Orodigital pemphigus vulgaris: a pathogenic role of anti-desmoglein-3 autoantibodies in pemphigus paronychia?

Paronychia is a rare complication of pemphigus vulgaris (PV), and the immunological profile of patients with digital disease has not been assessed so far. We report 2 cases of PV with oral mucosa and periungual involvement, who had high titers of anti- desmoglein (Dsg)-3 circulating antibodies. These observations raise the possibility that expression of Dsg-1 and Dsg-3 in distinct areas of periungual skin is disease specific and that anti-Dsg-3 antibodies alone may have an as yet unrecognized importance for the development of paronychia in PV.     

Circulating pemphigus autoantibodies in healthy relatives of pemphigus patients: coincidental phenomenon with a risk of disease development?

Pemphigus is a severe autoimmune disease characterized by circulating and bound in vivo pemphigus autoantibodies. It was revealed that the autoantibodies occur in healthy first-degree relatives of pemphigus patients; however, their significance is not fully elucidated. Thus, the aim of the study was to assess the frequency of circulating IgG pemphigus autoantibodies in the healthy relatives of pemphigus patients and of their ability to bind in vivo in the epidermis. We also analyzed IgG subclasses distribution, both in the serum-positive relatives and in the patients. Our study included 67 healthy relatives, 50 healthy normal controls and 33 patients (25 at an active stage of the disease, 8 in clinical remission). To detect circulating pemphigus antibodies we applied indirect immunofluorescence and anti-desmoglein ELISA. Monoclonal anti-human IgG1, IgG2, IgG3, IgG4 antibodies were used to assess subclass distribution. The frequency of circulating pemphigus autoantibodies in the relatives, detected by IIF (30/67) was statistically higher (P < 0.001) than in the control group (0/50). ELISA revealed anti-desmoglein 1 and/or 3 antibodies in 13 out of 67 relatives. Direct immunofluorescence performed in 25 out of 32 seropositive relatives did not show intercellular bound in vivo IgG and/or C3 in the epidermis in any cases. Circulating IgG2 subclass was observed in 60% of the examined relatives and IgG4 was detected in 23.3% of them. In the patients at an active stage of pemphigus IgG4 and IgG1 were the dominant subclasses (96 and 76% relatively) while in clinical remission antibodies predominantly belonged to the IgG2 (75%) and IgG4 (37.5%) subclass. The obtained results confirmed polyclonal production of pemphigus autoantibodies and their different distributions dependent on the disease activity. Statistical analysis showed that the frequency of IgG1 and IgG4 subclasses was significantly higher in the patients at an active stage of the disease when compared to the patients in clinical remission (P < 0.001) or with seropositive healthy relatives (P < 0.001). The relevance of the presence of IgG4 autoantibodies in the healthy relatives' sera requires further studies that focus on their potential pathogenicity.     

Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris,or just ‘witnesses of disease'?

Pemphigus vulgaris (PV) is fascinating to dermatologists, epithelial biologists and immunologists alike, as its pathogenesis has been clarified to a much greater extent than that of most other organ-specific autoimmune diseases, and as it has provided abundant novel insights into desmoglein biology and pathology along the way. Historically, the most influential PV pathogenesis concept is that of Stanley and Amagai. This concept holds that autoantibodies against desmogleins are both essential and sufficient for epidermal blister formation (acantholysis) by impeding the normal functioning of these major adhesion proteins. However, as with most good theories, this landmark concept has left a number of intriguing and important questions open (or at least has not managed to answer these to everyone's satisfaction). Moreover, selected dissenting voices in the literature have increasingly called attention to what may or may not be construed as inconsistencies in this dominant PV pathogenesis paradigm of the recent past. The present debate feature therefore bravely rises to the challenge of re-examining the entire currently available evidence, as rationally and as undogmatically as possible, by provocatively asking a carefully selected congregation of experts (who have never before jointly published on this controversial topic!) to discuss how essential anti-desmoglein autoantibodies really are in the immunopathogenesis of PV. Not surprisingly, some of our expert "witnesses" in this animated debate propose diametrically opposed answers to this question. While doing so, incisive additional questions are raised that relate to the central one posed, and our attention is called to facts that may deserve more careful consideration than they have received so far. Together with the intriguing (often still very speculative) complementary or alternative pathogenesis scenarios proposed in the following pages, this offers welcome "food for thought" as well as very specific suggestions for important future research directions--within and beyond the camp of PV aficionados. The editors trust that this attempt at a rational public debate of the full evidence that is currently at hand will constructively contribute to further dissecting the exciting--and clinically very relevant!--immunopathogenesis of PV in all its complexity.     

Anti-TNFα therapy in the management of psoriasis: experience of a state referral center

BACKGROUND

Psoriasis is a chronic immune-mediated disease, characterized by increased levels of TNFα. Anti-TNFα agents have revolutionized the treatment of severe psoriasis by targeting an important molecule involved in its pathogenesis.

OBJECTIVES

We report the experience of a state referral center that uses anti-TNFα agents for psoriasis.

METHODS

We conducted a retrospective case series. Seventy-four out of 120 patients met the inclusion criteria. Clinical and laboratory data was analyzed using the chi-squared, Wicoxon and McNemar''s tests. Associations were considered statistically significant when p-value<0.05.

RESULTS

Forty-one subjects (55.40%) were male, with a mean age of 47.69±14.99 years. Median disease duration and pre-treatment PASI were 14.0 months (IQR 9.0-20.0), and 13.55 points (IQR 8.5-20.32). Sixty patients (81.10%) had arthropathic psoriasis. Forty-six subjects (62.20%) had comorbidities; the most frequent was dyslipidemia (25.70%). In 55.40% of patients, insufficient response to conventional therapies was the principal indication for using anti-TNFα drugs. Clinical improvement occurred in 93.20% of cases, and the post-treatment PASI median was 0.0 points (IQR 0.0-0.0). Adverse effects occurred in 6.80% of patients. Infections and elevation of transaminases occurred in 28.40% and 8.10% of cases, respectively.

CONCLUSION

Post-treatment reduction in PASI was satisfactory and the occurrence of adverse effects was minor, mostly mild infusion effects and local reactions at drug administration sites.     

Can rituximab be used in the treatment of pemphigus vulgaris during the COVID‐19 pandemic?

Rituximab is a monoclonal antibody that targets CD20, a B‐lymphocyte antigen; that leads to a decline in the B‐cell counts for at least a year. The patients who have received rituximab treatment in the previous 5 years with the diagnosis of pemphigus group of diseases at Cerrahpa?a Medical Faculty were questioned for COVID‐19 infection. A total of 48 patients were included in this study; only one male patient had COVID‐19 infection which had a mild course. There is no significant difference in the total number of lymphocytes between patients who have received rituximab within the previous 5 years or last year. The number of lymphocytes is independent of the number of courses of rituximab treatment received. Therefore, we suggest that all pemphigus patients who have received rituximab treatment within the previous 5 years should be careful of the preventive measures against the COVID‐19 infection irrespective of the number of treatment courses or the number of years which has passed since the treatment. The disease course was mild in the only infected patient. Thus, rituximab may be used in the treatment of pemphigus vulgaris during the COVID‐19 pandemic if its use is necessary.     

Concurrence of systemic lupus erythematosus and pemphigus: coincidence or correlation?

BACKGROUND: Pemphigus and systemic lupus erythematosus (SLE) have previously been reported to coexist in the same patient. However, the relationship between the 2 diseases has not been elucidated. OBJECTIVE: This review was conducted to examine the relationship between pemphigus and SLE when they occur together in the same patient. METHODS: We conducted a retrospective review of the literature to identify previously reported cases of pemphigus and SLE coexisting in the same patient. The temporal relationship, clinical course, response to therapy and effects of 1 disease on the other were examined. RESULTS: Eight patients with a dual diagnosis of pemphigus and SLE have been previously reported. Most were female and non-Caucasian, with a mean age of 41 years. In the 8 patients reviewed here clinical outcomes, organ system involvement and demographic profiles are more typical of SLE. Seven of these 8 patients had pemphigus vulgaris, and 1 had pemphigus erythematosus. The limited follow-up did not permit studying issues of disease interaction. An additional 17 patients with pemphigus have been reported who have features suggestive of SLE. Organ system involvement in these patients was less typical of SLE. CONCLUSION: It appears that a true dual diagnosis of pemphigus and SLE is less common than suggested by the literature. Comparing patients with only pemphigus or only SLE to those with both may provide insights into genetic predisposition and pathogenesis, and provide an opportunity to study the effects of drugs that influence their course.     

Poikilodermatous changes on the forearms of a woman practicing aroma-therapy: extracervical poikiloderma of Civatte?

We report the case of a 48-year-old, Caucasian female who presented with slowly progressing asymptomatic poikilodermatous changes of the extensor aspects of the forearms. She also had typical Poikiloderma of Civatte on the V of the neck and erythemato-telangiectatic rosacea of the central face. The patient had been practicing aroma-therapy for many years. Histologic examination revealed findings consistent with PC. Patch-testing revealed positive reactions to Fragrance mix and Nickel sulphate. Based on clinical and histological findings, a diagnosis of extracervical PC was suggested. PC with extra-cervical or extra-facial involvement is rare. In addition, this case supports the theory that contact sensitization to fragrances may contribute to the development of PC.     

Adult mastocytosis: a review of the Santo António Hospital 's experience and an evaluation of World Health Organization criteria for the diagnosis of systemic disease

BACKGROUND

Mastocytosis is a clonal disorder characterized by the accumulation of abnormal mast cells in the skin and/or in extracutaneous organs.

OBJECTIVES

To present all cases of mastocytosis seen in the Porto Hospital Center and evaluate the performance of World Health Organization diagnostic criteria for systemic disease.

METHODS

The cases of twenty-four adult patients with mastocytosis were reviewed. Their clinical and laboratorial characteristics were assessed, and the properties of the criteria used to diagnose systemic mastocytosis were evaluated.

RESULTS

The age of disease onset ranged from 2 to 75 years. Twenty-three patients had cutaneous involvement and 75% were referred by dermatologists. Urticaria pigmentosa was the most common manifestation of the disease. One patient with severe systemic mast cell mediator-related symptoms showed the activating V560G KIT mutation. The bone marrow was examined in 79% of patients, and mast cell immunophenotyping was performed in 67% of the participants. Systemic disease was detected in 84% of cases, and 81% of the sample had elevated serum tryptase levels. All the diagnostic criteria for systemic mastocytosis had high specificity and positive predictive value. Bone marrow biopsy had the lowest sensitivity, negative predictive value and efficiency, while the highest such values were observed for mast cell immunophenotyping. Patients were treated with regimens including antihistamines, sodium cromoglycate, alpha-interferon, hydroxyurea and phototherapy.

CONCLUSIONS

Cutaneous involvement is often seen in adult mastocytosis patients, with most individuals presenting with indolent systemic disease. Although serum tryptase levels are a good indicator of mast cell burden, bone marrow biopsy should also be performed in patients with normal serum tryptase, with flow cytometry being the most adequate method to diagnose systemic disease.     

Cutaneous melanoma in the State of S?o Paulo: a spatial approach

BACKGROUND

Cutaneous melanoma is a skin cancer with low incidence but high mortality rates. Several factors are associated with increased risk of melanoma, such as excessive sun exposure, fair skin, and family history, among others. Little is known about the spatial distribution of this cancer in Brazil.

OBJECTIVE

To identify, through the use of geostatistical tools, spatial clusters of municipalities in the state of São Paulo based on their incidence of cutaneous melanoma.

METHODS

This was an ecological and exploratory study of data on new cases obtained from Fundação Oncocentro for the period 1 January 2006-31 December 2011. Cases were separated by gender and rates per 100,000 inhabitants were calculated and used to compile thematic maps, Moran maps and kernel maps, using TerraView software.

RESULTS

There were 3,172 new cases of cutaneous melanoma in the study period. High rates were identified in the North, Northwest, Southwest, and Southeast regions of São Paulo state. Global Moran''s I values were statistically significant (p<0.05) at 0.12, 0.08, and 0.16, respectively, for males, females, and all cases. Areas such as the Southeast, North, and Northwest of São Paulo were identified as being of high priority for intervention.

CONCLUSION

Spatial clusters of municipalities with high incidence rates of cutaneous melanoma in the state of São Paulo were identified. These data can serve as an important input for public health agencies.     

Lichenoid dermatitis in paraneoplastic pemphigus: a pathogenic trigger of epitope spreading?

BACKGROUND: In select cases, lichen planus has been observed to be a paraneoplastic condition sometimes associated with paraneoplastic pemphigus, a disease featuring autoantibodies directed against plakin proteins, desmogleins 3 and 1, and a still uncharacterized 170-kd antigen. Epitope spreading describes the phenomenon where underlying chronic inflammation leads to the sequential recognition of new epitopes on self-proteins over time. OBSERVATIONS: Five of 6 patients diagnosed as having paraneoplastic pemphigus had concomitant clinical and histological features of lichen planus. In 1 patient, results of the initial indirect immunofluorescence on rat bladder were negative and only 2 of the 5 antigens were identified by immunoprecipitation. After 1 year of worsening disease, repeated testing confirmed the presence of antibodies directed against all 6 of the implicated antigens, supportive of our hypothesis that epitope spreading may occur in paraneoplastic pemphigus. CONCLUSIONS: Lichenoid eruptions may predispose to an early evolutionary stage of paraneoplastic pemphigus. Cell-mediated autoimmunity at the dermoepidermal junction may promote the exposure of self-antigens and the development of subsequent and progressive humoral autoimmunity. As such, paraneoplastic pemphigus may demonstrate epitope spreading in a human, humoral-mediated autoimmune disease.     

COVID outcome in pemphigus: Does rituximab make pemphigus patients susceptible to more severe COVID-19?

Background

The COVID-19 pandemic has raised some concerns regarding the management of chronic skin diseases, especially in patients on immunosuppressive therapy including patients with pemphigus vulgaris (PV). Literature review reveals conflicting results about the effect of monoclonal antibodies such as rituximab on clinical outcome of COVID-19.

Objectives

To assess the reciprocal interaction of COVID-19 and pemphigus and the effect of rituximab on prognosis of COVID-19 in patients.

Methods

We set up a retrospective study on adult patients with a confirmed diagnosis of pemphigus vulgaris and a history of COVID-19 with or without symptoms during 2020.

Results

Thirty-six adults with pemphigus vulgaris and SARS-CoV-2 infection were included. The SARS-CoV-2 infection was confirmed with positive RT-PCR test results in 31 cases (86.1%) and suspected in the 5 others (13.9%). Gender, total dose of rituximab, number of rituximab cycles, and involvement of head and neck were not associated to duration of COVID-19 symptoms (p values: 0.32, 0.23, 0.84, and 0.51, respectively), severity of disease (hospitalization) (p values: 0.46, 0.39, 0.23, and 0.72, respectively), or the percentage of lung involvement on CT scan (p values: 0.07, 0.36, 0.38, and 0.09, respectively). Regarding the impact of COVID-19 on pemphigus, the majority of patients did not experience any changes in their pemphigus regarding clinical phenotype (100%) or severity (83.3%), but PV was worsened in 6 (16.9%) patients which was controlled with increasing the prednisolone dosage.

Conclusion

Rituximab appears to be safe with no increased risk of severe form of COVID-19 in patients with pemphigus vulgaris.     

Paraneoplastic pemphigus: an association with fludarabine?

Paraneoplastic pemphigus is a relatively recently described immunobullous disease with characteristic features. We report three cases of paraneoplastic pemphigus in adult men with chronic lymphocytic leukaemia arising within a week of completion of treatment with fludarabine. In all cases, withdrawal of fludarabine and treatment of the blistering was associated with marked cutaneous improvement. Fludarabine, a synthetic nucleoside analogue, which has only been available in Britain since 1994, is known to be associated with autoimmune phenomena and may have been involved in the development of paraneoplastic pemphigus in these cases.