The DRESS Syndrome: A Literature Review

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-beta1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft-versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-alpha, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-beta1, TNF-alpha, IFN-gamma, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.

https://journals.sagepub.com/doi/pdf/10.1177/154411130201300405

The pathogenesis of oral lichen planus.

First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.

These guidelines for management of pemphigus vulgaris have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2133.2003.05665.x

Guidelines for the management of pemphigus vulgaris

Skin Barrier Disruption - A Requirement for Allergen Sensitization?

Background Pemphigus vulgaris (PV) and foliaceus (PF) are characterized by antibodies to the desmosomal proteins desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), respectively. Past studies using indirect immunofluorescence (IIF) as a measure of pemphigus antibody levels have failed to demonstrate consistently a relationship between disease severity and IIF titres. However, IIF is not able to measure separately Dsg1 and 3 antibodies, unlike enzyme-linked immunosorbent assays (ELISA), which utilize recombinant proteins.



Objectives To compare independently Dsg1 and 3 antibody levels with the severity of both cutaneous and oral involvement in PV and PF.



Patients and methods Four hundred and twenty-four serum samples were analysed from 80 subjects with PV and 24 with PF. IgG antibodies to Dsg1 and 3 were measured by ELISA. For every sample analysed, the associated severity of skin and oral disease were graded from 0 to 3; quiescent, mild, moderate and severe.



Results A relationship between Dsg1 antibodies and skin severity was demonstrated such that a 10-unit increase in Dsg1 ELISA value was associated with a 34% chance of having a higher severity score [95% confidence interval (CI), 25–45%, P < 0·0005]. This was observed in both PV and PF. Oral severity was associated with Dsg3 antibody levels and a 10-unit increase in the Dsg3 ELISA value was associated with a 25% chance of a higher oral severity score (CI 17–33%, P < 0·0005). We were unable to demonstrate a relationship between Dsg1 antibodies and oral severity, even after adjusting for the effect of Dsg3 antibodies. Similarly, there was no relationship between Dsg3 antibodies and skin severity.



Conclusions This study suggests that the clinical phenotype of pemphigus, in particular the balance of skin and oral disease, is determined principally by the quantities of Dsg1 and 3 autoantibodies, respectively.

The severity of cutaneous and oral pemphigus is related to desmoglein 1 and 3 antibody levels

High-dose intravenous immune globulin (IVIG) is used to treat a wide variety of autoimmune diseases. We report our experiences of its use in a retrospective study of 14 patients with autoimmune blistering diseases, namely epidermolysis bullosa acquisita (EBA), two; bullous pemphigoid (BP), two; pemphigoid gestationis (PG), one; nodular pemphigoid, two; and pemphigus vulgaris (PV), seven. Two patients with refractory EBA improved following regular courses of IVIG given as monotherapy. IVIG had a steroid-sparing effect in 10 patients with PV, BP and PG. However, the clinical effects were transient and of variable intervals, and repeated courses of IVIG were required. The rapid actions of IVIG were of particular benefit in two patients with extensive, rapidly progressive PV and in one patient with BP in whom swift disease control was required. In such cases, when rapid disease control is paramount, we recommend IVIG used in conjunction with conventional treatments as a safer and less invasive alternative to plasmapheresis. IVIG was ineffective in two patients with nodular pemphigoid. Analysis of indirect immunofluorescence (IIF) titres before and after IVIG showed that a fall in titre occurred after 78% of treatments and was observed in all disease groups. However, like the clinical improvements, the falls in IIF titres were transient and of variable interval, and titres rose back to pretreatment levels in all but one patient. IVIG appears to be beneficial under certain circumstances for the treatment of autoimmune blistering diseases but controlled trials are required to define its therapeutic role further.

High-dose intravenous immune globulin for the treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are characterized by autoantibodies to the desmosomal glycoproteins desmoglein 3 (Dsg 3) and Dsg 1 (Dsg 1), respectively. In this study, two enzyme-linked immunosorbent assays (ELISA) which detect IgG autoantibodies to Dsg 1 and Dsg 3 have been evaluated. A total of 317 normal and disease controls, 82 patients with PV and 25 with PF were studied. The Dsg 3 ELISA was positive in all 34 patients with untreated PV and the Dsg 1 ELISA was positive in all 10 with untreated PF. When patients undergoing treatment were included, the sensitivities fell to 95% and 92%, respectively, but still compared favourably to the sensitivity of indirect immunofluorescence which was 79% in PV and 84% in PF. All PF sera were negative in the Dsg 3 ELISA and the specificity of both assays was 98% or greater. Large numbers of samples could be analysed simultaneously over a relatively short time period. The Dsg 1 and Dsg 3 ELISAs also provided objective, quantitative, reproducible data which allowed differentiation of PV from PF and in view of these advantages, they are likely to become a routine technique in diagnostic laboratories.

Diagnosis of pemphigus by ELISA: a critical evaluation of two ELISAs for the detection of antibodies to the major pemphigus antigens, desmoglein 1 and 3.

Background Pemphigus vulgaris (PV) is characterized by pathogenic autoantibodies to desmoglein (Dsg) 3, but additional antibodies to Dsg1, the pemphigus foliaceus antigen, are detectable in some cases.  Objectives To investigate the clinical significance of the presence of both Dsg 1 and 3 antibodies.  Methods In 79 subjects with PV, enzyme-linked immunosorbent assays were used to detect IgG autoantibodies reactive with the ectodomain of Dsg1 and Dsg3.  Results There was a clear association between the clinical phenotype and the Dsg antibody profile. All subjects had Dsg3 autoantibodies and 61% had coexisting Dsg1 antibodies (Dsg3+/Dsg1+). PV limited entirely to the mucosal surfaces was seen only in Dsg3+/Dsg1– patients, while additional Dsg1 antibodies (Dsg3+/Dsg1+) predicted cutaneous in addition to mucosal involvement. Although minor cutaneous involvement was observed in most Dsg3+/Dsg1– patients, severe cutaneous involvement was seen only in Dsg3+/Dsg1+ patients. Dsg1 antibodies were detectable early in the course of disease and their appearance did not relate to the use of systemic therapy. The proportion of Dsg1+ patients was higher in those of Indian origin compared with white northern Europeans (P < 0·05).  Conclusions These data suggest that the presence of Dsg1 antibodies is predictive of a potentially more severe disease and that genetic factors may determine the Dsg antibody profile.

K E Harman

Papers

Guidelines for the management of pemphigus vulgaris

The severity of cutaneous and oral pemphigus is related to desmoglein 1 and 3 antibody levels

High-dose intravenous immune globulin for the treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases

Diagnosis of pemphigus by ELISA: a critical evaluation of two ELISAs for the detection of antibodies to the major pemphigus antigens, desmoglein 1 and 3.

A study of desmoglein 1 autoantibodies in pemphigus vulgaris: racial differences in frequency and the association with a more severe phenotype