Year : 2018 | Volume
: 38 | Issue : 1 | Page : 42--45
Results of intravenous immunoglobulin use and treatment in the South Province of Turkey
Hülya Nazik, Mehmet K Mülayim, Perihan Öztürk
Department of Dermatology, Faculty of Medicine, Kahramanmarasş Sütçü İmam University, Kahramanmarasş, Turkey
Department of Dermatology, Faculty of Medicine, Kahramanmarasş Sütçü İmam University, Kahramanmarasş 46100
Objective In this study, we aimed to evaluate the use of intravenous immunoglobulin (IVIG) in our clinic and investigate the effect of its treatment on diseases in patients with pemphigus.
Materials and methods Age, sex, disease, skin biopsy result, duration of illness, treatments received, IVIG adverse effects, and clinical course were recorded by screening medical records of patients with different diagnoses receiving IVIG. The findings were evaluated retrospectively.
Findings The total number of cases treated with IVIG was 21. A total of 14 cases were diagnosed as having pemphigus, and three cases were diagnosed as having pyoderma gangrenosum, one (4.8%) case as Sweet syndrome, one (4.8%) case as lichen planus, one (4.8%) case as resistant urticaria, and one (4.8%) case as hyperimmunoglobulin E syndrome. The mean time to start IVIG treatment from diagnosis in patients with pemphigus was 2.62±2.3 years (minimum–maximum: 1–10 years). The mean number of cure IVIG treatment cycles given to patients was 11.38±7.63 (minimum–maximum: 1–30). In patients with pemphigus, a partial remission was achieved with an average cure IVIG treatment cycle of 2.71±3.3 (minimum–maximum: 0–10 cures). In three (21.4%) of the pemphigus cases that received IVIG, the treatment was terminated owing to remission. In pemphigus cases where the treatment was terminated owing to remission, the mean number of IVIG cycles was 12.7±5.9 (minimum–maximum: 6–17).
Conclusion IVIG treatment has become a reliable treatment option in our clinic, which is preferred owing to successful treatment results and clinical experience in many different diseases, especially pemphigus.
|How to cite this article:|
Nazik H, Mülayim MK, Öztürk P. Results of intravenous immunoglobulin use and treatment in the South Province of Turkey.Egypt J Dermatol Venerol 2018;38:42-45
|How to cite this URL:|
Nazik H, Mülayim MK, Öztürk P. Results of intravenous immunoglobulin use and treatment in the South Province of Turkey. Egypt J Dermatol Venerol [serial online] 2018 [cited 2022 Oct 1 ];38:42-45
Available from: http://www.ejdv.eg.net/text.asp?2018/38/1/42/227098
Intravenous immunoglobulin (IVIG) is a biological agent consisting of natural polyclonal antibodies derived from plasma of thousands of healthy humans. IVIG therapy is effective by regulating the immune system, by anti-inflammatory effect in autoimmune and systemic diseases, and by substituting the missing one in cases such as in immunodeficiency . In dermatological diseases, efficacy has been shown especially in the cases of bullous diseases such as Steven-Johnson syndrome, toxic epidermal necrolysis, pemphigus, and bullous pemphigoid. In addition, its efficacy has also been shown with cases presenting with atopic dermatitis, chronic urticaria, pyoderma gangrenosum (PG), and erythema multiforme, which have many different pathogenesis, and it is being increasingly used in clinical practice ,,,. There are desmosome structures that provide adhesion in the multi-layered squamous epithelium in the skin and oral mucosa. Pemphigus describes a group of immunoglobulin (Ig) G-mediated autoimmune diseases that develop against desmoglein 1 and desmoglein 3 within the structure of desmosomes. Pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus are the three main types of disease that occur with bullae and erosions in the clinic . Damage to the protective epidermal barrier in pemphigus may result in serious morbidity or even death owing to loss of body fluids or bacterial entry. Before the use of systemic corticosteroids, within 1 year after diagnosis of pemphigus in the year 1950, death rates were 75%. With appropriate treatment, the mortality rate was significantly reduced and decreased to approximately 5–6%. Much of the deaths are owing to the adverse effects of the immunosuppressive agents used in the treatment rather than the disease itself . In this study, our experience with IVIG use in our clinic and the effect of treatment on disease in patients with pemphigus were investigated.
Materials and methods
We retrospectively investigated the data of 21 patients who were treated with IVIG in Dermatology Clinic between August 2013 and July 2017. Written and verbal information about IVIG was given to patients before the procedure, and the patient consent form was filled. The local ethics committee approved the study. Blood, urine, and serum samples were collected from all patients, and hemogram, glucose, urea creatinine, aspartate transaminase, alanine transaminase, amylase, albumin, globulin, total protein, sodium, potassium, calcium, magnesium, erythrocyte sedimentation rate, C-reactive protein, hepatitis markers, parasite screening, IgG, and IgA levels were determined. The patients were premedicated with 25 mg prednisone ampoule, chlorpheniramine maleate ampoule, famotidine ampoule, and 500 cm3 isotonic saline. The IVIG dose to be given at each treatment cure was calculated as 2 g/kg. The total dose calculated for a cure treatment was given in 5 days as slow infusion. Necessary precautions have been taken despite the possibility of developing anaphylaxis. For pemphigus, IVIG treatment has been given as one cycle in 4 weeks until partial remission of the disease. After the partial remission, it is planned to cut the cycle rates by decreasing the frequency. Patients’ age, sex, disease, skin biopsy results, disease duration, received treatment, adverse effects during or after IVIG treatment, and clinical response to IVIG treatment were evaluated by screening patient files. Patients who did not have a 1-month-long sustained lesion, and received 15 mg/day or less of prednisone with 100 mg/day of azothiopurine were accepted as having partial remission .
In this study, 21 cases with IVIG treatment in our clinic were evaluated in terms of demographic, clinical, and laboratory characteristics. A total of 14 (66.7%) cases were pemphigus, three (14.3%) cases were PG, one (4.8%) case was Sweet syndrome, one (4.8%) case was lichen planus, one (4.8%) case was resistant urticaria, and one (4.8%) case was diagnosed with hyperimmunoglobulin E syndrome.
The mean age of the patients included in the study was 43.19±15.6 years (minimum–maximum: 19–73). Overall, 16 (76.2%) patients were female and five (23.8%) patients were male. Before IVIG treatment, five patients received systemic corticosteroid; 13 patients received systemic corticosteroid and azothiopurine; one patient received systemic corticosteroid, azothiopurine, and mycophenolate mofetil; one patient received systemic corticosteroid and isotretinoin; and one patient received systemic corticosteroid, dual antihistaminic, cyclosporin, colchicine, and omalizumab treatments. All of the patients followed with pemphigus were diagnosed histopathologically by skin biopsy or pemphigus diagnosis was confirmed by biopsy in our clinic. Biopsy results were reported as pemphigus vulgaris in 12 (85.7%) cases and pemphigus foliaceus in 2 (14.3%) cases. Nine (64.3%) of the patients with pemphigus were female and five (35.7%) of them were male, and the mean age of the patients was 41.14±15.9 years (minimum–maximum: 19–73 years). The mean duration of illness in patients followed-up with pemphigus diagnosis was 4.24±2.6 (minimum–maximum: 1–10 years). Headache developed in the first course of treatment in two (14.3%) cases owing to IVIG treatment. For this reason, the IVIG brand used in the cases was changed. There was no headache after changing the IVIG brand. One (4.8%) patient with pemphigus described fatigue after IVIG treatment. In one (4.8%) patient with pemphigus, ninth cycle of cure with IVIG resulted in pulmonary embolism and the treatment was terminated. No complications were reported during or after treatment in the other cases. IVIG was started because of the ‘corticosteroid-sparing’ effect in pemphigus cases. The mean number of cure cycles received by patients with pemphigus was 11.38±7.63 (minimum–maximum: 1–30). Patients entered partial remission with mean treatment cure cycles of 2.71±3.3 (minimum–maximum: 0–10 cure cycles). In three (21.4%) of the pemphigus cases that received IVIG, the treatment was terminated owing to remission. In pemphigus cases where the treatment was terminated owing to remission, the mean number of IVIG cycles was 12.7±5.9 (minimum–maximum: 6–17). Treatment of eight (57.1%) cases is still continuing.
In two (14.3%) cases, despite one receiving 23 cycles and the other receiving 30 cycles of IVIG, rituximab therapy was started in addition to steroid and azothiopurine treatment as the desired clinical response could not be obtained.
In one (7.1%) of the cases, the treatment was terminated owing to the development of pulmonary embolism in the ninth cure cycle of IVIG.
IVIG therapy has been used since 1981 in a variety of autoimmune diseases, including autoimmune bullous disorders . Systemic corticosteroids and immunosuppressive drugs are widely used in the treatment of many diseases in the field of dermatology. However, owing to frequent adverse effects, their use is limited, and alternative treatment needs are being developed. Pemphigus is a disease that is treated with the use of long-term systemic corticosteroids and immunosuppressive drugs. In a study conducted by Huang et al.  in Taiwan, general mortality, cause of death, and cause-specific mortality in patients with pemphigus were investigated. It has been determined that mortality rate in patients with pemphigus is double as compared with the general population. Pneumonia (3.64%), septicemia (11.57%), cardiovascular disease (2.69%), and peptic ulcer disease (8.44%) were significantly higher in the death-cause analysis . Another study reported systemic infection, pneumonia, diabetes, arterial hypertension, cardiorespiratory disease, and peptic ulceration as complications of long-term corticosteroid and adjuvant immunosuppressive treatment for pemphigus . Hypertension occurred in two (14.2%), hyperglycemia occurred in three (21.4%), and hyperlipidemia occurred in three (21.4%) cases during the treatment of patients with pemphigus in our clinic. In a cohort study conducted by Leshem et al.  involving 172 newly diagnosed patients with pemphigus, follow-up regarding venous thromboembolism was done for 4 years. It was found that the risk of developing venous thromboembolism in patients with pemphigus was highest (5%) in the first year after diagnosis regardless of age and sex . A 41-year-old man with pemphigus who was followed-up in our clinic developed pulmonary embolism in the second year of his diagnosis. The mechanism of action of IVIG is quite complex. Its primary effect is selective uptake of pathogenic antibodies without affecting normal antibody levels. It also changes the expression and function of Fc receptors. It affects activation and differentiation of T cells and B cells and reduces response to autoantibodies by interfering with cytokine activation . Corticosteroid-sparing effects of IVIG have been reported in previous studies. This concept means that the dose of corticosteroid is kept low, avoiding high doses of corticosteroids . IVIG is used for this purpose in our clinic. IVIG therapy has been shown to be effective in combination with systemic steroids and immunosuppressive agents in the treatment of pemphigus . Ahmed and Dahl  suggested IVIG at a dose of 2 g/kg divided into 5 days every 4 weeks until the disease was controlled. When the disease is controlled in this treatment regimen, the interval between infusions is extended to 6, 8, 10, 12, 14, and 16 weeks and then the treatment is stopped. If the disease is exacerbated, the infusion rate is increased until the aggravation is under control and then the regimen is restarted . IVIG treatment in our clinic is used similar to this chart, taking the response received into account. In a study conducted by Svecova , the mean Pemphigus Disease Area Index score decreased by 98% (P=0.002) in the 12-month follow-up of patients with pemphigus treated with IVIG treatment. At the same time, the dose of steroid has been reported to be reduced by 90% compared with baseline. Similar to the literature, patients with pemphigus whose treatment was terminated in this study received an average of 12.7±5.9 cycles of IVIG treatment. A study conducted by Amagai et al.  reported that a single cure cycle of IVIG was rapidly effective in the treatment of pemphigus. In our clinic, partial remission was achieved in 2.71±3.3 treatment cure cycles. One study reported a clinical improvement of 91% in pemphigus treatment through the combination of IVIG with systemic steroids and/or immunosuppressive agents and a clinical improvement of 56% when IVIG is used as monotherapy . All patients who received IVIG treatment in our clinic were using systemic corticosteroids and azathioprine simultaneously. The efficacy of rituximab, a chimeric anti-CD20 monoclonal IgG antibody given by infusion, in the treatment of autoimmune bullous diseases has been demonstrated. A total of 12 patients with severe pemphigus were treated with rituximab by Cianchini et al. . They reported a good clinical response without infectious complications in the follow-up of 18 months. In our clinic, rituximab was started for two pemphigus cases that did not respond to systemic corticosteroids, azothiopurine, and IVIG treatments. Their treatment is ongoing.
IVIG treatment was initiated in our clinic for three PG cases that did not respond to systemic corticosteroid therapy, one Sweet syndrome case, one lichen planus case, one hyperimmune globulin E case that did not respond to systemic isotretinoin and steroid treatments, and one resistant urticarial case that did not respond to omalizumab treatment with steroids, cyclosporine, and colchicine. PG is a rare neurotrophic dermatosis. There is no standard treatment regimen for resistant PG cases. Successful results have been reported in the literature with the use of IVIG in combination with steroids . One of the PG cases followed in our clinic showed clinical improvement in the third cure treatment cycle. One case of PG was treated with one cure treatment cycle and the other case received seven cycles of IVIG treatment. Clinical follow-up and treatment of the cases continue.Sweet’s syndrome is also known as acute neutrophilic dermatosis. Effective treatment results have been reported in combination with steroids, dapsone, and colchicine in treatment-resistant Sweet syndrome cases . The patient with Sweet’s syndrome followed in our clinic died owing to pneumonia development during the treatment. Lichen planus is an inflammatory dermatosis associated with autoimmunity, which is common in the community (1%), affecting the skin and mucous membranes. In the literature, IVIG treatment was applied to a small number of resistant oral lichen planus, and effective results have been reported after the second cure treatment cycle . Clinically, the lesions were controlled under the second cure treatment cycle in the case of lichen planus followed in our clinic. Hyperimmunoglobulin E syndrome is a rare genetic disorder characterized by skin eczema, pyogenic ‘cold’ abscesses, synopulmonary infections, and high plasma IgE concentrations. In the literature, it has been reported that the use of IVIG in patients with acute pneumonia with hyperimmunoglobulin E syndrome has beneficial results . The case followed in our clinic died owing to sepsis. Urticaria is a relatively common disease affecting 10–20% of the population. The use of immunosuppressive agents may cause significant morbidity if antihistamines fail in treatment. It has been reported that urticarial symptoms are successfully controlled by immunomodulatory effect of using IVIG in the literature . Clinically, the lesions were controlled under the fourth treatment cure in the presence of resistant urticaria in our clinic.
In conclusion, IVIG therapy has become a reliable treatment option in our clinic, which is preferred owing to successful treatment results and clinical experience in many different diseases, especially pemphigus.
In the treatment of many diseases encountered in the field of dermatology, drugs targeting the patients’ immune system are used. In this context, it may be concluded that the efficacy of IVIG treatment is higher and the adverse effects are lower for patients with pemphigus compared with long-term systemic corticosteroids or other immunosuppressive agents.
Our work has several limitations. The limitations of our study are that Pemphigus Disease Index was not followed in patients with pemphigus, the data are obtained from patient records, and the antidesmoglein antibodies could be monitored following the response to treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Liumbruno GM, Bennardello F, Lattanzio A, Piccoli P, Rossettias G, Italian Society of Transfusion Medicine and Immunohaematology (SIMTI). Recommendations for the use of albumin and immunoglobulins. Blood Transfus 2009; 7:216–234.|
|2||Holm JG, Ivyanskiy I, Thomsen SF. Use of nonbiologic treatments in antihistamine-refractory chronic urticaria: a review of published evidence. J Dermatolog Treat 2017; 31:1–18.|
|3||Kawakami T, Koga H, Saruta H, Ueda A, Inoue Y, Soma Y et al. Four mild but refractory cases of pemphigus foliaceus successfully treated with intravenous immunoglobulin. J Dermatol 2013; 40:869–873.|
|4||Wallington T. New uses for IVIgG immunoglobulin therapies. Vox Sang 2004; 87:155–157.|
|5||Negi VS, Elluru S, Sibéril S, Graff-Dubois S, Mouthon L, Kazatchkine MD et al. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol 2007; 27:233–245.|
|6||Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, Amagai M. Pemphigus. Nat Rev Dis Primers 2017; 3:17026.|
|7||Sinha AA, Hoffman MB, Janicke EC. Pemphigus vulgaris: approach to treatment. Eur J Dermatol 2015; 25:103–113.|
|8||Herbst A, Bystryn J. Patterns of remission in pemphigus vulgaris. J Am Acad Dermatol 2000; 42:422–427.|
|9||Zandman-Goddard G, Krauthammer A, Levy Y, Langevitz P, Shoenfeld Y. Longterm therapy with intravenous immunoglobulin is beneficial in patients with autoimmune diseases. Clin Rev Allergy Immunol 2012; 42:247–255.|
|10||Huang YH, Kuo CF, Chen YH, Yang YW. Incidence, mortality, and causes of death of patients with pemphigus in Taiwan: a nationwide population-based study. J Invest Dermatol 2012; 132:92–97.|
|11||Ljubojević S, Lipozencić J, Brenner S, Budimcić D. Pemphigus vulgaris: a review of treatment over a 19-year period. J Eur Acad Dermatol Venereol 2002; 16:599–603.|
|12||Leshem YA, Atzmony L, Dudkiewicz I, Hodak E, Mimouni D. Venous thromboembolism in patients with pemphigus: a cohort study. J Am Acad Dermatol. 2017; 77:256–260.|
|13||Svecova D. IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects. Australas J Dermatol 2016; 57:141–144.|
|14||Czernik A, Toosi S, Bystryn JC, Grando SA. Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: an update. Autoimmunity 2012; 45:111–118.|
|15||Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol 2003; 139:1051–1059.|
|16||Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, Pemphigus Study Group, et al... A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol 2009; 60:595–603.|
|17||Jolles S. A review of high-dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders. Clin Exp Dermatol 2001; 26:127–131.|
|18||Cianchini G, Corona R, Frezzolini A, Ruffelli M, Didona B, Puddu P. Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch Dermatol 2007; 143:1033–1038.|
|19||Cummins DL, Anhalt GJ, Monahan T, Meyerle JH. Treatment of pyoderma gangrenosum with intravenous immunoglobulin. Br J Dermatol 2007; 157:1235–1239.|
|20||Haliasos E, Soder B, Rubenstein DS, Henderson W, Morrell DS. Pediatric Sweet syndrome and immunodeficiency successfully treated with intravenous immunoglobulin. Pediatr Dermatol 2005; 22:530–535.|
|21||Nakashima C, Otsuka A, Sonobe H, Kitoh A, Kato M, Kore-Eda S et al. Treatment of intractable oral lichen planus with intravenous immunoglobulin therapy. Eur J Dermatol 2012; 22:693.|
|22||Bilora F, Petrobelli F, Boccioletti V, Pomerri F. Moderate-dose intravenous immunoglobulin treatment of Job’s syndrome. Minerva Med 2000; 91:113–116.|
|23||Watkins C, Peiris E, Saleh H, Krishnaswamy G. Intravenous immunoglobulin as a potential therapy for refractory urticaria – a review. Inflamm Allergy Drug Targets 2012; 11:375–381.|