Australasian Journal of Dermatology (2016) 57, 141–144
doi: 10.1111/ajd.12422
SMALL CASE SERIES
IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects Danka Svecova Department of Dermatovenerology, Faculty of Medicine, Comenius University, University Hospital, Bratislava, Slovakia
ABSTRACT Background: Intravenous immunoglobulin (IVIG) is a biological agent composed of polyclonal antibodies prepared from a large cohort of human plasma pools. IVIG is increasingly used for the treatment of various antibody-mediated diseases, including pemphigus vulgaris (PV). Objective: The aim of the study was to evaluate the benefit and safety profiles of high dose IVIG therapy in PV patients determined by clinical remission, corticosteroid-sparing and immunomodulatory effects, and adverse events at 12 months’ follow up. Methods: Ten PV patients underwent 3–8 monthly cycles of IVIG therapy at a dose of 2 g/kg per cycle. The pemphigus disease area index (PDAI) score, direct immunofluorescence (DIF), indirect immunofluorescence (IIF), and corticosteroid dosage were evaluated before IVIG therapy, after each cycle, and at 6 and 12 months’ follow up. Results: The baseline PDAI score was 75.70 ± 21.0 and baseline prednisone dosage was 201.60 ± 71.7 mg/day. The PDAI score reduction of 98% was achieved at 12 months’ follow up and a corticosteroid dose reduction of 90% corresponded to clinical improvement. The decrease in both values was statistically significant (P = 0.002, respectively). At 12 months’ follow up, seven patients were shown to be negative on IIF, of whom three proved to be negative on DIF. Adverse events were mild and transient and did not require the cessation of IVIG therapy.
Conclusion: IVIG induced long-term clinical remission, while displaying a corticocorticosteroidsparing effect and evoking a long-standing immunomodulatory effect in PV patients. The safety profile of IVIG therapy was assessed as good. Key words: autoimmune bullous disease, corticosteroid-sparing effect, immunomodulatory effect, intravenous immunoglobulin (IVIG), pemphigus vulgaris, safety profile.
INTRODUCTION Intravenous immunoglobulin (IVIG) is a biological agent composed of natural polyclonal antibodies prepared from a large cohort of human plasma pools. Since 1981, IVIG has become an increasingly used therapy for the treatment of various antibody-mediated autoimmune diseases, including autoimmune bullous disorders.1,2 Although the precise mechanisms of high-dose IVIG effects in antibody-mediated diseases have not been elucidated, several mutual mechanisms have been proposed. However, antibodies are the first-line defence mechanism with a broad repertoire of activities, and they exert a wide range of effector functions. Moreover, IVIG has proven to be effective. Physiologically it can target the cellular immune compartment at multiple levels and is able to modulate the cellular immune system.3 The goal of this study was to evaluate the benefit and safety profiles of high-dose IVIG therapy in pemphigus vulgaris (PV) patients with severe refractory disease
Abbreviations: Correspondence: Professor Danka Svecova, Department of Dermatovenerology, Faculty of Medicine, University Hospital, Comenius University, Mickiewiczova 13, 81369 Bratislava, Slovakia. Email: [email protected] Danka Svecova, PhD. Conflict of interest: none Submitted 14 May 2015; accepted 7 October 2015. © 2015 The Australasian College of Dermatologists
DIF IIF IVIG PDAI PV SD
direct immunofluorescence indirect immunofluorescence intravenous immunoglobulin pemphigus disease area index pemphigus vulgaris standard deviation
142
D Svecova
determined by clinical remission, corticosteroid-sparing and immunomodulatory effects, and adverse events at 12 months’ follow up.
MATERIALS AND METHODS IVIG treatment was administered to 10 patients with PV who experienced disease relapses during the prednisone taper or adverse events in the previous treatment with corticosteroid-sparing agents, in the years 2009–2013. Before being given IVIG therapy, four patients had experienced adverse effects on azathioprine (myeolosuppression). In three patients, methotrexate therapy was ceased because of myelosuppression. The diagnosis was based on clinical signs, histological findings, DIF and IFF. Both DIF and IFF were used as a standard technique. Patients included in the study were treated with IVIG for at least three consecutive courses, with a maximum of eight courses. The disease severity was calculated using the pemphigus disease area index (PDAI) score.4 Overall, the treatment administered prior to IVIG was documented as pulse corticosteroids or only oral corticosteroids. IVIG was administered in a hospital setting according to the standard protocol. The total dose of 2 g/kg per cycle was divided into five equal doses and administered on five consecutive days.5 Photographic documentation was performed before and after each cycle. A blood analysis performed at monthly intervals included chemistry panel, complete blood count and IIF. Patients were maintained on their baseline corticosteroid treatment until there was no evidence of active disease. A gradual prednisone taper was used in patients with controlled disease. Upon disease flare, the prednisone dosage was increased to a level that was suitable for controlling the disease. The patients were followed up monthly over 12 months. Disease relapse was defined as the appearance of three or more new lesions per month that did not heal spontaneously within 1 week, or as the extension of an existing lesion
in a patient who had achieved disease control. Partial remission on therapy was defined as no new lesions for at least 2 months while receiving a prednisone dose above 10 mg/ day, but not exceeding 50% of the baseline dose, or the presence of one to three lesions while on a prednisone dose equal to or less than 10 mg.6 Data were complied as EXCEL files and analysed using IBM SPSS Statistics 20.0 (IBM, Armonk, NY, USA). Frequency tables were used for the statistical analysis of numerical variables, including the mean, median, standard deviation (SD), minimum, maximum and range. Normal distributions of numerical data were obtained using mean values and SD. Numerical data with abnormal distributions were evaluated using the non-parametric exact Wilcoxon signed–rank test to compare more than two databases. The association between categorised variables and outcomes were assessed using Fisher’s exact test. A P value of
doi: 10.1111/ajd.12422
SMALL CASE SERIES
IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects Danka Svecova Department of Dermatovenerology, Faculty of Medicine, Comenius University, University Hospital, Bratislava, Slovakia
ABSTRACT Background: Intravenous immunoglobulin (IVIG) is a biological agent composed of polyclonal antibodies prepared from a large cohort of human plasma pools. IVIG is increasingly used for the treatment of various antibody-mediated diseases, including pemphigus vulgaris (PV). Objective: The aim of the study was to evaluate the benefit and safety profiles of high dose IVIG therapy in PV patients determined by clinical remission, corticosteroid-sparing and immunomodulatory effects, and adverse events at 12 months’ follow up. Methods: Ten PV patients underwent 3–8 monthly cycles of IVIG therapy at a dose of 2 g/kg per cycle. The pemphigus disease area index (PDAI) score, direct immunofluorescence (DIF), indirect immunofluorescence (IIF), and corticosteroid dosage were evaluated before IVIG therapy, after each cycle, and at 6 and 12 months’ follow up. Results: The baseline PDAI score was 75.70 ± 21.0 and baseline prednisone dosage was 201.60 ± 71.7 mg/day. The PDAI score reduction of 98% was achieved at 12 months’ follow up and a corticosteroid dose reduction of 90% corresponded to clinical improvement. The decrease in both values was statistically significant (P = 0.002, respectively). At 12 months’ follow up, seven patients were shown to be negative on IIF, of whom three proved to be negative on DIF. Adverse events were mild and transient and did not require the cessation of IVIG therapy.
Conclusion: IVIG induced long-term clinical remission, while displaying a corticocorticosteroidsparing effect and evoking a long-standing immunomodulatory effect in PV patients. The safety profile of IVIG therapy was assessed as good. Key words: autoimmune bullous disease, corticosteroid-sparing effect, immunomodulatory effect, intravenous immunoglobulin (IVIG), pemphigus vulgaris, safety profile.
INTRODUCTION Intravenous immunoglobulin (IVIG) is a biological agent composed of natural polyclonal antibodies prepared from a large cohort of human plasma pools. Since 1981, IVIG has become an increasingly used therapy for the treatment of various antibody-mediated autoimmune diseases, including autoimmune bullous disorders.1,2 Although the precise mechanisms of high-dose IVIG effects in antibody-mediated diseases have not been elucidated, several mutual mechanisms have been proposed. However, antibodies are the first-line defence mechanism with a broad repertoire of activities, and they exert a wide range of effector functions. Moreover, IVIG has proven to be effective. Physiologically it can target the cellular immune compartment at multiple levels and is able to modulate the cellular immune system.3 The goal of this study was to evaluate the benefit and safety profiles of high-dose IVIG therapy in pemphigus vulgaris (PV) patients with severe refractory disease
Abbreviations: Correspondence: Professor Danka Svecova, Department of Dermatovenerology, Faculty of Medicine, University Hospital, Comenius University, Mickiewiczova 13, 81369 Bratislava, Slovakia. Email: [email protected] Danka Svecova, PhD. Conflict of interest: none Submitted 14 May 2015; accepted 7 October 2015. © 2015 The Australasian College of Dermatologists
DIF IIF IVIG PDAI PV SD
direct immunofluorescence indirect immunofluorescence intravenous immunoglobulin pemphigus disease area index pemphigus vulgaris standard deviation
142
D Svecova
determined by clinical remission, corticosteroid-sparing and immunomodulatory effects, and adverse events at 12 months’ follow up.
MATERIALS AND METHODS IVIG treatment was administered to 10 patients with PV who experienced disease relapses during the prednisone taper or adverse events in the previous treatment with corticosteroid-sparing agents, in the years 2009–2013. Before being given IVIG therapy, four patients had experienced adverse effects on azathioprine (myeolosuppression). In three patients, methotrexate therapy was ceased because of myelosuppression. The diagnosis was based on clinical signs, histological findings, DIF and IFF. Both DIF and IFF were used as a standard technique. Patients included in the study were treated with IVIG for at least three consecutive courses, with a maximum of eight courses. The disease severity was calculated using the pemphigus disease area index (PDAI) score.4 Overall, the treatment administered prior to IVIG was documented as pulse corticosteroids or only oral corticosteroids. IVIG was administered in a hospital setting according to the standard protocol. The total dose of 2 g/kg per cycle was divided into five equal doses and administered on five consecutive days.5 Photographic documentation was performed before and after each cycle. A blood analysis performed at monthly intervals included chemistry panel, complete blood count and IIF. Patients were maintained on their baseline corticosteroid treatment until there was no evidence of active disease. A gradual prednisone taper was used in patients with controlled disease. Upon disease flare, the prednisone dosage was increased to a level that was suitable for controlling the disease. The patients were followed up monthly over 12 months. Disease relapse was defined as the appearance of three or more new lesions per month that did not heal spontaneously within 1 week, or as the extension of an existing lesion
in a patient who had achieved disease control. Partial remission on therapy was defined as no new lesions for at least 2 months while receiving a prednisone dose above 10 mg/ day, but not exceeding 50% of the baseline dose, or the presence of one to three lesions while on a prednisone dose equal to or less than 10 mg.6 Data were complied as EXCEL files and analysed using IBM SPSS Statistics 20.0 (IBM, Armonk, NY, USA). Frequency tables were used for the statistical analysis of numerical variables, including the mean, median, standard deviation (SD), minimum, maximum and range. Normal distributions of numerical data were obtained using mean values and SD. Numerical data with abnormal distributions were evaluated using the non-parametric exact Wilcoxon signed–rank test to compare more than two databases. The association between categorised variables and outcomes were assessed using Fisher’s exact test. A P value of
