International consensus for a definition of disease flare in lupus.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

A systematic review of drug-induced subacute cutaneous lupus erythematosus.

The initial appearance of subacute cutaneous lupus erythematosus (SCLE) skin lesions in conjunction with Ro/SS-A autoantibodies occurring as an adverse reaction to hydrochlorothiazide [i.e. drug-induced SCLE (DI-SCLE)] was first reported in 1985. Over the past decade an increasing number of drugs in different classes has been implicated as triggers for DI-SCLE. The management of DI-SCLE can be especially challenging in patients taking multiple medications capable of triggering DI-SCLE. Our objectives were to review the published English language literature on DI-SCLE and use the resulting summary data pool to address questions surrounding drug-induced SCLE and to develop guidelines that might be of value to clinicians in the diagnosis and management of DI-SCLE. A systematic review of the Medline/PubMed-cited literature on DI-SCLE up to August 2009 was performed. Our data collection and analysis strategies were prospectively designed to answer a series of questions related to the clinical, prognostic and pathogenetic significance of DI-SCLE. One hundred and seventeen cases of DI-SCLE were identified and reviewed. White women made up the large majority of cases, and the mean overall age was 58·0 years. Triggering drugs fell into a number of different classes, highlighted by antihypertensives and antifungals. Time intervals ('incubation period') between drug exposure and appearance of DI-SCLE varied greatly and were drug class dependent. Most cases of DI-SCLE spontaneously resolved within weeks of drug withdrawal. Ro/SS-A autoantibodies were present in 80% of the cases in which such data were reported and most remained positive after resolution of SCLE skin disease activity. No significant differences in the clinical, histopathological or immunopathological features between DI-SCLE and idiopathic SCLE were detected. There is now adequate published experience to suggest that DI-SCLE does not differ clinically, histopathologically or immunologically from idiopathic SCLE. It should be recognized as a distinct clinical constellation differing clinically and immunologically from the classical form of drug-induced systemic lupus erythematosus.

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.

Ultraviolet light output of compact fluorescent lamps: comparison to conventional incandescent and halogen residential lighting sources.

Patients with photosensitive dermatologic and systemic diseases often question the ultraviolet light (UVL) output of household lighting sources. Such individuals have increasing concern about potential UVL exposure from energy-efficient compact fluorescent lamps (CFL), as little data have been presented concerning their UVL output. The objective was to compare, via pilot study, the levels of ultraviolet A (UVA) and ultraviolet B (UVB) leak between residential lighting sources. Equivalent wattage CFL, incandescent and halogen bulbs were purchased from local retailers in Oklahoma City, Oklahoma, USA. The UVA and UVB outputs of these sources were measured under controlled conditions at 10, 25, 50, 100 and 150 cm away from the light source using an IL-1700 research radiometer equipped with UVA and UVB detectors. Negligible UVB and UVA was detected at 100 and 150 cm. Therefore, data were analysed from measurements at 10, 25 and 50 cm only. The results demonstrated UVA leak highest from incandescent and halogen bulbs, and UVB leak highest from CFL. The overall UVA/UVB leak was lowest from CFL shielded during the manufacturing process. In conclusion, patients with photosensitivity have choices depending on their relative risk from different UVL wavelength spectra. UVB exposure risk may be reduced the greatest by utilising CFL with manufacturer-provided shields.

Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis.

BACKGROUND: Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments. OBJECTIVES: We sought to demonstrate reliability and validity of the CDASI, and to compare the CDASI with other potential tools for use in measuring disease severity in cutaneous dermatomyositis. PATIENTS AND METHODS: CDASI has four activity and two damage measures, with scores from 0 to 148. DSSI assesses activity based on body surface area and severity on a scale of 0-72. CAT uses 21 activity and damage items, for a range of 0-175 for activity and 0-33 for damage. Ten dermatologists used the instruments to score the same 12-16 patients in one session. Global validation measures were administered to physicians and patients. RESULTS: Global validation measures correlated with the three outcome instruments (P < 0.0001). CAT displayed lower inter- and intrarater reliability relative to the CDASI. All scales correlate better with physician than patient global skin measures. CONCLUSIONS: It appears that the CDASI may be a useful outcome measure for studies of cutaneous DM. Further testing to compare responsiveness of all three measures is necessary.

A systematic review of juvenile-onset clinically amyopathic dermatomyositis.

BACKGROUND: Dermatomyositis (DM) presenting during childhood or adolescence classically encompasses hallmark cutaneous changes, proximal muscle weakness, and laboratory evidence of myositis. When cutaneous manifestations of DM are present without muscle weakness for > 6 months, the term 'clinically amyopathic DM' applies (syn. DM sine myositis). OBJECTIVES: To review the clinical and epidemiological features of published cases of juvenile-onset clinically amyopathic DM, with comparison with adult-onset clinically amyopathic DM and juvenile-onset classical DM. METHODS: Systematic review of the published literature. RESULTS: We identified 68 cases of juvenile-onset clinically amyopathic DM published during 1963-2006. The disease in 18 of 68 (26%) patients subsequently evolved to classical DM. Overall, the mean age at diagnosis was 10.8 years (range 2-17) with nearly equal male/female ratio and mean follow-up of 3.9 years. Among cases with diagnostic testing, 10 of 19 had a positive antinuclear antibody titre, two of nine had elevated erythrocyte sedimentation rate and two of 51 had elevated creatine kinase (CK). Of patients with normal CK, three of 22 had abnormal electromyography, one of 19 had abnormal muscle biopsy, and one of nine had abnormal magnetic resonance imaging. Calcinosis was reported in three of 68. No cases of severe vasculopathy (resulting in ulceration), interstitial lung disease or internal malignancy were reported. CONCLUSIONS: This review suggests a good prognosis for children with clinically amyopathic DM. A minority of patients with negative muscle enzymes had positive ancillary testing for myositis, and these patients rarely developed muscle weakness. Predictive factors for progression to classical DM were not identified. Symptomatic treatment of cutaneous involvement and close clinical monitoring may be an alternative to aggressive immunosuppression.

Dermatology position paper on the revision of the 1982 ACR criteria for systemic lupus erythematosus.

The 1982 ACR classification criteria have become de facto diagnostic criteria for systemic lupus erythematosus (SLE), but a review of the criteria is necessary to include recent diagnostic tests. The criteria were not developed with the help of dermatologists, and assign too much weight to the skin as one expression of a multiorgan disease. Consequently, patients with skin diseases are classified as SLE based mostly on skin symptoms. We discuss specific problems with each dermatologic criterion, but changes must await a new study. We suggest the following guidelines for such a study, aimed at revision of the criteria. 1) The SLE patient group should be recruited in part by dermatologists. 2) The study should evaluate an appropriate international ethnic/racial mix, including late onset SLE as well as pediatric patients. 3) All patients should have current laboratory and clinical evaluations, as suggested in the paper, to assure the criteria can be up-to-date. This includes anti-SS-A and anti-SS-B antibodies and skin biopsies for suspected cutaneous lupus erythematosus except for nonscarring alopecia and oral ulcers. 4) The study should be based on a series of transparent power calculations. 5) The control groups should represent relevant differential diagnoses in numbers large enough to assess diagnostic problems that might be specific to these differential diagnoses. In order to demonstrate specificity of the criteria with a 95% confidence interval between 90 and 100%, each control group of the above should have at least 73 patients.

Antimalarial lichenoid tissue reactions in patients with pre-existing lupus erythematosus.

Recently a number of cases of drug induction or exacerbation of lupus erythematosus (LE) specific skin disease have been described in the literature. Many of the responsible medications are also known for their ability to induce a lichenoid tissue reaction. Aminoquinoline antimalarials are currently the first line of therapy in cutaneous LE specific skin disease. Lichenoid tissue reactions are among the most common cutaneous side effects of aminoquinolone antimalarials. We report three cases of aminoquinolone antimalarial induced or exacerbated LE specific skin disease. We also review the pathophysiology of LE specific skin disease and propose a mechanism by which induction of the lichenoid tissue reaction may result in Koebnerization of LE specific skin lesions.

Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP): a case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin lesions.

The acute clinical syndrome of toxic epidermal necrolysis (TEN) is currently thought to be a distinct clinical-pathological entity typically resulting from drug hypersensitivity. We describe an adult woman who experienced a fulminate pattern of apoptotic epidermal cell injury following tanning bed exposure while taking naproxen that resulted in a clinical presentation having combined features of drug-induced TEN and an infrequently recognized form of bullous cutaneous lupus erythematosus (LE). This case calls attention to the fact that TEN-like injury can occasionally be seen in settings other than drug hypersensitivity (e.g., LE, acute graft versus host disease) and illustrates the need for a unifying concept in this area. We therefore propose the term 'Acute Syndrome of Apoptotic Pan-Epidermolysis (ASAP)' to designate a clinical syndrome that is characterized by life-threatening acute and massive cleavage of the epidermis resulting from hyperacute apoptotic injury of the epidermis. We also review vesiculobullous skin disorders that can be encountered in LE patients and suggest a new classification scheme for such lesions.

Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus.

We report an association between a non-familial form of photosensitive Lupus-specific skin disease, subacute cutaneous lupus erythematosus (SCLE), and a new single nucleotide polymorphism (SNP) in the C1QA gene. We also describe an association between this SNP and lower levels of serum C1q. This SNP consists of adenine replacing the third guanine in the codon for aminoacid residue Gly70 (position excludes the 22 amino acid leading peptide) that is located in the second exon of the C1QA gene. We have designated this SNP C1qA-Gly70GGA (the GenBank sequence at this location is C1qA-Gly70GGG). A survey of 19 SCLE patients showed that 11 (58%) were homozygous for C1qA-Gly70GGA SNP, seven (37%) were heterozygous, and only one patient (5%) was homozygous for the GenBank sequence. In contrast, only 13 of 62 (21%) normal controls were homozygous for the C1qA-Gly70GGA SNP, 41 (66%) controls were heterozygous and eight (13%) controls were homozygous for the GenBank sequence. Thus, the C1qA-Gly70GGA SNP is strongly associated with SCLE (P-value = 0.005 by chi-square analysis with Yates correction). This SNP would traditionally be classified as clinically silent as it does not encode a different amino acid. However, our studies have suggested that this SNP appears to be associated with a functional abnormality of C1q expression since its presence correlates inversely with serum levels of C1q antigenic protein in both SCLE patients and normal controls. The mechanism by which this phenotypic change is associated with the translationally silent (synonymous) ClqA-Gly70GGA genetic variation is currently unknown.

Preserving medical dermatology. A colleague lost, a call to arms, and a plan for battle.

Change within dermatology as a clinical discipline is expected and inevitable. However dermatology may change as a medical specialty in the new millennium, there will still be patients with medical dermatologic disease whose optimal care will depend on skin disease specialists' having the highest level of training and experience in medical dermatology. Dermatologists who have subspecialized in medical dermatology will provide the role models for new generations of dermatologists, perform the patient-oriented research, and care for the more complicated patients. Thus, if during its evolution, dermatology loses the ability to train and support medical dermatologists, it will be weakened as the discipline that can best care for skin disease. Clearly, the loss of talented academicians such as the person whose career was outlined in the case report presented at the beginning of this article should be a huge warning sign that the future of medical dermatology as a specialty is uncertain. The Medical Dermatology Society hopes to develop a coalition with all other leadership organizations within dermatology to deal with this problem effectively. There is a need for a broader discussion within organized dermatology of the growing crisis in this area and how all dermatology leadership organizations working together can develop an action plan for effectively dealing with this important but challenging problem. Dermatology must ask itself what it wants to look like as a medical specialty in the future. Without an steady stream of young clinician-investigators focused on the many challenging problems in medical dermatology, dermatology will not exist as the specialty it is today.

The pathophysiology of photosensitivity in lupus erythematosus.

The strong association between photosensitivity and lupus erythematosus has led to the suggestion that abnormal photoreactivity participates in the pathogenesis of cutaneous lesions. In this review we discuss the evidence for abnormal cutaneous reactivity to sunlight in lupus and speculate on the cellular, molecular and genetic factors that may underlie this abnormality.

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.

Anti-calreticulin segregates anti-Ro sera in systemic lupus erythematosus: anti-calreticulin is present in sera with anti-Ro alone but not in anti-Ro sera with anti-La or anti-ribonucleoprotein.

OBJECTIVE: To examine a well characterized group of patients with systemic lupus erythematosus (SLE) for anti-calreticulin. METHODS: The sera of 77 patients with SLE were studied by immunodiffusion, solid phase immunoassay, and immunoblot for antibodies against ribonucleoprotein (RNP) autoantigens and calreticulin. RESULTS: Thirty-five had anti-calreticulin and 40 had anti-60 kDa Ro. There was no association of anti-60 kDa Ro and anti-calreticulin. However, among anti-60 kDa Ro positive sera that also contained either anti-La or anti-RNP, none of 18 had anti-calreticulin. All the remaining sera with anti-60 kDa Ro had anti-calreticulin and anti-52 kDa Ro. CONCLUSION: Anti-60 kDa Ro patients with SLE can be divided into those with anti-60 kDa Ro and either anti-La or anti-RNP or those with anti-60 kDa Ro, anti-52 kDa Ro, and anti-calreticulin.

Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis.

This review will focus on the work that has been reported over the past year attempting to better characterize the overall clinical significance of the cutaneous manifestations of dermatomyositis (DM). It will be organized under two headings--amyopathic dermatomyositis (ADM) and classic dermatomyositis (CDM). The distinction between these two clinical phenotypes of DM is the absence of clinically-evident muscle disease in ADM; to date it has not been possible to distinguish the cutaneous manifestations of ADM and CDM. The term hypomyopathic DM is introduced to distinguish those patients with the hallmark skin changes of DM and no clinical evidence of muscle disease who are found to have subclinical evidence of myositis upon electrophysiologic, histopathologic, and/or radiologic evaluation. Recent issues that have been raised concerning the definition, classification, epidemiology, etiopathogenesis, clinical features, treatment, differential diagnosis, and prognosis of ADM and CDM are discussed. In view of the irrefutable evidence documenting the existence of ADM for 20 years or more, the term idiopathic inflammatory dermato-myopathies may be more appropriate for this group of clinical disorders than the currently used designation, idiopathic inflammatory myopathies.

C1q inhibits autoantibody binding to calreticulin.

Calreticulin (CR) is a new rheumatic disease-associated autoantigen that is intimately associated with the Ro/SS-A ribonucleoprotein. CR autoantibodies are frequently observed in patients with photosensitive forms of lupus erythematosus (LE). CR has been shown to be highly homologous to cC1q-R, the cell surface receptor that binds the collagenous domain of the first component of complement, C1q. C1q has also been shown to directly bind to CR. We therefore asked whether the binding of C1q to CR might interfere with the binding of CR autoantibody to CR. Full-length recombinant human CR, an E. coli fusion proteins was used as antigen in a direct enzyme-linked immunosorbent assay (ELISA). CR autoantibody-containing sera were assayed before and after C1q removal by two different methods: by heating sera at 56 degrees C for 30 min or adding monoclonal anti-C1q antibodies. ELISA optical density (OD) values were found to be consistently higher in sera depleted of C1q by both methods compared to unmodified sera. The addition of purified C1q to C1q-depleted sera resulted in ELISA OD values similar to those of unmodified sera. These results suggest that C1q levels present in human serum can inhibit the binding of CR autoantibody to CR. One can speculate that the failure of C1q to mask CR autoepitopes in individuals with genetic deficiency of C1q could contribute to the high rate of photosensitive LE that occurs in such individuals.

Protein-protein interactions between native Ro52 and immunoglobulin G heavy chain.

Using a yeast two-hybrid system to search for proteins interacting with Ro52 autoantigen, we identified a novel protein-protein interaction. Two different cDNA clones, which interacted with Ro52 in the yeast two-hybrid system, were identified and isolated from a human B-cell library. Surprisingly, both clones encoded the heavy chain of human IgG1. The expression of both HIS3 and beta-galactosidase reporter genes in yeast suggested that the interaction between Ro52 and IgG occurred in vivo. In vitro studies utilizing recombinant Ro52 and purified immunoglobulins indicated that the interaction was immunoglobulin class and subclass specific. Ro52 interacted with IgG1 and IgG4, but not with IgG2, IgG3, IgA or IgM. Ro52 could also precipitate IgG directly from serum. The identified cDNA clones did not include the variable region of IgG, which suggested a non-classical interaction independent of antibody specificity. We further mapped the domain of Ro52 responsible for this interaction to the C-terminus rfp-like region. In conclusion, our data support an unusual interaction between native Ro52 and IgG. The potential biological significance of this unusual protein-protein interaction is discussed.