Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: an update.

High-dose intravenous immunoglobulin (IVIg) is being increasingly utilized as an off-label therapy for a variety of autoimmune and inflammatory conditions across various specialties. Numerous reports have shown that it is an effective treatment for autoimmune skin blistering disorders. Unlike most therapies for blistering disorders, IVIg is not immunosuppressive and has a favorable side effect profile. This has allowed its use to expand dramatically over the last decade. However, due to the rarity and severity of autoimmune skin blistering diseases, well-designed prospective trials are generally lacking. This work highlights major research developments and the best evidence to date regarding the treatment of autoimmune pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, and linear IgA dermatosis with IVIg, providing an update on its efficacy, proposed mechanisms of action, side effect profile, and indications for use.

Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

Effect of intravenous immunoglobulin with or without cytotoxic drugs on pemphigus intercellular antibodies.

BACKGROUND: Intravenous immunoglobulin (IVIg)--a relatively new approach to treat pemphigus--lowers serum levels of pemphigus antibodies; however, the optimal way to use this agent is unknown. OBJECTIVE: We sought to examine whether coadministration of a cytotoxic drug to patients with pemphigus improves the ability of IVIg to decrease serum levels of intercellular (IC) antibodies. METHODS: In this retrospective study, we analyzed changes in IC antibody levels in 20 patients with pemphigus who were treated with 24 courses of IVIg administered alone (n = 10) or with a cytotoxic drug (n = 14). Each course of IVIg consisted of 400 mg/kg daily of immunoglobulin given over 5 days every other week; this cycle was repeated 3 to 4 times. Serum levels of IC antibodies were measured at baseline, before treatment, and 1 week and 1 month after the last IVIg cycle. RESULTS: One week after the last IVIg cycle IC antibodies decreased by an average of 77% in the group treated with IVIg and cytotoxic drug compared with 48% in the group treated with IVIg alone (P = .54), and by 90% versus 43% 1 month later (P = .03). LIMITATIONS: A larger sample size is suggested for future studies. CONCLUSIONS: These observations confirm that IVIg can rapidly lower serum levels of autoantibodies in patients with pemphigus and its ability to do so is improved by the coadministration of a cytotoxic drug. These findings imply that the clinical effectiveness of IVIg in treating pemphigus, and possibly other autoantibody-mediated diseases, may be improved by the concurrent administration of a cytotoxic drug.

Potential role of interleukin-17 in the pathogenesis of bullous pemphigoid.

Bullous pemphigoid is an autoimmune blistering disease of the skin caused by autoantibodies directed against basement membrane zone adhesion molecules. Autoantibodies cannot fully explain several important features of the disease such as the difficulty transferring with the pathogenic autoantibodies, or the presence of heavy lesional infiltration of eosinophils and neutrophils that is necessary for disease production. There is increasing evidence that Th17 cells and the cytokines they release such as interleukin-17 are important regulators of innate and adaptive immune responses in many Th1 and/or Th2 mediated autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and allergic asthma. There is also evidence that Th17 cells have a role in pathogenesis of blistering skin diseases. Interleukin-17 is important in initiation and maintenance of many autoimmune reactions and it is involved in production of pro-inflammatory cytokines, matrix metalloproteinases, neutrophils, and eosinophils, all of which are important pathogenic factors in bullous pemphigoid. The hypothesis is that interleukin-17 has an important pathogenic role in BP and can describe features of the disease not explained by the autoantibody theory. This cytokine can be assessed in the blister fluid and sera of patients, and can be used as a marker of disease activity and response to therapy. The information obtained could also lead to the development of novel therapeutic strategies for this and other autoimmune blistering diseases.

Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis.

Understanding the acantholytic pathways leading to blistering in pemphigus vulgaris (PV) is a key to development of novel treatments. A novel paradigm of keratinocyte damage in PV, termed apoptolysis, links the suprabasal acantholytic and cell death pathways to basal cell shrinkage rendering a 'tombstone' appearance to PV lesions. In contrast to apoptolysis, the classic keratinocyte apoptosis mediating toxic epidermal necrolysis causes death and subsequent sloughing of the entire epidermis. Apoptolysis includes five consecutive steps. (1) Binding of autoantibodies to PV antigens. (2) Activation of EGF receptor, Src, mTOR, p38 MAPK and other signalling elements downstream of ligated antigens, elevation of intracellular calcium and launching of the cell death cascades. (3) Basal cell shrinkage due to: (i) collapse and retraction of the tonofilaments cleaved by executioner caspases; and (ii) dissociation of interdesmosomal adhesion complexes caused by phosphorylation of adhesion molecules. (4) Massive cleavage of cellular proteins by activated cell death enzymes leading to cell collapse, and tearing off desmosomes from the cell membrane stimulating secondary autoantibody production. (5) Rounding up and death of acantholytic cells. Thus, the structural damage (acantholysis) and death (apoptosis) of keratinocytes are mediated by the same cell death enzymes. Appreciation of the unifying concept of apoptolysis have several important implications: (i) linking together a number of seemingly unrelated events surrounding acantholysis; (ii) opening new avenues of investigation into the pathomechanism of pemphigus; and (iii) creating new approaches to the treatment of pemphigus based on blocking the signalling pathways and enzymatic processes that lead to blistering.

Reliability and convergent validity of two outcome instruments for pemphigus.

A major obstacle in performing multicenter controlled trials for pemphigus is the lack of a validated disease activity scoring system. Here, we assess the reliability and convergent validity of the PDAI (pemphigus disease area index). A group of 10 dermatologists scored 15 patients with pemphigus to estimate the inter- and intra-rater reliability of the PDAI and the recently described ABSIS (autoimmune bullous skin disorder intensity score) instrument. To assess convergent validity, these tools were also correlated with the Physician's Global Assessment (PGA). Reliability studies demonstrated an intra-class correlation coefficient (ICC) for inter-rater reliability of 0.76 (95% confirdence interval (CI)=0.61-0.91) for the PDAI and 0.77 (0.63-0.91) for the ABSIS. The tools differed most in reliability of assessing skin activity, with an ICC of 0.39 (0.17-0.60) for the ABSIS and 0.86 (0.76-0.95) for the PDAI. Intra-rater test-retest reliability demonstrated an ICC of 0.98 (0.96-1.0) for the PDAI and 0.80 (0.65-0.96) for the ABSIS. The PDAI also correlated more closely with the PGA. We conclude that the PDAI is more reproducible and correlates better with physician impression of extent. Subset analysis suggests that for this population of mild-to-moderate disease activity, the PDAI captures more variability in cutaneous disease than the ABSIS.

Enhanced immunogenicity of Plasmodium falciparum peptide vaccines using a topical adjuvant containing a potent synthetic Toll-like receptor 7 agonist, imiquimod.

Plasmodium sporozoites injected into the skin by malaria-infected mosquitoes can be effectively targeted by antibodies that block parasite invasion of host hepatocytes and thus prevent the subsequent development of blood stage infections responsible for clinical disease. Malaria subunit vaccines require potent adjuvants, as they lack known pathogen-associated molecular patterns found in attenuated viral or bacterial vaccines that function as Toll-like receptor (TLR) agonists to stimulate dendritic cells and initiate strong adaptive immune responses. A synthetic TLR7 agonist, imiquimod, which is FDA approved for topical treatment of various skin conditions, can function as a potent adjuvant for eliciting T-cell responses to intracellular pathogens and model protein antigens. In the current studies, the topical application of imiquimod at the site of subcutaneously injected Plasmodium falciparum circumsporozoite (CS) peptides elicited strong parasite-specific humoral immunity that protected against challenge with transgenic rodent parasites that express P. falciparum CS repeats. In addition, injection of a simple linear peptide followed by topical imiquimod elicited strong Th1 CD4(+) T-cell responses, as well as high antibody titers. The correlation of high anti-repeat antibody titers with resistance to sporozoite challenge in vivo and in vitro supports use of this topical TLR7 agonist adjuvant to elicit protective humoral immunity. The safety, simplicity, and economic advantages of a topical synthetic TLR7 agonist adjuvant also apply to other vaccines requiring high antibody titers, such as malaria asexual or sexual blood stage antigens to prevent red blood cell invasion and block transmission to the mosquito vector, and to vaccines to other extracellular pathogens.

Effect of intravenous immunoglobulin therapy on serum levels of IgG1 and IgG4 antidesmoglein 1 and antidesmoglein 3 antibodies in pemphigus vulgaris.

BACKGROUND: Intravenous immunoglobulin rapidly decreases serum levels of intercellular antibodies in patients with pemphigus vulgaris. However, little is known about the effects of this therapy on antibodies directed specifically against desmoglein 1 and desmoglein 3 and on the IgG subclasses of these antibodies. This study was conducted to study the effect of intravenous immunoglobulin therapy on serum levels of IgG1 and IgG4 antibodies against desmoglein 1 and desmoglein 3 in patients with pemphigus vulgaris. OBSERVATIONS: Within 6 to 16 days after initiating a single cycle of intravenous immunoglobulin therapy in 9 patients, a significant decrease in serum levels of IgG4 and IgG1 antibodies against desmoglein 1 and desmoglein 3 occurred in 60% to 100% of the patients, depending on the antibody subclass and specificity. The median decrease in the antibody levels ranged from 34% to 80%. In addition, most patients (n = 6) showed clinical improvement. The decrease in IgG4 antidesmoglein 3 levels seemed to correlate with improvement in disease activity. CONCLUSIONS: Intravenous immunoglobulin therapy rapidly lowers serum levels of IgG1 and IgG4 antidesmoglein 1 and desmoglein 3 antibodies. There seems to be a stronger association between the decrease in IgG4 antidesmoglein 3 levels and improvement in clinical activity than with changes in the other antibody levels, which suggests that IgG4 antibodies have a more important role in mediating pemphigus vulgaris.

Improvement of intravenous immunoglobulin therapy for bullous pemphigoid by adding immunosuppressive agents: marked improvement in depletion of circulating autoantibodies.

BACKGROUND: Various antibody-mediated autoimmune disorders are treated with intravenous immunoglobulin (IVIg). While the exact action of IVIg is unknown, it likely acts to rapidly and selectively lower the level of pathogenic antibodies. The most effective use of IVIg, an expensive and potentially toxic treatment of autoimmune disorders, remains undetermined. We propose that the addition of immunosuppressive agents to the IVIg regimen may increase the ability of IVIg to lower the level of pathogenic antibodies. OBSERVATIONS: For 16 months, we observed a 78-year-old patient with autoantibody-mediated bullous pemphigoid who was treated with IVIg and an adjuvant therapy on 2 separate occasions as well as IVIg alone on 2 other occasions. We observed the greatest depression of bullous pemphigoid antibodies when IVIg was combined with an immunosuppressive agent. CONCLUSION: These results support the hypothesis that agents that suppress antibody synthesis can offset the rebound in the level of individual antibody that follows their depletion and thus can improve the effectiveness of IVIg treatment while reducing the cost and the potential toxic effects of therapy.

Intravenous immunoglobulin selectively decreases circulating autoantibodies in pemphigus.

BACKGROUND: Autoantibody-mediated diseases such as pemphigus are caused by a single or very limited number of pathogenic autoantibodies. A major problem with all current therapies for these diseases is that they target all antibodies rather than selectively targeting only pathogenic antibodies. The following study was conducted to confirm observations made in a limited number of patients that suggest intravenous immunoglobulin (IVIg) may be able to selectively lower serum levels of only abnormal autoantibodies. METHODS: The study was conducted in 12 patients who received IVIg for the treatment of recalcitrant pemphigus. Serum levels of antibodies to desmoglein 1 (Dsg 1) and desmoglein 3 (Dsg 3) were measured by enzyme-linked immunosorbent assay immediately before IVIg treatment and following a median of 2 cycles (range, 1-3) of treatment. As control, serum levels of several normal antibodies (against herpes simplex virus types 1 and 2, mumps, and varicella) were measured concurrently. RESULTS: Within a median of 2 weeks following the last cycle of IVIg serum, anti-Dsg 3 declined in all patients who tested positive at baseline and in 8 of 10 (80%) patients testing positive for anti-Dsg 1. On average, anti-Dsg 3 decreased by 45% and anti-Dsg 1 by 32%. By contrast, serum levels of the 4 normal antibodies increased in almost all patients, by an average of 408% (P < .001). LIMITATIONS: Correlation of clinical response to treatment with IVIg was not performed. The sample size was limited. CONCLUSION: These results indicate that IVIg can selectively and markedly decrease serum levels of abnormal antibodies in pemphigus without decreasing the levels of normal antibodies. Thus IVIg appears able to achieve the ideal goal of treatment in autoantibody-mediated diseases--selectively removing from the circulation only those antibodies that cause the disease.

Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.

Our scientific knowledge of pemphigus has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in pemphigus. A major obstacle in comparing therapeutic outcomes between centers is the lack of generally accepted definitions and measurements for the clinical evaluation of patients with pemphigus. Common terms and end points of pemphigus are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. This consensus statement from the International Pemphigus Committee represents 2 years of collaborative efforts to attain mutually acceptable common definitions for pemphigus. These should assist in development of consistent reporting of outcomes in future studies.

TLR7 imidazoquinoline ligand 3M-019 is a potent adjuvant for pure protein prototype vaccines.

Cancer vaccines, while theoretically attractive, present difficult challenges that must be overcome to be effective. Cancer vaccines are often poorly immunogenic and may require augmentation of immunogenicity through the use of adjuvants and/or immune response modifiers. Toll-like receptor (TLR) ligands are a relatively new class of immune response modifiers that may have great potential in inducing and augmenting both cellular and humoral immunity to vaccines. TLR7 ligands produce strong cellular responses and specific IgG2a and IgG2b antibody responses to protein immunogens. This study shows that a new TLR7 ligand, 3M-019, in combination with liposomes produces very strong immune responses to a pure protein prototype vaccine in mice. Female C57BL/6 mice were immunized subcutaneously with ovalbumin (OVA, 0.1 mg/dose) weekly 4x. Some groups were immunized to OVA plus 3M-019 or to OVA plus 3M-019 encapsulated in liposomes. Both antibody and cellular immune responses against OVA were measured after either two or four immunizations. Anti-OVA IgG antibody responses were significantly increased after two immunizations and were substantially higher after four immunizations in mice immunized with OVA combined with 3M-019. Encapsulation in liposomes further augmented antibody responses. IgM responses, on the other hand, were lowered by 3M-019. OVA-specific IgG2a levels were increased 625-fold by 3M-019 in liposomes compared to OVA alone, while anti-OVA IgG2b levels were over 3,000 times higher. In both cases encapsulation of 3M-019 in liposomes was stronger than either liposomes alone or 3M-019 without liposomes. Cellular immune responses were likewise increased by 3M-019 but further enhanced when it was encapsulated in liposomes. The lack of toxicity also indicates that this combination may by safe, effective method to boost immune response to cancer vaccines.