Direct medical cost related to the management of pemphigus: A pilot Tunisian study.

INTRODUCTION: Pemphigus is a therapeutically challenging disease with high morbidity and economic burden. First-line prescription of rituximab remains limited in Tunisia due to its high cost. Systemic steroids remain the standard of care but are associated with a major risk of morbidities and higher treatment costs. AIM: To assess the direct medical costs of pemphigus in Tunisia. METHODS: Retrospective estimation of direct medical costs during the 18 months following the diagnosis using the "bottom-up approach" in the Dermatology Department of Hedi Chaker Hospital, Sfax, Tunisia. RESULTS: Total medical costs were estimated at 38745.7 €, with an average cost of 1 210 € per patient and per year: paraclinical investigations (46%), medical treatment (30%), hospitalization (21%) and outpatient visits (3%). The average cost was the highest in the age group of 15-24 years (1553 €). Treatment costs related to corticosteroid-induced morbidity were estimated at 1208 €. CONCLUSIONS: The management of pemphigus in Tunisia needs to be adapted to take into account the health economic analysis in order to reduce overall disease costs and the burden of steroid-induced morbidities.

Assessment of anti-desmoglein antibodies levels and other laboratory indexes as objective comprehensive indicators of patients with pemphigus vulgaris of different severity: a single-center retrospective study.

The aim of this study is to assess the utility of anti-desmoglein (Dsg) antibodies levels, hematological biomarkers levels, the albumin to globulin (A/G) ratio, blood lipids levels, and lymphocyte subpopulation percentages as objective laboratory indicators of disease severity of pemphigus vulgaris (PV). A retrospective study of 187 PV patients with 256 medical records between January 2013 and December 2020. PV patients were divided into three groups by disease severity according to the pemphigus disease area index (PDAI) score: mild (0-8), moderate (9-24), and severe (≥ 25). The levels of anti-Dsg antibodies, hematological biomarkers, A/G ratio, blood lipids, and the percentage of lymphocyte subpopulations were measured. We assessed the correlations of quantitative variables by Pearson correlation (r). Multivariable linear regression was used to identify the variables associated with the disease severity of PV (PDAI score). The results show that the levels of Dsg1 (r = 0.294, P < 0.001) and Dsg3 (r = 0.206, P = 0.011), monocyte count (r = 0.210, P = 0.001), neutrophil-to-lymphocyte ratio (NLR) (r = 0.123, P = 0.049), and platelet-to-lymphocyte ratio (PLR) (r = 0.170, P = 0.006) were positively correlated with the PDAI score. However, the A/G ratio (r = - 0.399, P < 0.001), and the levels of total serum cholesterol (r = - 0.140, P = 0.026) and HDL (r = - 0.143, P = 0.023) were negatively correlated with the PDAI score. Multiple linear regression showed that the factors associated with the PDAI score were higher level of anti-Dsg1 antibody (P = 0.001), a higher NLR (P = 0.005), and a lower A/G ratio (P < 0.001). The linear regression equation was Y(PDAI) = 32.798 + 0.058X(Dsg1) + 0.846 X(NLR)-16.472 X(A/G) (R2 = 0.586). Therefore, high levels of anti-Dsg1 antibody and NLR combined with a low A/G ratio could explain the PDAI score. These findings might provide a more comprehensive and objective evaluation system for reflecting the disease severity of PV based on laboratory indicators.

Prevalence and management of chronic hepatitis B in pemphigus and pemphigoid patients: New evidence for the safety of rituximab.

Although the treatments of pemphigus and pemphigoid patients have tended toward safer options, patients with chronic infections seem to be still at the risk of infection reactivation when they are exposed to any of immunosuppressive treatments. A retrospective study on 1646 registered pemphigus and pemphigoid patients was conducted between January 2017 and February 2019 and the prevalence of HBV, the association between the treatments, mainly prednisolone and rituximab with HBV reactivation as well as outcomes of patients after management with antiviral therapies were evaluated. From 1646 reviewed patients, 10 (0.60%) patients with chronic HBV were identified. We found a negative correlation between the ALT (p-value<0.001), AST (p-value = 0.090), and Pemphigus Disease Area Index (PDAI) (p-value = 0.034) and age of patients. At the time points that prednisolone dosage was higher, higher levels of ALT, but no difference in AST levels was noted. The portion of patients with normal ALT was significantly higher (p-value = 0.036; OR = 2.22) in those who had received rituximab within the previous 6 months (38 of 49; 77.6%) as compared to those who did not (81 of 133; 60.9%). We concluded that avoidance (high dose) systemic corticosteroids in patients with chronic HBV, and using rituximab instead in severe cases benefit this group of patients.

Assessment of Immune Cell Activation in Pemphigus.

(1) Background: Pemphigus is a blistering autoimmune disease of the skin and/or mucous membranes, characterised by the presence of specific autoantibodies directed against structural proteins of the human skin. Recent reports indicate that new haematological parameters, termed Extended Inflammation Parameters (EIP), can be used to assess the activation of immune cells during active inflammation. These include parameters assessing both neutrophil activation (NEUT-RI, NEUT-GI) and the number of activated lymphocytes (RE-LYMP). The aim of this study was to investigate the relationship between changes in NEUT-RI, NEUT-GI and RE-LYMP and the disease activity in patients with pemphigus. (2) Results: The study involved 32 patients with diagnosed different types of pemphigus. Neutrophil activation parameters (NEUT-RI and NEUT-GI) and lymphocytes (RE-LYMP) were significantly higher in these patients compared to the parameters in healthy participants (respectively p = 0.0127, p = 0.0011 and p = 0.0033). The increased quantity of activated lymphocytes (RE-LYMP) also correlated significantly with the extent of skin and/or mucosal lesions in patients assessed by the PDAI scale (p < 0.02). (3) Conclusions: The NEUT-RI, NEUT-GI and RE-LYMP parameters proved to be appropriate markers of inflammation severity in pemphigus, also in relation to local lesions, which was not possible with the inflammation markers (CRP, ESR) used so far on a routine basis.

Comparison of the efficacy and cost-effectiveness of an immunologically targeted low-dose rituximab protocol with the conventional rheumatoid arthritis protocol in severe pemphigus.

BACKGROUND: Various dosing protocols of rituximab have been used in pemphigus. B-cell repopulation following rituximab treatment can be considered a forerunner of clinical relapse. Immunologically guided dosing may remove the need for fixed timepoint maintenance dosing, hence being more cost-effective and perhaps safer. AIM: To compare the overall efficacy and cost-effectiveness of a low-dose rituximab regimen (500 mg, 2 weeks apart) with immunologically guided, ultralow-dose (200 mg) top-up infusions on immunological relapse vs. the use of a rheumatoid arthritis (RA) protocol with rituximab 500 mg repeat infusion to treat clinical relapse in severe pemphigus, over a 1-year period, METHODS: In total, 23 patients with severe pemphigus were randomized into Group A (RA protocol: 1000 mg given as two doses, 2 weeks apart) and Group B (low-dose rituximab 500 mg given as two doses, 2 weeks apart). Both groups also received short-term oral corticosteroids, and underwent clinical and immunological (3-monthly flow cytometry assessments of B-cell subtypes) monitoring. Group A received a top-up dose of rituximab 500 mg upon clinical relapse, while Group B received an ultralow top-up dose (200 mg) following detection of B-cell repopulation, which was intended to prevent clinical relapse. Outcome parameters [complete remission off treatment (CROT), relapse (clinical and immunological), total corticosteroid dose and direct cost of therapy] were compared. RESULTS: The mean ± SD time to CROT (Group A, 27.1 ± 1.6 weeks; Group B, 26 ± 1.2 weeks, P = 0.09) and the cumulative prednisolone dose (P = 0.28) were comparable between the two groups. In Group A, 3 of 9 (33.3%) patients had clinical relapse (mean ± SD time of 9.3 ± 0.4 months). In Group B, B-cell repopulation was seen in 10 of 11 (90.9%) patients within a mean time of 8.4 ± 2.4 months, and a single top-up dose of 200 mg successfully prevented clinical relapse. The overall cost of therapy was 37.4% cheaper in Group B. CONCLUSION: An immunologically guided low-dose rituximab regimen can be an equally effective but more affordable alternative to conventional rituximab regimens in pemphigus.

Management of Pemphigus Vulgaris.

INTRODUCTION: Pemphigus vulgaris (PV) is a chronic, autoimmune, vesiculobullous disease. As a result of the relative rarity of PV, published randomized controlled trials (RCTs) are limited, which makes it difficult to evaluate the efficacy of different treatment regimens in this disease. This also precludes conduct of a meta-analysis. METHODS: English-language publications describing treatment outcomes of patients with PV were identified by searches of electronic databases through May 2015, and additionally by review of the bibliography of these publications. A total of 89 papers, which included 21 case reports, 47 case series, 8 RCTs, and 13 observational studies, were identified. The findings from these publications, including information on disease course and prognosis, medications used, treatment responses, and side effects, are summarized in the tables and text of this review. RESULTS: Prior to availability of corticosteroid therapy, PV had a high fatality rate. Early publications from the 1970s reported high-dose, prolonged corticosteroid use and significant associated side effects. Later reports described use of corticosteroids along with steroid-sparing adjuvants, which allows a reduction in the total dose of corticosteroids and a reduction in observed mortality and morbidity. For the majority of patients in these reports, a long-term course on medications lasting about 5-10 years was observed; however, subgroups of patients requiring shorter courses or needing longer-term therapy have also been described. Early diagnosis of PV and early initiation of treatment were prognostic factors. In recent publications, commonly used initial regimens include corticosteroids in combination with mycophenolate or azathioprine; whereas, for patients with inadequate response to these regimens, adjuvants such as intravenous immunoglobulin (IVIg) or rituximab are used. CONCLUSION: The review findings emphasize the importance of early diagnosis, early initiation of treatment, and use of steroid-sparing adjuvants to allow a reduced total dose and duration on corticosteroids. Also highlighted is the need for more RCTs.

Salivary desmoglein enzyme-linked immunosorbent assay for diagnosis of pemphigus vulgaris: a noninvasive alternative test to serum assessment.

BACKGROUND: Serum desmoglein enzyme-linked immunosorbent assay (ELISA) is used for the diagnosis and monitoring of pemphigus diseases. OBJECTIVES: To compare the diagnostic accuracy of salivary antidesmoglein (Dsg) 1 and 3 ELISA in the diagnosis of pemphigus vulgaris (PV) patients with that of serum desmogleins ELISA. METHODS: Eighty-six untreated PV patients and 180 age- and sex-matched PV-free controls were recruited in this case-control study. PV was diagnosed based on clinical, histopathological, and direct immunofluorescence findings. After processing, serum and salivary anti-Dsg 1 and 3 were measured by the ELISA method using Euroimmun kit (Lübeck, Germany). RESULTS: Using the cut-off point of 20 relative units (RU)/mL, the serum anti-Dsg 1 and 3 ELISA were positive in 62 (72.1%) and 83 (96.5%) patients, respectively, and the salivary anti-Dsg 1 and 3 ELISA were positive in 31 (36.1%) and 63 (73.3%) patients, respectively. The specificity of salivary anti-Dsg 1 and anti-Dsg 3 were both 98.9%. Optimal cut-off values of 7.7 and 13.4 RU/mL were determined for the salivary anti-Dsg 1 and anti-Dsg 3 ELISA, respectively. CONCLUSION: Salivary anti-Dsg 1 and 3 ELISA with high specificities (98.9%) could be suggested as safe and noninvasive methods for the diagnosis of PV when obtaining a blood sample is difficult.

Detección de anticuerpos circulantes en suero para el diagnóstico de pénfigo / Detection of circulating antibodies in serum for the diagnosis of pemphigus

Objetivo: realizar una revisión, apreciación crítica y síntesis de la evidencia disponible sobre la validez diagnóstica de la detección de anticuerpos circulantes para el diagnóstico de pénfigo. Metodología: se realizó una búsqueda de evidencia en las bases de datos: MEDLINE, EMBASE, la Librería Cochrane y LILACS. Adicionalmente, se hizo se indagó por estudios locales a través del motor de búsqueda Google. Dos evaluadores de manera independiente, tamizaron las referencias obtenidas, resolviendo las discrepancias por consenso. Resultados: se identificaron 105 publicaciones. Con los resultados obtenidos, no fue posible identificar revisiones sistemáticas de la literatura ni estudios de validez diagnóstica. Se hizo una preselección de 4 estudios observacionales descriptivos que fueron excluidos. Conclusiones: con los hallazgos de las búsquedas de evidencia, no es posible evaluar la utilidad de las pruebas usadas en de la detección de anticuerpos circulantes en suero para el diagnóstico de pénfigo.(AU)

A sensitive and restricted enzyme-linked immunosorbent assay for detecting a heterogeneous antibody population in serum from people suffering from a new variant of endemic pemphigus.

We recently described a new variant of endemic pemphigus foliaceus (EPF) in El Bagre, Colombia, that resembles Senear-Usher syndrome and identified autoantibodies to desmoglein 1 (Dsg1), as well as to multiple known and unknown antigens including plectins, in the serum of these patients. Here, we developed a cost-effective ELISA assay capable of detecting the heterogeneous antibody population observed in these EPF patients, and useful for serum epidemiological studies. A protein extract obtained from trypsin-digested fresh bovine skin and further purified on a concanavalin A matrix was used as antigen. This extract contains an important conformational epitope (a 45 kDa tryptic fragment of the Dsg1 ectodomain), which is recognized by antibodies in serum from patients with all varieties of pemphigus foliaceus (PF), and from half of those with pemphigus vulgaris with active clinical disease. The cut-off and threshold values were normalized using human serum obtained from both endemic and non-endemic areas for PF. The efficiency of this ELISA was tested using 600 serum samples from controls and patients diagnosed with EPF, non-endemic PF and other bullous diseases. The overall sensitivity and specificity of the assay were determined to be 95% and 72%, respectively, with reproducibilities of 98% (intraassay) and 95% (interassay). Comparing the ELISA with other tests to detect EPF autoantibodies, this ELISA was the most sensitive, followed by direct immunofluorescence (DIF), indirect immunofluorescence using anti-IgG4 monoclonal antibodies and immunoprecipitation (IP), respectively. The most specific assay was IP, followed by DIF. Immunoblotting to Dsg1 exhibited both poor sensitivity and poor specificity, although plectins were well visualized. We conclude that this ELISA is an excellent tool for field serological studies, allowing testing of multiple serum samples simultaneously and for detecting, with appropriate restriction and sensitivity, the heterogeneous antibody population seen in patients with this variant of EPF. Finally, autoantibody serum levels obtained with this ELISA correlated well with the clinical activity and extent of disease in patients with El Bagre EPF.

Bullous autoimmune skin disease in the dog: (1) clinical and pathological assessment.

The clinical and pathological findings of two cases of pemphigus vulgaris and four cases of bullous pemphigoid in the dog are reported. Clinically these cases were typified by ulcerative lesions of the oral mucous membranes, mucocutaneous junctions and skin. Pathologically there were intraepithelial separation and bulla formation in one of the cases of pemphigus and subepithelial separation and bulla formation in all cases of pemphigoid.