Long-term Efficacy of Intravenous Immunoglobulin Therapy for Moderate to Severe Childhood Atopic Dermatitis

Atopic dermatitis (AD) is a persistent, chronically relapsing inflammatory skin disease in which abnormal hematopoietic cells circulate and infiltrate skin and respiratory tissue at sites perturbed by irritants, antigens, and infectious agents. AD is associated with multiple immunological abnormalities, and 80% of patients suffer from defective regulation of IgE production.1 AD can range from mild, localized lesions to generalized eczematous lesions. Although a number of patients with AD respond to topical therapy, others have severe resistant disease which is not controlled with first- or second-line topical therapies. Therefore, AD may be considered as a systemic disease for which there are no satisfactory systemic therapies, although topically applied medications, including corticosteroid and cyclosporine agents, give relief in some patients.2-4 Long-term, chronic application of topical steroids may supplant the need for systemic therapy in many cases. Newer therapies such as tacrolimus are effective, but are limited to second-line therapy after initial treatments have failed. Oral cyclosporine has also been shown to be effective; however, its use is limited by adverse effects such as renal toxicity. Approximately 20% of patients discontinue cyclosporine treatment within 2 years because of adverse effects.5, 6

Intravenous immunoglobulin (IVIg) is prepared by cold ethanol fractionation of pooled plasma, followed by additional viral inactivation procedures. The final product is a pure concentrate of IgG (with small amounts of IgA and IgM) with intact function and minimal impurities.7, 8 The immunomodulatory mechanism of IVIg is thought to be mediated by interactions of the Fc portion of IgG with Fc receptors and complement, interactions of the antigen-binding variable region F(ab)₂, or substances other than antibodies in IVIg preparations.9 Previous research has shown that IVIg significantly modulates the production of several cytokines, including interleukin (IL)-1, IL-2, IL-3, IL-4, IL-5, IL-10, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor, as well as cytokine antagonists (IL-1 receptor antagonist), by monocyte-macrophages and lymphocytes.10 It appears that the biological anti-inflammatory effects of IVIg involve the participation of both the F(ab)₂ and Fc regions in the formation of an IgG-antigen complex. These regions are associated with the inhibition of lymphocyte proliferative responses and the modulation of T-helper 1 (Th1) and Th2 cytokine production. This effect of IVIg is mediated by the inhibition of differentiation and maturation of dendritic cells (DCs) in vitro, with down-regulated expression of co-stimulatory molecules, thereby impairing the ability of mature DCs to produce IL-12 and enhancing their ability to produce IL-10. The consequences are the inhibition of autoreactive and alloreactive T-cell activation and proliferation.11, 12

IVIg therapy has consistently demonstrated activity in patients with AD, including severe AD,13 although its effectiveness has not been confirmed in prospective, blinded clinical trials. Patients with Kawasaki disease or idiopathic thrombocytopenic purpura and concomitant AD who received IVIg showed improvement of their dermatitis.14, 15 One study gave mixed results, with the best response occurring in patients with extremely high IgE levels.16 Reports on severe childhood AD suggest that IVIg can lead to improved symptoms when used as a monotherapy; nine out of 10 children improved when given 2 g/kg IVIg.17 However, most published research has evaluated only the short-term effects of IVIg.

The present study was conducted to assess the long-term effects of IVIg therapy in moderate to severe childhood AD.

The results of this long-term study demonstrate that the clinical severity of AD showed improvement for 3 months (V5) after the last IVIg injection, but the improvement had declined by 6 months post-treatment (V6). Total serum IgE and eosinophil count decreased during therapy and for 3 months post-treatment (V5), but had returned to initial levels after another 3 months (V6). Similarly, immunological parameters, including the levels of ECP, IL-5, and ICAM-1, in peripheral blood decreased until 3 months post-treatment (V5), but had increased by the 6-month follow-up visit (V6). The level of IFN-γ increased until 3 months after treatment, but decreased over the subsequent 3 months.

Cumulative toxicity and the lack of efficacy may limit systemic glucocorticoid use, and patients severely affected by AD often require immunosuppressive treatment, including IFN-γ, cyclosporine, and IVIg. Patients with Kawasaki disease or idiopathic thrombocytopenic purpura with concomitant AD who received IVIg showed improvement of the dermatitis.14 In that study, four patients with AD had marked improvement of dermatitis symptoms after one dose of IVIg therapy (400 mg/kg infused for 5 days), with significant improvement on days 4-7 after treatment. Two patients with idiopathic thrombocytopenic purpura entered remission for AD and did not require further treatment. However, an open label study of IVIg in patients with severe AD or hyper-IgE syndrome showed no clinical improvement,16 and a randomized prospective study of IVIg in adults with severe AD failed to show a significant clinical effect.17 Therefore, the use of IVIg in the treatment of AD remains controversial. To date, only a few individuals (10 children and 30 adults) have been treated with IVIg, and those studies were relatively short, with durations and response times of less than 3 months.

The current study included 30 eligible children who were treated with high-dose IVIg for 12 weeks and 10 children who were treated with placebo. The subjects were administered monthly injections of IVIg (2.0 g/kg body weight/month) over a 12-week period. Assessment was conducted after each treatment and at 3 and 6 months after treatment; thus, the final assessment was at 9 months after the start of the study. The improvements in AD, assessed based on clinical severity and immunological parameters such as ECP, lasted for 3 months after the last IVIg treatment. However, at the long-term follow-up at 6 months post-treatment, both the clinical and immunological improvements showed a trend back to the initial status.

Preparations of IVIg consist of intact IgE molecules with a distribution of IG subclasses corresponding to that in normal serum. Subclass distribution varies among preparations, and some products have lower physiological levels of IgG3 and/or IgG4. IVIg contains small amounts of other proteins and products, such as albumin, IgA, IgE, IgM, sugars, and salts. The monomer and dimer contents also vary among preparations and include up to 3% non-active polymers.19 These proteins and other molecules may affect the tolerability and half-life of IVIg infusions. Generally, the half-life of injected IVIg is approximately 2-3 weeks, but this varies depending on the immune status of the patient. The present study demonstrated that IVIg therapy (2.0 g/kg/month for 3 months) showed efficacy at 3 months, but not 6 months, after the final injection.

Previous studies have reported elevated serum levels of soluble ICAM-1 and endothelial leukocyte adhesion molecule (ELAM)-1 in patients with severe atopic eczema. Moreover, E-selectin and VCAM-1 are critical adhesion molecules for the trafficking of memory T cells and eosinophils into skin lesions of AD.20-22 Serum levels of the intracellular adhesion molecules ICAM-1 and ECP in previous studies correlated with improvements in AD; therefore, we measured ICAM-1 and ECP as markers for efficacy of IVIg in the present study. IVIg reduced the levels of ICAM-1 and ECP until 3 months after the final IVIg treatment. The decreased levels of ICAM-1 and ECP suggest that IVIg therapy may decrease the influx of inflammatory cells such as eosinophils in skin lesions.

It has been proposed that Th2 cells play a key pathogenic role in AD through regulatory T-cell modulation. There is further evidence that monocytes from AD patients secrete increased amounts of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13. A number of studies have indicated that the immunological balance shifts toward a Th2 response in AD,23, 24 while several other reports have suggested that Th1, rather than Th2, cells are important for AD pathogenesis. One study found high levels of IFN-γ mRNA and protein expression in 80% of the eczematous skin of AD patients.25 Further research has suggested that acute inflammation is mediated by Th2 cell cytokines, whereas chronic lesions had an increased number of cells expressing IL-12 mRNA compared with unaffected skin.26 However, these cells were limited to the skin lesion and were not found in the peripheral blood. In the present study, the IL-5 level was significantly decreased at 3 months post-treatment treatment, but the IFN-γ level did not change significantly during or after treatment. These findings suggest that IVIg therapy may not influence T-cells, but that Th1 cells become more dominant. The apparent switch from Th2 to Th1 dominance may explain the clinical improvement at 3 months after IVIg therapy and its absence 3 months later, although this requires further investigation.

There were a few minor side effects associated with IVIg infusion in the present study, but most were self-limiting and occurred only during the first few hours after infusion. The side effects may be reduced by slowing the rate of infusion or administering NSAIDs or acetaminophen prior to the next IVIg infusion. Side effects such as headache and nausea might have resulted from the high dose of IVIg or might have been a consequence of a low level of IgG aggregation, immune complex formation, or complement activation in the IVIg preparationt.27, 28

It is important to consider the balance between pharmacological efficacy and drug cost with respect to time commitment and financial implications of this therapy. The present study suggests that patients may need to receive IVIg therapy every 6 months, and this cost should be compared with the estimated improvement in the quality of life. Therefore, IVIg therapy should not be introduced until after the physician and patient have considered both the clinical efficacy and the cost of the therapy.