An alternate-day corticosteroid regimen for pemphigus vulgaris. A 13-year prospective study

BACKGROUND: Pemphigus vulgaris (PV) at the early, usually oral and relatively stable stage, represents the majority of PV patients. Treatment modalities usually do not differ compared to those for the fully established disease. OBJECTIVES: To prospectively assess a standardized and effective therapeutic approach that aims at less morbidity due to adverse reactions. METHODS: The following regimen, also known as Lever's mini treatment (LMT), was used. Forty mg of oral prednisone on alternate days plus 100 mg azathioprine every day were administered until the complete healing of all lesions. A gradual monthly and later bimonthly decrease of prednisone was followed by the tapering of a second immunosuppressive agent, in a one-year period. RESULTS: Seventy-four patients suffering from early-stage-PV, and representing 70% of all PV patients seen through the years 1991-2003, were eligible in the study. Total follow-up period was 76 +/- 37 (26-180) months. During the 53 +/- 26 months of LMT, 6 (8%) patients dropped out of therapy, 9 (12%) required a change to another treatment, two (3%) died and 57 (77%) achieved a lesion-free condition. Forty-five (61%) patients were in complete remission for 27 +/- 29 months. Significant morbidity was estimated 4/74 (5.2%). Disease 'breakthroughs' necessitating treatment adjustments occurred in 30 patients, usually throughout the last phase of therapy and post-treatment follow-up. CONCLUSION: LMT may be a standardized therapeutic approach for the early and relatively stable stage of PV, resulting in high efficacy, safety and quality of life profile.     

A 6‐year treatment experience for pemphigus: retrospective study of 69 Chinese patients

There is a lack of data on treatment and prognosis of pemphigus in China. The aim of this study was to evaluate long‐term follow‐up and prognosis of pemphigus. Forty‐seven inpatients with pemphigus vulgaris (PV) and 22 with pemphigus foliaceus (PF) were recruited in this retrospective study. The average age at onset was 51.6 and 54.9 years in PV and PF, respectively. High‐dose systemic steroids were administered in 47 PV and 21 PF, of which 18 PV and 8 PF with adjuvant therapies. CD4 lymphocytopenia was found in 5 PV and 2 PF patients at admission and successfully treated by intravenous thymopentin daily. During a mean follow‐up of 37.1 months, 41 PV and 19 PF reached remission, 30 PV and 9 PF relapsed, 4 PV and 2 PF died. Major causes of death were relapse of pemphigus due to discontinuation of oral steroids by the patients themselves (four cases) and severe infections (two cases, one with severe CD4 lymphocytopenia). The 1‐year mortality rate of PV and PF was 8.5% and 4.5%, respectively. Cox regression analysis indicated that age at onset of pemphigus was an independent risk factor related to the elevated mortality. Our report confirmed the high mortality rate of pemphigus in a Chinese population and stressed that patient education was urgently needed to prevent relapses and deaths.     

Intravenous dexamethasone‐cyclophosphamide pulse therapy in comparison with oral methylprednisolone‐azathioprine therapy in patients with pemphigus: Results of a multicenter prospectively randomized study

Background: Pemphigus is a potentially life‐threatening autoimmune blistering skin disease usually treated with high‐dose corticosteroids in combination with immunosuppressive drugs. In a multicenter, prospectively randomized study we compared efficacy and side effects of a dexamethasone‐cyclophosphamide (D/C) pulse therapy with a methylprednisolone‐azathioprine (M/A) therapy in 22 patients with newly diagnosed pemphigus vulgaris and pemphigus foliaceus. Patients and methods: The 11 patients of the M/A group were treated with daily doses of methylprednisolone (initially 2 mg/kg body weight) and azathioprine (2 – 2,5 mg/kg body weight) which were subsequently tapered. D/C pulse therapy in 11 patients consisted of intravenous administration of 100 mg dexamethasone/d on 3 consecutive days along with cyclophosphamide (500 mg) on day one. Pulses were initially repeated every 2 – 4 weeks and then at increasing intervals. In between the pulses, oral cyclophosphamide (50 mg) was given daily for 6 months. Results: Within 24 months after treatment initiation, 5/11 patients of the D/C group had a remission (complete remissions after discontinuation of therapy in 3 patients) and 6/11 patients had a progression. In the M/A group, there were remissions in 9/11 patients (complete remissions after discontinuation of therapy in 3 patients) and progression in 1/11 patients. There were more relapses in M/A therapy after remission than in D/C therapy. Side effects were more common in the M/A group. These differences were not significant (p > 0,05). Conclusion: Because of the high number of progressions in patients treated with D/C therapy, we can not confirm the encouraging results of earlier reports about pulse D/C therapy. Nevertheless D/C therapy seemed to be better tolerated and, in case of primary efficacy, was associated with fewer recurrences than M/A therapy.     

Low‐dose rituximab and concurrent adjuvant therapy for pemphigus: Protocol and single‐centre long‐term review of nine patients

Pemphigus is an autoimmune B‐cell mediated blistering disease associated with significant morbidity and mortality. Rituximab has proven effective for the treatment of steroid‐refractory pemphigus, although there is controversy over the optimum dosing protocol. Additionally, effective disease control often requires long‐term immunosuppression, even in disease‐free periods. We present a case series of a single‐centre long‐term follow up of nine patients with pemphigus, treated with two 500‐mg doses of rituximab separated by 14 days along with concurrent adjuvant therapy. In all these patients, low‐dose rituximab resulted in B‐cell depletion, along with a reduction in blistering disease. Three of these patients required repeat dosing cycles due to either relapsed disease or incomplete disease control following the first dosing cycle, and have remained disease free up to 154 weeks thus far. Six patients developed minor infections during the course of their treatment, but no major complications were observed.     

Adjuvant rituximab treatment for pemphigus: A retrospective study of 45 patients at a single center with long‐term follow up

To evaluate the long‐term outcomes of rituximab in the treatment of pemphigus and the influence of disease duration and different dose of rituximab on the clinical response, 45 patients with refractory pemphigus treated with at least one cycle of two infusions of rituximab (375 mg/m² per infusion weekly) were retrospectively studied. All patients were followed up for more than 2 years. All patients achieved complete or partial remission within 8 months of the first cycle. Thirty‐four (76%) patients relapsed at a median of 17 months. All patients who received additional cycles after relapse achieved new remissions. Early use of rituximab within 1 year of disease duration and high‐dose therapy induced better outcomes, although the results in early use were not statistically significant. Acute respiratory distress syndrome occurred in one patient. Rituximab is effective in treating pemphigus, but relapses are frequent during long‐term follow up, and additional cycles are beneficial in relapsed cases. Early and high‐dose rituximab therapy may be more effective.     

Rituximab as the treatment of pemphigus vulgaris in the COVID‐19 pandemic era: A narrative review

Pemphigus vulgaris (PV), an autoimmune blistering disease is treated with immunosuppressive medications. As the immunosuppressive effect of rituximab, the first‐line therapy of PV, lasts more than 6 months, many concerns have raised due to the ongoing novel coronavirus disease (COVID‐19) pandemic. With this background, our objective was to review the currently available literature as well as important websites for the evidence related to rituximab, PV and COVID‐19, adverse effects associated with drugs, and relevant guidelines. “PubMed” and “Google Scholar” database were systematically searched for retrieving all articles related to anti‐CD20 therapy in pemphigus vulgaris and COVID‐19 published up to 14 July 2020. A total of seven clinical studies are performed with anti‐CD20 therapy in COVID‐19, three of which are performed on pemphigus patients, and have shown concerns employing rituximab in patients with COVID‐19. Evidence for treating PV patients with rituximab in COVID‐19 pandemic is limited. Until sufficient evidence or guideline for pemphigus and COVID‐19 treatment is available, we advocate caution commencing rituximab in patients with pemphigus, due to the reported adverse outcomes.     

Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patients

BACKGROUND: Rituximab is a monoclonal antibody directed against the CD20 antigen expressed on B lymphocytes. There are reports of its efficacy in the treatment of autoimmune diseases, including pemphigus. OBJECTIVES: Prospectively to evaluate the efficacy of rituximab as adjuvant treatment for pemphigus vulgaris (PV). METHODS: Patients with PV were treated with intravenous rituximab (375 mg m(-2)) weekly for 4 weeks in this prospective open-label pilot study. Other concurrent immunosuppression was continued. RESULTS: Of five patients, one achieved complete remission and was able to cease all medication, while two achieved clearance of clinical lesions but continued on systemic therapy. Two patients had progressive disease. Time to response was 2-8 months, with a 13- to 18-month response duration. Response was associated with reduction in serum antiepithelial antibodies. Two patients had significant infectious complications (one developed community-acquired pneumonia associated with delayed-onset neutropenia and the other developed cytomegalovirus infection). CONCLUSIONS: Rituximab has shown efficacy in the treatment of PV. Patients on multiple immunosuppressives should be closely monitored for infectious complications.     

Effects of l‐carnitine supplementation on cardiovascular and bone turnover markers in patients with pemphigus vulgaris under corticosteroids treatment: A randomized,double‐blind,controlled trial

Pemphigus vulgaris (PV) is a severe, bullous, autoimmune disease of the skin and mucous membranes. Corticosteroids are usually the main core treatment for controlling PV, which could lead to several side effects such as insulin resistance, osteoporosis, and cardiovascular disorders. The aim of this study is to evaluate the protective effects of l ‐carnitine (LC) supplementation in PV patients under corticosteroid treatment. In this randomized, double‐blind, placebo‐controlled clinical trial, 48 patients with PV were divided randomly into two groups to receive 2 g LC (n = 24) or a placebo (n = 24) for 8 weeks, respectively. Serum levels of osteopontin (OPN), bone morphogenic protein 4 (BMP4), cystatin C, systolic and diastolic blood pressure, 25 hydroxyvitamin D3, and LC were evaluated at the beginning and at the end of the study. LC supplementation demonstrated a significant increase in serum carnitine (p < .001). In addition, at the end of the trial, LC supplementation significantly decreased serum BMP4 (p = .003), OPN (p = .03), and cystatin C (p = .001) levels. There was no significant effect on blood pressure in comparison with the placebo. During study, no harmful side effects were reported by patients. These findings indicate that LC supplementation significantly leads to favorable changes in OPN, BMP4, and cystatin C in PV patients under corticosteroid therapy. However, further investigations are required to confirm these results.     

The use of sulfasalazine and pentoxifylline (low-cost antitumour necrosis factor drugs) as adjuvant therapy for the treatment of pemphigus vulgaris: a comparative study

Background  Pemphigus vulgaris (PV) represents a potentially life-threatening autoimmune blistering disease in which IgG autoantibodies are directed against cell–cell adhesion molecules. Tumour necrosis factor (TNF)-α has been suggested to have a possible role in the mechanism underlying acantholysis.
Objectives  This comparative double-blinded study was carried out to estimate the use of both sulfasalazine (SSZ) and pentoxifylline (PTX) (low-cost anti-TNF drugs) as an adjuvant therapy for PV.
Methods  The study included 64 patients with PV: 42 patients received the full treatment regimen (with SSZ and PTX) and 22 patients followed the same regimen except they received placebo instead of PTX and SSZ. Five healthy subjects were included as controls. Serum samples were taken to measure TNF-α levels in the control group and before starting treatment in both the patient groups and this was repeated every 2 weeks for 8 weeks; a clinical assessment was made every week for all the patients.
Results  The serum level of TNF-α was statistically higher in both groups of patients than in the healthy individuals. There was a statistically significant decrease in the serum levels of TNF-α in patients in group 1 compared with those in group 2 at 6 and 8 weeks. There was also a significant clinical improvement in patients in group 1 compared with those in group 2.
Conclusion  The use of PTX and SSZ as adjuvant therapy in the treatment of PV induced a faster and more significant decrease in the serum level of TNF-α, and this decrease was associated with rapid clinical improvement.     

Use of low‐dose naltrexone in the treatment of severe Hailey–Hailey disease: One case report

Hailey–Hailey disease (HHD) or chronic benign familial pemphigus is an autosomal dominant genodermatosis with complete penetrance characterized by painful vesicles, erosions, and macerated intertriginous skin. We present a 66‐year‐old woman with a personal 35‐year history of pruritic recurrent vesicles and erosions in both axillae and inguinal folds. HHD was confirmed by cutaneous biopsy. Past treatments had failed, including topical corticosteroids, antibiotics and oral doxycycline, minocycline, dapsone, and acitretin. Phototherapy and intralesional injection of toxin botulinum A was performed in the axillae. The patient was started on naltrexone 6.25 mg nightly. Six weeks later, complete clearing was observed. At typical doses, naltrexone blocks μ and δ opiod receptors, thereby blocking the union of β ‐endorphins at those sites. Paradoxically, at low doses, the partial binding to those receptors leads to a homeostatic increase of opioid receptors and an upregulation of endogenous opioids. Low‐dose naltrexone (LDN) may also exert an anti‐inflammatory action through its antagonist effect on toll‐like receptor 4 found on macrophages. We consider that LDN is an effective and safe alternative for the HHD, representing an important progress in the management of this disease with limited therapeutic options.     

Melanin‐associated pigmented lesions of the oral mucosa: presentation,differential diagnosis,and treatment

Intraoral pigmentation is quite common and has numerous etiologies, ranging from exogenous to physiological to neoplastic. Many pigmented lesions of the oral cavity are associated with melanin pigment. The differential diagnosis of mucosal pigmented lesions includes hematomas, varices, and petechiae which may appear to be pigmented. Unlike cutaneous melanomas, oral melanomas are diagnosed late and have a poor prognosis regardless of depth of invasion. As such, the clinical presentation and treatment of intraoral melanoma will be discussed. Developing a differential diagnosis is imperative for a clinician faced with these lesions in order to appropriately treat the patient. This article will focus on the most common oral melanocytic lesions, along with mimics.