Psoriasis comorbidities: complications and benefits of immunobiological treatment*

During the last decade, different studies have converged to evidence the high prevalence of comorbidities in subjects with psoriasis. Although a causal relation has not been fully elucidated, genetic relation, inflammatory pathways and/or common environmental factors appear to be underlying the development of psoriasis and the metabolic comorbidities. The concept of psoriasis as a systemic disease directed the attention of the scientific community in order to investigate the extent to which therapeutic interventions influence the onset and evolution of the most prevalent comorbidities in patients with psoriasis. This study presents scientific evidence of the influence of immunobiological treatments for psoriasis available in Brazil (infliximab, adalimumab, etanercept and ustekinumab) on the main comorbidities related to psoriasis. It highlights the importance of the inflammatory burden on the clinical outcome of patients, not only on disease activity, but also on the comorbidities. In this sense, systemic treatments, whether immunobiologicals or classic, can play a critical role to effectively control the inflammatory burden in psoriatic patients.


Nonalcoholic steatohepatitis
We will discuss below the scientific evidence of the influence of immunobiological treatments for psoriasis available in Brazil (infliximab, adalimumab, etanercept and ustekinumab) on the main comorbidities related to psoriasis.

IMMUNOBIOLOGICALS
Immunobiologicals are proteinaceous drugs, obtained through modern biotechnological techniques that interfere in a specifically and timely manner in the immune system, blocking or stimulating one or more pathways of the immune response. Infliximab, etanercept and adalimumab are drugs that block the action of tumor necrosis factor alpha (TNF-α) while the ustekinumab is a drug that blocks the p40 subunit of the receptors of interleukin 12 and 23, inhibiting their action.
Despite differences in the mechanism of action, the response to the use of immunobiologicals includes a reduction in inflammatory burden observed in diseases such as psoriasis, rheumatoid arthritis, Crohn's disease and many other immune-mediated inflammatory diseases. In turn, this inflammatory burden also appears to relate to the occurrence of different comorbidities associated with these diseases. Consequently, it is worth considering that if the immunobiologicals decrease the inflammatory burden responsible for comorbidities, its use could inhibit their onset or aggravation. Moreover, immunobiologicals, like any other medication, have adverse events that can negatively interfere with these comorbidities. A meta-analysis demonstrated that patients with psoriasis have a higher prevalence of metabolic syndrome (from 14% to 40%) compared with the general population, and the greater the severity, the strongest is the disease association. 9,10 Despite the high frequency of smoking and increased alcohol consumption among individuals with psoriasis, the association between psoriasis and MS has been shown independent. Multivariate analysis models adjusted for age, gender and smoking condition of psoriasis patients showed that psoriasis was consistently associated with MS. 11 There are also indications that the severity of psoriasis has direct relation to the increased risk for the development of MS. 12 The increased prevalence of MS and its components seem to also be present in children with psoriasis. 13

Infliximab
There are no randomized placebo-controlled trials or even case series evaluating the relation between the use of infliximab and improvement or worsening of glucose tolerance in patients with psoriasis. 16 In animal models, there is evidence that the administration of infliximab can delay the onset of glucose intolerance and metabolic syndrome, during the induction of obesity in mice. The treated animals showed marked decrease in fasting glucose levels and steady decline in blood glucose levels during glucose tolerance test. 17 Some uncontrolled studies of patients with rheumatoid arthritis and ankylosing spondylitis show a potential benefit of infliximab in increasing insulin sensitivity. [18][19][20] In Crohn's disease, in the analysis of a series of cases, there appeared to be an improvement in glycemic indices in patients treated with infliximab during the maintenance phase of treatment for a year or more. 21 Wascher et al., on the other hand, in a randomized, placebo-controlled trial, compared the effect of infusion of infliximab during 32 weeks on glucose tolerance in obese men, otherwise healthy, and concluded that there is no influence of medication on glucose levels or on insulin sensitivity. It is noteworthy, however, that the study randomized only nine patients, five in the group receiving infliximab and four in the placebo group, which is an unrepresentative sample of the population under study. 22 Finally, there are reports of patients with rheumatoid arthritis who presented abrupt and symptomatic changes in blood glycemic levels (hypoglycemia and hyperglycemia) after the use of drugs that block TNF-α. 23,24 Etanercept Two studies examined the influence of treatment with etanercept on insulin resistance in patients with psoriasis. In a randomized, placebo-controlled study, Martinez-Abundis et al. studied the effect of infusion of 50 mg etanercept weekly or placebo in 12 patients with psoriasis and found no alteration in insulin secretion or insulin sensitivity after two weeks of treatment. Arguments against this study can be raised to the extent that the sample is modest and the follow-up is too short. 25  its discontinuation. 26,27 . 26,27 There is also a case report of a patient with rheumatoid arthritis and controlled diabetes mellitus that, after three weeks of initiating therapy with etanercept at a dose of 50 mg weekly, began to present unstable diabetes, with two episodes of severe hypoglycemia, separated by at least two days. Discontinuation brought stability to the treatment of diabetes and the introduction of a new anti-TNF-α (infliximab) did not cause the same problem. 24

Adalimumab
As in the case of infliximab, there is no data analyzing the relation between the use of adalimumab and the change in insulin sensitivity or in glucose levels in patients with psoriasis. 16 In patients with rheumatoid arthritis, the study of nine cases of patients receiving adalimumab revealed that, although a decrease in inflammatory burden occurred, there was no change in insulin resistance. 28

Ustekinumab
A randomized, placebo-controlled study evaluating the efficacy of ustekinumab within 24 weeks of use did not observe any changes in fasting glucose levels. 29 Papp et al., in a randomized, placebo-controlled, double-blind study, called PHOENIX 2, evaluated the effectiveness of the medication up to 52 weeks and, similarly, found no changes in fasting glucose. 30 It is noteworthy that the inclusion criteria for these studies is not quite detailed and there may have been selection bias, decreasing the chance of patients with altered glycemia were initially enrolled for the study.
We still lack randomized, controlled studies, specifically designed for psoriatic patients and that have sufficient statistical power to determine the real effect of immunobiologicals on blood glycemic levels, peripheral resistance and development of DM in psoriatic patients previously without comorbidities. However, the fact that there are many reports of hypoglycemia after using immunobiologicals seems to show a regulatory role of these drugs on the endocrine system still to be clarified.

1b. CENTRAL OBESITY
Obesity is associated with higher levels of chronic inflammation and has a central role in the development of metabolic syndrome, appearing to precede other components of the syndrome. 10 Metabolic syndrome and obesity occur commonly in patients with psoriatic arthritis and adversely affect the disease activi-ty and response to therapy. 15 Al-Mutairi et al. showed that the body weight reduction in obese patients with psoriasis receiving immunobiological therapy can increase the effectiveness of the drug, and Solomon et al. showed that the weight loss (greater than or equal to 5% of the initial weight) regardless of the type of diet is associated with a higher success rate in achieving control of disease activity in patients with overweight or obesity with psoriatic arthritis treated with anti-TNF-α. 31,32 Infliximab

Considerable increase in weight and body mass index (BMI)
with the use of infliximab was evidenced by Gisondi et al., and the relative risk of developing increased five kilograms would be 4.3 compared with that observed in the control group, which used methotrexate (MTX). 33 In another study, it was observed increased weight and BMI until the 46th week of treatment with infliximab, reaching plateau until the 78th week when, gradually, there was loss of weight gain, but no reduction in BMI. 34,35 Weight gain in patients using this immunobiological drug occurs in the first months and is higher among patients with normal BMI than among those previously obese or overweight. 35 Similar results were observed in patients with psoriatic arthritis. In the patients with rheumatoid arthritis, the weight increase was insignificant. 16 The reason why there is weight gain in patients who are on anti-TNF-α agents is not known. 36

Etanercept
Studies have shown increased weight and BMI with the use of etanercept, as has been described with infliximab. Mean weight gain of 1.5 kg and an increase in BMI of 0.5 kg/m 2 in the 24th week in retrospective cohort, as well as increasing weight gain up to the 48th week, were observed, particularly in thin patients. 33,34 Similar results were also observed in patients with psoriatic arthritis. In patients with rheumatoid arthritis, the increase was slightly significant and entirely based on lean body mass. 16

Adalimumab
The same study of Saraceno et al., evaluating use of infliximab and weight gain, also assessed the use of adalimumab and weight gain, reaching similar results. Mean weight gain in the 24th week was 2.23 kg, being held until the 78th week, when there was a gradual weight loss. 34 No studies involving the use of adalimumab and weight gain in patients with psoriatic arthritis and rheumatoid arthritis were found. 16

Ustekinumab
There are reports of increased weight or BMI and use of ustekinumab in patients with psoriasis, rheumatoid arthritis or psoriatic arthritis.
Mean weight of psoriatic patients tends to be higher than those of patients with rheumatoid arthritis, which can be explained by rheumatoid cachexia. 37 In patients with rheumatoid arthritis, even though they have insulin resistance or other components of the metabolic syndrome, the risk for weight gain with the use of biological drugs is counterbalanced by cachexia induced by TNF. 38,39 In patients with psoriasis, a large proportion starts treatment with anti-TNF-α with high BMI, without compensation, because TNF does not induce in these patients a "psoriatic cachexia".
Thus, the weight gain emerging from the use of anti-TNFs should be thoroughly evaluated and can even be deleterious because it leads to increased cardiovascular risk. This anabolic effect does not occur in patients using ustekinumab, which is an advantage of this drug in obese patients. 36 If this weight gain is balanced by a decrease in the inflammatory burden also observed in the treatment with anti-TNF-α this is still not known and further studies are necessary. 37

Infliximab
Few studies have evaluated changes in serum lipids after the use of infliximab in psoriasis patients. In a retrospective cohort study, Gisondi et al. found no changes in total cholesterol or in triglycerides after 24 weeks of infliximab. 33 Saraceno et al., in a case-control retrospective study, which compared the blood lipids of patients using infliximab with a control group that was in use of methotrexate and efalizumab, observed no significant changes in total cholesterol and its fractions and in triglycerides in a period of 48 weeks. 34 Studies with patients with psoriatic arthritis are conflicting.
While some showed a pro-atherogenic modulation of infliximab after 6 weeks of use, with reduced HDL cholesterol and increased triglycerides, others showed a consistent increase in HDL cholesterol from 4 to 24 weeks after the use of infliximab, without changes in LDL cholesterol or in triglycerides. 16 In patients with rheumatoid arthritis, however, trials show antiatherogenic modification of blood lipids in the short term and a modulation towards an atherogenic profile in the long term. 40,41 Most studies that evaluated patients for up to one year show an increase in HDL cholesterol and total cholesterol. 41 After one year, there is a tendency for HDL and total cholesterol levels to return to baseline levels or below these, with maintenance or increase of LDL cholesterol, total cholesterol and triglycerides. 40

Etanercept
It seems to be no deleterious influence of the drug on lipid profile of patients with psoriasis according to the studies, although none of these has been specifically designed for the observation of this event, but rather to determine increase of BMI and insulin tolerance in psoriatic patients. 33,34,44 A retrospective cohort study published in 2011 evaluated 45 patients with plaque psoriasis, moderate to severe, receiving etaner-cept, and found that there was no statistically significant change in the lipid profile of patients in 24 weeks of use. 45 In patients with psoriatic arthritis, there is also no indication that there is a change in blood levels of lipids in the long term. 34 As in psoriasis, there is little evidence on the influence of etanercept in blood lipids in patients with rheumatoid arthritis. A study with more than 24 weeks of duration showed increase in total cholesterol, especially of anti-atherogenic HDL cholesterol, with no increase in LDL or triglycerides. 46 Studies with less than 24 weeks does not support this finding, showing no lipid alterations in these patients. 47 An observational cohort in 2010, assessing 292 patients with rheumatoid arthritis, determined that the use of medication for a year would ensure a decrease in the ratio of ApoB molecules (found on the surface of LDL and VLDL-cholesterol molecules) and Apo-A1 (found in surface of the HDL-cholesterol molecule). Furthermore, the study showed that the greater the inflammatory burden measured by the disease activity, the greater the ApoB/Apo-A1.
Therefore, the less chance of modifying the lipid profile for an anti-atherogenic type. 48

Adalimumab
A single study, which examined the levels of blood lipids up to 48 weeks, showed no significant changes despite the increase in BMI and in body weight observed in psoriatic patients analyzed. 34 In patients with psoriatic arthritis, despite a reported case of a significant increase in lipid levels, there seems to be no change in serum lipids during the use of adalimumab. 34,49 In rheumatoid arthritis patients, the results are contradic-

Ustekinumab
There are no data specifically relating use of ustekinumab to lipid alterations. However, during efficacy studies on long-term use of the medication, consistent changes were not reported. 30 It is still unclear the role of biological drugs in the modu-

Infliximab
In individuals with rheumatoid arthritis and normotensive, it was observed that the use of infliximab can reduce blood pressure levels, especially during the day, and this may be related to a reduction in sympathetic activity, mediated by reduced serum levels of norepinephrine observed. 52 To date, there are no references on the impact of the use of this immunobiological on pressure levels of individuals with psoriasis, normotensive or hypertensive subjects.

Etanercept
Infusion of etanercept in experimental animals with spontaneous hypertension showed to improve the balance between neurotransmitters and pro and anti-inflammatory cytokines in the paraventricular nucleus of the hypothalamus, reducing disease progression and cardiac ventricular hypertrophy. 53 Its effect in hypertensive humans has not been studied.

Adalimumab
The clinical response of patients with psoriasis treated with adalimumab, measured by PASI-50 and PASI-75, was not affected by the diagnosis of hypertension in a study with 144 individuals with psoriasis and psoriatic arthritis. 54 References on the evolution of hypertension in patients with psoriasis during or after treatment with adalimumab were not found.

Ustekinumab
There are no data on the effects of this immunobiological on pressure levels in both animals and humans, healthy subjects or patients with psoriasis, psoriatic arthritis and/or hypertension.
Animal models seem to indicate that changes in neurotransmitters and balance of inflammatory cytokines in the hypothalamus may be related to a dysfunction of the renin-angiotensin-aldosterone system, which would be responsible for the higher prevalence of hypertension in patients with psoriasis. The action of TNF-α in this area could rebalance these substances and promote a reduction in blood pressure and progression of hypertension. However, further studies in humans are needed to confirm this association. The anti-IL 12/23 agents still need to have their influence on blood pressure levels studied.

CARDIOVASCULAR RISK AND PSORIASIS
It is known that patients with psoriasis are at increased risk of cardiovascular disease, especially those with severe disease at an early age. 55 Rose et al. compared the vascular inflammation in patients with psoriasis (n=10) and psoriatic arthritis (n=5) with healthy subjects (n=10) using fluorodeoxyglucose positron emission/ computed tomography and found high regional aortic vascular inflammation in patients with psoriasis and psoriatic arthritis compared with healthy individuals, reinforcing the previous finding of premature atherosclerosis in these patients. 56 The inflammatory response observed in psoriasis leads to insulin resistance, oxidative stress, endothelial dysfunction, and atherosclerosis development, which culminates with acute myocardial infarction or cardiovascular acidents. 15 Studies suggest that psoriasis may be an independent risk factor for premature cardio-vascular events. 57 It is likely, at least theoretically, that the inflammatory events that are perpetuated into the bloodstream in psoriasis lesions influence the appearance of vascular endothelium lesions and the development of atherosclerosis. From this theoretical situation also arises the possibility that, diminishing the inflammatory burden, the risk of onset of cardiovascular disease also diminishes. 58 On the other hand, it is well known the FDA (Food and Drug Administration) alert for the use of immunobiologicals in patients with severe heart failure, leading to considering that these drugs can cause greater damage than potential cardiovascular benefits. 59 In patients with heart failure, TNF-α levels are elevated and associated with the severity of clinical signs and symptoms. 60 A potential cause of problems when analyzing the effects of antipsoriatic therapies on comorbidities is the relation between anti-IL-12/23 immunobiologicals and possible serious cardiovascular events, leading to discontinuation of study with briakinumab and considerable concern in the prescription of ustekinumab. 65 So far, there are only studies that evaluated the association between use of immunobiologicals and incidence of cardiovascular events in patients with psoriasis. [65][66][67] There are no studies specifically designed to assess the impact of therapy on cardiovascular risk conferred by psoriasis.

ASIS
Nonalcoholic steatohepatitis (NASH) is insidious fatty infiltration of the liver and is recognized as a consequence of obesity, especially associated with metabolic syndrome. It is the leading cause of altered liver function tests in developed countries. 72 In psoriatic patients, NASH affects 47% of patients with chronic plaque psoriasis and 27% of the control non psoriatic population, matched by gender, age and BMI, and is more pronounced in more severe psoriasis and with longer disease duration. The steatotic liver produces proinflammatory and pro-atherogenic cytokines, basically C-reactive protein (CRP) and interleukin-6 (IL-6), and decreases the production of adiponectin that, unlike the leptin, has anti-inflammatory activity. This increases the risk of severe disease by increased inflammatory burden, increasing cardiovascular risk. 74 There are no controlled studies evaluating the impact of treatment with any of immunobiologicals on NASH.
Study of 89 patients with moderate to severe plaque psoriasis diagnosed with metabolic syndrome and NASH receiving therapy with etanercept or PUVA after 24 weeks of treatment showed a significant decrease in the levels of ALT, AST, CRP and insulin in the group that used the immunobiological. 75 Studies in non psoriatic murine animal model, fed with high fat diet, showed the possibility of infliximab reverse steatosis triggered by poor diet. 76 Another study in an animal model, with mice deficient in choline and with methionine-induced hepatitis, showed that infliximab (as anti-TNF-α drugs prototype) decreased fat infiltration and hepatic fibrosis. 77 A case report of a patient with rheumatoid arthritis using adalimumab demonstrated reduction of steatosis and improvement of liver function tests. 78 Patients with psoriatic arthritis treated with anti-TNF-α and associated MTX presented a lower risk of liver fibrosis than those treated with MTX alone. 15 It is not possible to state that immunobiologicals can alter the course of NASH due to the lack of studies specifically designed for this purpose. The evidence in animal models and theoretical evi-