New markers of oxidative stress in lichen planus and the influence of hepatitis C virus infection - a pilot study.

Introduction. Lichen planus (LP) is a mucocutaneous T-cell mediated disorder of unknown etiology. There is growing evidence that oxidative stress is an important player in the pathogenesis of LP. Therefore, we have investigated oxidative stress markers in LP and the influence of hepatitis C virus (HCV) infection, a frequently associated condition, on oxidative stress in LP patients. Method. We have determined the serum levels of 4- hydroxynonenal (4-HNE) and symmetric dimethylarginine (SDMA), as markers of oxidative stress, and total antioxidant capacity (TAC), as a marker of the antioxidant defence, in 4 groups: group A - HCV positive patients with LP (n=12), group B - HCV positive patients without LP (n=12), group C - HCV negative patients with LP (n=31) and group D - control group (n=26). Results. In LP patients, we have identified an increased level of lipid peroxidation (4-HNE - group A - 8.41±1.11 µg/mL, group B - 7.97±2.17 µg/mL, group C - 7.81±1.96 µg/mL and group D - 6.15±1.17 µg/mL) and alterations in arginine methylation (SDMA - group A - 1.10±0.24 µmol/L, group B - 1.03±0.16 µmol/L, group C - 0.84±0.19 µmol/L and group D - 0.50±0.06 µmol/L) associated with a diminished antioxidant defence (TAC - group A - 234.50±49.96, µmol/L group B - 255.83±41.41 µmol/L, group C - 269.83±43.33 µmol/L and group D - 316.46 ±29.33 µmol/L), processes augmented by the association with HCV infection. Conclusion. There is an imbalance between oxidants and antioxidants in patients with LP, an imbalance that is augmented by the presence of HCV infection. SDMA could be regarded as a novel biomarker of oxidative stress among these patients. To the best of our knowledge this is the first study to investigate the influence of HCV infection on oxidative stress in LP patients.

Epstein-Barr virus is not detected in mucosal lichen planus.

BACKGROUND: Lichen planus (LP) is a chronic inflammatory, immunological, mucocutaneous disease can affect skin, genital and oral mucosa. Oral lichen planus (OLP) is the most common noninfectious, chronic inflammatory oral disease affecting 1-2% of the general adult population. World Health Organization (WHO) classifies OLP as a potentially malignant disorder. Epstein Barr virus or human herpesvirus-4, is a member of the herpes virus family and one of the most ubiquitous viruses known to human, infecting approximately 90% of the world's adult population. The virus often infects B lymphocytes resulting in a wide spectrum of mucocutaneous and systemic diseases, ranging from mild lesions to aggressive malignancies. The aim of this study was to investigate expression of the EBV encoded RNAs EBER1 and EBER2 in oral and genital lichen planus and compare results with normal tissues in situ hybridization which is considered the golden standard for detection of EBER. MATERIAL AND METHODS: A total of 68 biopsies, 25 oral LP, 26 genital LP, 10 oral controls and finally 7 genital controls were analysed using situ hybridization. RESULT: All samples had RNA as shown by the control slide, whereas no case contained neither EBER1 nor EBER2. CONCLUSIONS: Based on results from our study EBV is not involved in aetiology of lichen planus.

Dermatologic Manifestations of Chronic Hepatitis C Infection.

Chronic hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, including dermatologic involvement mostly caused by immune complexes. Mixed cryoglobulinemia has a strong relationship with HCV with 95% of these patients being infected with HCV. Lichen planus is a disease of the squamous epithelium and may affect any part of the skin, with 4% to 24% of patients with lichen planus reported to have chronic HCV infection. Porphyria cutanea tarda is the most common form of porphyria, and it is thought that HCV interferes with iron stores, which can promote porphyria cutanea tarda. Finally, necrolytic acral erythema is a rare, psoriasis-like disease closely associated with HCV.

Hepatitis C virus and its cutaneous manifestations: treatment in the direct-acting antiviral era.

New all-oral direct-acting antivirals (DAA) have changed the hepatitis C virus (HCV) treatment landscape. Given that dermatologists frequently encounter HCV-infected patients, knowledge of the current treatment options and their utility in treating HCV-associated dermatologic disorders is important. In addition to highlighting the new treatment options, we review four classically HCV-associated dermatologic disorders - mixed cryoglobulinaemia (MC), lichen planus (LP), porphyria cutanea tarda (PCT) and necrolytic acral erythema (NAE) - and examine the role for all-oral direct-acting antiviral (DAA) regimens in their treatment. A literature search of English-language publications was conducted of the PubMed and EMBASE databases using search terms including 'hepatitis C', 'direct acting antivirals', 'cutaneous', 'mixed cryoglobulinemia', 'necrolytic acral erythema', 'lichen planus', 'porphyria cutanea tarda', 'rash', as well as specific drug names, related terms and abbreviations. Currently, limited data exist on the use of DAAs in HCV-infected patients with cutaneous side-effects, although treatment of the underlying HCV is now recommended for nearly all patients, with the new drugs offering much-improved dosage schedules and side-effect profiles. The most data exist for MC, in which several studies suggest that DAAs and achievement of sustained virologic response (SVR) improve cutaneous symptoms. Studies of both older and newer regimens are limited by their small size, retrospective nature, lack of appropriate controls and wide variability in study protocols. Given the strong association, screening for HCV should be considered in patients with MC, LP, PCT and NAE.

Association of classic lichen planus with human herpesvirus-7 infection.

BACKGROUND: Lichen planus is a mucocutaneous papulosquamous itchy disease with unknown etiology. A number of factors such as immune mechanisms, viral agents, and drugs have been implicated in pathogenesis of lichen planus. In recent years, several studies have indicated the role of viral agents in this disease, including human herpesvirus-7 (HHV-7). Studies have given contradictory results, which is why we decided to study the possible association between lichen planus with HHV-7. METHODS: In this case-control study, which was conducted on 60 cutaneous classic lichen planus samples as well as 60 healthy control skin samples after matching the two groups in terms of gender and age, tissue samples of patients and controls were studied by real time polymerase chain reaction to detect for HHV-7. RESULTS: According to this study, HHV-7 DNA was found in 18 samples of the case group (30.0%) and in six (10.0%) of the control group (P = 0.006). CONCLUSION: The results of this study support the likely role of HHV-7 in pathogenesis of lichen planus. As an exogenous antigen, this virus may be involved in cellular immune-mediated destruction of keratinocytes.

Extrahepatic Manifestations of Hepatitis C: A Meta-analysis of Prevalence, Quality of Life, and Economic Burden.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has hepatic and extrahepatic manifestations with various costs and impairments to health-related quality of life (HRQL). We performed a meta-analysis to determine the prevalence of extrahepatic manifestations in patients with HCV infection, how these impair HRQL, and their costs. METHODS: We performed systematic reviews of the literature using MEDLINE, CINAHL, and the Cochrane Systematic Review Database, from 1996 through December 2014, to identify studies of the following extrahepatic manifestations of HCV infection: mixed cryoglobulinemia, chronic kidney or end-stage renal disease, type 2 diabetes, B-cell lymphoma, lichen planus, Sjögren's syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, or depression. We performed a separate meta-analysis for each condition to determine prevalence rates of extrahepatic manifestations of HCV infection and their effects on HRQL. We determined the annual costs (inpatient, outpatient, and pharmacy) associated with extrahepatic manifestations of HCV infection. RESULTS: In an analysis of data from 102 studies, we found the most common extrahepatic manifestations to be diabetes (in 15% of patients) and depression (in 25% of patients). HRQL data showed that HCV infection had negative effects on overall physical and mental health. Total direct medical costs of extrahepatic manifestations of HCV infection, in 2014 US dollars, were estimated to be $1506 million (range, $922 million-$2208 million in sensitivity analysis). CONCLUSIONS: In a systematic review and meta-analysis we determined the prevalence, risks, and costs associated with extrahepatic manifestations of HCV infection. These estimates should be added to the liver-related burden of disease to obtain a more accurate assessment of the total burden of chronic HCV infection. Prospective, real-world studies are needed to increase our understanding of the total clinical and economic effects of HCV infection and treatment on patients and society.

Frequency of FOXP3+ Regulatory T-cells in the Blood of Chronic Hepatitis C Patients with Immune Mediated Skin Manifestations; Relationship to Hepatic Condition and Viral Load.

BACKGROUND: Chronic hepatitis C (CHC) infection causes a wide range of immune mediated hepatic and extrahepatic manifestations. Cutaneous manifestations constitute a major portion of the latter group. Host immune response to the virus - particularly regulatory T lymphocytes - is important in determining the outcome of the infection and the possibility of extrahepatic manifestations. The present study aims to investigate the relationship between immune-mediated cutaneous manifestations of CHC infection and the frequency of CD4+CD25 high FOXP3+ T regulatory lymphocytes. We also investigated the relationships to viral load and hepatic conditions. METHODS: A total of 58 CHC patients (30 had cutaneous manifestations and 28 did not) and 30 healthy HCV free subjects were enrolled in this study. The frequency of CD4+CD25 high FOXP3+ Treg cells was measured in the peripheral blood of all participants. Additionally, serum ALT, RNA viral load, and hepatic ultrasonographic studies were performed for all patients. RESULTS: Skin manifestations were dominated by small vessel vasculitis and to a lesser extent lichen planus. Treg cell frequency was significantly lower in CHC patients with skin manifestations compared to those without. Chronic hepatic insult was significantly more common among patients with skin manifestations, although serum ALT levels were significantly lower in this group. Treg frequencies did not correlate to either ALT level or viral load. CONCLUSIONS: HCV-associated skin lesions are associated with low frequency of Treg cells. They are not related to liver enzymes or viral load; however, they are associated with a more advanced gross liver insult.

Human endogenous retrovirus expression is inversely related with the up-regulation of interferon-inducible genes in the skin of patients with lichen planus.

Lichen planus (LP) is a common inflammatory skin disease of unknown etiology. Reports of a common transactivation of quiescent human endogenous retroviruses (HERVs) support the connection of viruses to the disease. HERVs are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancer and autoimmune diseases. We explored the transcriptional activity of HERV sequences as well as the antiviral restriction factor and interferon-inducible genes in the skin from LP patients and healthy control (HC) donors. The study included 13 skin biopsies from patients with LP and 12 controls. Real-time PCR assay identified significant decrease in the HERV-K gag and env mRNA expression levels in LP subjects, when compared to control group. The expressions of HERV-K18 and HERV-W env were also inhibited in the skin of LP patients. We observed a strong correlation between HERV-K gag with other HERV sequences, regardless the down-modulation of transcripts levels in LP group. In contrast, a significant up-regulation of the cytidine deaminase APOBEC 3G (apolipoprotein B mRNA-editing), and the GTPase MxA (Myxovirus resistance A) mRNA expression level was identified in the LP skin specimens. Other transcript expressions, such as the master regulator of type I interferon-dependent immune responses, STING (stimulator of interferon genes) and IRF-7 (interferon regulatory factor 7), IFN-ß and the inflammassome NALP3, had increased levels in LP, when compared to HC group. Our study suggests that interferon-inducible factors, in addition to their role in innate immunity against exogenous pathogens, contribute to the immune control of HERVs. Evaluation of the balance between HERV and interferon-inducible factor expression could possibly contribute to surveillance of inflammatory/malignant status of skin diseases.

Lichen planus-like lesions as the first manifestation of adult T-cell leukaemia/lymphoma.

Cutaneous involvement is frequent in adult T-cell leukaemia/lymphoma (ATLL), a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus type I (HTLV-I). Patients with ATLL manifest different types of skin lesions, including nodules, plaques, ulcers, erythroderma and purpura. It has been reported that this type of skin eruption is an independent prognostic factor for ATLL. We report here a rare case of a 62-year-old Japanese woman with smouldering-type ATLL, first manifested by lichen planus-like skin lesions on the lower leg. This case report highlights the multiplicity of skin manifestations in ATLL.

Detection of varicella-zoster virus antigens in lesional skin of zosteriform lichen planus but not in that of linear lichen planus.

BACKGROUND: Distinctions between 'linear lichen planus' (LP) and 'zosteriform LP' are difficult to determine solely based on clinical findings. OBJECTIVE: The aim of this study is to determine whether the presence of the varicella-zoster virus (VZV) antigens could be used to differentiate the zosteriform LP from the linear LP. METHODS: We immunohistochemically investigated the presence of in vivo localization of VZV antigens in 8 LP lesions (zosteriform LP: n = 5, linear LP: n = 3). RESULTS: We describe 2 cases of zosteriform LP without apparent prior episodes of herpes zoster, in whom VZV antigens were detected in the eccrine epithelium. Further analysis showed that VZV antigens were exclusively detected in the eccrine epithelium in the zosteriform LP lesions, but not in the linear LP lesions. CONCLUSION: Etiological differences exist between zosteriform LP and linear LP. The presence of VZV antigens in lesional skin of the former indicates a possible triggering role of this virus in the pathogenesis of this variant.

Comparison of diversity of torque teno virus 1 in different mucosal tissues and disorders.

Diversity of TTV1 was assessed in the head and neck region in patients with potentially malignant (oral lichen planus, oral leukoplakia) and malignant lesions (oral and laryngeal squamous cell cancers) and was compared to that found in the uterine cervix (cervical atypia and cervical cancer) by directly sequencing the NG061-063 segment of ORF1. These sequences were classified by the formerly used genogroup-genotype system as well as by the newly accepted species classification by aligning with the corresponding region of the type sequences of the 29 TTV species. All sequences obtained during the study clustered together with the TTV1 type sequence; to express diversity within TTV1, genotypes and subtypes of the former classification were used.The commonest subtypes were 2c followed by 2b, 1a and 1b. Subtypes 2b and 2c were evenly distributed among cervical samples; subtype 1a was more frequent in patients with cervical atypia or cancer. Subtypes 2c was more frequent than 2b in head and neck lesions. In conclusion, genotype and even subtype distribution may be important in association with diseases, therefore using this classification for characterization of intraspecies diversity of TTV1 is proposed.

Penile carcinogenesis in a low-incidence area: a clinicopathologic and molecular analysis of 115 invasive carcinomas with special emphasis on chronic inflammatory skin diseases.

BACKGROUND: Human papillomavirus (HPV) infections account worldwide for 50% of penile cancers. The role of lichen sclerosus and lichen planus in penile carcinogenesis needs further investigation. MATERIALS AND METHODS: Archival formalin-fixed high-grade penile intraepithelial neoplasias, differentiated penile intraepithelial neoplasias, and invasive carcinomas from a single pathology institution in a low-incidence area for penile cancer were analyzed for 28 HPV low-risk and HPV high-risk genotypes, p16 overexpression, presence of peritumoral lichen sclerosus, lichen planus, precursor lesions, and monoclonal rearrangement of the T-cell receptor γ locus. RESULTS: A total of 29 penile intraepithelial neoplasias (100%) and 69 of 115 (60%) invasive cancers contained HPV high-risk genotypes with a single HPV high-risk genotype (80% HPV16, 6% HPV33, 2% HPV45 and HPV18, 1% HPV73). Multiple HPV high-risk genotypes were identified in 4% with and in 5% without HPV16/18. p16 overexpression correlated in all but 1 case of HPV high-risk 45 cancer. No p16 overexpression and HPV genotype was found in 6 differentiated penile intraepithelial neoplasias and 46 of 115 (40%) invasive cancers, 30% of which were pT2/pT3 cancers. For 35 cancers, peritumoral tissue was available for analysis. Advanced lichen sclerosus was identified in 26, lichen planus in 9, and differentiated penile intraepithelial neoplasia in 18 carcinomas. Dense T-cell-dominant lymphocytic infiltrates were identified in 22 of 46 carcinomas and in 3 of 6 differentiated penile intraepithelial neoplasias, with 6 of 13 analyzed carcinomas/penile intraepithelial neoplasias showing a monoclonal rearrangement of the T-cell receptor γ locus. CONCLUSIONS: The prevalence of HPV high-risk in penile cancers from a low-incidence area was slightly higher than the global distribution. HPV-negative carcinomas were associated with advanced lichen sclerosus and lichen planus, differentiated penile intraepithelial neoplasia, and accumulation of T lymphocytes with monoclonal rearrangement of the T-cell receptor γ locus.

Skin diseases associated with hepatitis C virus: facts and controversies.

Hepatitis C virus (HCV) is a common infectious agent and may induce several systemic disorders like mixed cryoglobulinemia. In the geographic areas where HCV infection is hyperendemic, HCV is the predominant etiologic factor for porphyria cutanea tarda and lichen planus. Vasculitides and autoimmune disorders, such as sicca syndrome, are probably often related to the virus. Interferon-a2b, which is largely used in the treatment of HCV-positive patients, may induce cell-mediated autoimmune side effects. Dermatologists may help to identify those patients timely.

Hepatitis C virus infection and lichen planus: a systematic review with meta-analysis.

OBJECTIVE: Hepatitis C virus (HCV) is one of the major causes of chronic liver disease worldwide but its morbidity is also due to a variety of extra-hepatic manifestations including mixed cryoglubulinemia, non-Hodgkin lymphoma, diabetes, porphyria cutanea tarda and lichen planus. The aims of this study were to conduct a systematic review and a meta-analysis on the prevalence of HCV in lichen planus patients and on the prevalence of lichen planus in chronic HCV infection. MATERIALS AND METHOD: Bibliographic searches were conducted in several electronic databases. Pooled data were analysed by calculating odds ratios, using a random effects model. RESULTS AND CONCLUSIONS: Thirty-three studies comparing the seroprevalence of HCV in lichen planus patients and six reporting the prevalence of lichen planus in patients with HCV infection were included in the meta-analysis. The summary estimate showed that LP patients have significantly higher risk (odds ratio 4.85; 95% confidence interval 3.58-6.56) than controls of being HCV seropositive. A similar odds ratio of having lichen planus was found among HCV patients (4.47; 95% confidence interval 1.84-10.86). Sub-analyses indicated that variability of HCV/lichen planus association seemed only partially depending on geographic effect.

Detection of myxovirus resistance protein A in lichen planus lesions and its relationship to hepatitis C virus.

BACKGROUND: Lichen planus (LP) is an inflammatory disease of the skin and oral mucosa. Studies suggested that type I interferons (IFNs) could play an important role in the cytotoxic inflammation in LP. Type I IFNs stimulate the production of several IFN-induced proteins including myxovirus resistance protein A (MxA protein). The association of LP and chronic hepatitis C is well established, with variable prevalence rates among different populations. Many authors have considered hepatitis C virus (HCV) as a possible antigen for inducing cytotoxic immune response in LP. OBJECTIVES: To investigate the role of type I IFNs in LP through the detection of MxA protein, and to compare the expression of MxA protein between HCV-positive and HCV-negative patients with LP in an attempt to clarify the role of HCV in the pathogenesis of LP. METHODS: The study included 33 skin biopsies from patients with LP and 10 control biopsies. MxA mRNA was detected by reverse transcription-polymerase chain reaction. HCV-specific antibodies were detected in patient sera by enzyme-linked immunosorbent assay. RESULTS: Our analysis revealed a significantly higher level of MxA protein in all the LP skin biopsies compared with controls. The expression was significantly higher in HCV-positive patients than in HCV-negative patients. CONCLUSIONS: Type I IFNs play a role in the pathogenesis of LP, and HCV could induce LP through increasing the production of type I IFNs.

Lichen planus and other cutaneous manifestations in chronic hepatitis C: pre- and post-interferon-based treatment prevalence vary in a cohort of patients from low hepatitis C virus endemic area.

BACKGROUND: Several controversies exist regarding the relationship between hepatitis C virus (HCV) infection and some cutaneous manifestations, lichen planus (LP) in particular. OBJECTIVES: To determine the prevalence of LP and other cutaneous manifestations in a cohort of patients infected with HCV from low HCV endemic area of Slovenia, to correlate findings with chosen biological variables and to assess the role of interferon (IFN)-based treatment of HCV infection in cutaneous manifestations. Methods A total of 171 consecutive HCV-seropositive patients and 171 HCV-seronegative age- and gender-matched controls were studied prospectively. Prevalence of cutaneous manifestations, comparison between study patients and controls and correlation of skin findings with demographic, biochemical, virological and liver histologic findings as well as IFN-based therapy were assessed. RESULTS: Overall presence of LP in HCV-seropositives was 2.3%; although LP was not found in controls, the difference was not statistically significant (P = 0.123). Significantly higher than in controls was the prevalence of pruritus (31.0%, P < 0.001), dry skin (16.4%, P < 0.001) and hair loss (9.9%, P < 0.001). In IFN-based treatment naïves, skin findings were more frequent compared with controls, but not significantly, with no correlation to chosen biological variables. Current IFN-based treatment was significantly connected to pruritus (P < 0.001) and dry skin (P < 0.001). Compared with treatment naïves, in post-treated patients pruritus (odds ratio, 19.13; 95% confidence interval, 6.85-53.42; P < 0.001), dry skin (odds ratio, 4.21; 95% confidence interval, 1.44-12.31; P < 0.001) and hair loss (P < 0.001) were significantly more common. CONCLUSIONS: LP was not significantly related to HCV infection. Prevalence of pruritus, dry skin and hair loss was significantly higher in post-compared with pre-treated patients. The role of IFN in post-treatment persistence of skin manifestations needs to be assessed.

Detection of human papillomavirus in oral squamous cell carcinoma, leukoplakia and lichen planus in Thai patients.

Although tobacco, alcohol abuse and betel nut chewing habit are well recognized risk factors for oral squamous cell carcinoma (OSCC), there is evidence to indicate that human papillomavirus (HPV) may also play some inducing role. The purpose of this study was to investigate the presence of HPV in Thai patients with oral squamous cell carcinoma, leukoplakia and lichen planus using the polymerase chain reaction (PCR). Biopsies of oral squamous cell carcinoma, leukoplakia and lichen planus were obtained from 65 patients, 15 males and 50 females, aged between 30- 88 years old. Extracted DNA was evaluated for HPV infections by PCR analysis using consensus primers specific for L1 region of HPV. Only one sample (1.54%) was positive, suggesting that HPV may not play an important role in this group of Thai patients.

Lack of evidence for hepatitis C virus infection in association with lichen planus.

BACKGROUND: The association between hepatitis C virus (HCV) infection and lichen planus (LP) is a subject of controversy. Prevalence studies of HCV infection in LP patients in various countries reveal diverse results. The Slovenian population is rather homogenous with specific geographic and epidemiological characteristics. Lack of data or contradictory results from neighboring countries urged the need for a case-controlled study in our LP patients. METHODS: The retrospective study was performed on 173 LP patients. Control group included 218 patients with dermatological diseases other than LP. RESULTS: Anti-HCV antibodies were found in 2/173 patients (1.2%) with LP and in 0/218 controls. No statistically significant difference was found between the study and control group regarding anti-HCV antibody prevalence (P = 0.195; estimated OR 6.4, 95% CI 0.3-134.0) and risk factors for HCV infection. CONCLUSIONS: Based on our results, anti-HCV antibody testing is not necessarily required in LP patients with no risk factors for HCV infection in this geographic region.