Significance of autoimmunity to non-desmoglein targets in pemphigus

The pathogenesis of pemphigus vulgaris (PV) is a highly controversial, "hot" topic that has received considerable enrichment in recent years by both clinical and basic researchers. On the one hand, the classical view of desmogleins (Dsg) as main targets of this autoimmune disease is supported by the characterization of pathogenic anti-Dsg3 antibodies from both patients and animal models. On the other hand, fundamental doubt has been raised towards this monopathogenic view by several independent factors: (1) pemphigus lesions can be induced in Dsg3-knockout (KO) mice; (2) pemphigus sera contain multiple autoantibodies against different adhesion molecules and also cholinergic receptors; (3) experimental inhibition of PV IgG induced acantholysis can be obtained by interference with different signaling cascades regulating both calcium homeostasis and apoptosis; and (4) cholinergic agonists exhibit anti-acantholytic activity both in vitro and in vivo. The field is open for controlled clinical trials and further basic research to unfold the true story of the pemphigus enigma and provide the basis for a better treatment of pemphigus patients.     

Genetic factors in pemphigus

Epidemiological studies performed in different ethnic populations and family studies, notably based on a partial phenotype of the autoimmune process, indicate that genetic factors are involved in the occurrence of pemphigus. However, the precise heritability remains uncertain in the absence of twin concordance rate studies. Among the different strategies available to identify genetic factors participating in autoimmune disease susceptibility, only population studies based on case-control design have been performed in pemphigus. These studies consistently showed that MHC locus, in particular HLA class II alleles, are associated with pemphigus vulgaris and pemphigus foliaceus. Other genes of the MHC locus may also participate in disease susceptibility as shown by studies using microsatellite markers across different regions of the MHC. It is likely that other non-MHC genes are involved in the pathogenesis of pemphigus. In particular, involvement of a polymorphic variant of desmoglein 1 gene was shown to be associated with pemphigus foliaceus and to interact in an epistatic manner with MHC class II genes to contribute to the autoimmune process. Other candidate genes to which a role can be assigned in the disease pathogenesis should be considered to design case-control or family-based association studies. Genome scan studies which require a large number of multiplex families to reach statistical power, should also be considered in the endemic form of pemphigus foliaceus because of the high number of familial cases.     

Pemphigus autoimmunity: hypotheses and realities

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients.     

Targeted therapy comes of age in scleroderma

Systemic sclerosis (SSc, also known as scleroderma) has the highest case-specific mortality among the rheumatic diseases; however, advances in understanding of pathogenesis and an appreciation of the clinical heterogeneity of this disease, together with therapeutic advances in other areas, have raised the possibility of substantial improvements in its management. Key areas of advance include the development of clinical and laboratory methods for early detection of complications and the integration of vascular, immunomodulatory and antifibrotic therapies. Disease models have facilitated the identification of key mediators or processes that could be targeted therapeutically and have provided a platform for preclinical testing of novel candidate therapies. This review will consider current clinical aspects of SSc and the emergence of targeted therapy that is linked to key pathogenic processes or that targets pivotal mediators.     

Bucillamine-induced pemphigus vulgaris in a patient with rheumatoid arthritis and polymyositis overlap syndrome

Bucillamine is a disease modifying anti-rheumatic drug, structurally similar to D-penicillamine. Although D-penicillamine-induced pemphigus has been not infrequently demonstrated, pemphigus associated with bucillamine was rarely reported. We describe a patient complicating pemphigus vulgaris after bucillamine treatment in rheumatoid arthritis (RA) and polymyositis (PM) overlap syndrome. PM and RA overlap syndrome was diagnosed three years ago and bucillamine was administrated for 20 months. Skin lesions including erythematous flaccid blisters on her chest, axillae, and back were occurred and were compatible with pemphigus vulgaris by typical pathology. Withdrawal from bucillamine and prednisolone treatment made rapid improvement of pemphigus lesions.     

Diagnostic features of pemphigus vulgaris in patients with pemphigus foliaceus: detection of both autoantibodies, long-term follow-up and treatment responses

There are several studies that describe the simultaneous presence and conversion of pemphigus foliaceus into pemphigus vulgaris and vice versa. We describe eight patients with clinical, histological and immunopathological features of pemphigus foliaceus, at the time of the initial diagnosis. After a mean period of 2.5 years, additional serological features of pemphigus vulgaris were observed. During a long-term follow-up, systemic therapies, their durations and treatment outcomes were recorded. These patients did not respond to conventional systemic therapy and developed multiple side-effects from these drugs. Hence, they were treated with intravenous immunoglobulin therapy (IVIg). Prior to the initiation of IVIg therapy, different assays were performed to detect the presence of autoantibodies, including indirect immunofluorescence (IIF), immunoblot assay using bovine gingival lysate, and ELISA. Twenty-five healthy normal individuals, 12 patients with pemphigus vulgaris, and eight patients with pemphigus foliaceus served as controls for comparison of serological studies. At the time of initial diagnosis, the sera of all eight study patients also demonstrated binding on an immunoblot assay to a 160-kDa protein (desmoglein 1) only. This is typically observed in pemphigus foliaceus. Prior to staring IVIg therapy, binding was observed to both the 160 kDa and 130 kDa (desmoglein 3) proteins on an immunoblot assay which was characteristic of pemphigus vulgaris. The antidesmogleins, 1 and 3 autoantibodies, were predominantly of the IgG4 subclass in all eight patients studied. IVIg therapy induced remission in four patients and control in four of the eight patients. The total follow-up period ranged from 2.6 to 9.5 years (mean 5.3 years). It is difficult to determine the exact time at which these patients with pemphigus foliaceus developed pemphigus vulgaris. It is possible that the disease was nonresponsive to conventional immunosuppressive therapy owing to the simultaneous presence of two autoantibodies.     

Immunoadsorption in pemphigus

The principle of extracorporal immunoadsorption (IA) is based on affinity adsorption of pathogenic (auto-)antibodies and circulating immune complexes (CIC) which reversibly bind to an immobilized ligand of the adsorber. In pemphigus, a blistering autoimmune disease affecting skin and mucous membranes, autoantibodies, mainly of the IgG subclass are directed against desmosomal adhesion molecules and other non-desmosomal antigens on the surface of epidermal keratinocytes, such as acetylcholine receptors. The pathogenicity of these autoantibodies has been shown in various in vitro and in vivo systems. Recently, IA was applied in severe pemphigus demonstrating that a rapid and dramatic decline in desmoglein (Dsg)-reactive autoantibodies is accompanied by clinical remission of mucocutaneous blisters and erosions. As an adjuvant treatment, IA was combined with systemic immunosuppressive medication and current protocols initially apply treatment cycles of 3-4 IAs on consecutive days followed by immunoapheresis once a week or repeating the initial cycle in 4 week intervals depending on the disease activity. IA in pemphigus is generally safe and well tolerated.     

Immunoadsorption in pemphigus

The principle of extracorporal immunoadsorption (IA) is based on affinity adsorption of pathogenic (auto-)antibodies and circulating immune complexes (CIC) which reversibly bind to an immobilized ligand of the adsorber. In pemphigus, a blistering autoimmune disease affecting skin and mucous membranes, autoantibodies, mainly of the IgG subclass are directed against desmosomal adhesion molecules and other non-desmosomal antigens on the surface of epidermal keratinocytes, such as acetylcholine receptors. The pathogenicity of these autoantibodies has been shown in various in vitro and in vivo systems. Recently, IA was applied in severe pemphigus demonstrating that a rapid and dramatic decline in desmoglein (Dsg)-reactive autoantibodies is accompanied by clinical remission of mucocutaneous blisters and erosions. As an adjuvant treatment, IA was combined with systemic immunosuppressive medication and current protocols initially apply treatment cycles of 3–4 IAs on consecutive days followed by immunoapheresis once a week or repeating the initial cycle in 4 week intervals depending on the disease activity. IA in pemphigus is generally safe and well tolerated.     

Cutaneous lupus erythematosus: Understanding of clinical features,genetic basis,and pathobiology of disease guides therapeutic strategies

Cutaneous features of the protean disease lupus erythematous (LE) constitute 4 of 11 diagnostic criteria for systemic lupus erythematosus (SLE) and are exhibited by approximately 3/4 of patients during the course of their disease. Because the pathogenesis of LE is multifactorial and polygenic, many of the details of the pathogenesis remain unclear. We review here the clinical features of cutaneous lupus and recent genetic data that elucidate potential candidate genes for both cutaneous lupus erythematosus (CLE) and SLE. We discuss advances in elucidating the autoimmune pathogenesis of CLE and SLE. Furthermore, promising experimental therapies based on these advances are reviewed in the context of B cell directed therapies, T cell directed therapies, disruption of B and T cell interactions, cytokine directed therapies and finally, end-effector targeted therapies.     

Cutaneous lupus erythematosus: understanding of clinical features, genetic basis, and pathobiology of disease guides therapeutic strategies

Cutaneous features of the protean disease lupus erythematous (LE) constitute 4 of 11 diagnostic criteria for systemic lupus erythematosus (SLE) and are exhibited by approximately 3/4 of patients during the course of their disease. Because the pathogenesis of LE is multifactorial and polygenic, many of the details of the pathogenesis remain unclear. We review here the clinical features of cutaneous lupus and recent genetic data that elucidate potential candidate genes for both cutaneous lupus erythematosus (CLE) and SLE. We discuss advances in elucidating the autoimmune pathogenesis of CLE and SLE. Furthermore, promising experimental therapies based on these advances are reviewed in the context of B cell directed therapies, T cell directed therapies, disruption of B and T cell interactions, cytokine directed therapies and finally, end-effector targeted therapies.     

Recent Advances on Pathogenesis and Therapies in Systemic Sclerosis

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by extensive fibrotic changes in various organs, including skin and lung. Although the etiology of SSc remains unknown, three major abnormalities, abnormal humoral immunity, microvasculature, and fibroblast dysfunctions are considered to play important roles. Significant progress has been made in understanding the pathogenesis on SSc, and has been also providing clues to the treatment for this disease. This review summarizes recent advances on the pathogenesis and new therapeutic strategy for SSc.     

Mechanisms and Efficacy of Immunobiologic Therapies for Inflammatory Bowel Diseases

Current advances in understanding of the pathogenesis of inflammatory bowel disease have encouraged the development of many new therapies targeted at specific and non-specific mediators of the inflammatory bowel disease inflammatory pathway. Crohn's disease and ulcerative colitis, two common inflammatory bowel diseases likely result from interaction of multiple genetic and environmental risk and protective factors, deregulation of mucosal immunity in gut and breakdown of delicate balance of proinflammatory and anti-inflammatory cytokines. Immunobiologic agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-κB), and others are being assessed and will open exciting perspectives on development of therapies for inflammatory bowel disease.     

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.     

Treatment of pemphigus vulgaris: part 2 – emerging therapies

ABSTRACT

Introduction: Corticosteroids and immunosuppressive agents have been the mainstay for the treatment of pemphigus vulgaris (PV). While they have benefited patients, they have been associated with the risks of prolonged immune suppression and a high incidence of significant and catastrophic side effects. Relapses are common. Novel agents promising targeted therapies, that may provide better outcomes, are being studied.

Areas covered: Recently rituximab with corticosteroids has been recommended as the first-line treatment for PV. A number of known and new therapeutic agents currently investigated are BAFF, P13K, BTK inhibitors along with the use of IVIg and CAR-T therapy. The possible role of these therapeutic targets in the pathophysiology appears to be the rationale for the treatment of this potentially fatal disease.

Expert opinion: While there is significant enthusiasm for these therapies, certain concerns and consequences are being under-discussed. None of the current clinical trials in progress are specific for PV, except possibly CAR-T therapy. The major issue(s) that are unclear is whether these therapies would be successful in providing long-term clinical remissions. Will these therapies require additional agents to be effective? Will the benefits be limited in duration? The answers to many questions will determine their final place in the algorithm for the treatment of PV.     

Intravenous immunoglobulin for treatment of pemphigus

Pemphigus is a group of organ-specific, autoimmune, mucocutaneous blistering disorders with an established immunological basis. The goal of therapy in pemphigus is to eliminate or neutralize the pathogenic autoantibodies. As in other autoimmune diseases, early systemic therapy is important for control of the disease and for achieving sustained remissions. Because of the sparse number of controlled studies, the treatment of autoimmune bullous diseases remains controversial. In this article, we discuss the current therapeutical options in pemphigus with an emphasis on IVIg treatment and suggest guidelines for the use of IVIg in the treatment of pemphigus.     

Immunogenetics of pemphigus: an update

Pemphigus are rare but informative models of organ-specific autoimmune diseases, resulting from the interplay of environmental, genetic and stochastic factors. There are many arguments to consider that pemphigus have a genetic basis involving, as many other autoimmune diseases, several different genes with additive or synergistic effects. So far, the unique strategy used to identify the contributive loci has been direct analysis of candidate genes through conventional case-control association studies. The major histocompatibility complex in particular the class II locus was demonstrated to be associated with pemphigus with a high rate of replicability. The progresses in the understanding of pemphigus physiopathology and the development of new molecular tools offer new perspectives to unveiled the genetic basis of this group of autoimmune blistering diseases, as shown by recent studies of candidate genes expressed at different levels of the autoimmune process.     

The immunogenetics of pemphigus vulgaris

Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin of unknown etiology. While various environmental factors have been implicated as triggering agents, HLA association is probably the most important predisposing factor. The aim of this review is to highlight the association of HLA with pemphigus vulgaris. In addition, we present recent results showing a possible association with the nonclassical HLA-G antigen.     

Towards prevention of autoimmune diseases: The example of rheumatoid arthritis

Prevention is the ultimate aim for clinicians and scientists concerned with severe diseases, like many immune-mediated conditions. Here, we describe recent progress in the understanding of etiology and molecular pathogenesis of rheumatoid arthritis (RA), which make this disease a potential prototype for prevention that may include both public health measures and targeted and personalized approaches that we call “personalized prevention.” Critical components of this knowledge are (i) better understanding of the dynamics of the RA-associated autoimmunity that may begin many years before onset of joint inflammation; (ii) insights into how this immunity may be triggered at mucosal surfaces after distinct environmental challenges; (iii) better understanding of which features of the pre-existing immunity may cause symptoms that precede joint inflammation and predict a high risk for imminent arthritis development; and (iv) how molecular events occurring before onset of inflammation might be targeted by existing or future therapies, ultimately by specific targeting of Major histocompatibility complex (MHC) class II restricted and RA-specific immunity. Our main conclusion is that studies and interventions in the phase of autoimmunity preceding RA offer new opportunities to prevent the disease and thereby also understand the molecular pathogenesis of its different variants.     

Antigen mimicry, epitope spreading and the pathogenesis of pemphigus

The molecular and cellular pathogenesis of pemphigus remains unclear. However, the integrity of intraepidermal and dermoepidermal adhesion appears to be of special importance, and the presence of antibodies directed against desmosomal plaque proteins can provoke pemphigus-like pathologies. Antibodies reactive with various tissue antigens have been detected in pemphigus-like skin conditions. Two major factors determining the occurrence of different pemphigus subforms are antigen mimicry and epitope spreading, as these two phenomena underpin antibody generation in response to different antigens. This multiplicity of target antigens and antibody responses may lead to diagnostic problems early in the disease and may also explain the apparent transformation of one disease subform into another as time progresses.     

Altered pattern of connectivity in serum immunoglobulins from pemphigus vulgaris patients

Pemphigus vulgaris is a cutaneous autoimmune disease in which the occurrence of autoantibodies directed against desmoglein-3 and other self-antigens has been well established in patient sera. However, V-region interactions (connectivity) of serum IgG and IgM have not been analysed to date. In this report, it has been demonstrated that IgG and IgM in the sera of pemphigus vulgaris patients bind a preparation of F(ab')2 fragments fractionated according to their isoelectric points, and that a pattern of connectivity distinguishable from that of healthy donor sera arises when the sera are tested against 20 individual isoelectric-focusing-separated F(ab')2-containing fractions. This suggests that there are alterations in regulatory networks. In spite of the fact that prednisolone-based treatment of pemphigus patients has proved to be effective in controlling the disease, some undesirable effects associated with this form of treatment have prompted investigation into other therapeutic approaches. One possible approach to the treatment of this autoimmune disease is the use of high doses of normal polyclonal immunoglobulins. In fact there are a few reports of the empirical intravenous administration of immunoglobulins to pemphigus vulgaris patients. The results presented here provide the rational basis for using such a treatment, since it is demonstrated that a deviation from healthy V-region interactions can be attributed to pemphigus patients and that such a condition is considered to be modified by this type of immunotherapy.