Abstract
Background: Psoriasis has been shown to be associated with increased incidence of myocardial infarction (MI). The data on the effect of tumor necrosis factor (TNF) inhibitors on MI in psoriasis are scarce.
Objective: To evaluate the effect of TNF inhibitors on the risk of MI in psoriasis patients compared with methotrexate (MTX) and topical agents.
Methods: Data were obtained from the Electronic Health Records database of Farwaniya Hospital from psoriasis patients seen from January 2008 to December 2014. Patients were categorized into TNF inhibitor, MTX and topical cohorts.
Results: The study included 4762 psoriasis patients. Both TNF inhibitor and MTX cohorts showed a statistically lower rate of MI compared with topical cohort. However, there was no statistically significant difference in MI rate between TNF inhibitor and MTX cohorts (P = .32). The probability of MI was lower in TNF inhibitor responders compared with non-responders (p = .001).
Conclusions: The use of TNF inhibitors in psoriasis showed a significant reduction in the risk of MI compared with topical agents and a non-significant reduction compared with MTX. Responders to TNF inhibitor therapy showed a reduction in MI rate compared with non-responders.
Keywords:
Introduction
Psoriasis is a common chronic inflammatory disease affecting 0.91%–8.5% of the total population (Citation1). It has been associated with multiple co-morbidities including cardiovascular diseases (CVD), the metabolic syndrome, cancer, gastrointestinal diseases and chronic obstructive pulmonary diseases (COPD) (Citation2–4). Overlapping mechanism of systemic inflammation has been proposed to contribute to the common link between psoriasis and CVD (Citation5). Studies have found psoriasis to be an independent risk factor for diseases including diabetes, atherosclerosis, myocardial infarction and stroke, even after controlling of other well-known risk factors (Citation6–8).
Although psoriasis and atherosclerotic CVD share risk factors such as smoking and a poor diet, the increased risk of CVD in psoriasis cannot be explained by traditional risk factors alone. Inflammation and treatment, each may have an independent role to play. Several studies have shown link between the moderate to severe cases of psoriasis and increased risk of both cardiovascular mortality and overall mortality, when compared with the general population (Citation9–12).
Proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), are elaborated in modification of lipid profile and insulin resistance (Citation13) and the initiation and evolution of atherosclerosis (Citation14,Citation15), and atherosclerotic plaque rupture, which is the most important incident leading to an acute MI (Citation14). Both methotrexate (MTX) and TNF-α inhibitors may improve cardiovascular inflammatory biomarkers and CVD outcomes. Inhibition of TNF-α in patients with psoriasis may therefore lead to a reduction in MI rates by inhibiting one or more of these mechanisms. TNF-α inhibitor therapy may also improve the risk factors leading to CVD and atherosclerosis, due to reduced insulin resistance (Citation16), diminished C-reactive protein and interleukin (IL)-6 levels, and improved high-density lipoprotein levels (Citation17).
The aim of this study was to define whether the risk of occurrence of acute MI in psoriasis patients treated with TNF-α inhibitors is lower compared with patients treated with traditional systemic drugs as MTX and to inspect the impact of patient’s response to treatment on the rates of MI in TNF-α inhibitors treated patients.
Patients and methods
This is a retrospective data analysis conducted in Farwaniya Hospital, which serves about one third of the total 3.9 million population of Kuwait. The study was approved by the local ethical committee. We carried out an observational study in our hospital between the 1 January 2008 and the 31 December 2014. The study population included all patients more than 18 years of age diagnosed at least once as a case of psoriasis. Exclusion criterion was a history of MI documented before 1 January 2008.
All required necessary information about the study population for the purpose of this study was obtained from inpatient and outpatient electronic medical filling system database of the Electronic Health Records of Farwaniya Hospital. This database defines the patient according to the unique civil ID number, which enables us to access the patient’s history of any disease, investigations done, operations undergone, medications prescribed and the prognosis of the medical illness. This includes treatment with the biologic agents. The prescription information consists of the name of prescribed medications, dosage, frequency and number of days supplied.
We categorized 3 cohorts:
TNF-α inhibitor cohort: included patients with psoriasis who received TNF-α inhibitors (adalimumab, etanercept, infliximab) for at least three consecutive months during the study regardless of changes in treatment regimen, discontinuation or restarting TNF-α inhibitor use or their use combined with other agent or phototherapy.
MTX cohort: included patients who received oral or parenteral MTX therapy for at least three consecutive months. MTX was considered as the reference exposure, since it is the most commonly used systemic agent for psoriasis in Kuwait.
Topical cohort: included moderate cases that were not treated with TNF-α inhibitors, MTX or other oral agents or phototherapy but were treated with topical agents only.
The primary study outcome was occurrence of acute cardiovascular event namely MI, leading to hospitalization. However, the study outcome did not include out-of-hospital events, such as an out-of-hospital sudden death. The date of the first cardiovascular MI event was defined as the index date. Prescription drugs which may affect occurrence of MI risk were recognized using the Farwaniya Hospital database and included statins and β-blockers. Demographic and clinical characteristics of patients as well as data of several important cardiovascular risk factors, such as smoking, body mass index were summarized in our study database. The patients with history of acute MI prior to the start of the studied drugs were excluded from the study. Follow-up period continued until the primary outcome i.e. occurrence of acute MI attack, death of the patient during the study or until the end of the study period in 31 December 2014, whichever nearer.
Statistical analysis: All the statistical analyses were performed using SAS Enterprise Guide, version 4.3. Continuous patient characteristics were analyzed using mean and SD, and discrete data were summarized as counts and proportions. Association was examined using Chi square chart for categorical variables, and two-sided t-test/Wilcoxon rank test for continuous variables. Incidence rate of acute MI was calculated using the person–time method, after adjusting for age, sex, co morbid conditions like hypertension, diabetes, metabolic syndrome, dyslipidemias, and were compared using proportional hazards regression model. Significance was considered at p ≤ .05.
Results
Between 1 January 2008 and 31 December 2014, there were 4762 patients with psoriasis included in the study. The mean age of the cohort population was 49.6 years, and there were 2715 (57%) male patients.
Out of this cohort, 1058 (22.22%) patients were treated with TNF-α inhibitors for at least 3 consecutive months (TNF-α inhibitor cohort), 1331 (27.95%) were treated with MTX (MTX cohort) for at least same duration satisfied our inclusion criteria and were enrolled for further analysis. In addition, 2373 (49.83%) patients were treated with topical agents only (topical cohort). There were no significant differences between cohorts regarding demographic and clinical characteristics, the numbers of hospital visits and medications received.
However, patients in MTX cohort were relatively older than those in the TNF-α inhibitor cohort, with a mean age of 48.2 years in TNF-α inhibitor cohort, and 52.7 years in MTX cohort. The TNF-α inhibitor cohort had more male patients compared with MTX cohort (53.4% Vs 46.8%). Moreover, patients in the MTX cohort had less severe disease, and shorter duration of illness.
Compared with the MTX cohort, a lower percentage of TNF-α inhibitors treated patients had co-morbid conditions like hypertension, diabetes mellitus or a history of MI at the time of initiation of therapy, while the percentage of dyslipidemia patients was approximately the same in both groups. The rates of associated co-morbidities observed in both groups were as follows: hypertension: 31.29%, 37.34%; dyslipidemia: 17.58%, 17.15%, diabetes mellitus: 28.92%, 34.49%, and history of transient ischemic attack: 6.90%, 4.88%, in TNF-α inhibitor cohort and MTX cohort, respectively ().
Table 1. Baseline characteristics of psoriasis patients who were starters of TNF inhibitor, MTX and topical treatments between January 2008 and December 2014.
The cohort was observed for a median of 3.9 years (mean 2.6 ± 4.7 years), resulting in 35,835 patient-years of follow-up. We defined the index date as the time of the first MI event after follow-up. The median duration between the start of follow-up (first psoriasis diagnosis) and the index date was 33 months for TNF inhibitor cohort, 28 months for MTX cohort and 35 months for topical cohort.
There were nineteen (1.79%) MIs reported in the TNF-α inhibitor cohort compared with 21 (3.03%) in the MTX cohort and 72 (3.03%) in topical cohort. The incidence rates of MI were higher in men, as expected, in all cohorts. The crude incidence rate of MI was higher in the MTX cohort (5.38 events per 1000 person-years) than in the TNF-α inhibitor cohort (4.88 events per 1000 person-years), equivalent to an incidence rate ratio (95% CI) of 0.92 (0.51–1.33). However, after adjustment for age and sex, disease severity, traditional cardiovascular risk factors, and relevant baseline drug use resulted in an incidence rate ratio (95% CI) of 1.16 (0.66–2.78). There was again no significant difference in risk of MI with TNF-α inhibitors therapy for either sex ().
Table 2. Incidence rates of MI rate in TNF inhibitor and MTX cohorts.
The rate of occurrence of MI in TNF-α inhibitor cohort was significantly lower than that of topical cohort with a p values =.01. Similarly, the rate of MI in MTX cohort patients was significantly lower than that of topical cohort patients, p = .02. However, there was no significant difference between the rate of MI when comparing TNF-α inhibitor cohort and MTX cohort patients (p = .32).
Patients in the TNF-α inhibitor cohort were categorized according to the PASI score response into PASI 75 responders to treatment, PASI 50 responders to treatment and non-responders to investigate the response of treatment on the MI incidence. There were striking differences in MI rate between the subgroups with different responses to TNF-α inhibitors treatment (). The standardized MI rate was 1.35 (95% confidence interval [95% CI] 0.81–2.18) in the group of patients showing PASI 75 improvement after one year of TNF-α inhibitors treatment and 1.91 (95% CI 0.88–2.64) in the group with PASI 50 improvement. The standardized MI rate increased significantly in the group of patients with no improvement [4.17 (95% CI: 2.76–6.13)]. The probability of MI was significantly lower in the group of patients with improvement after one year (either PASI 75 or PASI 50 improvement), collectively called “responders”, compared with that in the group with no improvement “non-responders” (p = .001).
Table 3. MI Events in patients in TNF inhibitor cohort according to the PASI score response.
Discussion
Patients with psoriasis have an increased risk of heart attacks, and this risk is independent of other major risk factors such as hypertension, diabetes, obesity, dyslipidemia and smoking, which are also commonly seen in patients of psoriasis (Citation18). Psoriasis has been connected with an increased frequency of traditional cardiovascular risk factors since 1978, when McDonald and Calabresi (Citation19) presented the first study in 323 hospitalized patients. In which, they had shown that patients with psoriasis had more vascular occlusive events than patients without psoriasis. Later on, many other studies showed the link of psoriasis to cardiovascular events mainly MI (Citation20–22).
Al-Mutairi et al (Citation2) conducted a case–control study in 1835 patients with psoriasis vulgaris and age- and gender-matched cohort without psoriasis. Analysis of computerized patients’ records was done at two hospitals in Kuwait, including 1661 patients with mild to moderate psoriasis and 129 patients with severe psoriasis. They found a higher risk of cardiac-associated disorders in patients with severe psoriasis.
The inflammatory hypothesis has gained popularity as an explanation for atherogenesis and increased risk of CVD in diseases characterized by chronic inflammation such as rheumatoid arthritis, systemic lupus erythematosus and psoriasis. Inflammation in these diseases, including psoriasis, results in increased level of TNF-α and IL-6, and other signs of systemic inflammation, such as increased C-reactive protein levels or platelet activation. These factors seem to play a principal role in the development of atherosclerosis leading to myocardial infarction (Citation23–26).
The pro-inflammatory cytokines may lead to atherosclerosis and myocardial infarction by induction of a state of insulin resistance with subsequent development of certain pathological changes leading to atherosclerosis and ultimately increased risk for myocardial infarction (Citation23,Citation21,Citation26). TNF-α increases the levels of PAI-1, which suppresses the activity of tissue-type plasminogen activator. Therefore, elevated PAI-1 results in impaired fibrinolysis and uninhibited clotting (Citation13,Citation26,Citation27).
Churton et al. (Citation5) reviewed twenty-three original research publications, and presented preliminary evidence that some psoriasis therapies improve cardiovascular biomarkers and the incidence of cardiovascular risk.
Introduction of the TNF-α inhibitors therapy with infliximab, etanercept and adalimumab has intensely enhanced the outcome of severe psoriasis further than that achieved with traditional systemic drugs. Both MTX and TNF-α inhibitors improve cardiovascular inflammatory biomarkers and CVD outcomes (Citation5). A cardio-protective effect has been suggested with systemic agents such as MTX and TNF-α inhibitor agents in rheumatoid arthritis and psoriasis populations (Citation28). Therapeutic intervention by use of anti-inflammatory drugs including MTX and TNF-α inhibitors seems to diminish the insulin resistance state and consequently lessen cardiovascular risk in psoriatic patients (Citation16,Citation28).
In the current study, there was a significant reduction in the incident rate of MI in TNF-α inhibitor cohort patients compared with that of topical cohort patients. These findings were consistent with that of Wu et al. (Citation29). In their study that included 8845 patients of psoriasis, they found that patients treated with TNF-α inhibitors had approximately half the risk of developing MI compared with psoriasis patients treated with topical agents only. However, the longer duration of TNF-α inhibitors was not associated with significantly lower risk of MI compared with shorter treatment duration. Similarly, several studies found a reduction in MI rate with the use of TNF-α inhibitors but in patients with rheumatoid arthritis (Citation30–32). Ahlehoff et al (Citation33) found that among a Danish psoriasis cohort with severe psoriasis, biologic treatments (with TNF inhibitors) were associated with significantly lower risk of composite outcome of death, MI, and stroke compared with those treated with non-biologic, non-methotrexate, anti-inflammatory medications. Ahlehoff et al (Citation34) also suggested a protective effect of TNF-α inhibitors against cardiovascular events in treatment of patients with severe psoriasis. Moreover, recent data by Guilliver et al (Citation23) suggested that anti-TNF therapy in psoriasis may have a protective effect by significantly decreasing the risk of MI. It decreased the cardiovascular incidence by 86% (p < .01).
In the present study, MTX treated cohort was associated with lower incidence of MI compared with topical cohort patients. Previous results from the Danish nationwide cohort showed the beneficial effect on the CVD outcome with the use of MTX in patients with severe psoriasis (Citation33). In addition, a case–control study conducted by Prodanovich et al (Citation28) showed a protective effect of MTX against vascular diseases in psoriasis.
In their long-term follow-up of a nationwide cohort of patients with severe psoriasis, Ahlehoff et al (Citation34) observed that treatment with MTX was associated with lower rates of cardiovascular events compared with other therapies, including topical treatments, phototherapy and climate therapy.
In the present cohort, there was a non-statistically significant lower MI incident rate in patients treated with TNF-α inhibitors compared with psoriatic patients treated with oral MTX. Abuabara et al (Citation35) also reported that it did not seem that there was a reduced risk of MI in patients with psoriasis receiving systemic therapy (including TNF-α inhibitors) compared with a group undergoing UVB phototherapy. Wu et al. (Citation36) found no significant differences in physiologic and metabolic measures between users of TNF inhibitor and MTX or phototherapy for the treatment of psoriasis. Recently, Wu et al. (Citation37) showed that the use of TNF inhibitors concomitantly with MTX in patients with psoriasis and psoriatic arthritis was associated with a clinical and significant reduction in C-reactive protein compared with those treated with MTX alone. On the other hand, in another study by Wu et al. (Citation38), no significant difference in cholesterol level was found between psoriasis patients group treated with TNF and MTX compared with group treated with MTX only.
To our knowledge, this is the first study to compare the incidence of MI in responders and non-responders to TNF-α inhibitor therapy. The patients treated with TNF-α inhibitors were categorized into two categories, “responders” and “non-responders”, according to the change in PASI score from baseline. Patients who responded to TNF-α inhibitor therapy showed a reduction of MI rate compared with non-responders. In psoriasis patients who responded to TNF-α inhibitor therapy, the risk of MI was reduced by more than half compared with non-responders.
These data supports the hypothesis that the anti-inflammatory effect of TNF-alpha blockers might also potentially reduce the cardiovascular risk also in psoriasis patients and therefore suggest that adjusting the inflammatory activity of psoriasis not only leads to an improved outcome of psoriasis, but also contributes to a reduction of cardiovascular risk. TNF-α inhibitor treatment that efficiently diminishes inflammatory activity could reduce cardiovascular risk as well (Citation30).
Conclusion
The use of either TNF-α inhibitors or MTX was associated with a significant reduction in incident rate of MI compared with treatment with topical agents only. However, no significant difference in the protective effect against MI could be detected in psoriasis patients treated with TNF-α inhibitors compared with patients treated with MTX. Patients who responded to TNF-α inhibitor therapy showed a reduction in MI rate compared with non-responders. Large, prospective, effectively controlled and powered studies are required to discover the effects of such drugs on cardiovascular morbidity and mortality in psoriasis patients and to elucidate the relationship between treatment duration and MI.
Limitations to this study: The short duration of the study and follow-up. We could not go before January 2008 as this was the time of starting the electronic registry of the patients in Farwaniya hospital, so accurate data before this date would not be available. Although we were able to detect the relation between the response to therapy and the incidence rate of MI, we did not examine the relation between the duration of treatment and the risk of MI.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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