Intravenous Immunoglobulin for Autoimmune Bullous Diseases: A Case Series from a Central European Referral Center.

Background and Objectives: Autoimmune bullous diseases (AIBDs) may be treated with intravenous immunoglobulin (IVIG) infusions. This study aimed to evaluate the benefits and safety profiles of high-dose IVIG therapy in AIBD patients, as determined by clinical remission, the glucocorticosteroid-sparing effect, and adverse events at 12 months follow-up in a Central European university dermatology department setting. Materials and Methods: Our case series included 10 patients: five patients with pemphigus vulgaris, one with pemphigus herpetiformis, one with pemphigus foliaceus, one with bullous pemphigoid, two with epidermolysis bullosa acquisita. They underwent 4-12 monthly cycles of IVIG therapy at a dose of 2 g/kg per cycle. Results: The prednisone dosage reduction after 2, 6, and 12 months following the final IVIG course was 65.45%, 70.91%, and 76.37%, respectively. During the 12-month observation period, disease relapse was observed in 20% of patients, while others achieved complete or partial remission without or with minimal therapy. Side effects were seen in 80% of patients; they were transient and did not necessitate discontinuation of IVIG. Conclusions: IVIG demonstrates effectiveness as a treatment with a favorable safety profile. Nevertheless, its high cost remains a significant drawback, particularly in low-income countries. IVIG should be considered, especially in patients opposed to standard therapies or with contraindications to their use.

Epidermolysis bullosa acquisita as an adverse effect from rituximab therapy: A case report.

RATIONALE: Rituximab is a monoclonal antibody directed against B cells and is a first-line agent for the treatment of B cell lymphoma and a second-line agent for the treatment of idiopathic thrombocytopenic purpura (ITP). It has also been used for the treatment of several other autoimmune diseases. Epidermolysis bullosa acquisita (EBA) has never been reported as an adverse effect resulted from rituximab therapy. PATIENT CONCERNS: A 54-year-old female presented with relapse of the ITP for around eight months. She was treated with rituximab. Intramuscular chlorpheniramine and intravenous methylprednisolone and cimetidine were used as premedication before rituximab infusion. The infusion was initially started at 50 mg/h for 1 h followed by 100 mg/h till the end of infusion. The day after rituximab infusion, the patient noticed pruritic blisters on both arms and chest skin. The next day, the lesions increased in severity and extent. DIAGNOSIS: The skin biopsy established the diagnosis of EBA. H&E staining revealed subepidermal blisters infiltrated by inflammatory cells, including eosinophils and lymphocytes. Direct immunofluorescence (DIF) showed linear deposition of IgG and C3 at the dermoepidermal junction. Indirect immunofluorescence with the patient's serum on salt-split skin revealed exclusive dermal binding of circulating IgG antibasement membrane antibodies at a titer of 1:160. INTERVENTIONS: She was treated with intravenous methylprednisolone and was continued on oral prednisolone. OUTCOMES: The lesions regressed. Six weeks later, she had a recurrence of similar lesions but in milder form. This episode subsided in 4 to 5 days with topical steroid application. LESSONS: Physicians should consider this diagnosis when a patient develops bullous skin eruptions while undergoing Rituximab therapy.

Childhood epidermolysis bullosa acquisita during squaric acid dibutyl ester immunotherapy for alopecia areata.

Epidermolysis bullosa acquisita (EBA) is a rare acquired subepidermal blistering disease associated with autoantibodies against type VII collagen. Although EBA manifests more frequently in adults, it can occur in childhood. We describe a 6-year-old boy who developed the inflammatory variant of EBA shortly after initiation of immunotherapy with squaric acid dibutyl ester (SADBE) for scalp alopecia areata. The disease rapidly regressed following SADBE discontinuation and starting combined steroid and dapsone therapy, and never recurred after treatment tapering and withdrawal. The association of EBA with other autoimmune diseases is common, but EBA occurring during alopecia areata has not been described previously. The development of EBA during SADBE treatment is also notable: the clinical history and therapeutic response in our patient point to a possible role of SADBE in EBA onset.

T cells mediate autoantibody-induced cutaneous inflammation and blistering in epidermolysis bullosa acquisita.

T cells are key players in autoimmune diseases by supporting the production of autoantibodies. However, their contribution to the effector phase of antibody-mediated autoimmune dermatoses, i.e., tissue injury and inflammation of the skin, has not been investigated. In this paper, we demonstrate that T cells amplify the development of autoantibody-induced tissue injury in a prototypical, organ-specific autoimmune disease, namely epidermolysis bullosa acquisita (EBA) - characterized and caused by autoantibodies targeting type VII collagen. Specifically, we show that immune complex (IC)-induced inflammation depends on the presence of T cells - a process facilitated by T cell receptor (TCR)γδ and NKT cells. Because tissue damage in IC-induced inflammation is neutrophil-dependent, we further analyze the interplay between T cells and neutrophils in an experimental model of EBA. We demonstrate that T cells not only enhance neutrophil recruitment into the site of inflammation but also interact with neutrophils in lymphatic organs. Collectively, this study shows that T cells amplify the effector phase of antibody-induced tissue inflammation.

Heat-shock protein 90 inhibition in autoimmunity to type VII collagen: evidence that nonmalignant plasma cells are not therapeutic targets.

Blocking heat-shock protein 90 (Hsp90) induces death of malignant plasma cells by activation of the unfolded protein response, a signaling pathway activated by accumulation of misfolded proteins within the endoplasmic reticulum. We hypothesized that nontransformed plasma cells are also hypersensitive to Hsp90 inhibition because of their high amount of protein biosynthesis. To investigate this hypothesis, 2 different Hsp90 inhibitors, the geldanamycin derivative 17-DMAG and the nontoxic peptide derivative TCBL-145, were applied to mice with experimental epidermolysis bullosa acquisita, an autoimmune bullous disease characterized by autoantibodies against type VII collagen of the dermal-epidermal junction. Both inhibitors ameliorated clinical disease of type VII collagen-immunized mice, suppressed auto-antibody production, and reduced dermal neutrophilic infiltrate. Interestingly, total plasma cell numbers, type VII collagen-specific plasma cells, and germinal center B cells were unaffected by anti-Hsp90 treatment in vivo. However, T-cell proliferation was potently inhibited, as evidenced by the reduced response of isolated lymph node cells from immunized mice to in vitro restimulation with anti-CD3/CD28 antibody or autoantigen in the presence of Hsp90 inhibitors. Our results suggest that Hsp90 blockade has no impact on normal or autoreactive plasma cells in vivo and indentify T cells as targets of anti-Hsp90 treatment in autoimmunity to type VII collagen.

Epidermolysis bullosa acquisita-like reaction associated with penicillamine therapy for sclerodermatous graft-versus-host disease.

A case of a bullous eruption occurred in a patient being treated with penicillamine for sclerodermatous graft-versus-host disease following bone marrow transplantation. After 7 days of treatment with 150 mg penicillamine, a painful bullous eruption with accompanying purpuric lesions suddenly developed in previous sclerodermatous infiltrations. A diagnosis of epidermolysis bullosa acquisita-like eruption was made, and the patient was treated with drug withdrawal and administration of cyclosporine and methylprednisolone. Epidermolysis bullosa acquisita-like reaction is an extremely rare cutaneous side effect of penicillamine. The surprisingly early onset of this eruption in lesions of sclerodermatous graft-versus-host disease might have been due to severe immune alteration.

Drug-induced epidermolysis bullosa acquisita with antibodies to type VII collagen.

We describe a 73-year-old patient who had a subepidermal bullous eruption develop after a course of antibiotics, including vancomycin. The patient had deposits of IgA and IgG in the cutaneous basement membrane zone that were located on the dermal side of 1 M NaCl-treated autologous skin. By an enzyme-linked immunosorbent assay, the patient was found to have circulating IgG antibodies directed against type VII collagen, the target antigen of epidermolysis bullosa acquisita. Our observation expands the spectrum of immune-mediated subepidermal bullous skin eruptions precipitated by drugs and lends support to the idea that a subset of these cases represents an unusual variant of drug-triggered epidermolysis bullosa acquisita.

Immunohistochemical characterization of the basement membrane epitopes in bis(2-chloroethyl) sulfide-induced toxicity in mouse ear skin.

Sulfur mustard (bis(2-chloroethyl) sulfide (HD)), a potent cutaneous vesicant and bifunctional alkylating agent, produces significant time-dependent histopathological changes in the skin of the mouse. The right ears of male CD1 mice were exposed topically to 5.0 microl of 195 mM (0.16 mg) HD in dichloromethane and harvested at 6, 12, 18 and 24 h. The left ear control was dosed with 5.0 microl of dichloromethane. In all controls and HD-treated mouse ear, moderate immunofluorescence staining was seen at the epidermal-dermal junction with bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA) and laminin (Lam), and light staining was observed with bullous pemphigoid 180 (BP180), fibronectin (Fn) and type IV collagen (Coll IV). Mouse anti-human monoclonal antibodies for GB3, L3d and 19-DEJ-1 (Uncein) did not cross-react. In microvesicles, BP, BP180 and Fn showed areas of light focal epidermal staining and homogeneous dermal staining, and EBA, Lam and Coll IV showed moderate dermal staining. Both BP and Fn exhibited weak, inconsistent staining with time. Immunoelectron microscopy (IEM) revealed similar results, with an increase in cell damage from 6 to 24 h, which corresponded to a decrease in staining intensity. Cell proliferation, expressed as the growth fraction of proliferating cell nuclear antigen (PCNA), showed an increase in cell damage. The growth fraction was lower in the inner ear and showed time-dependent differences. The immunofluorescence and IEM results indicate that HD causes an undulating inconsistent separation in the uppermost lamina lucida with focal cleavage into the lower portion of the basal keratinocytes just above the plasma membrane. Although this pattern of separation differs from other in vivo models in which the split occurs exclusively within the lamina lucida, this should not preclude its role as a screening model to study the effects and development of specific prophylactic and therapeutic strategies.

Epidermolysis bullosa acquisita induced by GM-CSF: a role for eosinophils in treatment-related toxicity.

A patient treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) developed eosinophilia and epidermolysis bullosa acquisita. The bullae were subepidermal, and filled with an inflammatory infiltrate composed predominantly of eosinophils. Immunofluorescence studies disclosed linear deposition of IgG, IgA and C3 at the basement membrane zone and immunoelectron microscopy demonstrated antibody deposition in the lamina densa and sublamina densa region; however, the patient's serum did not contain circulating antibody to basement membrane zone antigens. Staining with monoclonal antibodies revealed dense deposits of both eosinophil peroxidase and eosinophil major basic protein at the dermal-epidermal junction. The eosinophilia and skin lesions resolved upon discontinuation of GM-CSF. This case provides evidence for two hypotheses: (1) GM-CSF induced proliferation and activation of eosinophils may contribute to some of the toxicities of GM-CSF treatment, and (2) activated granulocytes, including eosinophils, may mediate blister formation in epidermolysis bullosa acquisita.