Risk of infections in patients with pemphigus treated with rituximab vs. azathioprine or mycophenolate mofetil: a large-scale global cohort study.

BACKGROUND: The risk of infectious complications among patients with pemphigus managed by rituximab is yet to be precisely elucidated. OBJECTIVES: To evaluate the risk of infections in patients with pemphigus managed by rituximab vs. first-line corticosteroid-sparing agents [azathioprine and mycophenolate mofetil (MMF)]. METHODS: A global population-based cohort study compared patients with pemphigus initiating rituximab (n = 963) vs. azathioprine or MMF (n = 963) regarding the risk of 26 different infections. Propensity score matching was conducted to optimize comparability. RESULTS: During the initial 12 months following treatment, patients under rituximab experienced elevated risk of COVID-19 [hazard ratio (HR) 1.82, 95% confidence interval (CI) 1.06-3.14; P = 0.028], parasitic diseases (HR 3.22, 95% CI 1.04-9.97; P = 0.032) and cytomegalovirus (CMV) infection (HR 1.63, 95% CI 1.04-2.58; P = 0.033). When evaluating infections developing ≥ 12 months after drug initiation, rituximab was associated with greater risk of pneumonia (HR 1.45, 95% CI 1.00-2.10; P = 0.047), COVID-19 (HR 1.87, 95% CI 1.49-2.33; P < 0.001), osteomyelitis (HR 2.42, 95% CI 1.11-5.31; P = 0.023), herpes simplex virus (HR 2.06, 95% CI 1.03-4.11; P = 0.037) and CMV (HR 1.63, 95% CI 1.07-2.49; P = 0.023) infections. CONCLUSIONS: Within the first 12 months after treatment, patients under rituximab experience an elevated risk of COVID-19, parasitic and CMV infections. Rituximab is associated with pneumonia, osteomyelitis and viral diseases even beyond the first year after therapy. Pneumococcal vaccine and suppressive antiviral therapy should be considered even 1 year following therapy. There is no signal for elevated risk of tuberculosis, hepatitis B virus reactivation, Pneumocystis jiroveci pneumonia and progressive multifocal leukoencephalopathy.

Gene expression profiling of laminin α3-blocked keratinocytes reveals an immune-independent mechanism of blistering.

Laminin-332 pemphigoid is a rare and chronic autoimmune blistering disease which results in subepidermal blisters and erosive lesions predominantly localized to mucous membranes. As histologic inflammation is variable and non-complement-fixing IgG antibodies against laminin-332 are the predominant class of autoantibodies deposited at the epidermal basement membrane zone, we hypothesized that complement-independent pro-inflammatory and blistering pathways existed similarly to that previously shown in bullous pemphigoid. As autoantibodies to laminin α3 are most prevalent, we studied the major cellular response to blockade of laminin α3 using a well-characterized monoclonal antibody (P3H9-2). RNA-seq revealed upregulation of numerous desmosomal genes (DSG1, DSG3, DSC1, DSC3 and DSP) as well as KRT1 and KRT10. Additionally, P3H9-2-treated cells demonstrated downregulation of most hemidesmosomal genes. A pro-inflammatory response was not appreciated. Using pharmacological inhibitors, we identified both protein kinase C and NOTCH as key regulators of P3H9-2 induced differentiation. We lastly utilized 3D human skin equivalents to determine whether blockade of laminin α3 would lead to delayed blistering, consistent with keratinocyte differentiation. Significant blistering was noted after 72 h of treatment, with only minimal separation at 24 h. In summary, blockade of laminin α3 alters keratinocyte differentiation, representing a potential complement-independent mechanism of blistering.

The Immunogenetics of Autoimmune Blistering Diseases.

Dermatological conditions constituting the group of autoimmune blistering diseases (AIBD) are characterized by loss of immunotolerance and humoral, as well as cellular, autoimmune responses that result in the development of bullae and erosions on the skin and mucous membranes. AIBDs are broadly categorized into pemphigus and pemphigoid classes with several distinct subtypes amongst them. Advances in genetics have allowed for the study and identification of alleles, and even single nucleotide polymorphisms, that harbor increased susceptibility or confer protection for the development of these conditions. The focus of this chapter pertains to a comprehensive review of the known genetic associations with AIBDs, including HLA class I-III, as well as non-HLA genes and non-coding sequences that influence cellular processes and signaling pathways.

The role of Dipeptidyl Peptidase-4 in cutaneous disease.

Dipeptidyl peptidase-4 (DPP4) is a multifunctional, transmembrane glycoprotein present on the cell surface of various tissues. It is present in multiple molecular forms including cell surface and soluble. The role of DPP4 and its inhibition in cutaneous dermatoses have been a recent point of investigation. DPP4 exerts a notable influence on T-cell biology, the induction of skin-specific lymphocytes, and the homeostasis between regulatory and effector T cells. Moreover, DPP4 interacts with a broad range of molecules, including adenosine deaminase, caveolin-1, CXCR4 receptor, M6P/insulin-like growth factor II-receptor and fibroblast activation protein-α, triggering downstream effects that modulate the immune response, cell adhesion and chemokine activity. DPP4 expression on melanocytes, keratinocytes and fibroblasts further alters cell function and, thus, has crucial implications in cutaneous pathology. As a result, DPP4 plays a significant role in bullous pemphigoid, T helper type 1-like reactions, cutaneous lymphoma, melanoma, wound healing and fibrotic disorders. This review illustrates the multifactorial role of DPP4 expression, regulation, and inhibition in cutaneous diseases.

Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody-negative pemphigus vulgaris.

Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by IgG autoantibodies (AuAbs) binding to epidermal keratinocytes and inducing this devastating disease. Here, we observed that non-desmoglein (Dsg) AuAbs in the sera of patients with Dsg1/3 AuAb-negative acute PV are pathogenic, because IgGs from these individuals induced skin blistering in neonatal mice caused by suprabasal acantholysis. Serum levels of AuAbs to desmocollin 3 (Dsc3), M3 muscarinic acetylcholine receptor (M3AR), and secretory pathway Ca2+/Mn2+-ATPase isoform 1 (SPCA1) correlated with the disease stage of PV. Moreover, AuAb absorption on recombinant Dsc3, M3AR, or SPCA1 both prevented skin blistering in the passive transfer of AuAbs model of PV in BALB/c mice and significantly decreased the extent of acantholysis in a neonatal mouse skin explant model. Although acantholytic activities of each of these immunoaffinity-purified AuAbs could not induce a PV-like phenotype, their mixture produced a synergistic effect manifested by a positive Nikolskiy sign in the skin of neonatal mice. The downstream signaling of all pathogenic non-Dsg AuAbs involved p38 mitogen-activated protein kinase (MAPK)-mediated phosphorylation and elevation of cytochrome c release and caspase 9 activity. Anti-Dsc3 and anti-SPCA1 AuAbs also activated SRC proto-oncogene, nonreceptor tyrosine kinase (SRC). Of note, although a constellation of non-Dsg AuAbs apparently disrupted epidermal integrity, elimination of a single pathogenic AuAb could prevent keratinocyte detachment and blistering. Therefore, anti-Dsg1/3 AuAb-free PV can be a model for elucidating the roles of non-Dsg antigen-specific AuAbs in the physiological regulation of keratinocyte cell-cell adhesion and blister development.

IgA pemphigus: A systematic review.

BACKGROUND: The clinical, histologic, and immunopathologic features of IgA pemphigus have not been studied on a large scale. OBJECTIVE: To synthesize existing data on the epidemiologic, clinical, histologic, and immunologic features of IgA pemphigus. METHODS: We performed a systematic review using MEDLINE, Embase, and Web of Science databases. Case reports and series of patients with IgA pemphigus were included. RESULTS: A total of 119 eligible studies, comprising 137 patients with IgA pemphigus with a mean age of 51.5 ± 21.0 years, were included. Most patients presented with vesicles (80.8%), pustules (75.0%), and circinate plaques (63.6%). Pruritus was present in 65.6% of reported patients. Intercellular deposition of IgA was noted in almost all patients (97.0%), and the remaining 3.0% of patients had IgA positivity on indirect immunofluorescence or enzyme-linked immunosorbent assay confirming the diagnosis. IgA circulating intercellular antibodies were detected in only 66.7% patients. IgA gammopathy and ulcerative colitis were associated with IgA pemphigus in 9.5% and 6.6% patients, respectively. Oral dapsone and corticosteroids were the mostly commonly used treatments. LIMITATIONS: Results are mainly based on case reports and small case series. CONCLUSIONS: The diagnosis of IgA pemphigus may be considered in patients presenting with vesiculopustular eruption and circinate plaques with truncal and extremity involvement.

Mechanisms of pathogenic effects of eosinophil cationic protein and eosinophil-derived neurotoxin on human keratinocytes.

Cutaneous deposition of eosinophil degranulation proteins is a major feature of eosinophil-rich cutaneous diseases including bullous pemphigoid (BP). We sought to better understand the effect of two of these proteins - eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), on human keratinocytes using the Het-1A cell line. To evaluate expression of key cytokines and chemokines observed in BP as well as metal metalloprotease 9 (MMP9), we performed qPCR and in-cell Western assays on cells treated with either ECP or EDN. We further evaluated the effect of ECP and EDN on keratinocyte survival, generation of reactive oxygen species (ROS) and apoptosis. Lastly, we assessed ECP and EDN's ability to induce keratinocyte detachment from provisional matrix. Treatment of keratinocytes with ECP and EDN resulted in significant increases in IL-5, eotaxin-1 and CCL5 (RANTES) expression at both mRNA and protein levels, but not IL-17 or IL-31. ECP and EDN also upregulate MMP9 production. Inhibiting MMP9, we confirmed that keratinocyte expression of IL-5, eotaxin-1 and RANTES was independent from MMP9. Both ECP and EDN were cytotoxic to keratinocytes, inducing ROS formation and apoptosis through a mitochondrion-dependent pathway as evidenced by results of terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) and cytochrome c release assays, respectively. ECP but not EDN led to significant keratinocyte detachment from provisional matrix. These findings demonstrate that the pathogenic effects of ECP and EDN in BP may result from their direct action on keratinocytes, and as such may became a target for future therapies in eosinophil-rich cutaneous diseases.

Syringotropic Mycosis Fungoides: A Rare Form of Cutaneous T-cell Lymphoma Enabling a Histopathologic "Sigh of Relief".

Syringotropic mycosis fungoides (STMF) is a very rare variant of cutaneous T-cell lymphoma. It follows a much milder disease course than its clinically indistinguishable adnexal counterpart, folliculotropic mycosis fungoides (FMF). We report a case of a 36-year-old man who presented with erythematous, studded papules and plaques on the left upper extremity and right anterior thigh diagnosed as mycosis fungoides (MF) Stage 1A on initial superficial shave biopsy. Lesions recurred after initial improvement with narrow-band ultraviolet light therapy demonstrating a concentration of abnormal lymphocytes around eccrine sweat glands on repeat biopsy consistent with STMF. Although the deeper, periadnexal infiltrate found in both STMF and FMF confers increased resistance to skin-directed therapies effective in classic MF, these entities diverge with respect to their clinical behavior. Syringotropism is a marker for increased disease-specific survival, whereas even FMF carries a prognosis worse than conventional MF. Increased awareness among the dermatopathology community of the histopathologic distinction between STMF and FMF is essential to guide treatment type, duration, and intensity in adnexal disease.

Thrombotic thrombocytopenic purpura in a postoperative patient taking cephalexin responding to plasmapheresis: A case report and review of cephalosporin-induced TTP.

The clinical presentation of thrombotic thrombocytopenic purpura (TTP) is often atypical delaying diagnosis and treatment. A number of drugs have been implicated in the development of TTP, including cyclosporine, tacrolimus, clopidogrel, and quinine. To our knowledge, only three cases of cephalosporin-induced TTP have been described, with two of these cases occurring with these use of cephalexin. We herein describe a case of TTP occurring in a postoperative patient taking cephalexin, requiring plasmapheresis. Following plasmapheresis, the patient's mental status and platelet count significantly improved. J. Clin. Apheresis 31:473-475, 2016. © 2015 Wiley Periodicals, Inc.

An increased risk of non-Hodgkin lymphoma and chronic lymphocytic leukemia in US patients with Merkel cell carcinoma versus Australian patients: A clinical clue to a different mechanism of pathogenesis?

The US and Queensland populations both demonstrate an increased risk of secondary malignancies following the diagnosis of Merkel cell carcinoma (MCC). A recent Queensland study failed to demonstrate a significantly increased risk of developing non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukaemia (CLL) in these patients. In contrast, using the US Surveillance, Epidemiology, and End Results database, we demonstrate there is an increased risk in CLL and NHL following the diagnosis of MCC in the USA. We hypothesise that this difference may be a result of a differing pathogenesis.