Decreasing tobacco use promotes ulcer healing in a patient with Buerger's disease.

Tobacco cessation remains the mainstay treatment for Buerger's Disease; however, limited research exists examining the effect of decreased tobacco use rather than cessation in improving symptoms. We describe a case of a patient with Buerger's disease who experienced ulcer healing and pain improvement through reduced tobacco use.

Acute Cutaneous Necrosis: A Guide to Early Diagnosis and Treatment.

Acute cutaneous necrosis is characterised by a wide range of aetiologies and is associated with significant morbidity and mortality, warranting complex considerations in management. Early recognition is imperative in diagnosis and management of sudden gangrenous changes in the skin. This review discusses major causes of cutaneous necrosis, examines the need for early assessment, and integrates techniques related to diagnosis and management. The literature, available via PubMed, on acute cutaneous necrotic syndromes was reviewed to summarise causes and synthesise appropriate treatment strategies to create a clinician's guide in the early diagnosis and management of acute cutaneous necrosis. Highlighted in this article are key features associated with common causes of acute cutaneous necrosis: warfarin-induced skin necrosis, heparin-induced skin necrosis, calciphylaxis, pyoderma gangrenosum, embolic phenomena, purpura fulminans, brown recluse spider bite, necrotising fasciitis, ecthyma gangrenosum, antiphospholipid syndrome, hypergammaglobulinemia, and cryoglobulinemia. This review serves to increase recognition of these serious pathologies and complications, allowing for prompt diagnosis and swift limb- or life-saving management.

Molecular Subsetting of Interferon Pathways in Sjögren's Syndrome.

OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features. METHODS: Clinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed. RESULTS: A total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high-titer antinuclear antibody, anti-SSA, and high focus score on labial salivary gland [LSG] biopsy). Three distinct patterns of IFN were evident: type I-predominant, type II-predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II-predominant IFN. CONCLUSION: The SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN-targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient.

Palmoplantar pustular psoriasis following initiation of a beta-blocker: disease control with low-dose methotrexate.

Palmoplantar pustular psoriasis is a debilitating chronic disease that can have a serious impact on patients' quality of life. There currently is no therapeutics standard for controlling palmoplantar pustular psoriasis, but various treatments, many of which have serious toxic side effects, have been used to treat this disease, including methotrexate. We report a case of palmoplantar pustular psoriasis in a 76-year-old woman that was triggered by initiation of a beta-blocker. The patient's condition was controlled with a low-dose regimen of methotrexate. It is important for dermatologists to recognize that pustular psoriasis can be treated with low-dose methotrexate to avoid potentially toxic effects of higher doses of methotrexate, which is especially true in cases of drug-induced disease, as seen in our patient.

Anti-melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum.

OBJECTIVE: Autoantibodies against melanoma differentiation-associated protein 5 (MDA-5) have been described in several Asian dermatomyositis (DM) cohorts, often associated with amyopathic DM and rapidly progressive interstitial lung disease (ILD). A recent study of a DM cohort seen at a US dermatology clinic reports that MDA-5 autoantibodies are associated with a unique cutaneous phenotype. Given the widening spectrum of clinical findings, we evaluated the clinical features of anti-MDA-5-positive patients seen at a US myositis referral center. METHODS: One hundred sixty DM patients were screened for MDA-5 autoantibodies by immunoprecipitation and antibody titers were analyzed in longitudinal serum samples. Anti-MDA-5-positive patients were evaluated for the presence of additional myositis autoantibodies. Patient clinical characteristics were compared by retrospective chart review. RESULTS: MDA-5 was targeted in 11 (6.9%) of 160 patients with DM. Of these, 9 presented with a symmetric polyarthropathy, 6 demonstrated overt clinical myopathy, and 8 had ILD. Eight anti-MDA-5-positive patients exhibited the clinical attributes of the antisynthetase syndrome in the absence of Jo-1 or other antisynthetase autoantibodies. MDA-5 autoantibody titers did not correlate with clinical course. CONCLUSION: MDA-5 autoantibodies are found in DM patients presenting with a symmetric polyarthritis, clinically similar to rheumatoid arthritis. These patients often have features of the antisynthetase syndrome, but in the absence of antisynthetase autoantibodies. Most anti-MDA-5-positive patients had overt clinical myopathy and ILD. The latter, while occasionally severe, typically resolved with immunosuppressive therapy. In this cohort, the MDA-5 phenotype is frequently a clinical mimic of the antisynthetase syndrome and is not associated with rapidly progressive ILD.

Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases.

Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ-induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy.

Use of outcome events in surgical trials: a systematic review.

BACKGROUND: Surgical trials sometimes fail to clearly identify the primary outcome events of interest. This results in trials that are diffuse and difficult to interpret. OBJECTIVE: The objective of this study was to systematically review the use of outcome events in surgical trials. DATA SOURCES: Surgical trials published between 1 January 2007 and 30 June 2010 in 26 peer-reviewed journals representing a wide range of specialty interests were used in this study. REVIEW METHODS: Copies of all potentially relevant articles were scrutinized to identify the admissible surgical trials. Two investigators experienced in health research methods used a standardized form to extract discrete information (i.e. it was an 'identifying and counting' exercise that did not require subjective evaluations). All forms were double-checked. RESULTS: Twenty-four per cent (130 out of 531) of the trials failed to declare the primary outcome events - 11% (56 out of 531) of the trials indicated the primary outcome events in the abstract, but not in the body of the article. The compliant trials used a median of three primary outcome events (interquartile range: 2-5, absolute range: 1-17), and a median of 19 statistical comparisons (interquartile range: 9-32, absolute range: 1-130). Only 2% (11 out of 531) of the trials made an adjustment for the multiple testing of statistical significance (9 of these trials declared a single primary outcome event). Composite outcome events appeared in 9% (48 out of 531) of the trials and these studies contained a median of 24 statistical comparisons. CONCLUSIONS: Many surgical trials fail to clearly define the specific outcome events of interest, and this is often accompanied by a subversive number of statistical comparisons.

Identification of novel autoantigens by a triangulation approach.

High titer autoantibodies, which are often associated with specific clinical phenotypes, are useful diagnostically and prognostically in systemic autoimmune diseases. In several autoimmune rheumatic diseases (e.g. myositis and Sjogren's syndrome), 20-40% of patients are autoantibody negative as assessed by conventional assays. The recent discovery of new specificities (e.g., anti-MDA5) in a subset of these autoantibody-negative subjects demonstrates that additional specificities await identification. In this manuscript, we describe a rapid multidimensional method to identify new autoantigens. A central foundation of this rapid approach is the use of an antigen source in which a pathogenic pathway active in the disease is recapitulated. Additionally, the method involves a modified serological proteome analysis strategy which allows confirmation that the correct gel plug has been removed prior to sending for sequencing. Lastly, the approach uses multiple sources of information to enable rapid triangulation and identification of protein candidates. Possible permutations and underlying principles of this triangulation strategy are elaborated to demonstrate the broad utility of this approach for antigen discovery.

Isolated elevation of aldolase in the serum of myositis patients: a potential biomarker of damaged early regenerating muscle cells.

OBJECTIVES: Elevated serum aldolase A levels occur in the absence of elevated creatine kinase M (CK) levels in a subset of myositis patients. This study was undertaken to investigate the cell biology of this unexplained clinical observation. METHODS: Cultured human myoblasts were differentiated in vitro. RNA and protein lysates were prepared and used to determine aldolase and CK gene and protein expression by QPCR and immunoblotting. Cardiotoxin was used to induce muscle injury and repair in an experimental mouse model, and aldolase A and CK were immunoblotted in the muscle lysates. Immunohistochemical staining was performed on myositis patient muscle paraffin sections to assess aldolase A and CK staining in vivo. RESULTS: Aldolase A mRNA and protein expression is highest in differentiating myoblasts, and remains robust throughout differentiation. In contrast, CK mRNA and protein levels are low in undifferentiated myoblasts and become strikingly upregulated as differentiation progresses. Aldolase A protein expression is high in regenerating muscle in the mouse model of injury/repair, while CK expression was low. Immunohistochemical staining of human myositis biopsies showed that muscle cells with the highest levels of aldolase and no CK staining have features of regeneration. CONCLUSIONS: In undifferentiated muscle cells, and those early in the differentiation process, aldolase A is expressed in the absence of CK. Thereafter, both are expressed. We propose that isolated serum aldolase A elevation in myositis patients (i) reflects preferential immune-mediated damage of early regenerative cells, and (ii) is a biomarker of damaged early regenerating muscle cells.

Use of drug therapy to manage acute cutaneous necrosis of the skin.

Acute cutaneous necrosis is defined as a sudden onset of gangrenous skin changes in the skin, associated with significant morbidity and mortality. The following diseases are included in this discussion: coumadin necrosis, heparin necrosis, brown recluse spider bite, necrotizing fasciitis, vasculitis, pyoderma gangrenosum, calciphylaxis, clotting abnormalities and embolic phenomena. The importance of early diagnosis, early distinction and early drug therapy or drug withdrawal must match the diagnosis for maximal preservation of the skin and underlying tissue.

Type I interferons: crucial participants in disease amplification in autoimmunity.

A significant body of data implicates the type I interferon (IFN) pathway in the pathogenesis of autoimmune rheumatic diseases. In these disorders, a self-reinforcing cycle of IFN production can contribute to immunopathology through multiple mechanisms. Type I IFN cytokines are pleiotropic in their effects, mediating antiviral and antitumor activities, and possess numerous immunomodulatory functions for both the innate and adaptive immune responses. A key principle of the type I IFN system is rapid induction and amplification of the signaling pathway, which generates a feed-forward loop of IFN production, ensuring that a vigorous antiviral immune response is mounted. Although such feed-forward pathways are highly adaptive when it comes to rapid and effective virus eradication, this amplification can be maladaptive in immune responses directed against host tissues. Such feed-forward loops, however, create special opportunities for therapy.