An interferon-gamma release assay as a novel biomarker in systemic lupus erythematosus.

OBJECTIVE: The mycobacterium tuberculosis (TB) IFN-γ release assay (TB-IGRA) assesses peripheral blood cell release of IFN-γ upon ex vivo exposure to mitogen (IGRA-MT), TB antigen or a negative/nil control (IGRA-NL); IGRA-NL is a measure of spontaneous IFN-γ release (SIR). Here, we investigate the diagnostic associations of elevated SIR and the potential use of IGRA-NL as a novel biomarker in SLE. METHODS: We analysed diagnostic code frequencies among 11 823 individuals undergoing TB-IGRA testing between 2010 and 2015 in a large urban US health-care system. To study the relationship between IGRA-NL and SLE, we identified 99 individuals with SLE and TB-IGRA test results then assessed correlations between IGRA-NL, normalized IGRA-NL (the quotient of IGRA-NL/IGRA-MT), disease manifestations and disease activity. RESULTS: We identified a discovery cohort of 108 individuals with elevated SIR (>5 S.d. above median) that was significantly enriched for a limited set of diagnoses, including SLE, TB infection, haemophagocytic lymphohistiocytosis and HIV infection. In SLE patients undergoing TB-IGRA testing, normalized IGRA-NL correlated better with disease activity than did anti-dsDNA or complement levels. This relationship appeared to reflect interactions between normalized IGRA-NL and the presence of acute skin disease, hypocomplementemia, fever and thrombocytopenia. CONCLUSION: Elevated SIR appears to be associated with a limited number of disease processes, including SLE. The diagnostic utility of SIR remains to be determined. IFN-γ activation, as measured by the TB-IGRA test, may offer a readily available tool for assessing disease activity in patients with SLE.

Cutaneous hemophagocytosis: Clinicopathologic features of 21 cases.

BACKGROUND: Hemophagocytosis is well known in cytotoxic cutaneous T-cell lymphomas (CTCLs), in which it may represent a sign of hemophagocytic lymphohistiocytosis syndrome (HLHS), and is also typical of cutaneous Rosai-Dorfman disease (cRDD) (without prognostic relevance). Only rarely, has cutaneous hemophagocytosis (CH) been described in other skin conditions. OBJECTIVE: To characterize the clinicopathologic features of CH in skin biopsy specimens from patients with conditions other than CTCL or cRDD. METHODS: Case series analyzing clinicopathologic features and follow-up data on patients presenting with histopathologic signs of CH. RESULTS: Biopsy specimens from 21 patients were included. None of the patients had HLHS. The majority (n = 11) presented with leukocytoclastic vasculitis. Other associated diseases were lupus erythematous (n = 2), arthropod bite reaction (n = 2), erysipelas (n = 1), acne conglobata (n = 1), and Sweet syndrome (n = 1). Three patients had a nonspecific rash concomitant with Chlamydia pneumonia, middle ear infection, and pharyngitis, respectively. LIMITATIONS: This was a single-center, retrospective study. CONCLUSION: Isolated CH in conditions other than CTCL and cRDD is a histopathologic finding related mostly to leukocytoclastic vasculitis. Extensive investigations should be performed only if patients have other signs or symptoms of HLHS.

Cutaneous lupus erythematosus: clinico-pathologic correlation.

Cutaneous lupus erythematosus (CLE) is a chronic-relapsing disease. It is defined as a LE localized to the skin without any significant systemic symptoms. Its annual incidence is of 4 cases per 100,000 persons with a prevalence of 73 cases per 100,000 persons. The etiology is unknown but it is considered as a prototype of autoimmune disease in which genetic factors (HLA), environmental factors (photo exposure and cigarette smoking) and pharmacological agents play an important role. The most accepted classification includes three clinical variants: acute (ACLE), subacute (SCLE) and chronic (CCLE). A fourth variety is the intermittent form (ICLE) also called "lupus tumidus" (LET) which is considered by some authors a distinct form from CCLE. The skin lesions are subdivided into LE specific and LE non-specific. The latter have a considerable importance as a symptom of evolution of the disease towards a systemic form of lupus (SLE). The histopathology of CLE is characterized by an interface dermatitis with vacuolization of the basal layer, a predominantly lymphocytic, perivascular and periadnexal infiltrate, epidermal and follicular hyperkeratosis, deposit of positive PAS material at the dermo-epidermal junction leading to atrophic-cicatricial evolution. Depending on the clinical variants, these microscopic features are more or less evident and are associated with peculiarities such as deposits of mucin (SCLE and LET), involvement of the panniculus in LE panniculitis, disappearance of the adnexa (cicatricial alopecia). The relationship between SLE/CLE is still under study: the progression of CLE in SLE is reported in a variable percentage of cases ranging from 12 to 18%. CLE therapy is aimed at preventing recurrences and scarring outcomes. Photoprotection with clothing, chemical and physical sunscreens active on UVA and UVB radiations is very important. Topical therapy is based on the use of steroids and calcineurin inhibitors, while the systemic therapy includes hydroxychloroquine as the first drug of choice.

A comparison of patients' and physicians' assessments of disease activity using the Swedish version of the Systemic Lupus Activity Questionnaire.

OBJECTIVES: We compared patients' assessments of systemic lupus erythematosus (SLE) disease activity by a Swedish version of the Systemic Lupus Activity Questionnaire (SLAQ) with physicians' assessments by the Systemic Lupus Activity Measure (SLAM) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). We also explored the performance of the SLAQ in patients with short (< 1 year) versus long (≥ 1 year) disease duration. METHOD: Patients filled out the SLAQ before physicians' assessments. Correlations between SLAQ total, subscales (Symptom score, Flares, Patients global) and SLAM and SLEDAI-2K, as well as between the corresponding items in SLAQ and SLAM, were evaluated using Spearman's ρ. Comparisons between patients with different disease durations were performed with Mann-Whitney U or chi-squared tests. RESULTS: We included 203 patients (79% women), with a median age of 45 years [interquartile range (IQR) 33-57 years] and disease duration of 5 years (IQR 0-14 years). Correlations between physicians' SLAM without laboratory items (SLAM-nolab) and patients' assessments were: SLAQ total, ρ = 0.685, Symptom score, ρ = 0.651, Flares, ρ = 0.547, and Patients global, ρ = 0.600. Of the symptom items, fatigue (ρ = 0.640), seizures (ρ = 0.635), and headache (ρ = 0.604) correlated most closely. Neurology/stroke syndrome, skin, and lymphadenopathy correlated less well (ρ < 0.24). Patients' and physicians' assessments were notably more discordant for patients with short disease durations. CONCLUSION: We confirm that the SLAQ can be used to monitor disease activity. However, the discrepancy between patients' and physicians' assessments was greater for patients with short versus long disease duration. We encourage further use of the SLAQ, but would like to develop a shorter version which would be valuable in modern, partly web-based, clinical care.

Pathophysiology of cutaneous lupus erythematosus.

The pathophysiology of cutaneous lupus erythematosus (CLE) encompasses the complex interactions between genetics, the environment, and cells and their products. Recent data have provided enhanced understanding of these interactions and the mechanism by which they cause disease. A number of candidate genes have been identified which increase the risk of developing CLE. Ultraviolet radiation, the predominant environmental exposure associated with CLE, appears to initiate CLE lesion formation by inducing apoptosis, precipitating autoantigen presentation, and promoting cellular production of specific cytokines. Autoantibodies are a well-known entity in CLE, but their exact role remains unclear. Finally, cells ranging from native skin cells to innate and adaptive immune cells produce cytokines and other molecules and play specific roles in lesion formation and perpetuation. Native skin cells implicated in CLE include keratinocytes and endothelial cells. Innate immune cells crucial to CLE pathophysiology include dendritic cells and neutrophils. The primary adaptive immune cells thought to be involved include Th1 cells, Th17 cells, cytotoxic T cells, and invariant natural killer T cells. Though the pathophysiology of CLE has yet to be fully characterized, current research provides direction for future research and therapies.

TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.

Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus.

IMPORTANCE: Patients with cutaneous lupus erythematosus (CLE) who develop systemic lupus erythematosus (SLE) may have few and mild systemic symptoms. OBJECTIVE: To characterize the types and severity of systemic symptoms in a longitudinal cohort of patients with CLE. DESIGN, SETTING, AND PARTICIPANTS: Prospective, longitudinal cohort study of 77 patients with CLE who presented between January 2007 and April 2011 at a university autoimmune skin disease clinic. MAIN OUTCOMES AND MEASURES: Systemic symptoms and severity were determined from data recorded at each study visit and from medical records. RESULTS: Of 77 patients with CLE, 13 (17%) went on to meet criteria for SLE, with a mean (SD) time from CLE diagnosis to SLE of 8.03 (6.20) years. Of the 13 patients, 1 (8%) solely met the mucocutaneous American College of Rheumatology (ACR) criteria of malar rash, discoid rash, photosensitivity, and oral ulcers, and 3 (23%) met the mucocutaneous ACR criteria plus positive antinuclear and other antibody titers. After a mean (SD) follow-up time of 2.81 (1.34) years, only 5 of the 13 patients with CLE (38%) who progressed to meet SLE criteria developed moderate to severe additional systemic disease. CONCLUSIONS AND RELEVANCE: Patients with CLE who developed SLE during our study did so mostly by meeting the mucocutaneous ACR criteria, and the majority developed none to mild additional systemic disease during the study period. Thus, our study suggests that a small percentage of patients with CLE eventually develop SLE and that even if they do, most patients will have mild systemic disease.

Cytokine and chemokine ligand expression in cutaneous lupus erythematosus.

There is increasing evidence that cytokines as well as chemokines are important players in the pathogenesis of lupus erythematosus (LE). We aimed to compare cytokine and chemokine profiles in different types of cutaneous LE. We investigated lesional mRNA and protein expression of various cytokines and chemokines in patients with chronic discoid LE (CDLE, n=15), subacute cutaneous LE (SCLE, n=11), and lupus erythematosus tumidus (LET, n=21). TNF-α, INF-γ, TGF-ß, IL-6, IL-10, IL-12p40, CXCL9, and CXCL10 mRNA expression were significantly increased in SCLE when compared to CDLE. Moreover, LET also showed significantly increased mRNA expression of TNF-α, TGF-ß, IL-10, IL-12p40 and CXCL9, as compared to CDLE. In all LE subtypes, CXCL9 and CXCL10 mRNA expression significantly correlated with INF-γ mRNA expression, as indicated by r-values ranging from 0.71 - 0.87. Immunohistochemistry for TNF-α, INF-γ, and IL-10 gave support to our RT-PCR results. In conclusion, our results suggest that T helper 1, as well as T helper 2 cytokines are differentially expressed in CDLE, SCLE, and LET. Compared to CDLE, the highest cytokine and chemokine ligand profiles are found in SCLE followed by LET. Our correlation studies also support the importance of an IFN-driven inflammation in cutaneous LE.

[What's new in internal medicine?]. / Quoi de neuf en médecine interne?

This paper summarizes a review of the medical literature focused on the field of internal medicine and dermatology, particularly cutaneous lupus erythematosus, dermatomyositis, cutaneous sarcoidosis, systemic sclerosis and cutaneous scleroderma, from September 2011 to October 2012. Our objective was to select the main articles that bring new information and significant advances useful for the dermatologist and internist in their daily practice and for the pathophysiological understanding of these affections. Thus, recent advances in the field of the following diseases were selected: cutaneous lupus erythematosus, sarcoidosis and systemic sclerosis treatments, neutrophilic dermatosis associated with lupus erythematosus, NETosis mechanism and myositis autoantibodies associated with dermatomyositis.

Environment and lupus-related diseases.

Clinical manifestations of lupus are encountered in a variety of disease entities, including isolated cutaneous lupus, undifferentiated connective tissue disease, mixed connective tissue disease, drug-induced lupus, overlap syndrome, and systemic lupus erythematosus (SLE). While each entity has been recognized as a specific disease with its own diverse clinical and serological pattern, one could argue that many findings are common. Could it be that all of these entities actually represent a spectrum of one disease? Could it be that rather than the genetic predisposition and hence controlled factors that govern this spectrum of diseases, that environmental factors associated with SLE could also play a role in the different entities of this spectrum? The traditional environmental triggers in SLE include sunlight and ultraviolet (UV) light, infections, smoking, and medications including biologics such as tumor necrosis factor alpha (TNF-a) blockers. In this review, we update and further substantiate these traditional factors in the various lupus-related syndromes. We will also discuss the association with vaccine exposure, industrial estrogens, and other factors.

Lúpus eritematoso crônico: uma abordagem clínica, epidemiológica, laboratorial e terapêutica / Chronic lupus erythematosus: a clinical approach, epidemiological, laboratory and therapeutic

O lúpus eritematoso cutâneo crônico, caracterizado, sobretudo, pelo lúpus discoide, é uma entidade clínica incomum, porém de elevada prevalência em mulheres em idade fértil. A sua etiologia é desconhecida, mas fatores genéticos, autoimunes, hormonais e ambientais compõem o processo fisiopatológico da doença. Os meios diagnósticos utilizados para que se possa iniciar o tratamento específico, composto de protetores solares, corticosteroides tópicos e, se preciso, medicações sistêmicas, principalmente os antimaláricos, são o exame clínico, a imunofluorescência direta e o estudo histopatológico. Este artigo descreve de maneira sucinta os principais aspectos epidemiológicos, clínicos, diagnósticos e terapêuticos do lúpus eritematoso cutâneo crônico, conforme revisão de literatura.

Drug-induced lupus erythematosus: incidence, management and prevention.

The generation of autoantibodies and autoimmune diseases such as systemic lupus erythematosus has been associated with the use of certain drugs in humans. Early reports suggested that procainamide and hydralazine were associated with the highest risk of developing lupus, quinidine with a moderate risk and all other drugs were considered low or very low risk. More recently, drug-induced lupus has been associated with the use of the newer biological modulators such as tumour necrosis factor (TNF)-α inhibitors and interferons. The clinical features and laboratory findings of TNFα inhibitor-induced lupus are different from that of traditional drug-induced lupus or idiopathic lupus, and standardized criteria for the diagnosis of drug-induced lupus have not been established. The mechanism(s) responsible for the development of drug-induced lupus may vary depending on the drug or even on the patient. Besides lupus, other autoimmune diseases have been associated with drugs or toxins. Diagnosis of drug-induced lupus requires identification of a temporal relationship between drug administration and symptom development, and in traditional drug-induced lupus there must be no pre-existing lupus. Resolution of symptoms generally occurs after cessation of the drug. In this review, we will discuss those drugs that are more commonly associated with drug-induced lupus, with an emphasis on the new biologicals and the difficulty of making the diagnosis of drug-induced lupus against a backdrop of the autoimmune diseases that these drugs are used to treat. Stimulation of the immune system by these drugs to cause autoimmunity may in fact be associated with an increased effectiveness in treating the pathology for which they are prescribed, leading to the dilemma of deciding which is worse, the original disease or the adverse effect of the drug. Optimistically, one must hope that ongoing research in drug development and in pharmacogenetics will help to treat patients with the maximum effectiveness while minimizing side effects. Vigilance and early diagnosis are critical. The purpose of this review is to summarize the most recent developments in our understanding of the incidence, pathogenesis, diagnosis and treatment of drug-induced lupus.

Expression of antimicrobial peptides in different subtypes of cutaneous lupus erythematosus.

BACKGROUND: Antimicrobial peptides (AMPs) are small effector molecules of the innate immune system with well-known antimicrobial activity. Skin infections rarely occur in patients with cutaneous lupus erythematosus (CLE), and AMP expression in CLE has not been previously evaluated. OBJECTIVES: We aimed to determine the expression of several important AMPs in 3 different subtypes of CLE. METHODS: Skin lesions were analyzed for the gene and protein expression of human ß-defensin (hBD)-1, -2, and -3; RNase-7; the cathelicidin LL-37; and psoriasin (S100A7) using real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: Skin biopsy specimens of 96 study participants including 47 patients with CLE (15 patients with discoid lupus erythematosus [LE], 11 patients with subacute CLE, and 21 patients with LE tumidus), 34 patients with psoriasis, and 15 healthy control subjects were evaluated in this study. HBD-2, hBD-3, LL-37, and psoriasin were significantly more highly expressed in CLE as compared with healthy controls, and most AMPs were significantly more highly induced in subacute CLE as compared with discoid LE and LE tumidus. AMP gene expression paralleled well with AMP protein expression in CLE and controls. Subacute CLE and discoid LE showed a similar correlation of AMP gene expression (significant correlations between hBD-1 and RNase-7, hBD-2 and hBD-3, hBD-2 and psoriasin, and hBD-3 and psoriasin). LIMITATIONS: The relatively small number of samples and the lack of analysis of the lesional bacterial colonization are a limitation. CONCLUSIONS: Several AMPs are increased in CLE at both gene and protein levels. This could explain the low prevalence of skin infections in CLE. It remains to be elucidated whether AMPs play a pathogenic role in CLE.

Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFNλ) in cutaneous lupus erythematosus.

Type I IFNs (IFNα/ß) have been shown to have a central role in the pathophysiology of lupus erythematosus (LE). The recently discovered type III IFNs (IFNλ1/IL29, IFNλ2/IL28a, IFNλ3/IL28b) share several functional similarities with type I IFNs, particularly in antiviral immunity. As IFNλs act primarily on epithelial cells, we investigated whether type III IFNs might also have a role in the pathogenesis of cutaneous LE (CLE). Our investigations demonstrate that IFNλ and the IFNλ receptor were strongly expressed in the epidermis of CLE skin lesions and related autoimmune diseases (lichen planus and dermatomyositis). Significantly enhanced IFNλ1 could be measured in the serum of CLE patients with active skin lesions. Functional analyses revealed that human keratinocytes are able to produce high levels of IFNλ1 but only low amounts of IFNα/ß/γ in response to immunostimulatory nuclear acids, suggesting that IFNλ is a major IFN produced by these cells. Exposure of human keratinocytes to IFNλ1 induced the expression of several proinflammatory cytokines, including CXCL9 (CXC-motiv ligand 9), which drive the recruitment of immune cells and are associated with the formation of CLE skin lesions. Our results provide evidence for a role of type III IFNs in not only antiviral immunity but also autoimmune diseases of the skin.

Manifestaciones específicas del lupus cutáneo / Specific manifestations of cutaneous lupus

El lupus eritematoso sistémico es una enfermedad autoinmune con compromiso multisistémico. La piel es el segundo órgano más afectado. Las lesiones del lupus cutáneo pueden ser clasificadas en específicas y no específicas, dependiendo de la presencia de dermatitis de interfase. Las lesiones específicas pueden ser divididas en tres categorías –crónico, subagudo u agudo– basados en la morfología, duración de las lesiones y la histopatología. Las lesiones cutáneas pueden producir considerable morbilidad y resultar en lesiones dolorosas, alopecia, desfiguración, etc. Este trabajo describe las lesiones específicas del lupus cutáneo, de modo de facilitar el diagnóstico clínico.

Systemic lupus erythematosus is an autoimmune disease with multiorgan involvement. The skin is the second most commonly affected organ. Cutaneous lupus erythematosus may be classified in specific and not specific lesions, according to the presence of interphase dermatitis. Specific skin lesions are subdivided into three categories –chronic, subacute and acute cutaneous lupus– based on clinical morphology, average duration of skin lesions and routine histopathologic examination. Lupus skin lesions can produce considerable morbidity resulting from painful skin lesions, alopecia, disfigurement, etc. This paper describes specific skin manifestations of cutaneous lupus, in order to facilitate clinical diagnosis.

Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates.

The skin is the second most frequently affected organ system in lupus erythematosus. Although only very rarely life threatening--an example is lupus erythematosus-associated toxic epidermal necrolysis--skin disease contributes disproportionally to disease burden in terms of personal and psychosocial wellbeing, vocational disability, and hence in medical and social costs. Since several manifestations are closely associated with the presence and activity of systemic lupus erythematosus, prompt and accurate diagnosis of cutaneous lupus erythematosus is essential. This review aims to cover common, rare, and atypical manifestations of lupus erythematosus-associated skin disease with a detailed discussion of histopathological correlates. Cutaneous lupus erythematosus covers a wide morphological spectrum well beyond acute, subacute and chronic cutaneous lupus erythematosus, which are commonly classified as lupus-specific skin disease. Other uncommon or less well-known manifestations include lupus erythematosus tumidus, lupus profundus, chilblain lupus, mucosal lupus erythematosus, and bullous lupus erythematosus. Vascular manifestations include leukocytoclastic and urticarial vasculitis, livedoid vasculopathy and livedo reticularis/ racemosa. Finally, we discuss rare presentations such as lupus erythematosus-related erythema exsudativum multiforme (Rowell syndrome), Kikuchi-Fujimoto disease, extravascular necrotizing palisaded granulomatous dermatitis (Winkelmann granuloma), and neutrophilic urticarial dermatosis.

Cutaneous manifestations and serological findings in 260 patients with systemic lupus erythematosus.

The prevalence and prognostic value of cutaneous manifestations in patients with systemic lupus erythematosus (SLE) is not clear due to a lack of distinct criteria. Our aim was to investigate the prevalence of cutaneous manifestations in SLE patients according to strict dermatological classification, compare the results with other studies and to assess differences in serological markers between patients with and without cutaneous lupus erythematosus (CLE). Secondary aims were to investigate the validity of the criteria 'malar rash' and 'photosensitivity' for SLE diagnosis. We included 260 consecutive SLE patients, and 164 with skin complaints were examined by a dermatologist. CLE was found in 23% of the 260 SLE patients. There was agreement on the presence of malar rash in only 60% of patients seen by both rheumatologists and dermatologists. A history of polymorphous light eruption (PLE) was found in 42% of patients. Raynaud's phenomenon was significantly more common in patients with CLE. In addition, four malignant melanomas were found. Based on our findings, we suggest that the American College of Rheumatology (ACR) criteria for SLE diagnosis include histopathologically confirmed CLE as one criterion, and that the criteria photosensitivity and malar rash should be re-defined. Regular examination by a dermatologist is called for in SLE patients.

The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells.

Mechanisms linking innate immunity and autoimmune responses are poorly understood. Myeloid-related protein-8 (Mrp8) and Mrp14 are damage-associated molecular pattern molecules (DAMPs) highly upregulated in various autoimmune disorders. We show in a mouse autoimmune model that local Mrp8 and Mrp14 production is essential for the induction of autoreactive CD8+ T cells and the development of systemic autoimmunity. This effect is mediated via Toll-like receptor 4 (TLR4) signaling leading to increased interleukin-17 (IL-17) expression. Notably, expression of Mrp8 and Mrp14 was upregulated in cutaneous lupus erythematosus, and stimulation of CD8+ T cells from individuals with lupus erythematosus with MRP proteins resulted in an upregulation of IL-17, suggesting a key role for MRP8 and MRP14 for the development of autoreactive lymphocytes during human autoimmunity as well. These results demonstrate a link between local expression of DAMP molecules and the development of systemic autoimmunity.

Rheumatic manifestations of skin disease.

PURPOSE OF REVIEW: There is an increasing interest in improving the understanding of pathophysiology, outcome measures, and therapies of rheumatic skin disease. Increasingly, studies are using the skin as a primary endpoint for evaluating therapies. This will review the current state of the art for the most common rheumatic skin diseases. RECENT FINDINGS: A number of medications, including biologics such as tumor necrosis factor alpha and interferon, have been associated with onset of cutaneous lupus. The cutaneous lupus erythematosus area and severity index has been further validated and utilized in a number of studies. Smoking continues to be associated both with presence and refractoriness of cutaneous lupus erythematosus to therapy. There are several tools now available for evaluating the skin disease of dermatomyositis, but there is a need for new effective therapies. Measurement of skin disease in scleroderma continues to be a challenge, and there is a need for more effective therapies. Several studies show efficacy of intravenous iloprost for severe Raynaud's and skin ulcers, and of bosentan for digital ulcers. SUMMARY: The present review covers new outcome measures, treatments, and unusual manifestations of cutaneous lupus, dermatomyositis, scleroderma, and rheumatoid arthritis. There have been a number of new studies related to validation of disease activity measures, as well as their use in evaluation of new therapies for these conditions. Validated outcome measures are required to perform meaningful studies, and will facilitate organized epidemiologic, quality of life, and therapeutic studies.