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.

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.

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.

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.

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.

Primary care clinicians' performance for detecting actinic keratoses and skin cancer.

BACKGROUND: If skin cancer screening is to become widely adopted, its effectiveness depends on the ability of primary care clinicians to detect cutaneous malignancies. OBJECTIVE: To assess primary care clinicians' proficiency for detecting skin cancers and actinic keratoses in a clinic population. METHODS: A convenience sample of 190 white male patients aged 40 years or older presenting to a university-affiliated Veterans Affairs general internal medicine or dermatology clinic were included in the study. Each patient was independently examined by a primary care clinician and a dermatologist to measure interobserver agreement. We compared the ability of primary care clinicians to diagnose actinic keratoses and skin cancers using dermatologists' examinations as a pragmatic reference standard. RESULTS: Agreement was moderate as to whether a patient had single actinic keratosis (kappa, 0.36; 95% confidence interval [CI], 0.22-0.50), multiple actinic keratoses (kappa, 0.48; 95% CI, 0.34-0.61), or skin cancer (kappa, 0.48; 95% CI, 0.34-0.62). Agreement decreased when individual lesions were the unit of analysis. When the patient was the unit of analysis, primary care clinicians identified the presence of skin cancer with a sensitivity of 57% (95% CI, 44%-68%), specificity of 88% (95% CI, 81%-93%), positive likelihood ratio of 4.9 (95% CI, 3.0-8.3), and negative likelihood ratio of 0.48 (95% CI, 0.35-0.63). When the lesion was the unit of analysis the sensitivity was 38% (95% CI, 29%-47%), the specificity was 95% (95% CI, 93%-96%), the positive likelihood ratio was 7.1 (95% CI, 4.8-10.3), and the negative likelihood ratio was 0.66 (95% CI, 0.56-0.75). CONCLUSIONS: Examinations performed by primary care clinicians for diagnosing skin cancer lacked sensitivity. Without improved diagnostic skills, primary care clinicians' examinations may be ineffective as a screening test.

The influence of history on interobserver agreement for diagnosing actinic keratoses and malignant skin lesions.

BACKGROUND: Quantifying interobserver diagnostic agreement is necessary to evaluate skin cancer screening programs, but estimates of variability are incomplete. OBJECTIVE: We sought to measure agreement between dermatologists for diagnosing actinic keratoses (AKs) and malignant skin lesions and to determine the way in which blinding examiners to patient history affects agreement. METHODS: We varied the amount of historical information available to examiners in two consecutive patient series (n = 50) presenting to a Veterans Affairs Medical Center dermatology clinic. Two dermatologists examined each patient independently. RESULTS: Assessing historical features increased the kappa statistic for malignancy recognition from -0.04 to 0.76. kappa Statistics for diagnosing single AKs were 0.17 and 0.15, respectively, and 0.62 and 0.55 for multiple AKs. CONCLUSION: Agreement was high for diagnosing malignant skin lesions when history was included in the evaluation. Agreement for multiple AKs was higher than for single AKs, although neither was influenced by inclusion of historical features.

Peripheral blood mononuclear cells from patients with bullous pemphigoid have an increased frequency of response to synthetic peptides encoded by BPAG1.

We determined the response of peripheral blood mononuclear cells from patients with bullous pemphigoid and normal subjects to synthetic peptides encoded by BPAG1. Peripheral blood mononuclear cells from patients and normal subjects were cocultured in the presence of 15-22-amino-acid-long amphipathic and hydrophilic peptides selected from the BPAG1 sequence. Seven of 10 patients (70%) with bullous pemphigoid had an increased response of peripheral blood mononuclear cells (> 3.25/10(6) cells) when cultured with amphipathic sequences encoded by BPAG1 compared to 3 of 10 (30%) normal subjects. Peripheral blood mononuclear cells from 3 of 15 (20%) patients and 3 of 15 normal subjects (20%) demonstrated an increased response when cultured with hydrophilic peptides. Peptides associated with an increased peripheral blood mononuclear cell response in patients with bullous pemphigoid were adjacent to regions of BPAG1 recently demonstrated to contain epitopes recognized by circulating autoantibodies in the sera of patients with bullous pemphigoid. Increased peripheral blood mononuclear cell responses were more commonly observed in patients with bullous pemphigoid with generalized disease and those who had their disease for longer than 2 months (p < 0.05). The observation that increased duration and generalized disease was associated with increased peripheral blood mononuclear cell responses to peptides encoded by BPAG1 supports the hypothesis that responses to BPAG1 may occur as a consequence of ongoing inflammation at the basement membrane.

Rabbits immunized with a peptide encoded for by the 230-kD bullous pemphigoid antigen cDNA develop an enhanced inflammatory response to UVB irradiation: a potential animal model for bullous pemphigoid.

Previous attempts to develop an animal model of bullous pemphigoid (BP) have failed to result in inflammatory disease in the skin. P1-2 is an 18-amino acid peptide encoded for by the 230-kD BP antigen cDNA that has been shown to contain an epitope recognized by circulating antibodies from patients with BP. The purpose of this study was to determine if ultraviolet B irradiation of rabbits after immunization with the P1-2 peptide would result in an enhanced inflammatory response in the skin to that injury. Three rabbits were immunized with either P1-2 or a control peptide. All rabbits immunized with P1-2, and none of the control rabbits, developed antibodies against P1-2 that bound in vitro to both human and rabbit skin in a linear pattern at the basement membrane zone. Immunized rabbits were irradiated on the flank with ultraviolet light. Rabbits immunized with P1-2 developed an enhanced inflammatory reaction to ultraviolet B irradiation leading to epidermal necrosis and sloughing of some sites in 6-9 d. Control rabbits showed only mild erythema without sloughing, which healed in 4-6 d. Histology in the P1-2 immunized rabbits at 24 h revealed an inflammatory infiltrate of neutrophils at the dermal-epidermal junction, whereas control rabbits showed only mild edema and a sparse inflammatory infiltrate. All the rabbits immunized with P1-2 had linear deposits of immunoglobulin G and C3 at the basement membrane zone of healed skin compared to none of the controls. These findings demonstrate that antibodies against a synthetic peptide encoded by the BP antigen 1 sequence can lead to an enhanced inflammatory response after epithelial injury in rabbit skin.

Expression of cross-reactive idiotypes at the basement membrane zone in patients with bullous pemphigoid.

The purpose of the present study was to determine whether tissue-bound anti-basement membrane zone (BMZ) autoantibodies in patients with bullous pemphigoid (BP) express a cross-reactive idiotype. We assayed 34 skin biopsies from 26 patients with BP and nine biopsies from control subjects, including normal subjects and patients with epidermolysis bullosa acquisita for the presence of a cross-reactive idiotype at the BMZ. Perilesional split-skin biopsies were assayed for the presence of immunoreactants, immunoglobulin G, and complement and for reactivity with a monoclonal anti-idiotypic antibody specific for a circulating anti-BMZ antibody, anti-Id 3-17. Anti-Id 3-17 bound in a linear band to the BMZ in 12 of 26 patients with BP (46%) and in 0 of 9 control subjects. In serial biopsy specimens, the presence or absence of cross-reactive idiotype at the BMZ in six patients was stable during the disease course. This cross-reactive idiotype has been previously identified in the serum of 36% of patients with BP; however, in this study, no correlation was noted between the presence of the cross-reactive idiotype in skin and serum of individual patients. Because cross-reactive idiotypes occur as a consequence of restricted variable-region gene utilization, the demonstration of a cross-reactive idiotype at the BMZ previously identified in the serum of patients with BP supports the hypothesis that circulating and tissue-bound autoantibodies in this disease arise from a common genetic origin.

IgA-binding structures in dermatitis herpetiformis skin are independent of elastic-microfibrillar bundles.

Dermatitis herpetiformis (DH) is characterized in part by the presence of granular deposits of IgA in the papillary dermis just beneath the dermal-epidermal junction. The nature of the structures to which IgA binds in DH skin, however, has not been clearly demonstrated. Previous immunoelectron-microscopy studies using the peroxidase-antiperoxidase technique have concluded that the IgA may bind to abnormal elastic microfibrillar bundles. Recently, antibodies have been developed against a major component of the elastic microfibril bundles, fibrillin. In addition, another dermal matrix protein, hexabrachion, has been characterized and found in normal human skin in a distribution similar to the IgA deposits of DH. Utilizing antibodies against fibrillin, hexabrachion, and human IgA and immunoelectronmicroscopy with immunogold staining techniques, we have examined the skin from patients with DH in order to localize the IgA deposits. Normal-appearing skin from five patients with DH exhibited electron-dense patches within the dermis, which were not seen in skin from normal subjects. These structures were sometimes adjacent to the basement membrane zone, but appeared amorphous and without a well-defined fibrillar structure. The electron-dense patches were labeled with anti-human IgA, but not with antibodies to fibrillin or hexabrachion. The anti-IgA antibody did not label the normal basement membrane. These studies confirm the presence of abnormal electron-dense, amorphous structures in the skin of patients with DH. Due to this lack of association with the elastic microfibril bundles and the lack of labeling with antibodies against fibrillin, we suggest that these deposits are distinct from the microfibrillar bundles of elastic tissue and may represent IgA bound to degraded basement membrane or isolated dermal deposits of IgA.

Dermatitis herpetiformis in two American blacks: HLA type and clinical characteristics.

Dermatitis herpetiformis is a rare blistering skin disease characterized in part by granular IgA deposits at the dermoepidermal junction, an associated gluten-sensitive enteropathy, and a strong association with the human histocompatibility leukocyte antigen (HLA)-A1 (74% of patients with dermatitis herpetiformis), -B8 (88%), -DR3 (95%), and -DQw2 (100%). Dermatitis herpetiformis is rarely seen in American blacks and some investigators have postulated that this finding may be due to the decreased frequency of HLA-A1 and -B8 in American blacks compared with Caucasians (American blacks: HLA-A1 = 15.3%, HLA-B8 = 10.7%; Caucasian: HLA-A1 = 26.4%, HLA-B8 = 18.3%). This report describes two American blacks with dermatitis herpetiformis and reports the results of HLA typing of these subjects for HLA-A, -B, -C, -DR, and -DQ antigens. HLA typing revealed that neither patient expressed HLA-A1 or -B8; however, both patients did express the class II antigens most frequently seen in dermatitis herpetiformis, HLA-DR3 and -DQw2. Comparison of HLA class II antigen frequency in normal American blacks and Caucasians reveals a similar frequency of HLA-DR3 and -DQw2 (American blacks: HLA-DR3 = 27.6%, HLA-DQw2 = 40.9%; Caucasian: HLA-DR3 = 22.6%, HLA-DQw2 = 32.9%). These data confirm the importance of the HLA class II region in the pathogenesis of dermatitis herpetiformis. In addition, these data suggest that the rare occurrence of dermatitis herpetiformis in American blacks is not due to the decreased frequency of the HLA class I antigens -A1 and/or -B8 but rather is related to differences in the HLA class II region not detected by routine HLA typing.

Anti-idiotypic antibodies as vaccine candidates. The immune network.

Antibodies specific for determinants within the variable region of an antibody molecule are known as anti-idiotypic antibodies. Anti-idiotypic antibodies specific for determinants within the antigen binding site of the antibody may mimic the original antigen and are said to bear an "internal image" of the antigen. These anti-idiotypic antibodies have been shown in animal studies to function as surrogate antigens in stimulating an immune response and may ultimately be useful therapeutically as vaccines to prevent infectious diseases, to enhance the immune response to neoplasms, and to modulate autoantibody production in autoimmune diseases.

Idiotypes, anti-idiotypes, and autoimmunity.

Over the past two decades it has become clear that the ability of a host to generate antibodies against a wide variety of potential antigens is due to structural diversity in the antibody molecule within the variable region. This diversity results in sites within the molecule that are themselves immunogenic. These immunogenic sites are called idiotopes, and the collection of idiotopes on a single antibody molecule determines that antibody's idiotype. The idiotype of an antibody molecule is defined serologically by a second antibody termed an anti-idiotype. Anti-idiotypic antibodies can recognize antibody molecules bearing similar or identical structures within the variable regions, which are often on or near sites of antigen binding. Investigation into the nature of idiotype and anti-idiotype interactions has increased our knowledge of antibody structure, antigen-antibody interactions, the regulation of antibody production, and the nature of autoimmune disorders. This review will discuss the nature of idiotypes and anti-idiotypes and their potential role in the diagnosis, management, and treatment of autoimmune, infectious, and malignant diseases.

Dietary management of dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is an extremely itchy, papulovesicular skin disease characterized in part by the presence of IgA at the dermal-epidermal junction. Eighty-five percent to 90% of DH patients have granular deposits of IgA at the dermal-epidermal junction, and essentially all of these patients have an associated, for the most part asymptomatic, gluten-sensitive enteropathy (GSE). The association of GSE and DH suggested that the cutaneous manifestations of DH could be controlled by the use of a gluten-free diet. Institution of a gluten-free diet in patients with DH and granular IgA deposits has been shown to be effective in controlling the cutaneous eruption of DH. Seventy percent to 100% of patients who begin a strict gluten-free diet have been shown to be able to decrease the dosage of medication needed to control their DH after a mean of eight to 18 months on the diet. Furthermore, 40% to 70% of patients with DH can control their skin disease completely, without any medication, after longer periods of time on the gluten-free diet (two years and longer). Although the gluten-free diet has been shown to be of great benefit in the control of the skin manifestations of DH, at the present time there is no evidence to suggest that the gluten-free diet is in any way protective against the risk of intestinal lymphoma that has been documented in GSE. Evaluation of the cutaneous IgA deposits in DH skin after long periods of time on a gluten-free diet suggests that there may be a slight decrease in the intensity of the IgA deposits, but the true pathogenetic relationship between the cutaneous IgA deposits, the cutaneous manifestations of DH, and the associated GSE remains unknown.

IgA-containing immune complexes in patients with psoriatic arthritis.

Using a sensitive, specific Raji cell radioimmunoassay we have analyzed the sera of 35 patients with psoriatic arthritis (PsA) for IgA-containing circulating immune complexes. In addition, the 125I-Clq binding assay and the Raji IgG radio-immunoassay were used to measure IgG or IgM containing circulating immune complexes. Twenty-eight of thirty five (80%) patients with PsA were found to have IgA-containing circulating immune complexes. In contrast, only 13 of 35 (37%) had IgG-containing circulating immune complexes detected using the Raji IgG assay and 10 of 33 (33%) had IgG- or IgM-containing immune complexes detected using the 125I-Clq binding assay. There was no significant difference in the frequency, level, or type of immune complexes detected in any of the clinical subtypes. There was however a significant correlation between the level of IgA-containing circulating immune complexes and the severity of the arthritis as determined by linear regression analysis (p less than 0.05). The finding of IgA-containing circulating immune complexes in 80% of patients with psoriatic arthritis as well as the significantly higher levels of these complexes in the patients with more severe arthritis suggests that IgA-containing circulating immune complexes may play a role in the pathogenesis of psoriatic arthritis.