The association between psoriasis and hepatitis C virus (HCV) infection has been reported in the literature. It has been suggested that HCV infection can be an inducing factor for psoriasis 1–3, and the association between psoriasis and hepatitis C was considered to be independent of interferon (IFN) use 4. However, the exact pathomechanism linking psoriasis and hepatitis remains to be determined. Although Egypt is estimated to have the highest worldwide disease prevalence of HCV infection, with a reported average rate of 14.7% 5, little is known about the link between the two diseases in Egyptian patients. In addition, a higher prevalence of hepatitis C has been reported in patients with severe psoriasis in some studies 6. Therefore, it remains to be determined whether the presence of HCV alters the severity of psoriasis.
Treating patients with psoriasis and hepatitis is challenging because most of the systemic therapies for psoriasis can aggravate hepatitis. Furthermore, psoriasis can be induced or exacerbated by anti-HCV therapy, particularly IFN-α 7.
Although no significant studies were held to understand the common pathogenic pathways that may link both diseases, immune-mediated mechanisms are the most probably involved 8,9.
Psoriasis is an immunologically mediated chronic inflammatory skin disease; the clinical phenotype results from cutaneous T-cell infiltration and release of inflammatory cytokines by keratinocytes, immune cells, and endothelial cells. Interleukin (IL)-12 and, lately, IL-23 have been shown to play an immunopathogenic role in psoriasis 10. IL-12 is a 70-kDa heterodimeric cytokine composed of two disulfide-bound subunits: IL-p35, designated p35 (35 kDa), and ILp40 (40 kDa). It induces differentiation of CD4-naive T cells to T-helper 1 (Th1) cells and activates natural killer cells. These cells produce cytokines including IFN-γ 11. IL-23 is a heterodimer of a unique p19 subunit, and a common p40 subunit shared with IL-12. Unlike IL-12, IL-23 does not induce Th1 cell development and IFN-γ-production, but it promotes the expansion of the distinct Th17 cells and the production of proinflammatory cytokines including IL-17 12. IL-17 synergizes with IFN-γ to stimulate keratinocyte production of proinflammatory cytokines, which likely results in the development of skin inflammation characteristic of psoriasis 13.
Several immunological abnormalities might be associated with hepatitis and have been found to play a role in the progression of hepatic disease. Previous studies have suggested that IL-12 may be implicated in inflammatory liver damage in hepatitis C 14,15.
Previous studies have demonstrated that both Th17 cells were increased and serum levels of IL-17 and IL-23 were significantly upregulated in patients with chronic hepatitis C and they were positively correlated with viral load and serum alanine aminotransferase (ALT) levels, which often serve as markers of liver injury 16,17. Therefore, psoriasis and viral hepatitis might have pathophysiological events in common, where IL-12 and IL-23 promote pathogenic pathways in both diseases. Investigating such pathogenic pathways may help explain the relationship between HCV infection and psoriasis.
In the current study, we compared the serum levels of IL-12 and IL-23 in psoriatic patients with and without concomitant hepatitis C and investigated their relationship with both disease processes.
Patients and methods
During the period from January to December 2013, all patients with a diagnosis of chronic plaque type psoriasis, who visited the Dermatology Outpatient Clinic at our hospital, were evaluated for eligibility for this study.
Type of study
This was designed as a case–control comparative study.
Exclusion criteria included being less than 18 years of age, having systemic or other dermatological diseases affecting the immune system, receiving systemic therapy or phototherapy during the last 6 weeks, evidence of concurrent hepatitis B virus (HBV) or HIV infection, receiving anti-HCV treatment (including IFN) during the last 6 months, and refusal to participate in the study. Finally, 49 patients (36 men and 13 women) who met the study criteria were enrolled in the study; no selected patients refused to participate. They included 14 HCV-positive and 35 HCV-negative patients. In addition, a group of 49 age-matched and sex-matched controls, selected from individuals attending for cosmetic procedures at our department, were included. They were HIV/HBV/HCV negative, had no diagnosis of psoriasis, or a history, clinical, or routine laboratory findings consistent with hepatitis. They were matched for age (±2 years) and sex (36 men and 13 women) to avoid potential sources of bias. The study was approved by our institutional ethical review board. Informed consent was obtained from all patients and controls participating in the study, in accordance with the Helsinki Declaration.
All patients were subjected to full history taking, general examination, and dermatological examination. Data including age, sex, disease duration, and previous treatment were recorded. Assessment of psoriasis severity was done, using psoriasis area and severity index (PASI) score, by the same observer who was blinded to the HCV status of the evaluated patients 18.
Venous blood samples (5 ml) were obtained from all participants. Samples were centrifuged and the separated sera were subdivided into small aliquots to be stored at −80°C until used for analysis. Sera of patients and controls were assessed for liver enzyme levels; aspartate aminotransferase (AST) and ALT and serological tests for HCV were carried out. Serum levels of IL-12 and IL-23 were measured.
Serum AST and ALT levels were measured using the Boehringer Mannheim/Hitachi 911 analyzer (reference value of ALT up to 41 U/l for men and up to 33 U/l for women and AST up to 40 U/l for men and up to 32 U/l for women).
Serological tests for HCV infection were performed using the ARCHITECT system for anti-HCV, which is a chemiluminescent microparticle immunoassay for the qualitative detection of antibodies to HCV (anti-HCV) in human serum and plasma (Abbott GmbH, Wiesbaden-Delkenheim, Germany). A positive anti-HCV result was defined by signal-to-cutoff ratio of greater than or equal to 5, which is predictive of a true antibody-positive result (as defined by the results of supplemental testing) greater than or equal to 95% of the time.
IL-12 and IL-23 levels were assayed using the enzyme-linked immunosorbent assay (ELISA) kits. IL-12 was measured using the Human IL-12(P70) RayBio ELISA Kit (RayBiotech, Inc., Norcross, Georgia) (cat#: ELH-IL12P70-001). Human IL-23 ELISA Kit (CK-E10077; Glory Science, Del Rio, Texas, USA), was used to measure IL-23. The experimental procedures were performed according to manufacturers’ instructions. Blinding for cases and controls was done at the time of laboratory assessment.
Data were verified, coded by the researcher, and analyzed using SPSS, version 21; 2012 (SPSS Inc., Chicago, Illinois, USA). For quantitative variables, means, SDs, medians, and interquartile range were used, and for qualitative variables, numbers and percentages were calculated. The χ2-test was used to compare the difference in distribution of frequencies among different groups. For continuous variables the Student t-test was carried out to compare the means of normally distributed data, whereas the Mann–Whitney U-test was used to test the median differences of the data that do not follow normal distribution. One-way analysis of variance with Bonferroni corrections for the P-value was carried out to compare the means of more than two groups. Stratification of confounding variables such as age (<40 and ≥40 years), duration of psoriasis (<10 and ≥10 years), and PASI (<10 and ≥10) was used, and the mean values of IL-12 and IL-23 levels were compared. Correlation analysis was used to test the association between variables (Spearman’s rank correlation). P-values were considered significant when they were less than 0.05.
Of an initial sample of 72 patients with clinical diagnosis of psoriasis, 57 patients who met the study criteria were included. Fifteen patients were excluded from the study: 12 receiving systemic therapy and/or phototherapy, one with HBV infection, and two HCV-positive patients receiving IFN therapy. Another eight patients with missing data were excluded from the analysis. Finally, 49 psoriatic patients (36 men and 13 women) with no missing data were analyzed.
They were of mean age 45.79±10.9 years (range: 23–76 years), had a median disease duration of 9 years (range: 0.5–50), and a median PASI score of 8.4 (range: 2–40.2 years). The control group included 49 age-matched and sex-matched participants (36 men and 13 women) who agreed to participate in the study. They were psoriasis-free, had normal liver enzymes, and negative serological tests. They were of mean age 45.75±10.7 years (range: 21–75 years). There were statistically nonsignificant differences in age (P=0.84) and sex (P=1) between the patients and controls.
Among the 49 studied patients, 14 (28.6%) patients having both psoriasis and HCV infection were identified (as detected by anti-HCV). The demographic and clinical data of HCV-positive and HCV-negative patients were compared (Table 1). There were no statistically significant differences between the two patient subgroups as regards age, sex, and psoriasis duration or severity. Although the median PASI score was higher in the HCV-positive group, it did not reach the significant level.
Serum liver tests revealed significantly higher levels of transaminases – AST and ALT – in the HCV-positive group (P<0.001) (Table 1). AST and ALT levels were raised in nine out of the 14 (64.3%) HCV-positive patients, whereas all patients in the HCV-negative group had normal liver enzyme levels.
Compared with controls, patients with psoriasis had significantly higher serum levels of IL-12 (29.66±6.82 vs. 36.31±12.77 pg/ml, respectively; P=0.004) and IL-23 (108.27±25.08 vs. 132.49±32.69 ng/l, respectively; P=0.001).
The serum IL-12 and IL-23 levels of the different subgroups of psoriasis patients categorized according to their sex, age (<40 and ≥40 years), duration of psoriasis (<10 and ≥10 years), and PASI scores (<10, ≥10) are summarized in Table 2. The duration of psoriasis was the only factor affecting serum IL-12 levels, as significantly higher serum levels of IL-12 were observed in patients with longer duration of psoriasis (P=0.026). However, psoriasis severity was the significant factor affecting serum IL-23 levels, which were significantly higher in patients with higher PASI scores (P=0.043).
Both HCV-negative and HCV-positive groups of psoriatic patients showed significantly higher levels of IL-12 and IL-23 compared with controls. However, comparing the two psoriasis subgroups, it was IL-23 only that was significantly elevated in HCV-positive compared with HCV-negative patients (P=0.026). In contrast, no significant difference was noted in serum IL-12 levels between the two subgroups (P=0.32) (Table 3).
It was also noticed that IL-23 was positively correlated with psoriasis severity (PASI) in all studied patients, as well as with ALT levels in HCV patients. However, no significant correlations were detected between IL-12 levels and psoriasis severity or between IL-12 and liver enzymes. Nevertheless, IL-12 was shown to be positively associated with duration of psoriasis, and with IL-23 level (Table 4).
To our knowledge, no published study has compared the serum IL-12 and IL-23 levels in psoriatic patients with and without hepatitis C. In the present study, significantly higher levels of IL-12 and IL-23 were noted in psoriatic patients compared with controls as well as in each of the patient subgroups compared with controls. IL-23 levels directly correlated with psoriasis severity. Psoriatic patients with concomitant HCV infection were found to have significantly higher levels of serum IL-23 compared with the HCV-negative subgroup. However, no significant difference in IL-12 levels was detected between HCV-positive and HCV-negative subgroups. Moreover, IL-23 showed a positive correlation with ALT levels.
HCV infection was reported in 28.6% of our studied cases of psoriasis, which is relatively higher than that in the general Egyptian population (∼14.7%) 5. Despite our small sample size, our results may support an association between the two conditions.
In accordance with our observations, a number of studies have reported an increased rate of HCV infection in psoriatic patients 1–3,6,8. Furthermore, a study on Egyptian patients reported the presence of HCV infection in 47.1% of psoriatic patients versus 19% of controls 19. In contrast, few studies did not detect such an association 20,21, probably due to the relatively low prevalence of HCV infection in their population.
On comparing HCV-positive and HCV-negative psoriatic patients, the median PASI scores were higher in the HCV-positive subgroup, but the difference did not reach the statistically significant level. A relationship between HCV infection and psoriasis severity has been observed in some studies 3,6; such an observation may need to be confirmed in a larger sample.
Interestingly, IL-12/IL-23 pathways, which have been known to play an important role in the pathogenesis of psoriasis 22,23, have been also found to be dysregulated in hepatitis C and may contribute to HCV-mediated inflammatory damage and progression of liver disease 15–17,24.
In the present study, higher serum levels of both IL-12 and IL-23 were detected in psoriatic patients compared with controls, but only IL-23 showed a significant positive correlation with PASI scores. Therefore, the severity of psoriasis is probably directly related to the level of IL-23. It has been suggested that IL-23, through its influence on the expansion of Th17 cells, plays a dominant role in the maintenance and amplification of inflammation in psoriasis 23.
Previous studies evaluating the serum IL-12 levels in psoriasis have yielded inconsistent results; some demonstrated increased serum IL-12 25,26, whereas other studies showed no increase in IL-12 27,28.
In agreement with our observations, multiple studies 27,29 suggested that IL-23 rather than IL-12 plays a pivotal role in the pathogenesis of psoriasis. Increased expression of both IL-12/IL-23 p40 and IL-23 p19 has been detected in psoriasis, with no elevation of IL-12 p35 29. In addition, the clinical improvement of psoriasis by various therapies has been shown to correlate with IL-17 and IL-23 downregulation 30,31.
IL-23 was significantly elevated in the HCV-positive subgroup compared with the HCV-negative subgroup with no statistically significant difference in IL-12 levels between the two subgroups. This may suggest that IL-23 is more likely to be modulated by the presence of HCV infection.
Moreover, we found a positive correlation of IL-23 with serum ALT levels in hepatitis C patients. ALT is a commonly used indicator of liver inflammation. Accordingly, IL-23 seems to be involved in the inflammatory process during HCV infection. In contrast, IL-12 was not significantly changed by the presence of HCV infection and showed no correlation with liver enzymes.
There are conflicting data in the literature regarding the expression of IL-12 in hepatitis C. Some studies stated that IL-12 stimulates Th1 response, which is required for host defense and viral clearance 32. This was evident by higher serum levels of IL-12 in association with ALT normalization and clearance of viremia, observed after anti-HCV therapies 33,34. Another study also suggested that HCV induces upregulation of IL-23 expression while inhibiting the production of IL-12 and thereby favors viral persistence and autoimmune inflammation during HCV infection 35. In contrast, other studies reported increased expression of IL-12 in hepatitis C, which showed correlation with the severity of hepatic affection 15,24. A potential explanation for this conflict is that the latter studies probably used the p40 subunit for IL-12 assay. Being shared by IL-23, the high p40 subunit levels detected might be attributed to the rise in IL-23 rather than IL-12.
Recent case reports have suggested that ustekinumab, a monoclonal antibody to the p40 subunit common to IL-12 and IL-23 (IL-12/23p40), may represent a successful therapeutic strategy for psoriasis with chronic hepatitis C without causing aggravation of hepatitis 36,37. In this regard, evolving therapies blocking the unique IL-23p19 and sparing IL-12 38 could be an attractive treatment option for those patients.
In the present study, the correlation of IL-12 with the duration of psoriasis as well as with IL-23 level may indicate that IL-12 is more likely produced late in the setting of long-term chronic inflammation and may be involved in maintaining the inflammatory state in psoriasis.
In conclusion, we observed an increased rate of HCV infection in psoriatic patients, as well as significant positive correlation of IL-23 with both PASI scores and ALT levels in such patients. Our findings do provide preliminary evidence that overproduction of IL-23 might be amplified in the presence of both psoriasis and HCV infection. It is possible that the presence of HCV could trigger psoriasis through the upregulation of IL-23, leading to the appearance or flare of preexisting psoriasis in individuals with certain predisposition. In this regard, IL-23 could be a potential therapeutic target in patients with the two coexisting disorders, especially in those with severe psoriasis.
A limitation of the present study is the relatively small sample size. In addition, this study could not detect the temporal sequence for psoriasis and hepatitis C. Further studies on a larger population of patients are required to assess the effect of HCV on IL-23, as well as on other ILs such as IL-17, in psoriasis and to elucidate the possible common pathogenic pathways linking psoriasis and hepatitis C and their potential therapeutic applications.
The authors are grateful to all paramedical personnel and technicians who aided in this research.
Conflicts of interest
There are no conflicts of interest.
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