Utility of oral mucosa as a substrate for the serodiagnosis of pemphigus: A descriptive analysis.

BACKGROUND: The indirect immunofluorescence test is useful in the serodiagnosis of pemphigus. As indirect immunofluorescence titers correlate with disease activity in pemphigus, it is often used as a monitoring tool. The sensitivity of indirect immunofluorescence depends on the substrate used, and the preferred substrates are monkey esophagus for pemphigus vulgaris and normal human skin for pemphigus foliaceus. AIMS: We evaluated oral mucosa as a substrate for indirect immunofluorescence in pemphigus. METHODS: Fifty patients with pemphigus (40 with pemphigus vulgaris and ten with pemphigus foliaceus) and 50 controls were enrolled for study. Demographic and clinical details were recorded and indirect immunofluorescence using two substrates (oral mucosa and normal human skin) was carried out in serial dilution. Desmoglein (Dsg) 1 and 3 enzyme-linked immunosorbent assay was also evaluated simultaneously. RESULTS: Indirect immunofluorescence was positive in 40 patients (80%) with oral mucosa substrate and 34 patients (68%) with normal human skin substrate. Circulating antibodies were detected with oral mucosa in 33 (82.5%) of the 40 pemphigus vulgaris patients and in 26 (65%) patients using normal human skin. Antibodies were detected in eight of the ten pemphigus foliaceus patients (80%) with normal human skin and in seven (70%) patients with oral mucosa. Dsg enzyme-linked immunosorbent assay was positive in 45 (90%) patients, and 37 of these were also indirect immunofluorescence positive with oral mucosa. In the five Dsg enzyme-linked immunosorbent assay-negative patients, indirect immunofluorescence with oral mucosa was positive in three. LIMITATIONS: A comparison of oral mucosa with monkey esophagus could not be performed. CONCLUSION: Oral mucosa is a suitable and sensitive substrate for indirect immunofluorescence in pemphigus. Further studies comparing the sensitivity of indirect immunofluorescence using oral mucosa with monkey esophagus are recommended.

Family dermatology life quality index in patients with pemphigus vulgaris: A cross-sectional study.

BACKGROUND AND AIMS: Pemphigus vulgaris is a rare autoimmune intraepidermal vesiculobullous disease involving the skin and mucosa. It impacts the quality of life of both patients and their families. METHODS: A total of 70 patients with pemphigus vulgaris (either outpatient or hospitalized) were enrolled using the simple sampling method between 2016 and 2017 from the dermatology clinic at Faghihi Hospital, Shiraz, Iran. A validated Persian version of the Family Dermatology Life Quality Index (FLDQI) questionnaire was filled by a family caregiver. The questionnaire contained 10 items assessing the quality of life of the family. Demographic variables were recorded in a separate form. RESULTS: The mean age of the patients was 51 ± 11.3 years and that of the family caregivers was 32 ± 8.8 years. The FLDQI score was higher (poorer quality of life) if the patient was male, older, had shorter disease duration or had fewer disease recurrences (P = 0.046, 0.01, 0.001 and >0.001, respectively). Higher scores were also obtained in the less-educated caregivers (P = 0.026) but there was no association with either gender or age (P = 0.399, 0.1). CONCLUSION: Pemphigus vulgaris significantly affects the Family Dermatology Life Quality Index. Education and counseling of family caregivers by various support groups such as Pemphigus Family Associations could be effective in improving the quality of life of the caregivers. LIMITATIONS: This study did not assess the effect of comprising domain analysis, severity of disease, patients' Dermatology Life Quality Index (DLQI), mucosal involvement, response to treatment, outpatient or admitted status, socioeconomic status, or the quality of life among the various family members.

Identification of clinical and immunological factors associated with clinical relapse of pemphigus vulgaris in remission.

BACKGROUND: Pemphigus vulgaris is a potentially fatal autoimmune epidermal blistering disease with a chronic and relapsing course. It is difficult to predict clinical relapse. Identification of clinical and immunological factors that are associated with early clinical relapse in a prospective study design may help in planning treatment for better maintenance of clinical remission. AIM: The aim of our study was to identify clinical and immunological factors associated with clinical relapse within 9 months of study inclusion in patients with pemphigus vulgaris in clinical remission. METHODS: Forty consecutive consenting patients who had been diagnosed to have pemphigus vulgaris and were in clinical remission on minimal therapy or off therapy were included. The patients were followed up every 3 months until 9 months. Clinical factors considered relevant were recorded at the beginning of the study. Immunological factors such as CD19+ B-cell count and CD19+CD27+ memory B cells/plasma cell count in peripheral blood were assessed at baseline [anti-desmoglein (Dsg) 1 and 3 titers were first assessed at 3 months, not at baseline] and repeated every 3 months, until 9 months or clinical relapse whichever was earlier. Direct immunofluorescence (DIF) of skin biopsy specimen was performed at study initiation and again at the time of clinical relapse or study completion, whichever occurred earlier. All patients completed the study. RESULTS: Of 40 patients, 11 (27.5%) experienced relapse as per definition, while 29 (72.5%) remained in complete remission. Clinical relapse during study duration was significantly more common in those who had onset of disease in oral mucosa [odds ratio (OR), 10.71; 95% confidence interval (CI) 1.21-94.86, P = 0.02], pruritus (OR 8.4; 95% CI 1.76-40.02, P = 0.01), and extensive cutaneous involvement during previous disease activity (OR 7.36; 95% CI 1.34-40.55, P = 0.03) and also pruritus during remission (P = 0.004). Immunological factors found to be significantly associated with early clinical relapse were raised CD19+ B-cell count at baseline (OR 7.84; 95% CI 1.39 - 53.41, P = 0.01), immunoglobulin G (OR 4.85; 95% CI 1.09-23.44, P = 0.04), and C3 (OR 20.33; 95% CI 3.02-199.5, P < 0.001) positivity in the intercellular space of the epidermis on DIF at study onset and rising anti-Dsg 3 antibody titers (OR 19.96; 95% CI 1.85- 310.9, P = 0.03). LIMITATIONS: Limited sample size, short follow-up duration, and inability to perform anti-Dsg enzyme linked immunosorbent assay for all the patients at all the time points of assessment are limitations of this study. CONCLUSION: Immunological relapse can be determined before clinical relapse, so that treatment can be restarted/modified and clinical remission can be maintained.

Clinical and pathological characterization of oral mucosal 'lichen planus-like lesions' in patients with pemphigus vulgaris: An observational study.

BACKGROUND: Lichen planus-like lesions on oral mucosa occasionally occur in Indian patients with pemphigus vulgaris. Its significance, both clinical and pathological, is yet to be elucidated. AIMS AND OBJECTIVES: To study the clinical and pathological characteristics of clinically apparent oral mucosal lichen planus-like lesions in pemphigus patients and to assess their relation with pemphigus disease activity. MATERIALS AND METHODS: A total of 32 patients with pemphigus vulgaris who had oral lichen planus-like lesions were included and classified as 'cases,' and eight diagnosed cases of pemphigus vulgaris without lichenoid 'hue' were included as controls. The biopsy specimens were subjected to routine histopathologic examination, immunohistochemistry with FasL, and caspase-3 and direct immunofluorescence. RESULTS: On histopathologic examination, the diagnosis of pemphigus vulgaris, lichen planus, 'overlap' and 'nonspecific' were rendered in 19 (59.4%), 4 (12.5%), 5 (15.6%) and 4 (12.5%) cases, respectively. On immunohistochemistry, FasL was positive in epithelial cells in 16 (50%) cases and 4 (12.5%) controls (P = 0.066). Caspase-3 stained positively in 18 (56.2%) cases and 20 (62.5%) controls (P = 0.77). Direct immunofluorescence was positive in 77.8% (21/27) of the cases. LIMITATIONS: Relatively small number of controls is the limitation of this study. CONCLUSION: Lichen planus-like lesions in pemphigus should not be labeled as inactive disease or postinflammatory hyperpigmentation. Apoptosis followed by pigment incontinence seems to explain such lesions with 'lichen planus-like appearance' in oral pemphigus vulgaris. Active pemphigus smoulders in a majority of these lesions.

Effectiveness and safety analysis of rituximab in 146 Indian pemphigus patients: A retrospective single-center review of up to 68 months follow-up.

BACKGROUND: Rituximab is being increasingly used for the treatment of pemphigus. Data derived from single-center studies following a uniform treatment protocol are limited. Effect of demography and disease type on treatment response is poorly characterized. OBJECTIVE: Our aim was to assess the effectiveness of biosimilar rituximab in pemphigus patients who had received rituximab as per rheumatoid arthritis protocol (2 doses, 1g each, infused 14 days apart). METHODS: It was a retrospective review of 146 eligible patients to assess the proportion of patients achieving complete remission off treatment, time to achieve complete remission off treatment, proportion of patients who relapsed after achieving complete remission off treatment, time taken to relapse, duration and total cumulative dose of corticosteroids administered after rituximab. Additionally, we tried to find whether a correlation existed between age, gender, total duration of illness before rituximab and pemphigus disease type with the above-mentioned outcome measures. RESULTS: Of 146 patients, 107 (73.3%) attained complete remission off treatment. Mean interval between first dose rituximab administration and complete remission off treatment was 6.6 ± 3.4months. Complete remission off treatment was sustained for a mean duration of 9.1 ± 8.5 months before relapse. Over a mean follow-up duration of 24.9 ± 17.1 months (median 23, maximum 68 months), 75 of 107 patients (76.5%) who had achieved complete remission after first cycle of rituximab relapsed. A mean total cumulative dose of 3496 ± 2496 mg prednisolone was prescribed over a mean duration of 7.2 ± 4.7 months after first cycle of rituximab. Time taken to achieve remission was significantly longer in pemphigus foliaceus and these patients required significantly higher cumulative dose of prednisolone over a longer duration after rituximab. No deaths and long-term complications were recorded. LIMITATIONS: Only clinical parameters were assessed. Immunological parameters including B-cell counts and enzyme-linked immunosorbent assay for anti-desmoglein antibody titers were not carried out. CONCLUSION: This study reinforces the beneficial role of rituximab in pemphigus. Pemphigus foliaceus patients required a higher total cumulative dose of prednisolone over a longer time to achieve remission and the remission lasted longer than that in pemphigus vulgaris.

Association between human leukocyte antigen-DRB1 and human leukocyte antigen-DQB1 alleles and pemphigus vulgaris in Indian patients: A case-control study.

BACKGROUND: HLA-DRB1*04, -DRB1*08, -DRB1*14, -DQB1*03 and -DQB1*05 are reported to have significant association with pemphigus vulgaris; however, this is partially dependent on ethnicity. This study was done to determine the HLA-DR and -DQ types prevalent in Indian patients with pemphigus vulgaris. METHODS: A prospective case-control study was done for a period of 9 months in Christian Medical College Vellore, India. HLA typing was done by PCR-SSOP method in 50 cases and 50 healthy controls. Allele frequencies in cases and controls were compared and odds ratios with 95% confidence interval were calculated. RESULTS: The mean age of the patients (29 females, 21 males) and that of controls (36 males, 14 females) were 41.3 ± 13.65 and 35.42 ± 11.09 years, respectively. HLA-DRB1*14 was present in 47 patients and 18 controls (OR, 27.85; 95% CI, 7.57-102.42) and HLA-DQB1*05 was seen in 47 patients and 24 controls (OR, 16.97; 95% CI, 4.66-61.80). The haplotype DRB1*14, DQB1*05 was present in 44 patients and 14 controls (OR, 18.86; 95% CI, 6.58-54.05). DRB1*15 was present in 7 cases and 16 controls (OR, 0.35; 95% CI, 0.13-0.94) and DQB1*06 was present in 8 cases and 19 controls (OR, 0.31; 95% CI, 0.12-0.80). HLA-DQB1*03 was associated with significantly higher pemphigus disease area index scores. LIMITATIONS: The main limitations were that the numbers studied were small as the study was conducted at a single center, and the haplotype analysis was limited only to the proband. PDAI scores could have been influenced by prior treatment. CONCLUSION: There was a significant association between HLA-DRB1*14 and HLA-DQB1*05 and pemphigus vulgaris in our patients. A negative association was seen with DRB1*15 and DQB1*06.

Psoriasiform Pemphigus Foliaceus in an African American Female: An Important Clinical Manifestation.

A 50-year-old African-American woman presented to the dermatology clinic with a pruritic eruption of 3 years' duration. On clinical examination, the patient had well-demarcated, pink, atrophic plaques and superficial erosions over the inframammary folds and mid-chest. She also had well-demarcated, hyperpigmented, hyperkeratotic scaly plaques over the abdomen, suprapubic region, elbows, knees, and back with sporadic small superficial blisters. A punch biopsy of the right abdomen was performed and revealed psoriasiform epidermal hyperplasia, focal parakeratosis, and acantholysis throughout the superficial spinous and granular layers. Only a sparse inflammatory infiltrate was present in the underlying dermis. Clinical and histological findings supported the diagnosis of pemphigus foliaceus (PF), but psoriasis was included in the differential diagnosis due to the presence of discrete plaques with an erythematous border. We hypothesize that patients with psoriasiform presentations of PF may be misdiagnosed with plaque psoriasis. It is important to distinguish between PF and psoriasis as there is evidence that ultraviolet light, a common treatment for psoriasis, may exacerbate PF. We document and highlight this atypical psoriasiform presentation of PF in a patient with skin of color to raise awareness and improve diagnosis and outcomes.

J Drugs Dermatol. 2018;17(4):471-473.

Clinical, immunological profile and follow up of patients with pemphigus: A study from India.

BACKGROUND: Pemphigus has a protracted course and multiple factors influence its prognosis. The objective of this study was to describe the epidemiology and clinical profile of pemphigus patients and to study its influence on treatment end points. METHODS: : This was a retrospective chart review done in an Indian tertiary care hospital from December 1991 to December 2013. Patients with less than 3 months' follow up and those who had paraneoplastic pemphigus were excluded. RESULTS: : There were 132 patients with pemphigus, of which 118 (89.4%) had pemphigus vulgaris and 14 (10.6%) had pemphigus foliaceous. The time to disease control (TDC) was available for 100 patients (n = 100, 75.7%); patients with a minimum follow up of 3 months (n = 80) were included for studying the end points like time to first disease remission (TDR) and time to first disease relapse (TDRe). The median period of follow up was 23 months (range 3-245). Out of the 100 patients, 61.9% were on oral steroids with adjuvant therapy. The steroid dose required for disease control for n = 100, ranged from 0.2 to 1.5 mg/kg body weight. Of these, 60% were treated with steroid dose of 1 mg/kg, 22% with >1 mg/kg, and 18% with <1 mg/kg. The mean time to disease control (in months) in the group which received <1 mg/kg steroid was 1.02 ± 0.68, 1 mg/kg was 0.72 ± 0.51, and >1 mg/kg was 1.02 ± 0.62 (P = 0.017); with a significant difference between the groups 2 and 3 (P = 0.007), implying a faster disease control in those who received 1 mg/kg dose. This difference was significant after adjusting for the steroid sparing drugs taken at baseline (P = 0.009, C.I. - 1.44-13.59). The mean time to first disease remission (TDR) was 11.46 ± 2.06 months. Out of the 80 patients with a minimum follow up of 3 months, 75% had achieved either partial or complete remission. None of the other epidemiological, clinical or immunological parameters had an impact on the TDC or TDR. CONCLUSIONS: The epidemiological, clinical or immunological parameters had no impact on the treatment end points like time to disease control and time to first disease remission. The dose of steroids required for disease control higher than 1 mg/kg offered no advantage in the time to disease control as compared to 1 mg/kg. LIMITATIONS: The study was retrospective and disease severity scores were not applied. In view of the shorter follow up period, long term prognostic end points and mortality could not be well represented. The median period of follow up was 23 months. The serum anti- desmoglein antibody titres were not available at various treatment end points for correlation at different time intervals.

Nail changes in autoimmune blistering disorders: A case-control study.

BACKGROUND: Pemphigus and pemphigoid disorders produce blistering cutaneous lesions. Earlier case reports state that nail involvement is uncommon in these autoimmune blistering disorders. AIMS AND OBJECTIVES: To study nail changes in autoimmune blistering disorders. METHODS: A case-control study was conducted where 40 cases and 40 controls were evaluated for nail changes. RESULTS: Nail changes were seen in 72.5% of cases and 17.5% of controls. The most common nail findings were paronychia and onychorrhexis. LIMITATIONS: Small sample size; short study duration; nail biopsy could not be done. CONCLUSION: Our findings indicate that the inflammatory nature of the blistering cutaneous disease is often reflected conspicuously in the nails.

Urocytological evaluation of pemphigus patients on long term cyclophosphamide therapy: A cross sectional study.

BACKGROUND: Cyclophosphamide therapy is associated with several urological complications including urinary bladder malignancy. Data on urologic complications of chronic cyclophosphamide therapy for dermatologic conditions is not available. OBJECTIVES: To study the urocytological profile of pemphigus patients on long-term cyclophosphamide therapy. MATERIALS AND METHODS: In a cross-sectional study, consecutive patients who had received cyclophosphamide therapy for pemphigus for more than 12 months were included. All patients were subjected to urinalysis including microscopy, culture, and urine cytology. Immunocytochemical staining for cytokeratin 20 (CK-20) on urine sediments and ELISA (enzyme-linked immunosorbent assay) for nuclear membrane protein-22 (NMP-22) were performed in all cases. In patients with urinary symptoms, microscopic hematuria, or those detected with abnormal urine sediment cytology, NMP-22, and CK-20 positivity, cystoscopy, and other relevant investigations were also done. RESULTS: A total of 44 patients (43 of pemphigus vulgaris and one of pemphigus foliaceus) were recruited. Mean duration of cyclophosphamide intake was 2.9 ± 1.7 years (range 1-8 years) with a mean cumulative dose of 53 ± 28.4 g (range 6.5-141 g). Twenty-one cases (47.7%) each were asymptomatic and symptomatic with episodic urinary symptoms [of which two had urinary tract infection (UTI)] and two patients had gross hematuria. Urine cytology revealed mild urothelial nucleomegaly with hyperchromasia in four patients. However, CK-20 and NMP-22 were negative in all samples. Cystoscopy was performed in 21 cases and did not reveal any sign of bladder malignancy. LIMITATIONS: A relatively small sample size and lack of long-term follow-up were limitations. CONCLUSIONS: In our study, no serious urologic complications were found in pemphigus cases on chronic cyclophosphamide therapy.