Cutaneous Lupus Erythematosus Lesions Research Articles

Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA

Infiltrating T lymphocytes are considered to play a major pathological role in skin lesions of cutaneous lupus erythematosus (CLE), a cutaneous autoimmune disease of unknown aetiology. Earlier histological studies revealed that the inflammatory infiltrate in CLE skin lesions is predominantly composed of T lymphocytes, with a slight predominance of CD4+ over CD8+ T cells, but failed to explain the development of scarring skin lesions, characteristic for chronic discoid lupus erythematosus (CDLE). Because recent investigations have highlighted the relevance of cytotoxic lymphocytes in autoimmune tissue destruction, we hypothesized that the scarring CDLE lesions might be caused by cytotoxic T lymphocytes. To analyse skin biopsies of 15 patients with CLE [10 female, five male; localized CDLE (lCDLE), n = 5; disseminated CDLE (dCDLE), n = 5, subacute CLE (SCLE), n = 5] and five control biopsies taken from healthy controls and to characterize the inflammatory infiltrate. Methods We used immunohistochemistry, including staining for the cytotoxic molecule granzyme B, the skin-homing molecule cutaneous lymphocyte antigen (CLA) and the protein MxA, which is specifically induced by type I interferons (IFNs). We found a strong coexpression of granzyme B and CLA on lesional lymphocytes of patients with scarring lCDLE and dCDLE, which was significantly enhanced when compared with nonscarring SCLE and healthy controls. The increased expression of granzyme B was closely associated with the lesional expression of the type I IFN-induced protein MxA. Our results provide evidence that type I IFNs and potentially autoreactive cytotoxic lymphocytes targeting adnexal structures are highly associated with scarring lupus erythematosus lesions and might be responsible for their scarring character.

Cytokine profiles of skin lesions in murine lupus models

Summary Background Skin lesions of cutaneous lupus erythematosus (LE) have a number of infiltrating T cells, and these T cells and their related cytokines are involved in the development of skin lesions. Objective In order to verify the roles of T cells and their related cytokines, we compared the cytokine profiles of LE-like skin lesions in experimentally-induced knock out (KO) mice and autoimmune-prone mice. Methods Lesional skin samples were obtained from CD4 KO mice and TCRα KO mice of the B6 background treated with ultraviolet B light (UVBL) and fluorouracil (FU), and MRL/lpr mice. The levels of mRNAs for TNF-α, IFN-γ, IL-2, IL-4, IL-10 and IL-12 were determined by RT-PCR in these skin samples. Results Combination treatment with UVBL and FU to TCRα KO mice and CD4 KO mice revealed the importance of CD4+ CD8− γδT cells in the induction of drug induced cutaneous LE. Moreover, IL-12, IFN-γ and TNF-α were upregulated in TCRα KO mice treated with UVBL and FU. In contrast, IFN-γ was not elevated in the spontaneous LE-like skin lesions of MRL/lpr mice. Conclusions Cytokine profile pattern varies from strain to strain, and that murine cutaneous LE models, like human LE patients, manifest a wide range of immunological abnormalities, including cytokines.

Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients

The therapy of cutaneous lupus erythematosus (CLE) is often challenging, especially in patients resistant to topical treatment and established first-line systemic drugs such as antimalarials. Systemic corticosteroids are effective, but their use is limited due to well-known side-effects, especially in long-term treatment. In recent years several other immunosuppressive agents have been successfully applied in CLE. However, there are no large studies or explicit guidelines on the use of these drugs in CLE. To perform a retrospective investigation of the efficacy of low-dose methotrexate (MTX) in the treatment of CLE. One hundred and thirty-nine patients with CLE were seen at our department between 2001 and 2003, of whom 43 patients required low-dose MTX. All had histologically confirmed CLE lesions. Clinical data including disease activity, additional treatment, laboratory parameters and side-effects were recorded carefully at the time of presentation. Statistical analyses were performed by paired nonparametric Wilcoxon test and Student's t-test using SPSS 11 software. MTX led to a highly significant (P < 0.01) decline in disease activity. An improvement of the cutaneous lesions was recorded in nearly all patients treated with MTX (42 of 43; 98%). Severe side-effects necessitating discontinuation of MTX treatment were recorded in seven patients (16%), which quickly resolved when MTX was discontinued. Life-threatening complications were not observed. Intravenous application was tolerated better than oral administration. Interestingly, we observed a significant increase in circulating lymphocyte numbers in patients with lymphopenia (< 1.0 x 10(9) cells L(-1)) prior to MTX treatment. Our study supports earlier findings reporting the efficacy of low-dose MTX in CLE lesions, particularly in recalcitrant clinical courses. MTX treatment appears to be safe if patients are carefully selected and monitored, with particular attention to side-effects and contraindications.

Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a 65 series of Brazilian patients

Thalidomide has been reported as efficacious in refractory cutaneous lupus erythematosus (LE). The most fearful side-effects are teratogenicity and neuropathy. We reported clinical efficacy of long-term low-dose use of thalidomide in 65 patients with LE, emphasizing the prevalence of adverse effects, especially of neuropathy and its related factors. Data obtained from medical records included age, sex, disease duration, and the presence of diagnostic criteria for systemic lupus erythematosus (SLE), the extent and activity of cutaneous lesions and previous treatments. Sixty-three patients (98.9%) presented complete or partial improvement with thalidomide therapy. Drowsiness occurred in 50 patients (77%). Twenty-eight patients (43.2%) presented neuropathy symptoms. Nerve conduction studies were done in 21 (75%) of them and were abnormal in 12 (57%). With the interruption of thalidomide, 24 (82.5%) had complete or partial improvement of neuropathy symptoms and 23 (82%) of them had cutaneous relapse. There were no significant differences between those who developed or not neuropathy in treatment duration, age, total dose and systemic versus cutaneous LE. In conclusion, thalidomide can be used in refractory cutaneous LE with great efficacy and relative security. Controlled studies with schemes with lower doses or intermittent usage or alternative drugs are wanted to reduce the burden of cutaneous morbidity of lupus erythematosus.

Ultraviolet radiation–induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus

To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE). Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine- and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo. In the present study, we identified the CXCR3 ligands CXCL9 (interferon-gamma [IFNgamma]-induced monokine), CXCL10 (IFNgamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant) as being the most abundantly expressed chemokine family members in cutaneous LE. Expression of these ligands corresponded with the presence of a marked inflammatory infiltrate consisting of mainly CXCR3-expressing cells, including skin-homing lymphocytes and blood dendritic cell antigen 2-positive plasmacytoid dendritic cells (PDCs). Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFNalpha-inducible genes IRF7 and MxA. IFNalpha, in turn, was a potent and rapid inducer of CXCR3 ligands in cellular constituents of the skin. Furthermore, we demonstrated that the inflammatory CXCR3 ligands cooperate with the homeostatic chemokine CXCL12 (stromal cell-derived factor 1) during the recruitment of pathogenically relevant leukocyte subsets. Moreover, we showed that UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine) from epidermal compartments into dermal compartments and up-regulates the expression of a distinct set of chemokines in keratinocytes. Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate the recruitment and activation of autoimmune T cells and IFNalpha-producing PDCs, which subsequently release more effector cytokines, thus amplifying chemokine production and leukocyte recruitment, finally leading to the development of a cutaneous LE phenotype.

Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus

Recent studies have suggested that type I interferons (IFN) play a role in the pathogenesis of lupus erythematosus (LE), an autoimmune disease of unknown aetiology. Natural interferon-producing plasmacytoid cells have been demonstrated in cutaneous LE (CLE) lesions, along with elevated levels of IFN-alpha mRNA. The hypothesis in the current study was that local production of type I IFNs in CLE induces Th1-biased inflammation via induction of IFN-inducible chemokines such as IP10/CXCL10 leading to the recruitment of chemokine receptor CXCR3 expressing T-cells into skin lesions. Skin biopsies from 21 patients suffering from different types of active cutaneous LE were analysed for the expression of MxA, a protein specifically induced by type I interferons, the IFN-inducible protein IP10/CXCL10, and the chemokine receptor CXCR3, characteristic for Th1 cells, by immunohistochemistry. Additionally, peripheral CD4+ and CD8+ T-cells were investigated for the expression of MxA and CXCR3 by flow cytometry. Cutaneous LE lesions were characterized by strong expression of MxA indicating the induction of localized type I IFN signalling in the skin. Large numbers of infiltrating CXCR3 positive lymphocytes were detected in CLE skin lesions, and correlated closely with lesional MxA expression (epidermis: Spearman's rho = 0.56, p < 0.001; dermis: rho = 0.82, p < 0.001). Intracellular MxA levels of circulating CD4+ and CD8+ T-cells were significantly enhanced in patients with active CLE lesions. The percentage of peripheral T-cells expressing CXCR3 was significantly decreased in specific CLE subtypes. Expression of IP10/CXCL10 in the epidermis links type I IFN signalling and recruitment of CXCR3+ T cells. These results suggest an important role for type I interferon signalling in the pathogenesis of cutaneous lupus erythematosus. It is proposed that type I IFNs induce a Th1-biased inflammatory immune response, with recruitment of CXCR3-expressing T-lymphocytes into the skin.

Efficacy of topical tacrolimus in the treatment of various cutaneous manifestations of lupus erythematosus

Efficacy of topical tacrolimus in the treatment of various cutaneous manifestations of lupus erythematosus

Investigating Clofazimine for LE Lesions

Few well-controlled, randomized studies have compared therapeutic agents for cutaneous lesions of lupus erythematosus (LE). Antimalarial agents such as chloroquine are FDA-approved and considered effective but can be toxic, particularly with chronic use. An equally effective but nontoxic alternative would be a welcome addition to our therapeutic armamentarium. Clofazimine is approved for the treatment of leprosy and erythema nodosum leprosum but has limited distribution in the U.S. These authors compared clofazimine with chloroquine for treating 33 patients …

Thalidomide treatment for hypertrophic cutaneous lupus erythematosus

INTRODUCTION: In recent years numerous reports have been published regarding satisfactory thalidomide therapy for refractory chronic cutaneous lesions of lupus erythematosus (CCLE); to date, in the literature, there is just one report describing two patients affected by hyperkeratotic CCLE successfully treated with thalidomide. METHODS: Six patients affected by a hypertrophic/verrucous variant of CCLE were treated with thalidomide during the period October 1999 to December 2002 and their medical records were retrospectively reviewed. The initial dose of thalidomide was 100 mg/die by mouth for all the cases, while the duration of therapy was variable among the patients. RESULTS: All six patients responded to treatment: two had partial resolution of the lesions and four achieved almost complete clearing of cutaneous disease. Response to treatment was seen in the first month of therapy in all the patients. Follow-up nerve conduction studies were negative but a patient had to discontinue the drug because of neurological problems. DISCUSSION/CONCLUSION: Our case series confirms the efficacy of a 'low-dose' thalidomide regimen in verrucous/hyperkeratotic CCLE, which is normally unresponsive to conventional treatment; in this setting, thalidomide should be kept in mind as an extremely valid therapeutic option despite the lack of prospective, randomized, double-blind, placebo-controlled studies.

Topical Tacrolimus: Adjunctive Therapy for Cutaneous Lupus Erythematosus?

Cutaneous lesions of lupus erythematosus (LE) may persist despite aggressive therapy with topical and systemic agents. To determine the efficacy of 0.1% tacrolimus ointment in such cases, researchers treated 12 patients who had treatment-resistant lesions of various types with the agent in an open-label study. …

Histopathologic findings in lupus erythematosus tumidus: Review of 80 patients

Background: In a recent study, we demonstrated that lupus erythematosus (LE) tumidus (LET) is a distinct subset of cutaneous LE (CLE), which is clinically characterized by erythematous, urticaria-like, nonscarring plaques in sun-exposed areas. Objective: Our purpose was to analyze skin biopsy specimens from 80 patients with this disease and to determine whether it could be differentiated from other variants of CLE on histopathologic grounds. Methods: Skin biopsy specimens from 53 primary and 38 UVA- and/or UVB-induced lesions of 80 patients with LET were examined and compared with skin biopsy specimens from patients with discoid LE (DLE) and subacute CLE (SCLE). Results: Specimens from LET lesions showed a characteristic and diagnostic pattern of perivascular and periadnexal cellular infiltrates in the papillary and reticular dermis composed almost entirely of lymphocytes. In some cases, few scattered neutrophils were present. Furthermore, interstitial mucin deposition was observed in all specimens, as confirmed by colloidal iron staining. In contrast to discoid LE and subacute CLE lesions, epidermal atrophy or alteration at the dermoepidermal junction was not detected. Conclusion: Skin lesions of patients with LET present with specific histopathologic features, and the differences compared with subacute CLE and discoid LE further support the concept to consider LET as a separate entity of CLE. (J Am Acad Dermatol 2003;48:901-8.)

Treatment of lupus erythematosus with pulsed dye laser.

The treatment of cutaneous lupus erythematosus (CLE) with dye and argon laser has been evaluated in a number of articles in recent years. The improvement of telangiectasias and chronic erythema of the cutaneous lesions was based on the selective photothermolysis ablation of the dilated capillaries and venules. We describe the results of the treatment of cutaneous lesions of 14 patients; eight with discoid lupus erythematosus (DLE) and six with systemic lupus erythematosus (SLE). Three patients received a treatment with flashlamp pulsed dye laser (FPDL) (585 nm, 450 microseconds) with fluences in the range from 5 to 7.75 J/cm(2); the other 11 patients were treated with long pulsed dye laser (LPDL) (595 nm, 1.5-10 milliseconds) with fluences in the range from 6 to 13 J/cm(2) depending on the pulse duration. During a median follow-up of 10 months, we observed an average improvement in over 60% of the lesions. A few side effects were observed in all patients: four had transient hyperpigmentation and one patient had light scarring. Three patients had a relapse after more than 1 year; they were then offered conventional treatment. We confirm that pulsed dye laser is a good alternative treatment for the erythema in active cutaneous lesions of lupus erythematosus (LE).

Functional melanonychia due to involvement of the nail matrix in systemic lupus erythematosus

Longitudinal melanonychia is an unusual finding in systemic lupus erythematosus. We report the case of a patient of Arabic extraction with cutaneous lesions of lupus erythematosus on the cheek and chest and longitudinal melanonychia affecting several fingers. Results of histologic examination of the skin and direct immunofluorescence analysis confirmed the diagnosis of systemic lupus erythematosus. The distal matrix revealed changes suggestive of systemic lupus erythematosus accompanied by increased activity of melanocytes but without melanocytic hyperplasia. In this case, longitudinal melanonychia associated with systemic lupus erythematosus was of functional origin. (J Am Acad Dermatol 2002;47:S187-8.)

Plasmacytoid Dendritic Cells (Natural Interferon- α/β-Producing Cells) Accumulate in Cutaneous Lupus Erythematosus Lesions

Plasmacytoid dendritic cell (P-DC) precursors in peripheral blood produce large amounts of interferon (IFN)-alpha/beta when triggered by viruses. However, when incubated with interleukin-3 and CD40 ligand, the same precursors differentiate into mature DCs that stimulate naïve CD4(+) T cells to produce Th2 cytokines. We recently reported that P-DCs accumulate in nasal mucosa of experimentally induced allergic rhinitis, supporting a role for this DC subset in Th2-dominated inflammation. Here we examined whether P-DCs accumulate in cutaneous lesions of lupus erythematosus (LE), a disorder associated with increased IFN-alpha/beta production. Our results showed that P-DCs were present in 14 out of 15 tissue specimens of cutaneous LE lesions, but not in normal skin. Importantly, the density of P-DCs in affected skin correlated well (r(s) = 0.79,P < 0.0005) with the high number of cells expressing the IFN-alpha/beta-inducible protein MxA, suggesting that P-DCs produce IFN-alpha/beta locally. Accumulation of P-DCs coincided also with the expression of L-selectin ligand peripheral lymph node addressin on dermal vascular endothelium, adding further support to the notion that these adhesion molecules are important in P-DC extravasation to peripheral tissue sites. Together, our findings suggested that P-DCs are an important source of IFN-alpha/beta in cutaneous LE lesions and may therefore be of pathogenic importance.

Therapy of cutaneous lupus erythematosus

: Patients with cutaneous lesions of lupus erythematosus (LE) can generally be managed with standard therapies. The patient should have a firmly established diagnosis. Evaluation will allow the treating physician to assign a prognosis. Patients with discoid LE and subacute cutaneous LE are generally photosensitive and therefore sunscreens, protective clothing, and behavioral alteration should be discussed with all patients. Topical corticosteroids are a standard form of therapy, but “newer” agents such as retinoids, calcipotriene, and tacrolimus might be effective. Antimalarial agents are generally effective. Attempts to reduce or stop smoking may aid in the control of cutaneous LE (CLE). The choice of alternative therapy is personal and discussions of the risks and benefits should be carefully documented. Successful therapy for CLE is possible in almost all well-motivated, cooperative patients.

Local therapy for cutaneous and systemic lupus erythematosus: practical and theoretical considerations.

Local therapeutic measures should be maximized in the management of lupus erythematosus (LE), particularly for patients with forms of LE-specific skin disease such as SCLE and CCLE. Local therapy consists of sun protection and locally-applied pharmacologic agents, e.g. topical/intralesional corticosteroids. Patients should be advised to avoid direct sun exposure, wear lightweight tightly woven clothing and broad-brimmed hats, and use broad-spectrum, water-resistant sunscreens. There are several modalities that enhance permeability of local therapeutics through the stratum corneum that could be applied to topical therapy of cutaneous LE, e.g. polar solvent, liposomal encapsulation, ethosomal system, iontophoresis, electroporation and sonophoresis. As novel and more effective modalities to deliver pharmacologic agents across the stratum corneum become available, therapeutics that have been experimental and untested thus far may become part of the local armamentarium in the near future. In addition, physical/contact therapy as well as dermatosurgical methods can be invaluable in enhancing self-image and quality of life of patients with disfiguring cutaneous LE lesions.

Proliferation and effects of UVA irradiation in cultured fibroblasts from lesions in cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (LE) often presents clinically as chronic cutaneous lesions, healing with scar formation, and acute cutaneous lesions that are seen in systemic and subacute LE and heal without scarring. UV-light plays a role in the pathogenesis of the skin lesions, but the pathomechanism is still unclear. The aim of this study was to compare fibroblast proliferation and response to UV-light by cultured fibroblasts from scarring and non-scarring LE lesions. Fibroblasts were cultured from skin lesions from 5 patients with classic discoid LE, 5 patients with subacute cutaneous LE and healthy, age-matched donors. Proliferation rate was assessed by cell counts at days 3, 6 and 9. The fibroblast cultures were irradiated with UVA and the supernatants were analysed for IL-6, TGF-beta, IL-4, soluble ICAM-1 and soluble VCAM-1. Fibroblast cultures from scarring lesions showed significantly lower cell-counts at days 3 (P = 0.01) and 9 (P = 0.009), than cultures from nonscarring lesions or controls. There were no significant differences in levels of IL-6 or TGF-beta in supernatants of irradiated fibroblasts from patients compared to controls and IL-4 and the soluble forms of ICAM-1 and VCAM-1 were below detection level. The response to UV-irradiation was similar to that of normal cells in the parameters studied. In summary, cultured fibroblasts from scarring LE lesions displayed significantly decreased proliferation rates compared to non-scarring LE lesions and controls. This may be secondary to inflammatory factors, or due to a functional defect in LE fibroblasts.

Aberrant Timing in Epidermal Expression of Inducible Nitric Oxide Synthase After UV Irradiation in Cutaneous Lupus Erythematosus

Photosensitivity is a main criterion for the diagnosis of systemic lupus erythematosus (LE), and ultraviolet (UV) irradiation plays a key role in the pathogenesis of cutaneous LE. Patients with a tentative diagnosis of LE are routinely tested for skin lesion development after experimental UV irradiation, providing an ideal opportunity to evaluate early, preclinical events involved in the pathogenesis of LE. Several reports have shown expression of the cytokine-inducible nitric oxide synthase (iNOS) in autoimmune diseases. Therefore, we investigated the role of iNOS expression at mRNA and protein level in the pathogenesis of LE lesions. Skin biopsies from patients with different subtypes of LE were examined, and iNOS expression was found in six of 18 biopsies from cutaneous LE patients and two of three biopsies from systemic LE patients. In biopsies taken 4-20 d after UV irradiation, epidermal iNOS expression was seen in all patients (n = 10) after UVB and in four of 10 patients provoked by UVA. In healthy controls (n = 8) epidermal iNOS expression was detected 24 h after UV irradiation, persisting for another day before subsiding on day 3. In LE patients (n = 8) the exact reverse situation was seen: an iNOS-specific signal was undetectable in keratinocytes for 2 d after UV irradiation, but became positive on day 3 and persisted for up to 25 d in the evolving skin lesions. Our findings demonstrate a time-restricted, UV-induced iNOS expression in human skin; moreover, the results indicate that both the kinetics of iNOS induction as well as the time span of local iNOS expression may be critical to the development of cutaneous LE lesions.

Pulsed Dye Laser Treatment of Telangiectatic Chronic Erythema of Cutaneous Lupus Erythematosus

Telangiectases and chronic erythema are the usual components of the cutaneous lesions of lupus erythematosus (LE). These vascular alterations are found in the discoid, subacute, or systemic varieties of LE. Steroids, antimalarial drugs, thalidomide, immunosuppresive drugs, sunscreens, and cosmetic agents have been employed in the treatment of these lesions, showing different results. The flashlamp pulsed dye laser (FPDL) (585 nm) has proven useful in a variety of vascular lesions. We have treated four patients with systemic LE (SLE) using an FPDL. <h3>Report of Cases.</h3><h3>Case 1.</h3> A 42-year-old woman was diagnosed with SLE in 1983. She had a malar rash, photosensitivity, and leukopenia and positive findings for antinuclear antibodies and anti-DNA. Facial bilateral telangiectasias were the main cutaneous findings, and a diagnosis of LE telangiectoides was made. Cutaneous examination revealed bilateral and symmetric facial telangiectasias. A skin biopsy specimen and an direct immunofluorescence examination showed features of LE. <h3>Case 2.</h3>

Treatment of severe cutaneous lupus erythematosuswith a chimeric CD4 monoclonal antibody, cM-T412

Monoclonal CD4 antibodies are among the most potent immunomodulatory agents in various experimental models of autoimmune disease, including murine lupus erythematosus. The aim of this study was to evaluate the toxicity and therapeutic efficacy of a chimeric monoclonal CD4 antibody, cM-T412, in patients with cutaneous lupus erythematosus (LE). Five patients with severe cutaneous LE lesions received intravenously a total of 275, 400, or 475 mg of cM-T412 in single doses of 20 to 50 mg during a period of 5 to 8 weeks. CD4 antibody treatment induced a long-lasting decrease in disease activity. It resulted in healing of LE skin lesions, a reconstituted responsiveness to conventional treatment, or both. Despite a substantial depletion of circulating CD4+ T lymphocytes, no clinical signs of immunosuppression were noted. Monoclonal CD4 antibodies should be considered as a novel treatment for the management of severe cutaneous LE.