Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions.

Background: Cutaneous lupus erythematosus (CLE) is an interferon (IFN) -driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Methods: Lesional skin of patients with different CLE subtypes and healthy controls (N = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated in vitro using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed in vivo using an established lupus-prone mouse model. Results: Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE in vitro models and also improves skin lesions in lupus-prone TREX1-/- -mice markedly. Conclusion: IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1-/- -mouse model and appears to be a promising therapeutic approach for CLE patients.

Tofacitinib for the treatment of lichen planopilaris: A case series.

Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia for which many different therapies are attempted with varying success. The Janus kinase (JAK) inhibitor, tofacitinib, has been shown to be effective in treating the noncicatricial alopecia, alopecia areata. As in alopecia areata, upregulation of interferon and JAK signaling may play a role in LPP. We retrospectively reviewed the cases of 10 patients with recalcitrant LPP who were treated with oral tofacitinib. Patients received oral tofacitinib 5 mg twice or three times daily for 2-19 months as either monotherapy or adjunctive therapy to other ongoing treatments including intralesional triamcinolone, hydroxychloroquine, and tacrolimus ointment. Eight patients had clinical improvement in LPP with tofacitinib as either monotherapy (4/10) or adjunctive therapy (4/10). LPP Activity Index (LPPAI) before and after treatment was measured in seven patients and was significantly different (6.22 before treatment, 3.08 after treatment; p value = .0014). Reduction in LPPAI ranged from 30 to 94%. One patient complained of 10 pound (4.5 kg) weight gain after 12 months on tofacitinib. No other adverse effects were reported. Treatment with oral tofacitinib either as monotherapy or adjunctive therapy can lead to measurable improvement in recalcitrant LPP.

Measurement of serum monoamine oxidase in lichen planus patients and its clinical significance.

OBJECTIVE: To study the role of serum Monoamine oxidase (MAO) in Lichen planus(LP). METHODS: 82 cases of Lichen planus patients and 35 healthy controls were selected in the investigation. The total serum MAO levels were measured. RESULTS: The levels of serum MAO in Lichen planus patients were significantly higher than those in healthy controls (P<0.01). The severity of Lichen planus was not correlated with serum MAO levels (r =0.4873, t=0.73, p>0.05). CONCLUSION: According to the findings, there might be a coincidence of MAO and lichen planus. However, further studies are required to clarify the immunological mechanisms which are responsible for MAO synthesis during immunoreaction.

Antioxidant status in patients with lichen planus.

BACKGROUND: Lichen planus (LP) is an autoimmune inflammatory disease of the mucocutaneous tissue, whose exact pathological course is not yet understood. Many studies have implicated the role of reactive oxygen species (ROS) and the protective role of antioxidants in several autoimmune skin disorders. In this study, serum levels of antioxidants in patients with LP were determined and compared with those of healthy controls. METHODS: In total, 30 patients with LP (mean ± SD age 41.63 ± 13.03), who had never received treatment for their disease, were enrolled; 30 healthy people (aged 41.17 ± 13.24) were recruited as the control group. Serum levels of glutathione peroxidase (GPX), vitamin C, selenium, bilirubin and uric acid were determined. RESULTS: The mean plasma level of vitamin C was significantly lower (P < 0.001) in patients compared with controls. A significant positive correlation was found between selenium and GPX in both patients (Spearman ρ = 0.99, P < 0.001) and controls (ρ = 0.10, P < 0.001). CONCLUSIONS: Lower serum levels of vitamin C in patients with LP indicates that free radicals and the resulting oxidative damage may be important in the pathogenesis of LP lesions.

The potential role of c-Jun activation in patients with cutaneous lichen planus.

c-Jun, a component of the activating protein-1 transcription factor family, has been known to play an important role in the control of cell proliferation. It is also suspected to be a critical mediator of tumor promotion. However, investigations of c-Jun activation patterns in inflammatory and inflammatory transforming skin diseases have not been described so far. In this work, we show the c-Jun activation pattern in skin samples of patients with cutaneous lichen planus (LP), squamous cell carcinoma (SCC), psoriasis and normal skin using an immunohistochemical approach and Western blot analysis. In addition, we studied the c-Jun activation pattern in histological samples of three patients in whom LP transformed to SCC. We show that c-Jun is rarely activated in normal skin and psoriasis in contrast to LP and SCC. Our results suggest that c-Jun activation in human skin is involved in (1) proliferation and (2) could potentially participate in the transformation of LP from an inflammatory to a carcinogenic state. Nevertheless, JNK1/2, an important c-Jun activating kinase, was not found to be differentially regulated in LP and SCC compared with normal skin.

Liver enzymes in Nigerians with lichen planus.

INTRODUCTION: Lichen planus has been reported in association with liver diseases. Clinical signs such as jaundice may not be reliable indicator of ongoing inflammation or the presence of an ongoing liver disease. Liver function test in spite of its variability may serve as a more reliable indicator of liver disease. The objective of this study is to assess the discriminant power of liver enzymes with lichen planus and control. METHODS: Sixty Nigerians with lichen planus (LP group) and 30 patients with other dermatoses control group A) and 30 apparently normal individual (control group B) had their liver enzymes assayed using the automated Hitachi 70 auto-analyzer. RESULT: There was no a statistically significant difference in the level of liver enzymes between the LP group and controls. CONCLUSION: Liver enzymes in Nigerian with lichenplanus are generally within normal limits and are comparable to individuals without lichen planus.

Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation?

Recent studies have provided evidence that a type I interferon (IFN)-driven immune response might play an important role in the pathogenesis of lichen planus (LP), an inflammatory disorder of the skin of unclear etiology. Plasmacytoid dendritic cells in affected skin from LP have been proposed to produce IFN-alpha/beta locally, which leads to the expression of IFN-inducible chemokines such as IP10/CXCL10 in the epidermis. This chemokine recruits chemokine receptor CXCR3-expressing T-lymphocytes into the skin via CXCR3/IP10 interactions. Indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan and suppresses T-cell proliferation, is induced by IFNs and other inflammatory cytokines. We show that type I IFN-mediated skin disorders, such as LP, strongly express IDO in lesional skin. This expression closely correlates to the expression of the highly specific type I IFN marker MxA. We further demonstrate that the IDO+ cells in LP are large myeloid CD11c+S100+CD68(-) dendritic cells. Accordingly, CD11c+ antigen-presenting cells significantly up-regulate IDO gene expression and intracellular IDO protein expression after stimulation with IFN-alpha in vitro. These findings reveal that both proinflammatory and counterregulatory mechanisms are operative in cutaneous lesions of LP. We propose that the balance of these mechanisms may be involved in the pathogenesis of this disorder.

Lipid peroxidation and antioxidant status in lichen planus.

BACKGROUND: Lichen planus (LP) is an inflammatory skin disease of unknown aetiology. Recently, increased oxidative stress has been implicated in the pathogenesis of various skin diseases such as atopic dermatitis, psoriasis vulgaris and vitiligo. AIM: To evaluate the status of the oxidative stress and antioxidant defence system in patients with LP. METHODS: In total, 40 patients with LP (23 men, 17 women; mean +/- SD age 43.27 +/- 1.96 years) and 40 control subjects, matched for age and gender, were enrolled in this prospective study. The exclusion criteria included medication with immunosuppressive agents, history of trauma and surgery, and history of alcohol ingestion for at least 1 month prior to the study. The serum nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD) levels and the erythrocyte catalase (CAT) levels were investigated in both groups. RESULTS: Mean +/- SD levels of serum NO (74.60 +/- 17.96 micromol/L) and MDA (18.24 +/- 5.21 micromol/L) in patients with LP were higher than those of the control group (P = 0.007 and P = 0.031, respectively). Serum SOD levels (18.19 +/- 3.71 U/mL) in patients with LP were also higher than in healthy controls (P = 0.002). In contrast, erythrocyte CAT levels (13 557.80 +/- 4134.42 U/kg haemoglobin) were significantly lower in the patient group than in the control group (P = 0.009). CONCLUSIONS: The findings of this study suggest that increased oxidative stress, increased lipid peroxidation and an imbalance in the antioxidant defence system may be involved in the pathogenesis of LP.

Serum and tissue angiotensin converting enzyme in patients with lichen planus.

Serum and tissue angiotensin-converting enzyme (ACE) was measured in 20 patients with lichen planus before and after therapy, and in 20 healthy individuals. Serum and tissue ACE activity was determined by spectrophotometric method using hippuryl-l-histidyl-l-leucine as a substrate. The enzyme activity is expressed in the following units: 1 U corresponds to 1 nmol of hippuric acid released by hydrolysis of hippuryl-l-histidyl-l-leucine per minute and one liter of serum or 50 mg tissue. Before therapy, serum ACE activity was significantly increased in patients with lichen planus (35.9 +/- 2.33 U/L) in comparison to healthy individuals (28.16 +/- 1.7 U/L). Tissue ACE activity was increased in patients with lichen planus (2.24 +/- 0.41 U/50 mg) in comparison to healthy individuals (1.86 +/- 0.16 U/50 mg), but the difference was not significant. After therapy, serum and tissue ACE activity decreased and no significant difference in ACE activity was found. The determination of serum ACE activity may be a good non-specific parameter for the assessment of therapeutic effects.

Decreased antioxidant enzyme expression and increased oxidative damage in erosive lichen planus of the vulva.

The aim of this study was to investigate whether increased oxidative stress occurs in erosive lichen planus of the vulva. Skin biopsies from six patients with untreated, histologically confirmed erosive lichen planus of the vulva were examined immunohistochemically using antibodies against antioxidant enzymes. The protein-bound lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenale (4-HNE) and the oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were investigated. Protein carbonyls as markers of protein oxidation were visualised using the dinitrophenylhydrazone (DNPH) method. Normal vulval tissues from 12 subjects served as controls. In vulval lichen planus tissue the enzymatic antioxidant defence was found to be significantly decreased in the epidermal layers. Furthermore, a significant increase of lipid peroxidation products and oxidative DNA damage was found within the epidermis. Protein oxidation occurred predominantly in the papillary dermis. This is the first study to demonstrate a decreased antioxidant defence and increased oxidative damage to lipids, DNA and proteins in lichen planus. These oxidative modifications point to pathophysiological alterations mainly within the basal cell layers of the epidermis and at the dermoepidermal junction. Further studies are warranted to investigate the potential role of oxidative stress in the development of autoimmunity in this disease.

[Evaluation of clinical data and immuno-modulating treatment of patients with oral lichen planus]. / Lichenes betegeink klinikai adatainak feldolgozása és immunmoduláns kezelésük értékelése.

The number of patients with oral lichen planus increases all over the world. The treatment of this disease is not yet definitive. Although the etiology is not clear until now increasing number of data show relations between the environment and immune-responsiveness. In this study the data (medical history and laboratory test results) of 33 lichen oris patients were processed. The prevalence of diabetes mellitus was much higher in lichen patients, than in persons without lichen oris. Likewise, higher transaminase serum levels in lichen patients were found, and there were two HCV positive cases among them. In contrast to the literary data instead of immune suppressive treatment the immune modulant treatment has been applied: 78% of beta levamisole treated and 90% of interferon alpha treated patients were cured. Only lichen patients without symptoms of general diseases could be stabilized.

The activity of fatty acid synthase of epidermal keratinocytes is regulated in the lower stratum spinousum and the stratum basale by local inflammation rather than by circulating hormones.

The epidermal keratinocytes produce and secrete lipids to maintain the water barrier of the epidermis. To clarify the regulation of epidermal lipid synthesis, we investigated the hormonal effect on the activity of fatty acid synthase (FAS) of the keratinocytes, and the expression of FAS in the human skin. In cultured keratinocytes, the FAS activity, assayed by measuring the oxidation of NADPH, was slightly increased by hydrocortisone or testosterone, but not influenced by thyroid hormone, estrogen, progesterone or insulin. In immunohistochemical study of normal human epidermis, FAS was expressed strongly in the stratum granulosum and moderately in the uppermost layer of the stratum spinousum (SS), suggesting that fatty acid synthesis may increase during normal epidermal differentiation. In inflammatory disorders, such as psoriasis, lichen planus, and atopic dermatitis, FAS was also expressed in the lower SS and the stratum basale (SB), resulting in strong staining in the whole layers of the epidermis. Remarkable increase of FAS expression was only observed in the lower SS and the SB. Therefore, the activity of FAS in the epidermis may be regulated in the lower SS and the SB by local inflammation rather than by circulating hormones. In other components of the skin, FAS was strongly expressed not only in adipose tissue and sebaceous glands, which are known as active sites of lipid synthesis, but also in sweat glands, suggesting that the sweat glands can synthesize abundant fatty acids de novo.

Altered expression of basement membrane proteins and their integrin receptors in lichen planus: possible pathogenetic role of gelatinases A and B.

Lichenoid lesions of the skin are characterized by a band-like dermal inflammatory infiltrate and structural alterations of the basement membrane (BM). The etiopathogenesis of these lesions, of which lichen planus (LP) is perhaps the prototypic example, is unknown. Acute cases of LP are accompanied by the destruction of epidermal BM, degeneration of basal keratinocytes with loss of tonofilaments and hemidesmosomes, vesicular alterations, and even blister formation. Chronic LP is characterized by hyperkeratosis and acanthosis in the epidermis, fibrosis, and dense infiltrate in dermis. We found that acute LP lesions are characterized by uneven or absent immunostaining for laminin-5, laminin-1, and collagen type IV. Distribution and activity of gelatinases matrix metalloproteinase (MMP)-9 and MMP-2, and a specific inhibitor of MMP-2, tissue inhibitor of metalloprotein-2, were analyzed. The expression and activity of MMP-2 were increased, whereas tissue inhibitor of metalloprotein-2 expression was weak in the involved areas during the acute phase of LP. Moreover, we demonstrated in vitro that MMP-2 is directly capable of digesting laminin-5 gamma 2 chains to yield a 80-kd fragment. We also observed a weak or absent staining of all examined integrin receptors in the acute LP lesions. In chronic lesions, the staining of BM components was similar to normal controls. In these sections, normal expression of gelatinases and inhibitor was observed. There was, however, up-regulation and altered polarity of integrin receptors. These results indicate a link between overexpression of gelatinases, BM disruption, and altered integrin expression. In LP, the digestion of BM by MMP-2 may contribute to the pathogenesis by inducing altered integrin expression in basal keratinocytes and ultimately blister formation.

Clinical and histopathologic analysis of the relationship between lichen planus and chronic hepatitis C.

A prospective clinical investigation of 45 patients with lichen planus (LP) demonstrated a significant association between LP and chronic hepatitis C. Anti-hepatitis C virus (HCV) antibodies were found in 17 (37.8%) of the 45 LP patients. This was significantly higher than in the controls. This higher prevalence of anti-HCV antibodies was found equally in both male and female patients in the three types of LP; cutaneous only type, mucous only type, and both cutaneous and mucous type. Most of the patients with positive anti-HCV antibodies had abnormal values of transaminase enzymes and/or a past history of chronic hepatitis. Histological and immunohistological investigations of three cases with LP and chronic hepatitis C demonstrated some morphologic similarities between these two diseases. Histopathologic findings of both LP and chronic hepatitis C were based on a T lymphocytic infiltrate with keratinocyte or hepatocyte damage. The degrees of infiltrating cells positive to UCHL-1, MX-panB, Leu-7, and human leukocyte antigen (HLA)-DR antibodies in the chronic hepatitis C lesions seemed to be similar to those in the LP lesions. These results may support a possible relationship between LP and chronic hepatitis C and the hypothesis that LP may be associated with chronic liver diseases as a result of a cytotoxic attack on the hepatocytes.

Analysis of mast cell subpopulations (MCT, MCTC) in cutaneous inflammation using novel enzyme-histochemical staining techniques.

In order to gain insights into the dynamics of mast cell subpopulations in normal and diseased skin, a novel enzyme-histochemical double and triple staining method was employed that allowed the detection of metachromasia (toluidine blue) and the mast cell proteases tryptase and chymase within the same cell. Cryostat sections were used of skin biopsies from the following specimens: normal skin (N = 4), psoriasis (N = 13), atopic eczema (N = 7), lichen planus (N = 6), interferon alpha 2a injection sites (N = 1) of a leukemic infiltrate and corresponding normal skin of the same patient before and after treatment. (i) Equal numbers of tryptase- and chymase-positive mast cells (MCTC) were obtained in all normal and diseased specimens in papillary and reticular dermis, with threefold increases around appendages. (ii) Tryptase-positive mast cells (MCT) were absent in normal skin, but were markedly increased in a disease-specific pattern within the papillary dermis, the inflammatory infiltrate and around appendages. (iii) Marked increases of MCT were also noted at interferon injection sites within the leukemic infiltrate, but not in the normal skin of the same patient. These data suggest that disease-dependent mast cell dynamics involve only MCT in cutaneous inflammation and that MCT numbers are controlled by distinct, disease-specific local tissue factors.

Elastolysis in lichen ruber planus.

The dermal elastic fiber network was studied in specimens from five patients with lichen ruber planus, using a standard elastin staining procedure (orcein), results being compared with those for the elastin-associated microfibrillar network stained using anti-fibrillin antibodies in an immunofluorescence and an avidin-biotin-peroxidase complex technique. Additional specimens of healed apparently normal skin were taken from two of the patients. Orcein-stained fibers were scarce or absent in the inflammatory zone in all the lesions. In contrast, an extensive fibrillin immunoreactive network was present in the papillary zone in all the specimens, in a pattern similar to that of normal skin. In specimens from healed lesions of lichen ruber planus, dermal orcein-stained fibers were present in the papillary dermis. The findings indicate that the amorphous component of elastic fibers is destroyed during the acute phase of lichen ruber planus. Hypothetically, the elastolysis is caused by elastases released from macrophages known to be present in the lichenoid infiltrate. In contrast, the fibrillin fiber network seems to be less or not at all affected by proteolytic events during the inflammatory phase of lichen ruber planus.

The specificity and cellular origin of phenylethanolamine N-methyltransferase (PNMT)-like immunoreactivity in psoriatic skin.

Phenylethanolamine N-methyltransferase (PNMT)-like immunoreactivity has been found in psoriatic skin and in this study, PNMT-like immunoreactivity was investigated in the involved and uninvolved skin of six patients with lichen planus and four patients with lichen simplex. No PNMT immunoreactivity was observed in these diseases. Studies were carried out using cultured fibroblasts from two patients with psoriasis from uninvolved and involved areas of skin and from two controls using antibodies to PNMT, as well as antibodies to the chemical messengers somatostatin, substance P, parathyroid hormone and peptide histidine isoleucine amide. No immunoreactivity to these substances was found, and fibroblasts are unlikely to be the cellular origin of the PNMT-like immunoreactivity as seen in psoriatic skin.

A unique phospholipase A2 in human epidermis: its physiologic function and its level in certain dermatoses.

It is now well established that epidermis, like many other tissues, contains a phospholipase A2 that is responsible for the initiation of the arachidonic acid cascade. Here we report that human epidermis also contains a second, quite distinct enzyme of the phospholipase A2 group, which is unique in its extreme activity against phospholipids in true solution. It also differs from the classic cutaneous enzyme in that (a) its activity is not reduced by pretreatment of the skin with corticosteroids in vivo nor by treatment of the epidermal homogenate with alkaline phosphatase in vitro, and (b) its activity is reduced, rather than increased, in the lesions of inflammatory diseases such as psoriasis. The enzyme seems to occur mainly in fully differentiated keratinocytes, its level being low in the basal cell layer of epidermis and in keratinocytes cultured in vitro. On the basis of these observations, we suggest that this new phospholipase A2 is responsible for the degradation of phospholipids that accompanies the terminal keratinization process.