriguez et al., 2009, Seminara et al., 2011, Watson et al., 2002, Watson et al., 2003) A priori we hypothesized an interaction between disease and prescriptions for systemic therapies, abbreviated ST, (i.e.: methotrexate, sulfasalazine, azathioprine, leflunamide, cyclosporine, mycophenolate, hydroxychloroquine, adalimumab, etanercept, infliximab, ustekinumab, golimumab, and certolizumab for patients with PsA or RA). Similarly, patients with PsO with a code for phototherapy (including ultraviolet B or psoralen and ultraviolet A [PUVA]), methotrexate, cyclosporine, oral retinoids, etanercept, infliximab, adalimumab, or ustekinumab were classified as PsO “prescribed a systemic therapy (ST)”. In the UK, systemic therapies can be prescribed by consultants (specialists) but may be captured by GP records with the exception of the biologic medications, which are rarely recorded in THIN.(Ogdie et al., 2014a).

Outcomes: Definitions of Liver Disease

The primary outcome of interest was a new code for any liver disease (i.e. non-alcoholic fatty liver disease, cirrhosis, viral hepatitis, etc). This definition excluded nonspecific liver function test abnormalities. We also did not examine death from liver disease as this is a challenging outcome to assess and requires manual review of the records and making assumptions of cause of death. (Ogdie et al., 2017b) Additionally, as liver fibrosis is a pathological description, we were not able to specifically assess for liver fibrosis. Secondary outcomes of interest were non-alcoholic fatty liver disease (NAFLD) and cirrhosis from any cause. Liver disease has previously been studied in THIN and similar databases; a list of Read diagnostic codes was created for each outcome and after review of existing code lists from these studies.(Lo Re et al., 2009, Loomis et al., 2016, Noe et al., 2017, Ratib et al., 2014a, Ratib et al., 2015) Liver function tests were available for a smaller portion of patients in THIN and were used in a sensitivity analysis described in Supplemental Table 4.

Covariates of interest

All covariates of interest were measured on or before start date and are listed in the Supplemental Methods.

Statistical Analyses

Statistical analyses were performed using STATA 13.0 (College Station, TX). Demographics and covariate distribution were descriptively reported by disease category (PsO, PsA, RA, control). Incidence was reported as the number of new outcomes divided by the total person years of follow up after the start date for each category. Cox proportional hazards models were used to estimate the unadjusted, age- and sex- adjusted, and fully adjusted hazard ratios (aHR) with 95% confidence intervals. A purposeful selection modeling approach was used.(Bursac et al., 2008) Covariates were initially included in the multivariable “full” model if they had a biologically plausible relationship to the exposure and outcome, or if they had a p value of <0.05 when individually added to the age and sex adjusted Cox regression models. Covariates were then individually removed, starting with the highest p-value. If removal did not change the main effects > 10% for any of the disease categories, the covariate was eliminated in order to create the most parsimonious model. We additionally examined the prevalence of liver disease within the iHOPE cohort stratified by psoriasis severity (mild, moderate, or severe) compared to matched controls. Prevalence was reported as the number of outcomes at any point during follow up divided by the total number of patients for each disease category. Age- and sex-adjusted logistic regression models were used to compare the prevalence in each disease category to controls. We used a complete case analysis for the main analysis but examine the impact of missing data on alcohol intake, smoking, and body mass index in a sensitivity analysis. Several additional sensitivity analyses were conducted and are described in more detail in the Supplemental Data.

Ethics approval

The study was approved by the University of Pennsylvania Institutional Review Board and the IMS/THIN Scientific Review Committee. STROBE guidelines were followed in reporting the results.(von Elm et al., 2014)

Supplementary Material

Suppl Data

ACKNOWLEDGEMENTS:

We thank Yihui Jiang and Suzette Baez Vanderbeek for administrative support. This study was supported in part by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases K24-AR064310 (Gelfand), K23-AR063764 (Ogdie), K23-AR068433 (Takeshita), a Medical Dermatology Fellowship from The National Psoriasis Foundation (Noe), NIH Pharmacoepidemiology Training Grant T32-GM075766 (Noe), NIH Training Grant T32-AR007465-32 (Grewal), Dermatology Foundation Career Development Award (Takeshita), an unrestricted grant from Pfizer to the trustees of the University of Pennsylvania (Gelfand), an NIH grant K08-AA021424 (Carr), Robert Wood Johnson Foundation (Carr), Harold Amos Medical Faculty Development Award, 7158 (Carr), IDOM DRC Pilot Award P30 DK019525 (Carr) and in part by NIH P30-DK050306 and its pilot program (Carr), Health Resources and Services Administration: Grant number D34HP24459,Center of Excellence for Diversity in Health Education and Research (Carr), Perelman School of Medicine, University of Pennsylvania (Carr). Funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation or approval of the manuscript; or decision to submit the manuscript for publication. Pfizer participated in reviewing the manuscript only. All other sponsors had no role in the review of the manuscript.

Financial Support: This study was supported in part by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases K24-AR064310 (Gelfand), K23-AR063764 (Ogdie), K23-AR068433 (Takeshita), a Medical Dermatology Fellowship from The National Psoriasis Foundation (Noe), NIH Pharmacoepidemiology Training Grant T32-GM075766 (Noe), NIH Training Grant T32-AR007465-32 (Grewal), Dermatology Foundation Career Development Award (Takeshita), an unrestricted grant from Pfizer to the trustees of the University of Pennsylvania (Gelfand), an NIH grant K08-AA021424 (Carr), R01 AA026302-01 (Carr), Robert Wood Johnson Foundation (Carr), Harold Amos Medical Faculty Development Award, 7158 (Carr), IDOM DRC Pilot Award P30 DK019525 (Carr) and in part by NIH P30-DK050306 and its pilot program (Carr), Health Resources and Services Administration: Grant number D34HP24459,Center of Excellence for Diversity in Health Education and Research (Carr), Perelman School of Medicine, University of Pennsylvania (Carr). Funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation or approval of the manuscript; or decision to submit the manuscript for publication. Pfizer participated in reviewing the manuscript only. All other sponsors had no role in the review of the manuscript.

List of Abbreviations

aHR

adjusted hazard ratio

BMI

body mass index

CI

confidence interval

CKD

chronic kidney disease

CVD

cardiovascular disease

NSAID

non-steroidal anti-inflammatory drug

OR

odds ratio

PsO

psoriasis

PsA

psoriatic arthritis

RA

rheumatoid arthritis

ST

systemic therapy

Footnotes

Conflict of interest statement: Dr. Ogdie has served as a consultant for Novartis, Pfizer, BMS, Lilly, and Takeda is a co-investigator on a research grant from Pfizer (PI: Gelfand). Dr. Takeshita receives a research grant from Pfizer Inc. (unrelated to this study) and payment for continuing medical education work related to psoriasis that was supported indirectly by Eli Lilly. In the previous 12 months. Dr. Gelfand served as a consultant for Abbvie., Coherus, Janssen Biologics (formerly Centocor), Merck, Novartis Corp, Valeant, and Pfizer Inc., receiving honoraria; and receives research grants (to the Trustees of the University of Pennsylvania) from Abbvie, Eli Lilly, Janssen, Novartis Corp, Regeneron, Sanofi, and Pfizer Inc.; and received payment for *continuing medical education work related to psoriasis that was supported indirectly by Lilly, and Abbvie. Dr. Gelfand is a co-patent holder of resiquimod for treatment of cutaneous T cell lymphoma. Dr. Carr is a co-investigator on a research grant from Intercept and a sub-investigator on a clinical trial from Audentes. Dr. Chiesa-Fuxench has received payment for continuing medical education work related to atopic dermatitis and is a PI for clinical trials sponsored by Regeneron, Vanda, and Tioga pharmaceuticals.

Contributor Information

Alexis Ogdie, Department of Medicine/Division of Rheumatology, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, White Building, Room 5024, 3400 Spruce St, Philadelphia, PA 19104.

Sungat K. Grewal, Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, sungatg@gmail.com.

Megan H. Noe, Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, megan.noe@uphs.upenn.edu.

Daniel Shin, Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, dbshin@mail.med.upenn.edu.

Junko Takeshita, Department of Dermatology, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, junko.takeshita@uphs.upenn.edu.

Zelma C. Chiesa Fuxench, Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, zelma.chiesafuxench@uphs.upenn.edu.

Rotonya M. Carr, Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, rotonya.carr@uphs.upenn.edu.

Joel M. Gelfand, Department of Dermatology, Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, joel.gelfand@uphs.upenn.edu.

REFERENCES

  1. Abedini R, Salehi M, Lajevardi V, Beygi S. Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. Clinical and experimental dermatology 2015;40(7):722–7. [DOI] [PubMed] [Google Scholar]
  2. Blak BT, Thompson M, Dattani H, Bourke A. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Informatics in primary care 2011;19(4):251–5. [DOI] [PubMed] [Google Scholar]
  3. Bursac Z, Gauss CH, Williams DK, Hosmer DW. Purposeful selection of variables in logistic regression. Source code for biology and medicine 2008;3:17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carr RM, Oranu A, Khungar V. Nonalcoholic Fatty Liver Disease: Pathophysiology and Management. Gastroenterol Clin North Am 2016;45(4):639–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coates LC, FitzGerald O, Helliwell PS, Paul C. Psoriasis, psoriatic arthritis, and rheumatoid arthritis: Is all inflammation the same? Seminars in arthritis and rheumatism 2016. [DOI] [PubMed] [Google Scholar]
  6. Desai SS, Myles JD, Kaplan MJ. Suboptimal cardiovascular risk factor identification and management in patients with rheumatoid arthritis: a cohort analysis. Arthritis research & therapy 2012;14(6):R270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dey AK, Joshi AA, Chaturvedi A, Lerman JB, Aberra TM, Rodante JA, et al. Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography. JAMA cardiology 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dubreuil M, Hee Rho Y, Man D, et al. The Independent Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Diabetes Incidence: A UK Population-Based Cohort Study. Rheumatology (Oxford) 2014;53(2):346–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Garcia Rodriguez LA, Perez Gutthann S. Use of the UK General Practice Research Database for pharmacoepidemiology. Br J Clin Pharmacol 1998;45(5):419–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gisondi P, Barba E, Girolomoni G. Non-alcoholic fatty liver disease fibrosis score in patients with psoriasis. Journal of the European Academy of Dermatology and Venereology : JEADV 2016;30(2):282–7. [DOI] [PubMed] [Google Scholar]
  11. Gisondi P, Targher G, Zoppini G, Girolomoni G. Non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. Journal of hepatology 2009;51(4):758–64. [DOI] [PubMed] [Google Scholar]
  12. Gladman DD, Schentag CT, Tom BDM, Chandran V, Brockbank J, Rosen C, et al. Development and initial validation of a screening questionnaire for psoriatic arthritis: the Toronto Psoriatic Arthritis Screen (ToPAS). Ann Rheum Dis 2009;68:497–501. [DOI] [PubMed] [Google Scholar]
  13. Haynes K, Bilker WB, Tenhave TR, Strom BL, Lewis JD. Temporal and within practice variability in the health improvement network. Pharmacoepidemiol Drug Saf 2011;20(9):948–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Humphreys JH, Warner A, Costello R, Lunt M, Verstappen SM, Dixon WG. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Annals of the rheumatic diseases 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. J. C The Read clinical classification. British Medical Journal 1990;300(6732):1092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. Journal of the American Academy of Dermatology 2009;60(5):824–37. [DOI] [PubMed] [Google Scholar]
  17. Lewis JD SR, Bilker WB, Wang X, Strom BL. Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research. Pharmacoepidemiology Drug Saf 2007;16(4):393–401. [DOI] [PubMed] [Google Scholar]
  18. Lo Re V 3rd, Haynes K, Forde KA, Localio AR, Schinnar R, Lewis JD. Validity of The Health Improvement Network (THIN) for epidemiologic studies of hepatitis C virus infection. Pharmacoepidemiology and drug safety 2009;18(9):807–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Loomis AK, Kabadi S, Preiss D, Hyde C, Bonato V, St Louis M, et al. Body Mass Index and Risk of Nonalcoholic Fatty Liver Disease: Two Electronic Health Record Prospective Studies. The Journal of clinical endocrinology and metabolism 2016;101(3):945–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Madanagobalane S, Anandan S. The increased prevalence of non-alcoholic fatty liver disease in psoriatic patients: a study from South India. The Australasian journal of dermatology 2012;53(3):190–7. [DOI] [PubMed] [Google Scholar]
  21. Mantovani A, Gisondi P, Lonardo A, Targher G. Relationship between Non-Alcoholic Fatty Liver Disease and Psoriasis: A Novel Hepato-Dermal Axis? International journal of molecular sciences 2016;17(2). [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Maybury CM, Jabbar-Lopez ZK, Wong T, Dhillon AP, Barker JN, Smith CH. Methotrexate and liver fibrosis in people with psoriasis: a systematic review of observational studies. The British journal of dermatology 2014;171(1):17–29. [DOI] [PubMed] [Google Scholar]
  23. Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, et al. Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. Journal of hepatology 2009;51(4):778–86. [DOI] [PubMed] [Google Scholar]
  24. Noe MH, Grewal SK, Shin DB, Ogdie A, Takeshita J, Gelfand JM. Increased prevalence of HCV and hepatic decompensation in adults with psoriasis: a population-based study in the United Kingdom. Journal of the European Academy of Dermatology and Venereology : JEADV 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ogdie A, Alehashemi S, Love TJ, Jiang Y, Haynes K, Hennessy S, et al. Validity of psoriatic arthritis and capture of disease modifying antirheumatic drugs in the health improvement network. Pharmacoepidemiol Drug Saf 2014a;23(9):918–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ogdie A, Haynes K, Troxel AB, Love TJ, Hennessy S, Choi H, et al. Risk of mortality in patients with psoriatic arthritis, rheumatoid arthritis and psoriasis: a longitudinal cohort study. Ann Rheum Dis 2014b;73(1):149–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ogdie A, Kay McGill N, Shin DB, Takeshita J, Jon Love T, Noe MH, et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. European heart journal 2017a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ogdie A, Maliha S, Shin D, Love TJ, Baker J, Jiang Y, et al. Cause-specific mortality in patients with psoriatic arthritis and rheumatoid arthritis. Rheumatology (Oxford) 2017b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ogdie A, Schwartzman S, Husni ME. Recognizing and managing comorbidities in psoriatic arthritis. Current opinion in rheumatology 2015a;27(2):118–26. [DOI] [PubMed] [Google Scholar]
  30. Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Annals of the rheumatic diseases 2015b;74(2):326–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: apopulation-based cohort study. Ann Rheum Dis 2015c;74(2):326–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ratib S, Fleming KM, Crooks CJ, Aithal GP, West J. 1 and 5 year survival estimates for people with cirrhosis of the liver in England, 1998-2009: a large population study. Journal of hepatology 2014a;60(2):282–9. [DOI] [PubMed] [Google Scholar]
  33. Ratib S, Fleming KM, Crooks CJ, Walker AJ, West J. Causes of death in people with liver cirrhosis in England compared with the general population: a population-based cohort study. The American journal of gastroenterology 2015;110(8):1149–58. [DOI] [PubMed] [Google Scholar]
  34. Ratib S, West J, Crooks CJ, Fleming KM. Diagnosis of liver cirrhosis in England, a cohort study, 1998-2009: a comparison with cancer. The American journal of gastroenterology 2014b;109(2):190–8. [DOI] [PubMed] [Google Scholar]
  35. Rocha-Pereira P, Santos-Silva A, Rebelo I, Figueiredo A, Quintanilha A, Teixeira F. The inflammatory response in mild and in severe psoriasis. The British journal of dermatology 2004;150(5):917–28. [DOI] [PubMed] [Google Scholar]
  36. Rodriguez LA, Tolosa LB, Ruigomez A, Johansson S, Wallander MA. Rheumatoid arthritis in UK primary care: incidence and prior morbidity. Scandinavian journal of rheumatology 2009;38(3):173–7. [DOI] [PubMed] [Google Scholar]
  37. Rosenberg P, Urwitz H, Johannesson A, Ros AM, Lindholm J, Kinnman N, et al. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. Journal of hepatology 2007;46(6):1111–8. [DOI] [PubMed] [Google Scholar]
  38. Saporito FC, Menter MA. Methotrexate and psoriasis in the era of new biologic agents. Journal of the American Academy of Dermatology 2004;50(2):301–9. [DOI] [PubMed] [Google Scholar]
  39. Seminara NM, Abuabara K, Shin DB, Langan SM, Kimmel SE, Margolis D, et al. Validity of The Health Improvement Network (THIN) for the study of psoriasis. Br J Dermatol 2011;164(3):602–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tsai TF, Wang TS, Hung ST, Tsai PI, Schenkel B, Zhang M, et al. Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. Journal of dermatological science 2011;63(1):40–6. [DOI] [PubMed] [Google Scholar]
  41. van der Voort EA, Koehler EM, Dowlatshahi EA, Hofman A, Stricker BH, Janssen HL, et al. Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: Results from a population-based study. Journal of the American Academy of Dermatology 2014;70(3):517–24. [DOI] [PubMed] [Google Scholar]
  42. van der Voort EA, Koehler EM, Nijsten T, Stricker BH, Hofman A, Janssen HL, et al. Increased Prevalence of Advanced Liver Fibrosis in Patients with Psoriasis: A Cross-sectional Analysis from the Rotterdam Study. Acta dermato-venereologica 2016;96(2):213–7. [DOI] [PubMed] [Google Scholar]
  43. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. International journal of surgery (London, England) 2014;12(12):1495–9. [DOI] [PubMed] [Google Scholar]
  44. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM, Alarcon GS, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis and rheumatism 1993;36(3):329–35. [DOI] [PubMed] [Google Scholar]
  45. Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Archives of internal medicine 2002;162(10):1105–10. [DOI] [PubMed] [Google Scholar]
  46. Watson DJ, Rhodes T, Guess HA. All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. The Journal of rheumatology 2003;30(6):1196–202. [PubMed] [Google Scholar]
  47. Whiting-O’Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnormalities: a meta-analysis. The American journal of medicine 1991;90(6):711–6. [PubMed] [Google Scholar]
  48. Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. The British journal of dermatology 2011;165(5):1037–43. [DOI] [PubMed] [Google Scholar]
  49. Yazici Y Long-term safety of methotrexate in the treatment of rheumatoid arthritis. Clinical and experimental rheumatology 2010;28(5 Suppl 61):S65–7. [PubMed] [Google Scholar]
  50. Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA dermatology 2013;149(10):1173–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Suppl Data
NIHMS981624-supplement-Suppl_Data.docx (78.8KB, docx)

RESOURCES