Sporadic pemphigus foliaceus and class II human leucocyte antigen allele associations in the white British and Indo-Asian populations in the UK.

BACKGROUND: Pemphigus foliaceus (PF) has both genetic and environmental susceptibility factors. Current data on human leucocyte antigen (HLA) in patients with sporadic PF are limited. AIM: To better define the distribution of HLA alleles in patients with PF in the UK. METHODS: We recruited 36 patients [26 of white British (WB) descent, 10 of Indo-Asian (IA) descent] with PF who were living in the UK and 159 ethnically matched normal controls, and analysed their class II HLA DRB1 and DQB1 allele distribution. RESULTS: There was an increased frequency of DRB1*1404 in association with DQB1*0503 in IA patients with PF. The DRB1*04 allele group as a whole had an increased frequency (P < 0.001) in the WB patient group compared with controls. The alleles contributing to this significance were DRB1*0401 (P = 0.03) and DRB1*0404 (P < 0.01). CONCLUSION: This is the largest HLA association study in sporadic PF from the UK to date. There appears to be a difference in PF susceptibility alleles between WB and IA patients, highlighting the importance of racial variation in genetic susceptibility to disease development.

Crescendo response to rituximab in oral pemphigus vulgaris: a case with 7-year follow-up.

Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin and mucous membranes. Rituximab, a CD20 chimeric monoclonal antibody, has efficacy in PV management. We report a case of severe oral PV that showed a progressive response to repeated courses of rituximab, culminating in a rapid response within 4 weeks following severe relapse 4 years after initial therapy. It demonstrates the progressively shorter time to achieve partial or complete remission following rituximab infusions, combined with minimal adjuvant therapy over a 7-year follow-up period.

Immunopathological characteristics of patients with bullous pemphigoid and neurological disease.

BACKGROUND: The relationship between bullous pemphigoid (BP) and neurological disease has been the subject of numerous recent studies and BP antigens and their isoforms have been identified in the central nervous system (CNS). Whilst epidemiological data support this association, little is known about the pathomechanism behind this link and the immunological characteristics of patients with BP and neurological disease, other than multiple sclerosis (MS), has not been studied. OBJECTIVE: We aimed to compare the cutaneous immune response in BP patients with and without neurological disease, to investigate whether or not there is a distinctive immunopathological profile in patients with concomitant BP and neurological disease. METHODS: Seventy-two patients with BP were included and divided into two groups; those with neurological disease (BP+N, n = 43) and those without (BP-N, n = 29). Patients in BP+N group had a confirmed neurological disease by a hospital physician, neurologist or psychiatrist with positive neurological imaging where appropriate, or a Karnofsky score of 50 or less due to mental impairment. All sera were analysed with indirect immunofluorescence (IIF) using serial dilutions up to 1:120000, immunoblotting (IB) and Enzyme-linked immunosorbent assay (ELISA) for BP180 and BP230. RESULTS: Median antibody titres by IIF were 1:1600 vs. 1:800 for BP-N and BP+N, respectively, although the difference did not reach statistic significance (P = 0.93, Mann-Whitney U-test). ELISA values for both BP180 and BP230 did not differ significantly between the two groups. Similarly, autoantibodies to specific antigens as identified by ELISA and IB were not related to the presence of neurological disease. CONCLUSION: The results of this study indicate that patients with BP and neurological disease exhibit an immune response to both BP180 and BP230, thus the link between the CNS and the skin is not dependent on a specific antigen, but possibly both antigens or their isoforms may be exposed following a neurological insult, and play a role in generation of an immune response.

Prognostic factors in pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND: Pemphigus typically has a chronic course, although there is great variability in disease duration (DD) and time taken to disease remission (DR) between individuals with the disease. The reasons for this are unclear. OBJECTIVES: To explore the prognostic influence of epidemiological, clinical, immunological and genetic factors on disease course and remission in pemphigus vulgaris (PV) and pemphigus foliaceus (PF). METHODS: This was a retrospective study of patients with PV and PF, recruited from a single UK centre. Direct and indirect immunofluorescence and enzyme-linked immunosorbent assay studies for antidesmoglein (Dsg) antibodies were used to assess immunological factors. Polymerase chain reaction with sequence specific primers (PCR-SSP) was used to assess the Class II human leukocyte antigen status of patients. Prognostic endpoints investigated were time to initial first DR and total DD. RESULTS: Ninety-five patients were recruited (79 PV and 16 PF). Patients of Indo-Asian origin were significantly associated with longer DD than White-British patients (P = 0.029). In addition, younger age at onset was associated with a worse prognosis in terms of DD: the mean age at presentation of patients with DD of < 5 years was 49 years (SEM = 3.4) compared with 40 years (SEM = 1.9) in those with DD > 5 years (P = 0.039). A higher initial intercellular antibody titre on normal human skin substrate was associated with a greater time to initial DR (P = 0.007) and high anti-Dsg 3 levels at baseline were associated with a longer total DD (P = 0.03). CONCLUSIONS: Ethnic group, age at presentation, initial intercellular antibody titre and initial Dsg 3 antibody levels all had a significant impact on prognosis of pemphigus.

Evaluating the use of the interferon-γ response to Mycobacterium tuberculosis-specific antigens in patients with psoriasis prior to antitumour necrosis factor-α therapy: a prospective head-to-head cross-sectional study.

BACKGROUND: Targeted biological therapies have transformed the treatment of chronic inflammatory disease. However, reactivation of latent tuberculosis infection (LTBI) is a significant risk with the use of antitumour necrosis factor (anti-TNF)-α therapy and screening is mandatory prior to treatment. The tuberculin skin test (TST) may be difficult to interpret in patients with inflammatory disease or receiving immunosuppressive therapies. OBJECTIVES: The aim of this study was to evaluate and compare the QuantiFERON(®) -TB Gold In-Tube (QFR) and T-SPOT.TB (TSTB) interferon-γ-release assays (IGRA) against the TST in a cohort of patients commencing anti-TNF-α therapies for chronic inflammatory disease. METHODS: A prospective cross-sectional study was undertaken at a London tertiary referral centre. Demographic data collected included TB risk factors. TST, QFR and TSTB were performed in all patients. RESULTS: Seventy patients with chronic plaque psoriasis were included in the study. Agreement between QFR and TSTB, excluding indeterminate results, was 89% (κ = 0.567), between QFR and TST 85% (κ= 0.313) and 81% (κ = 0.244) between TSTB and TST. There was no significant association with concomitant immunosuppression and either TST or IGRA results. Seven patients received chemoprophylaxis for LTBI diagnosed after clinical risk assessment together with positive TST and/or IGRA. Three patients had positive results in all three tests. CONCLUSIONS: While there was moderate overall agreement between QFR and TSTB and fair correlation between TST, QFR and TSTB, there were a number of discordant results, suggesting that a three-pronged approach using TST, QFR and TSTB may be of additional benefit.

Bullous pemphigoid in a patient with suspected non-Herlitz junctional epidermolysis bullosa.

A 56-year-old man with lifelong trauma-induced blisters, nail dystrophy and dental enamel hypoplasia presented with a new spontaneous blistering eruption. Clinicopathologically, he had evidence of both an inherited and an acquired blistering disorder: non-Herlitz junctional epidermolysis bullosa (nHJEB) and bullous pemphigoid (BP). HIstological examination of a skin biopsy found reduced (but not absent) collagen XVII in nonlesional skin, in vivo bound anticollagen XVII antibodies in perilesional skin, and prominent eosinophils in perilesional and lesional skin, with subepidermal blistering. Circulating anticollagen XVII antibodies were also present. Treatment with oral corticosteroids and mycophenolate mofetil led to clinical control of the BP but had no effect on the mechanobullous blistering. Our patient is unusual in that his skin retains some labelling for collagen XVII rather than having the complete absence of immunoreactivity expected in patients with generalized nHJEB. Moreover, we were unable to identify any pathogenic mutations in the COL17A1 gene encoding collagen XVII (or in other EB-associated basement membrane genes). It is plausible that the long-term consequences of basement membrane disruption in our patient, perhaps associated with atypical inherited COL17A1 pathology, might result in a conformationally altered and more immunogenic protein with the subsequent development of anticollagen XVII antibodies and BP as a secondary pathology.

Childhood vulval lichen sclerosus: autoimmunity to the basement membrane zone protein BP180 and its relationship to autoimmunity.

Lichen sclerosus (LS) is associated with autoimmune disease in female children and adults. In adult women, there are antibody and T-cell responses to proteins in the basement membrane zone (BMZ). The aim of this study was to investigate reactivity to the BMZ in girls with LS. Nine girls with vulval LS were studied clinically and serologically. The presence of circulating BMZ autoantibodies was investigated. Autoimmunity was assessed by personal and family history of autoimmune diseases and autoantibodies. We detected circulating BMZ antibodies in four of the nine children, all with IgG responses. Three patients were positive by indirect immunofluorescence, one had a positive ELISA reaction to bullous pemphigoid antigen (BP)180, and three had a positive reaction on BP180 immunoblots. There was no association with autoimmune disease or clinical features. To our knowledge, this is the first study to find BMZ autoantibodies in children with vulval LS. The autoantibodies were directed at BP180 and were exclusively of the IgG class.

Pulsed intravenous cyclophosphamide and methylprednisolone therapy in refractory pemphigus.

BACKGROUND: Pemphigus is a rare autoimmune blistering disorder. The mainstay of current treatment is high-dose oral corticosteroid therapy in combination with a steroid-sparing agent. Adjuvant therapy is important for disease control and to reduce the iatrogenic effects of oral prednisolone. Pulsed therapy with intravenous methylprednisolone and cyclophosphamide (PPC) has been shown to be an effective treatment but there are currently few data on its use in patients who have failed to respond to conventional immunosuppression. OBJECTIVES: To report the clinical and immunological responses of 21 patients with pemphigus refractory to prednisolone and azathioprine or mycophenolate mofetil treated in our department with a standard protocol of monthly PPC. METHODS: Patients with pemphigus were identified who had undergone PPC therapy during the period between 1997 and 2006. Initial clinical severity and response to treatment was assessed. In addition, change in intercellular antibody titres and desmoglein 1 and 3 antibodies to PPC therapy was also recorded. RESULTS: Of the 21 patients treated, seven had an excellent response, two a good response, five a moderate response, six a minimal response and one patient had no clinical response. Four patients achieved complete clinical remission and the number of pulses for these patients varied between 11 and 22. We observed significant reductions in indirect immunofluorescence titres for normal human skin substrate (P = 0.0078) and antidesmoglein 1 and 3 autoantibody levels (P = 0.007 and P = 0.0085, respectively) from pre-PPC therapy to 1 year after the last pulse. All patients were able to reduce their prednisolone dose from a pre-pulsing median dose of 40-10 mg at the last pulse with a median dose reduction of 66% (P < 0.001). The most common adverse effect was transient lymphopenia (12 patients); nonlife-threatening sepsis (seven patients) and premature ovarian failure (two patients) also occurred. CONCLUSIONS: PPC can be an effective treatment for refractory pemphigus but its adverse effects should be considered prior to therapy and closely monitored in patients on treatment.

T cells reactive with the NC16A domain of BP180 are present in vulval lichen sclerosus and lichen planus.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin condition. The recent demonstration of circulating autoantibodies to extracellular matrix protein 1 and to basement membrane zone (BMZ) components, chiefly BP180, suggests that autoimmunity to these components might contribute to pathogenesis. However, there is no binding of autoantibodies in vivo and as LS is characterized by a lymphocytic infiltrate, it seems likely that LS is mediated, in part, by antigen-specific lymphocytes. Similar mechanisms may apply to vulval lichen planus (LP), an interface dermatitis, with clinical and immunological overlap with LS. OBJECTIVES: This study aims to test the hypothesis that T cells reactive with the NC16A domain of BP180 are present in the peripheral blood of patients with vulval LS and LP. METHODS: Isolated peripheral blood mononuclear cells from 14 patients with vulval LS, 5 with vulval LP and 4 healthy controls were grown in vitro. We examined for immunogenicity of overlapping peptides spanning the NC16A domain of BP180 using interferon-gamma enzyme-linked immunospot assay (ELIspot) on the cultured T-cell lines. BMZ antibodies were assayed, HLA type determined and clinical parameters noted. RESULTS: Significant interferon-gamma production was observed in response to the NC16A peptides in 6 of the 14 vulval LS and 2 of the 5 LP patients, but not in the control subjects. There was an associated autoantibody response to BP180 in 3 LS and 1 LP patient with T-cell responses. These data suggest that in some vulval LS and LP patients, NC16A domain-specific T cells circulate at sufficiently high frequency to be detectable in vitro and show rapid effector function. There was no association with HLA type or clinical parameters. CONCLUSION: We have demonstrated that in > 40% of our vulval LS and LP patients, the NC16A domain of BP180 is a target for circulating T cells, and in vulval LS and LP there are associated autoantibodies to BP180.

Adalimumab for psoriasis patients who are non-responders to etanercept: open-label prospective evaluation.

BACKGROUND: Targeted biologic therapies have made a significant impact on the treatment for moderate to severe psoriasis. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends etanercept, a human recombinant tumour necrosis factor (TNF) receptor fusion protein, for moderate to severe psoriasis patients who have failed conventional therapies. There is, however, no data available on the role of other TNF antagonists for patients who have failed etanercept. Adalimumab, a fully human, anti-TNF monoclonal antibody, is approved for treatment of moderate to severe psoriasis. OBJECTIVES: To assess the efficacy and safety of adalimumab (40 mg weekly) in psoriasis patients who were non-responders to high-dosage etanercept (50 mg twice weekly). METHODS: All patients attending a tertiary referral service for severe psoriasis who were non-responders to high-dosage etanercept [i.e. failed to achieve >or= 50% improvement in Psoriasis Area and Severity Index (PASI 50) after 12 weeks of treatment] were considered for open-label adalimumab therapy for 12 weeks. Details on clinical course, PASI, Dermatology Life Quality Index (DLQI) and adverse events were recorded at baseline and weeks 2, 4, 8, and 12. Results Four of five patients in this study had reached at least PASI 50 by week 12. Of these, two patients achieved a 75% improvement in PASI (PASI 75). No serious adverse events were reported. CONCLUSIONS: Initial data from this open-label prospective evaluation suggests that weekly adalimumab therapy is an effective treatment for patients with severe psoriasis who had failed to respond to at least 3 months of high-dosage etanercept.

Haemorrhage into chronic plaque psoriasis as a consequence of disseminated intravascular coagulation.

We describe a patient with chronic plaque psoriasis who developed haemorrhage into pre-existing lesions during an episode of disseminated intravascular coagulation secondary to sepsis. Disseminated intravascular coagulation is a complex disorder characterized by widespread intravascular deposition of fibrin with consumption of coagulation factors and platelets and occurs as a consequence of many disorders that release procoagulant material into the circulation or cause widespread endothelial damage or platelet aggregation. As both disseminated intravascular coagulation and psoriasis occur relatively frequently in the general population we were surprised to find no previous reports of this phenomenon in the literature.