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CURRENT PERSPECTIVE
Year : 2009  |  Volume : 54  |  Issue : 1  |  Page : 77-79
Intravenous immunoglobulin in dermatology


Institute of Child Health and AMRI Hospitals, Kolkata, India

Correspondence Address:
Sandipan Dhar
Flat 2A2, Block II, 5, NSC Bose Road, Kolkata-700 040
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.48996

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How to cite this article:
Dhar S. Intravenous immunoglobulin in dermatology. Indian J Dermatol 2009;54:77-9

How to cite this URL:
Dhar S. Intravenous immunoglobulin in dermatology. Indian J Dermatol [serial online] 2009 [cited 2019 Jun 24];54:77-9. Available from: http://www.e-ijd.org/text.asp?2009/54/1/77/48996



   Introduction Top


The intravenous administration of exogenous pooled human immunoglobulin (intravenous immunoglobulin - i.v. IG) was originally licensed as antibody replacement therapy in patients with primary immunodeficiencies. However, subsequently it has been successfully used in a host of diseases not amenable to other modalities of treatment. There are currently six FDA-approved uses for this agent. Despite a current lack of FDA approval, off-label treatment of a multitude of dermatologic disorders with i.v. IG has shown exciting potential for this unique treatment modality. [1],[2],[3] The dermatoses successfully treated with i.v. IG include autoimmune bullous diseases, connective tissue diseases, vasculitis,  Stevens-Johnson syndrome More Details (SJS), toxic epidermal necrolysis (TEN) and infectious disorders (such as streptococcal toxic shock syndrome). [4] Currently the biggest drawback in the consideration of i.v. IG therapy in dermatologic disorders is the lack of randomized controlled trials (RCTs). Nevertheless, there is a significant body of evidence demonstrating the efficacy of i.v. IG in patients with skin diseases that are resistant to treatment with standard agents. [3],[4],[5]


   Composition of Intravenous Immunoglobulin Top


Intravenous immunoglobulin (i.v. IG) is a sterile highly purified IgG preparation made from pooled human plasma and typically contains more than 95% of unmodified IgG, which has functionally intact Fe-dependent effector functions and only trace amount of IgA or IgM. It is composed of polyspecific immunoglobulin molecules prepared by cold ethanol fractionation of pooled human sera harvested from thousands of donors. Several measures are used to ensure the safety of the product [4],[5] :

  1. Careful selection of donors
  2. Screening of every donation for hepatitis B surface antigen, antihepatitis C virus antibodies, anti-HIV 1 and 2 antibodies, syphilis serology and normal liver function
  3. Use of viral inactivation procedure in addition to the already high viral inactivation afforded by cold ethanol fractionation



   Mechanism of Action of High-Dose Intravenous Immunoglobulin Top


The mechanism by which high-dose intravenous immunoglobulin (hd i.v. IG) mediates anti-inflammatory activity is not well understood. These effects are mediated via the Fc portion of IgG or the antigen-binding site and the variable regions of the antibody molecule. Proposed mechanisms of action of hd i.v. IG include the following [5],[6] :

  1. Anti-idiotype interactions
  2. Fc receptor modulation
  3. Modulation of the production of cytokines and cytokine antagonists
  4. Neutralization of causative microbe or toxin
  5. Superantigen neutralization
  6. Effects on complement - inhibition of complement-mediated damage
  7. Acceleration of IgG catabolism



   Pharmacokinetics Top
[4],[5],[6]

Peak serum concentrations occur immediately after intravenous injection and are dose related. Within 24 hours, up to 30% of the dose may be removed by distribution and catabolism. i.v. IG distributes itself throughout the intravascular (60%) and extravascular (40%) spaces, crosses the placenta and may be excreted into milk. Serum half-life is 3 to 5 weeks [Table 1].


   Autoimmune Bullous Diseases Top


High-dose i.v. IG is useful for patients when [6] -

  1. Conventional therapy has failed
  2. Significant adverse effects of conventional therapy exist
  3. Absolute and relative contraindications to the use of high-dose long-term systemic steroids or immunosuppressive agents exist
  4. Disease is progressive in spite of administering appropriate maximum yet safe conventional systemic therapy
  5. Rapidly progressive epidermolysis bullosa acquisita (EBA) with generalized cutaneous disease exists



   Other Conditions Treated with hd i.v. IG Top


Dermatomyositis represents the most extensively studied dermatological condition with regards to hd i.v. IG therapy. [7] Gιnιreau et al. [8] reported a case in which antimalarial-resistant cutaneous LE was treated successfully with hd i.v. IG. Prins et al. [9] and Trent et al. [10] reported beneficial effect of hd i.v. IG in TEN. Its beneficial effect has been documented in a number of reports across the globe. [11],[12],[13] The standardized mortality ratio (SMR) showed a trend to lower actual mortality with i.v. IG treatment as compared to the predicted mortality. [13] On the contrary, Bachot et al. [14] report ineffectiveness of hd i.v. IG in a study of 34 patients with TEN. Wolff et al. [15] in their editorial comments try to explain this divergent conclusion as batch-to-batch variation in the capacity of hd i.v. IG to inhibit FAS-mediated cell death.


   Dose Top


A dose of 1-2 g/kg is recommended, usually delivered as a 5-consecutive-day cycle of 0.4 g/kg/day, although a 3-day cycle may be used. A cycle consists of the dose divided into 3 to 5 equal doses depending upon the schedule fixed. The infusion is given slowly over 4 to 4 h. During the fusion, vital signs should be monitored.

The initial frequency is generally 1 cycle every 3 to 4 weeks. High-dose i.v. IG is tapered maintaining the same dose but increasing the time interval between infusions. The proposed end point is 2 infusions, each given 16 weeks apart. The cessation of all systemic therapy, including hd i.v. IG, in the absence of clinical disease, is defined as the beginning of the remission period.


   Pretreatment Investigations Top


Serum levels of immunoglobulins, especially IgA, should be determined. Patients with low or absent levels of IgA may have antibodies to IgA, and such patients develop anaphylaxis. A complete blood cell count, hepatic and renal function tests, and screening for rheumatoid factor and cryoglobulin are recommended. Patients with cryoglobulin have a higher risk to develop acute renal failure. Therapy with hd i.v. IG should be used cautiously in patients with renal insufficiency or impaired cardiac function because fluid overload may occur.

Periodical investigations during treatment consist of complete blood cell count, renal and liver function, and antibodies to HIV, hepatitis A, B and C virus.


   Adverse Effects Top


Adverse reactions associated with the use of hd i.v IG are usually mild and self limiting. [16] Most adverse reactions will disappear if the infusion is temporarily discontinued or if the infusion rate is lowered. Reactions such as headache, back pain, chills, flushing, fever, hypertension, myalgia, nausea and vomiting appear to be related to infusion rate rather than the dose. Erythema, pain, phlebitis and eczematous dermatitis may occur at the infusion site.

Aseptic meningitis has been reported in patients receiving hd i.v.IG. [17] Stroke and deep vein thrombosis have been reported as complications of hd i.v. IG therapy. [18] Use of hd i.v. IG has been associated with acute renal failure. Patients receiving hd i.v. IG reconstituted from powder products or hd i.v. IG preparations containing sucrose are at a greater risk of renal failure. Jolles et al. [17] have tabulated different products available and their constitutes. Since hd i.v. IG is isolated from pooled human plasma, the therapy carries the potential risk of transferring infectious agents. A small sample of i.v. IG should be stored before each infusion for further analysis in the event of infectious disease transmission. The ideal i.v. IG preparation would be sugar free with low sodium content and physiological osmolarity.

Cutaneous adverse events reported with the use of i.v. IG include petechiae, pruritus, urticaria, lichenoid eruptions, alopecia and leukocytoclastic vasculitis.[19]

 
   References Top

1.Buckley RH, Schiff RI. The use of intravenous immunoglobulin in immunodeficiency diseases. N Engl J Med 1991;325:110-7.  Back to cited text no. 1  [PUBMED]  
2.Colsky AS. Intravenous immunoglobulin in autoimmune and inflammatory dermatoses: A review of proposed mechanisms of action and therapeutic applications. Dermatol Clin 2000;18:447-57.  Back to cited text no. 2  [PUBMED]  
3.Fernandez AP, Kerdel FA. The use of i.v. IG therapy in dermatology. Dermatol Ther 2007;20:288-305.   Back to cited text no. 3    
4.Jolles S, Hughes J, Whittaker S. Dermatological uses of high-dose intravenous immunoglobulin. Arch Dermatol 1998;134:80-6.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Dahl MV, Bridges AG. Intravenous immunoglobulin: Fighting antibodies with antibodies. J Am Acad Dermatol 2001;45:775-83.  Back to cited text no. 5    
6.Ahmed AR, Dahl MV. Consensus statement in the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering disease. Arch Dermatol 2003;139:1051-9.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al . A controlled trial of high dose intravenous immune globulin infusion as treatment for Dermatomyositis. N Engl J Med 1993;329:1993-2000.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Genereau T, Chosidow O, Danel C, Chιrin P, Herson S. High-dose intravenous immunoglobulin in cutaneous lupus erythematosus. Arch Dermatol 1999;135:1124-5.  Back to cited text no. 8    
9.Parins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, et al . Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: Multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003;139:26-32.  Back to cited text no. 9    
10.Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of intravenous immunoglobulin for the treatment toxic epidermal necrolysis using SCORTEN: The university of Miami experience. Arch Dermatol 2003;139:39-43.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Schwartz R, Avello E, Palisson F. Lamotrigine-induced toxic epidermal necrolysis treated with intravenous immunoglobulin and amniotic membranes. Arch Dermatol 2008;144:724-6.   Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Bahna SL, Khalili B. New concepts in the management of adverse drug reactions. Allergy Asthma Proc 2007;28:17-24   Back to cited text no. 12    
13.Mittman N, Chan B, Knowles S, Cosentino L, Shear N. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome. Am J Clin Dermatol 2006;7:359-68.   Back to cited text no. 13    
14.Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008;58: 33-40.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Steven-Johnson syndrome and toxic epidermal necrolysis: A prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 2003;139:33-6.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Wolff K, Tappeiner G. Treatment of toxic epidermal necrolysis: The uncertainty persists but the fog is dispersing. Arch Dermatol 2003;139:85-6.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Jolles S, Hughes J, Whittaker S. Dermatological uses of high-dose intravenous immunoglobulin. Arch Dermatol 1998;134:80-6.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Rutter A, Luger TA. High-dose intravenous immunoglobulins: A promising approach to treat severe immune-mediated and autoimmune diseases of the skin. J Am Acad Dermatol 2001;44:1010-24.  Back to cited text no. 18    
19.Katz KA, Hivnor CM, Geist DE, Shapiro M, Ming ME, Werth VP. Stroke and deep venous thrombosis complicating intravenous immunoglobulin infusions. Arch Dermatol 2003;139:991-3.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]



 
 
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  [Table 1]

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    Introduction
    Composition of I...
    Mechanism of Act...
    Pharmacokinetics
    Autoimmune Bullo...
    Other Conditions...
    Dose
    Pretreatment Inv...
    Adverse Effects
    References
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