Molecular genetic investigation, clinical features and response to treatment in 21 patients with Schnitzler's syndrome

To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1β (IL-1β) production, although interest in the contribution of genetic factors has been fueled by detection of somatic NLRP3 mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic NLRP3, TNFRSF1A, NLRC4, or NOD2 mutations, apart from 1 patient with a germ line NLRP3 p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic NLRP3 mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients’ serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients

Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans

Background: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e. g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome. Methods: A prospective follow-up study of 109 patients with EM was conducted at the A land Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-gamma, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines. Findings: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-gamma in the EM biopsies (p = 0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels. Conclusion: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.Original Publication: Johanna Sjöwall, Linda Fryland, Marika Nordberg, Florence Sjögren, Ulf Garpmo, Christian Jansson, Sten-Anders Carlsson, Sven Bergstrom, Jan Ernerudh, Dag Nyman, Pia Forsberg and Christina Ekerfelt, Decreased Th1-Type Inflammatory Cytokine Expression in the Skin Is Associated with Persisting Symptoms after Treatment of Erythema Migrans, 2011, PLOS ONE, (6), 3, 0018220. http://dx.doi.org/10.1371/journal.pone.0018220 Copyright: Public Library of Science (PLoS) http://www.plos.org

The relation between mortality from malignant melanoma and early detection in the Cancer Research Campaign Mole Watcher Study

Between 1987 and 1989 the Cancer Research Campaign funded a health education programme for the early detection of cutaneous malignant melanoma in the general population in 6 health districts of England and 1 health board in Scotland (population of 3 million). The intervention was evaluated by studying its effects on annual and cumulative mortality rates for melanoma. Population-based data on mortality from melanoma were collected in the intervention areas, the health regions covering those areas, and 5 other health regions of England from 1981 to 1996. Deaths from melanoma in cases diagnosed after the start of the intervention were used to study cumulative mortality rates. The annual mortality rates for melanoma, 1981 to 1996, showed no significant difference in their trends between the intervention areas, and other areas of England and Wales. After adjustment for pre-intervention rates, there was also no significant reduction in cumulative mortality from melanoma in the intervention areas compared with the non-intervention areas: rate ratio 1.2 (95% Cl 0.9–1.7) in men, 0.9 (95% Cl 0.7–1.3) in females. The lack of a significant reduction in melanoma mortality associated with the intervention raises questions about this approach to early detection and emphasises the need for new strategies. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

The Cutaneous Spectrum of Lupus Erythematosus.

Systemic lupus erythematosus is a complex autoimmune disease with a wide spectrum of clinical and immunopathological features. Cutaneous and articular manifestations are the most common signs in patients with systemic lupus erythematosus. We here review the pathogenesis and the new classification of cutaneous lupus erythemathosus with a discussion of the significance of the various cutaneous signs. The lesions are classified according to the level of the cellular infiltrate and tissue damage in the epidermis, dermis, and/or subcutis. Furthermore, cutaneous lesions pointing to the presence of a thrombotic vasculopathy and those due to a distinct inflammatory, neutrophilic-mediated reaction pattern are highlighted. Particular attention will be given in describing the histology of skin manifestation. Treatment options for cutaneous lupus erythemathosus have increased with the introduction of new biological therapies. However, the majority of the patients still benefit from antimalarials, which remain the cornerstone of treatment. The evaluation and management of cutaneous lupus erythemathosus patients depend on the clinical findings and associated symptoms

Case Report: Capnocytophaga canimorsus A Novel Pathogen for Joint Arthroplasty

We report the case of a 59-year-old man with Waldenstrom’s macroglobulinemia and active alcohol use who presented with bilateral knee pain 5 years after a bilateral staged TKA. Cultures of synovial fluid and periprosthetic tissue specimens from both knees yielded, after prolonged anaerobic incubation, a catalase- and oxidase-positive gram-negative bacillus, which was identified as Capnocytophaga canimorsus by 16S ribosomal RNA PCR analysis. C canimorsus, an organism that is commonly found in dog and cat saliva, is a rare cause of various infections in immunocompromised and healthy individuals. However, a review of the medical literature indicates C canimorsus has not been reported previously to cause infection after joint arthroplasty. The patient was immunocompromised by cytotoxic chemotherapy, corticosteroids, and alcohol use. The patient was managed successfully with bilateral two-stage exchange and 6 weeks of intravenous ertapenem therapy. Because of its fastidious and slow-growing characteristics, C canimorsus may be an unrecognized cause of culture-negative joint arthroplasty infections, especially in cases when dog and cat exposure is evident in the clinical history

Complement in the immunopathogenesis of rheumatic disease.

The complement system has vital protective functions as a humoral component of the innate immune system and also through interactions with the adaptive immune system; however, when inappropriately activated or regulated, complement can cause inflammation and organ damage, and such processes are involved in the pathogenesis of many inflammatory conditions, not least rheumatic diseases. Furthermore, states of complement deficiency can predispose not only to infections, but also to autoimmune disorders, including rheumatic diseases such as systemic lupus erythematosus. In this Review, the mechanisms behind the pathogenic activities of complement in rheumatic diseases are discussed. Potential approaches to therapeutic intervention that focus on regulating complement activities in these disorders are also considered