Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.

Minocycline-Induced Gum Pigmentation during Treatment for Acne Vulgaris.

Minocycline, a type of tetracycline, is a broad-spectrum antibiotic that is commonly prescribed in dermatology for the treatment of acne vulgaris. Common side effects of minocycline include nausea, vertigo, and dizziness while less common side effects include hyperpigmentation. In this case study, we found an 18-year-old female who presented with dark blue pigmentation in her upper gum after using minocycline on and off for 4 years. After discontinuation of the minocycline for 2 years, the pigmentation decreased gradually.

Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice.

The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.

Neonatal Dermatology: The Normal, the Common, and the Serious.

The objective of this review is to help practitioners of neonatal and pediatric medicine become more familiar with diagnosing and managing neonatal skin conditions. This article will discuss normal neonatal skin care and benign and common rashes, as well as some of the serious dermatologic conditions that require specialists for further evaluation and/or treatment.

Light, including ultraviolet.

Ultraviolet (UV) light is intricately linked to the functional status of the cutaneous immune system. In susceptible individuals, UV radiation can ignite pathogenic inflammatory pathways leading to allergy or autoimmunity. In others, this same UV radiation can be used as a phototherapy to suppress pathogenic cutaneous immune responses. These vastly different properties are a direct result of UV light's ability to ionize molecules in the skin and thereby chemically alter them. Sometimes these UV-induced chemical reactions are essential, the formation of pre-vitamin D(3) from 7-dehydrocholesterol, for example. In other instances they can be potentially detrimental. UV radiation can ionize a cell's DNA causing adjacent pyrimidine bases to chemically bond to each other. To prevent malignant transformation, a cell may respond to this UV-induced DNA damage by undergoing apoptosis. Although this pathway prevents skin cancer it also has the potential of inducing or exacerbating autoreactive immune responses by exposing the cell's nuclear antigens. Ultraviolet-induced chemical reactions can activate the immune system by a variety of other mechanisms as well. In response to UV irradiation keratinocytes secrete cytokines and chemokines, which activate and recruit leukocytes to the skin. In some individuals UV-induced chemical reactions can synthesize novel antigens resulting in a photoallergy. Alternatively, photosensitizing molecules can damage cells by initiating sunburn-like phototoxic reactions. Herein we review all types of UV-induced skin reactions, especially those involving the immune system.

Erythema induratum of Bazin.

An 81-year-old woman with a history of renal cell carcinoma and years of slowly, progressively enlarging pulmonary nodules of uncertain etiology presented with several weeks of painful lower extremity nodules. A biopsy revealed changes consistent with nodular vasculitis. A purified protein derivative and QuantiFERON test were positive, favoring the diagnosis of erythema induratum of Bazin. Treatment with a standard four-drug antituberculous regimen resulted in radiographic and clinical improvement. This case emphasizes the importance of dermatologic manifestations in the detection of systemic disease.

Innate immunity: a cutaneous perspective.

The first responsibility for protection against microbial infection rests on the normal function of the innate immune system. This system establishes an antimicrobial barrier, recognizes attempts to breach this barrier, and responds rapidly to danger, all based on an innate defense system. Here, we review this system as it applies to mammalian skin, highlighting how a physical, cellular, and chemical barrier is formed to resist infection. When challenged, the diverse cellular components of the skin recognize the nature of the challenge and respond with an appropriate antimicrobial program including the release of antimicrobial peptides and, when necessary, recruitment and coordination with adaptive immune responses. Recent insights into these processes have advanced the understanding of disease pathogenesis and provided new therapeutic options for a variety of skin diseases.

Biologic therapies in the treatment of psoriasis: a comprehensive evidence-based basic science and clinical review and a practical guide to tuberculosis monitoring.

The treatment of psoriasis has undergone a revolution with the advent of biologic therapies including infliximab, etanercept, adalimumab, efalizumab, golimumab, certolizumab, alefacept, secukinumab, abatacept, and ustekinumab. These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications. Herein, we present a comprehensive, unbiased comparison of these medications focusing on their differences. For example, TNF antagonists can differ in the way they are dissolved and administered, the effector molecules they can bind, serum peak and trough levels, the types of intracellular signals they can induce, the in vivo complexes that they can form, their protein structure, and their incidence and timing of rare adverse events, among other things. A critical review of the clinical studies that have tested the efficacy of these molecules is also presented including head-to-head comparison trials. The safety of biologics in terms of their long-term adverse events is discussed, as is their use in different types of psoriasis and in different patient populations. Finally, all anti-TNF agents have been associated with a variety of serious and "routine" opportunistic infections, particularly tuberculosis. For this reason, anti-tuberculosis testing both prior to the initiation of a biologic therapy and annually during treatment is pertinent. The uses and limitations of both the tuberculin skin test (TST) and QuantiFeron®-TB Gold (QFT) are discussed, as is the care of patients who present with latent tuberculosis infection prior to the initiation of biologic therapy. Recommendations for tuberculosis monitoring are provided.

The etiology of paraneoplastic autoimmunity.

Although they may sometimes appear similar, paraneoplastic autoimmunity has a unique pathogenesis, different from the classical autoimmune diseases not associated with cancer. When distinguished clinically, paraneoplastic autoimmunity is more severe and often presents with a broader range of clinical signs and symptoms. Management of these patients is difficult and is usually centered in part on treatment of the underlying malignancy. Self-antigens recognized in the setting of paraneoplastic autoimmunity can be diverse, and the number of determinants recognized within a single antigen can be numerous. This review uses prototypic examples of paraneoplastic immune-mediated diseases and their associated malignancies to describe the mechanisms by which immune dysregulation can occur in the setting of cancer. Specific diseases covered include paraneoplastic pemphigus, Sweet's syndrome, pyoderma gangrenosum, thymoma-associated multiorgan autoimmunity, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, and the paraneoplastic neurological syndromes. The malignancies discussed include thymoma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia, among others. The mechanisms by which cancers induce autoimmunity are broken down into the following categories: disruption of central tolerance, peripheral immune dysregulation, and alteration of self-antigens. For each category, examples of paraneoplastic autoimmune diseases and their associated malignancies are discussed. Finally, mechanisms by which cancer treatment can lead to autoimmunity and examples of polymorphisms that are linked to both cancer and autoimmunity are discussed.

Effective Strategies for the Management of Pyoderma Gangrenosum.

BACKGROUND: Pyoderma gangrenosum (PG) is an inflammatory disease characterized by painful ulcerations. It is often associated with other systemic inflammatory diseases, especially inflammatory bowel disease (IBD) and autoimmune arthritis. THE PROBLEM: PG does not have characteristic serologic or histologic features. Therefore, other potential causes such as malignancy, vasculitis, infection, and coagulation disorders should be ruled out. In addition, patients often have aggressive disease that is refractory to immunosuppressive therapy, but there is only a paucity of clinical data to help direct therapy. BASIC/CLINICAL SCIENCE ADVANCES: There are several lines of evidence to support an immunologic etiology of PG. Although the pathogenesis is still not well understood, it is clear that PG is associated with the upregulation of several cytokines including interleukin 8 (IL-8), tumor necrosis factor (TNF), IL-1ß, IL-6, and interferon gamma, among many others. TNF and IL-1ß are of particular interest, because some biologic medications that target these cytokines have been effective in treating PG. CLINICAL CARE RELEVANCE: Multiple drugs are available to help control PG. Biologics, intravenous immunoglobulin (IVIG), and conventional immunosuppressive drugs have been reported to be effective. Multidrug therapies should be considered for refractory cases. CONCLUSION: PG is a complex inflammatory disease with multiple involved pathways. Anti-TNF agents and IVIG represent a significant advancement in treatment options. Since some biologic therapies are relatively new, their unknown long-term side effects should be taken into consideration.

IgE, mast cells, and eosinophils in atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with specific immune and inflammatory mechanisms. Atopy is among the major features of the diagnosis criteria for AD but is not an essential feature. Thus, patients diagnosed with AD can be atopic or non-atopic. This review focuses on the role of IgE, mast cells, and eosinophils in the pathogenesis of AD. The known functions of IgE in allergic inflammation suggest that IgE and IgE-mediated mast cell and eosinophil activation contribute to AD, but direct evidence supporting this is scarce. The level of IgE (thus the degree of allergic sensitization) is associated with severity of AD and contributed by abnormality of skin barrier, a key feature of AD. The function of IgE in development of AD is supported by the beneficial effect of anti-IgE therapy in a number of clinical studies. The role of mast cells in AD is suggested by the increase in the mast cell number and mast cell activation in AD lesions and the association between mast cell activation and AD. It is further suggested by their role in mouse models of AD as well as by the effect of therapeutic agents for AD that can affect mast cells. The role of eosinophils in AD is suggested by the presence of eosinophilia in AD patients and eosinophil infiltrates in AD lesions. It is further supported by information that links AD to cytokines and chemokines associated with production, recruitment, and activation of eosinophils.

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream.

There are limited treatment options for metastatic melanoma, which is almost universally fatal. We report the successful treatment of 64 of 64 cutaneous and subcutaneous melanoma metastases in three patients using high-dose (22 million units per 1.2 ml) intralesional interleukin 2 (IL-2) in combination with topical imiquimod and a retinoid cream. Before intralesional therapy, all patients had been treated surgically and were no longer considered surgical candidates. Rebiopsy of 15 of the treatment sites and long-term follow-up (10, 12, and 27 months) showed regression of all treated tumors. Six months after discontinuation of therapy, one patient developed multiple new cutaneous metastases, but these were also responsive to treatment with intralesional therapy. The other two patients did not experience recurrence of their cutaneous melanoma. However, one of the two patients developed lymph node and brain metastases 18 months after initiation of intralesional therapy, but is still alive, now at 27 months. The concentration of IL-2 used for the intralesional therapy was much higher than in previously reported cases, which may explain the excellent responses that were observed. These results support intralesional high-dose IL-2 as a very effective therapy for controlling cutaneous metastatic melanoma. Additional studies are needed to determine whether this therapy is associated with a survival benefit.

Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2.

Inflammation under sterile conditions is not well understood despite its importance in trauma and autoimmune disease. To investigate this process we established mouse models of sterile injury and explored the role of hyaluronan in mediating inflammation following injury. The response of cultured monocytes to hyaluronan was different than the response to lipopolysaccharide (LPS) despite both being dependent on Toll-like receptor 4 (TLR4). Cultured cells exposed to hyaluronan showed a pattern of gene induction that mimics the response seen in mouse skin after sterile injury with an increase in molecules such as transforming growth factor-beta2 and matrix metalloproteinase-13. These factors were not induced by LPS despite the mutual dependence of both hyaluronan and LPS on TLR4. Explanation for the unique response to hyaluronan was provided by observations that a lack of TLR4 or CD44 in mice diminished the response to sterile injury, and together with MD-2, was required for responsiveness to hyaluronan in vitro. Thus, a unique complex of TLR4, MD-2, and CD44 recognizes hyaluronan. Immunoprecipitation experiments confirmed the physical association of TLR4 and CD44. Taken together, our results define a previously unknown mechanism for initiation of sterile inflammation that involves recognition of released hyaluronan fragments as an endogenous signal of tissue injury.