Subacute cutaneous lupus erythematosus and dermatomyositis associated with anti-programmed cell death 1 therapy.

Programmed cell death 1 (PD-1) blockade has rapidly emerged as an effective therapy for a wide variety of metastatic malignancies. It has been associated with multiple immune-related adverse effects, including cutaneous eruptions. We describe two patients with clinical and histological findings that were consistent with subacute cutaneous lupus erythematosus (SCLE) after receiving PD-1 inhibitor therapy for metastatic lung cancer. We successfully treated our first patient with systemic and topical steroids, photoprotection and hydroxychloroquine. However, he subsequently developed dermatomyositis after continuing PD-1 inhibitor therapy. Our second patient presented with a protracted course of a cutaneous eruption in spite of discontinuation of anti-PD-1 therapy and treatment with systemic corticosteroids and infliximab. This patient's SCLE resolved after the addition of topical steroids and photoprotection and discontinuation of anti-tumour necrosis factor therapy. She and her oncology team decided to pursue non-PD-1 inhibitor treatment for lung cancer owing to a lack of tumour response. We add SCLE and dermatomyositis to the growing list of autoimmune complications of PD-1 blockade. Our cases raise a number of questions, particularly in relation to the viability of continuing anti-PD-1 therapy after developing SCLE and the role of immunosuppressive therapy in patients with PD-1 inhibitor-associated connective tissue disease. What's already known about this topic? Programmed cell death 1 (PD-1) blockade, which is rapidly emerging as a therapy for a wide variety of metastatic malignancies, has been associated with multiple immune-related adverse effects. These include systemic autoimmune diseases such as colitis and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects of PD-1 inhibitors most commonly reported in clinical trials include lichenoid reactions, eczematous dermatitis and vitiligo. What does this study add? We report two cases of PD-1 inhibitor-associated subacute cutaneous lupus erythematosus (SCLE), with one patient progressing to dermatomyositis with continued PD-1 inhibitor treatment. In addition to being a novel cutaneous adverse event, we also demonstrate the possibility of development of multiple autoimmune diseases in one patient, which is different from classic drug-related SCLE. We discuss the treatment challenges for patients with autoimmune skin disease receiving PD-1 inhibitor therapy.

Should all patients undergoing treatment with biologic agents be screened annually for latent tuberculosis infection with an interferon gamma release assay?

Systemic biologic therapy has become commonplace for the treatment of a variety of inflammatory dermatologic conditions, particularly psoriasis. Screening for latent tuberculosis infection (LTBI) is recommended prior to initiation of systemic biologic agents, and an interferon gamma release assays (IGRA) is often used as the screening modality. Annual screening for LTBI is also recommended for patients while on systemic biologic therapy, but the literature does not clearly support how often screening should be performed. In addition, serial testing with IGRAs, particularly among low-risk populations without any new tuberculosis (TB) exposures, has proven to be unreliable with frequent reversions and conversions. We propose that in low-incidence TB regions, repeat LTBI screening should only be considered for patients on systemic biologic therapy if any new TB exposures occurred since initial LTBI screening was performed prior to starting biologic therapy. This strategy aims to reduce false-positive LTBI testing that can expose patients to hazardous antibiotics and result in the unnecessary interruption of systemic biologic therapy.

A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone.

BACKGROUND: Pemphigus vulgaris (PV) is a blistering disease and tumour necrosis factor-α has a role in its pathogenesis. OBJECTIVES: To evaluate the safety of infliximab (IFX) with prednisone compared with prednisone alone in the treatment of PV. In addition, treatment response was assessed and mechanistic studies were performed. METHODS: Subjects with PV who had ongoing disease activity while being maintained on prednisone were randomized to receive either IFX or placebo in addition to prednisone. Response status and immunoglobulin (Ig) G anti-desmoglein (Dsg)1 and Dsg3 antibodies were assessed at 18 and 26 weeks. RESULTS: Ten subjects were randomized to each group. There were no safety signals during the course of the study. At week 18, one subject in each group had responded. At week 26, three IFX-treated subjects vs. none in the placebo group had responded (P = 0·21). At weeks 18 and 26, the median IgG anti-Dsg1 and anti-Dsg3 levels were lower in the IFX-treated patients [IgG anti-Dsg-1 (week 18, P = 0·035; week 26, P = 0·022); IgG anti-Dsg3 (week 18, P = 0·035; week, 26 P = 0·05)]. CONCLUSIONS: This study is limited by the relatively small sample size. There was no significant difference between study arms in the proportion of subjects with treatment-related adverse events > grade 3. IFX therapy was not shown to be effective for the treatment of patients with PV in this randomized, placebo-controlled trial, although IFX treatment may be associated with a decrease in anti-Dsg1 and Dsg3 antibodies.

Effects of Y27632 on keratinocyte procurement and wound healing.

A number of Rho-kinase inhibitors have been developed for various clinical applications. We examined the effects of the Rho-kinase inhibitor Y27632 on keratinocyte proliferation and migration, and found that it promoted primary human keratinocyte proliferation and migration in both monolayer and skin explant cultures. In addition, topical application of Y27632 enhanced cutaneous wound closure in the majority of wounds in mice. The growth and migration effects of Y27632 appeared to be specific to keratinocytes compared with dermal fibroblasts, and required intact Jun kinase function. Y27632 seems to be a promising agent for keratinocyte procurement and wounding healing.

Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function.

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.

Neutrophil CD11b, L-selectin and Fc IgA receptors in patients with dermatitis herpetiformis.

BACKGROUND: The skin lesions found in patients with dermatitis herpetiformis (DH) are characterized by the presence of neutrophils at the dermal papillary tips in areas where the diagnostic cutaneous IgA deposits are found. Although the presence of the skin lesions of DH is known to be associated with gluten-sensitive enteropathy, the mechanisms that control the development of skin lesions are not known. OBJECTIVES: To determine if circulating neutrophils from patients with DH have evidence of priming as shown by increased expression of CD11b, decreased expression of L-selectin and increased function of neutrophil Fc IgA receptor. METHODS: Neutrophils from 12 normal subjects and 10 DH patients with active, ongoing disease and 14 DH patients with quiescent disease activity were examined by fluorescence-activated cell sorter for expression of cell surface CD11b, L-selectin expression, Fc IgA expression (CD89) and for the function of the Fc IgA receptor by determining the binding capacity of neutrophils for monoclonal human IgA. RESULTS: Neutrophils from patients with active, ongoing DH had increased expression of CD11b when compared with patients with inactive DH or normal subjects [mean net geometric mean channel fluorescence (GMCF): active DH, 403.3; inactive DH, 237.8; normal subjects, 290.5; P < 0.05]. L-selectin expression in both groups of DH patients was significantly lower than that seen in normal subjects (mean net GMCF: active DH, 363.2; inactive DH, 375.2; normal subjects, 432.7; P < 0.05). No difference in CD89 expression was seen in any of the groups; however, the function of Fc IgA receptor was increased in patients with active DH when compared with patients with inactive DH and normal subjects. CONCLUSIONS: Neutrophils from patients with active, ongoing DH show an increased expression of CD11b, decreased expression of L-selectin and increased ability to bind IgA, consistent with a pattern of priming of the neutrophils. This priming may occur in the gut as a result of the ongoing mucosal immune response that is present in patients with DH on a gluten-containing diet and may predispose neutrophils to localize in the skin of patients with DH.

Combination treatment of bullous pemphigoid with anti-CD20 and anti-CD25 antibodies in a patient with chronic graft-versus-host disease.

In this case report we describe a novel treatment with two chimeric monoclonal antibodies (MoAb) targeting the autoimmune B cell clone responsible for bullous pemphigoid (BP) as a manifestation of steroid refractory chronic graft-versus-host disease (GVHD) that developed after unrelated cord blood transplantation. Monitoring the BP-specific circulating antibodies and CD25-expressing activated T lymphocyte subset led us to combine anti-CD20 (Rituximab) mediated B cell ablation with anti-CD25 (Daclizumab) therapy to block CD4(+) T cell help. Complete clinical and serologic response was achieved within 4 weeks of initiation of therapy allowing global immunosuppression to be dramatically reduced.

Increased production of IL-4 by gut T-cell lines from patients with dermatitis herpetiformis compared to patients with isolated gluten-sensitive enteropathy.

Dermatitis herpetiformis (DH) and isolated gluten-sensitive enteropathy (GSE) are gluten-sensitive diseases in which ingestion of dietary gluten results in the development of clinical disease. Patients with DH develop cutaneous IgA deposits and a severe skin disease, but rarely develop gastrointestinal symptoms. Patients with isolated GSE develop clinically significant gastrointestinal symptoms, but not skin disease or cutaneous IgA deposits. The aim of this study was to investigate the mechanism by which a mucosal immune response to the same dietary antigen can result in two distinct clinical phenotypes. T-cell lines were derived from activated T-cells in the small bowel mucosa of five patients with DH and 14 patients with isolated GSE and analyzed for T-cell markers and cytokine production in vitro. T-cell lines from DH and isolated GSE patients produced IFN-gamma after stimulation (mean: DH = 2,619 pg/ml; isolated GSE = 1,993 pg/ml; NS). T-cell lines from patients with DH, however, produced significantly more IL-4 than the T-cell lines from patients with isolated GSE (IL-4: DH = 2,010 pg/ml; isolated GSE = 235 pg/ml; P < 0.05). Analysis of intracytoplasmic cytokine production by the T-cell lines showed that T-cell lines from patients with DH were CD4+ predominant, with a greater proportion of CD4+/IL4+ cells than CD4+/IFN-gamma+ cells. In contrast, isolated GSE T-cell lines were predominantly CD8+, with an equal proportion of IL-4- and IFN-gamma-positive cells. These studies demonstrate that T cell lines from patients with DH produce significantly more IL-4 than T-cell lines from patients with isolated GSE, while producing similar amounts of IFN-gamma. This difference in cytokine pattern may play an important role in the different clinical manifestations of these two forms of gluten sensitivity.

TCR Vbeta expression in the small bowel of patients with dermatitis herpetiformis and gluten sensitive enteropathy. Limited expression in dermatitis herpetiformis and treated asymptomatic gluten sensitive enteropathy.

Dermatitis herpetiformis (DH) is a blistering skin disease characterized by cutaneous deposits of IgA and an associated, most often asymptomatic, gluten sensitive enteropathy (GSE). Gluten sensitive enteropathy is also seen in patients that do not have skin disease or cutaneous IgA deposits, but do have significant gastrointestinal (GI) complaints. Patients with DH and with GSE without skin disease have similar small bowel morphologic changes and HLA associations and both the skin disease and the GI symptoms can be controlled by a gluten free diet. It is not known what factors allow almost all patients with DH to continue to eat gluten and not develop symptomatic gastrointestinal disease. We have examined the expression of the Vbeta T-cell receptor (TCR) in the small bowel of patients with DH (n=11) and of patients with both symptomatic (n=10) and asymptomatic (n=7) GSE without skin disease to determine if differences in the pattern of TCR Vbeta expression are associated with differences in the clinical manifestations of these diseases. TCR Vbeta expression was analyzed using RT-PCR from small bowel biopsies. Patients with DH and those with GSE without skin disease that were on a gluten free diet and asymptomatic were found to express 6.6 and 5.6 out of 20 Vbeta families respectively, with no single family preference. Examination of peripheral blood lymphocytes from these patients did not reveal any restriction of TCR Vbeta family expression. In contrast, patients with symptomatic GSE expressed 12.6 Vbeta families (P< 0.05), with no consistent preferential expression of any single Vbeta family between patients. Patients with DH, who are continuing to ingest wheat, show a more restricted pattern of TCR Vbeta utilization, similar to that of treated patients with GSE without skin disease, and significantly different from GSE without skin disease patients eating gluten. These findings suggest that the restricted nature of the TCR Vbeta expression may play a role in the different clinical manifestations of dermatitis herpetiformis and isolated gluten sensitive enteropathy.

The 120-kDa soluble ectodomain of type XVII collagen is recognized by autoantibodies in patients with pemphigoid and linear IgA dermatosis.

BACKGROUND: Type XVII collagen promotes adhesion of basal keratinocytes to epidermal basement membrane, and is the target of disease in patients with certain inherited or acquired blistering diseases. Two forms of type XVII collagen are produced by cultured human keratinocytes: a 180-kDa full-length, transmembrane protein, and a recently identified 120-kDa soluble fragment that corresponds to its collagenous ectodomain. OBJECTIVES: We aimed to determine the incidence and pattern of reactivity of autoantibodies against the 180- and 120-kDa forms of type XVII collagen in sera from 40 patients with bullous pemphigoid (BP), pemphigoid gestationis or cicatricial pemphigoid (CP), as well as six patients with linear IgA dermatosis (LAD). METHODS: Various immunochemical techniques were used. RESULTS: These studies found that the 120-kDa fragment of type XVII collagen was bound by circulating autoantibodies in 13 of 38 patients with BP or CP and all six patients with LAD. While many pemphigoid sera had specific reactivity against one but not both forms of this protein, autoantibodies from patients with LAD bound only the soluble ectodomain. CONCLUSIONS: These findings are consistent with the presence of both neoepitopes and cross-reactive epitopes on the ectodomain of type XVII collagen. The finding that sera from patients with LAD showed specific reactivity to epidermal basement membrane suggests that such neoepitopes are present in human skin and that their targeting by autoantibodies may contribute to disease pathogenesis.

Expression of interleukin-4 and interferon-gamma in the small bowel of patients with dermatitis herpetiformis and isolated gluten-sensitive enteropathy.

Although possessing a morphologically similar small bowel abnormality to patients with isolated gluten-sensitive enteropathy (GSE), patients with dermatitis herpetiformis (DH) have few gastrointestinal symptoms and exhibit blistering skin lesions and cutaneous IgA deposits. To determine whether clinical discrepancies between these gluten-sensitive conditions might be the result of different patterns of small bowel cytokine expression, duodenal biopsies were obtained from eight DH patients and nine isolated GSE patients. Biopsies were evaluated for interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) expression by reverse-transcriptase polymerase chain reaction (message) and immunohistochemistry (protein). In DH patients, most of whom had no gut symptoms, IFN-gamma mRNA expression was significantly less than in isolated GSE patients with symptomatic gut disease. Conversely, IL-4 mRNA expression in DH patients was greater than that found among isolated GSE patients. These findings suggest that the different clinical phenotypes of gluten sensitivity may be caused by variation in cytokine expression in the small bowel response to gluten.

Reliability and accuracy of dermatologists' clinic-based and digital image consultations.

BACKGROUND: Telemedicine technology holds great promise for dermatologic health care delivery. However, the clinical outcomes of digital image consultations (teledermatology) must be compared with traditional clinic-based consultations. OBJECTIVE: Our purpose was to assess and compare the reliability and accuracy of dermatologists' diagnoses and management recommendations for clinic-based and digital image consultations. METHODS: One hundred sixty-eight lesions found among 129 patients were independently examined by 2 clinic-based dermatologists and 3 different digital image dermatologist consultants. The reliability and accuracy of the examiners' diagnoses and the reliability of their management recommendations were compared. RESULTS: Proportion agreement among clinic-based examiners for their single most likely diagnosis was 0. 54 (95% confidence interval [CI], 0.46-0.61) and was 0.92 (95% CI, 0. 88-0.96) when ratings included differential diagnoses. Digital image consultants provided diagnoses that were comparably reliable to the clinic-based examiners. Agreement on management recommendations was variable. Digital image and clinic-based consultants displayed similar diagnostic accuracy. CONCLUSION: Digital image consultations result in reliable and accurate diagnostic outcomes when compared with traditional clinic-based consultations.

Characterization of skin cytokines in bullous pemphigoid and pemphigus vulgaris.

The purpose of this study was to determine cytokine and cell marker expression in perilesional skin biopsies from patients with the autoimmune blistering diseases bullous pemphigoid (BP, n = 21) and pemphigus vulgaris (PV, n = 7). Immunohistochemistry and in situ hybridization were used to detect T helper (Th)1 [interleukin (IL)-2, interferon (IFN)-gamma] and Th2 (IL-4, IL-5, IL-13) protein and mRNA. Perilesional skin biopsies from patients with BP were characterized by the deposition of IL-4, IL-13 and IL-5. In patients with BP, IL-4 and IL-13 localized to mononuclear cells within the dermal infiltrate while IL-5 was predominately expressed at the dermal-epidermal junction. BP skin sections also expressed vascular cell adhesion molecule 1 on endothelial cells, not seen in patients with PV. PV biopsies were remarkable for a mixed Th1/Th2 pattern of cytokine expression, including the presence of IL-2, IFN-gamma and IL-4 and the absence of IL-5 and IL-13. In situ hybridization detected mRNA for IL-4 and IL-5 in the cellular infiltrate of BP patients, and IL-2 in a patient with PV. In vitro binding assays demonstrated that normal human eosinophils, activated by coculture in IL-5, bound preferentially to BP skin sections that contained detectable in vivo bound IL-5. The predominance of Th2 cytokines in BP, in association with increased binding of eosinophils in vitro, suggests that Th2 cytokines are relevant in the recruitment and adhesion of eosinophils within the dermal infiltrates of patients with BP, and may play a part in the pathogenesis of blister formation.

A pilot trial of digital imaging in skin cancer.

We have used inexpensive off-the-shelf equipment for store-and-forward teledermatology and compared the precision and accuracy of digital image consultations with conventional, clinic-based consultations. Thirteen lesions were studied on 12 patients referred to a dermatology clinic for a suspected skin cancer. Patients were examined by two dermatologists. Subsequently, digital images were examined by two different dermatologists. There was almost complete agreement, both among and between the clinical and digital examiners, on different diagnosis and biopsy recommendations. Agreement on the single most likely diagnosis was also good. Digital imaging shows promise in teledermatology.

Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune skin diseases caused by autoantibodies against desmoglein (Dsg) 3 and Dsg1, respectively. Routine immunofluorescence testing of skin and serum from patients cannot distinguish between these two severe diseases since both have IgG Abs directed against keratinocyte cell surfaces. In this study, recombinant Dsg3 and Dsg1, produced as secreted proteins by baculovirus expression, have been utilized to develop ELISAs for the specific characterization of their autoantibodies. Of 49 PV sera, 46 were positive in the Dsg3 ELISA and 44 of 46 PF sera were positive in the Dsg1 ELISA, compared with only 3 of 23 sera of bullous pemphigoid, and none of 53 normal control sera in both ELISAs. Both the Dsg3 and Dsg1 ELISAs were more specific and sensitive than conventional immunofluorescence staining. These Ag-specific ELISAs revealed that more than one-half of PV sera (26 of 49) had anti-Dsg1 Abs in addition to anti-Dsg3 Abs. PV patients who had not only oral mucous lesions but also significant skin involvement tended to have higher titers of anti-Dsg1 Abs. Furthermore, the ELISA reactivity correlated well with clinical disease activity in 5 of 6 PV and 5 of 5 PF patients. This ELISA provides a sensitive and highly specific assay for the diagnosis of patients with PV and PF, the correlation of disease activity with serum Ab levels, and a novel tool for investigating the immunopathogenesis of pemphigus.