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Pompholyx and eczematous reactions associated with intravenous immunoglobulin therapy
Pompholyx and eczematous reactions associated with intravenous immunoglobulin therapy Meg R. Gerstenblith, MD, Ashley K. Antony, BA, Jacqueline M. Junkins-Hopkins, MD, and Rachel Abuav, MD Baltimore, Maryland Introduction: Intravenous immunoglobulin (IVIG) is used to treat many inflammatory and autoimmune disorders and although generally well tolerated, cutaneous side effects occur. Objective: We reviewed reports of pompholyx and eczematous reactions associated with IVIG. Methods: A literature search was performed using the PubMed and MEDLINE databases with the search terms ‘‘intravenous immunoglobulin pompholyx,’’ ‘‘intravenous immunoglobulin eczema,’’ ‘‘intravenous immunoglobulin cutaneous adverse effects,’’ ‘‘intravenous immunoglobulin cutaneous effects,’’ ‘‘intravenous immunoglobulin skin effects,’’ and ‘‘intravenous immunoglobulin adverse effects.’’ Relevant Englishlanguage articles or articles in other languages cited in English-language articles were included. Results: We identified 64 cases of eczematous reactions associated with IVIG therapy, including a patient treated on our inpatient consult service. In reported cases, the majority of patients (62.5%) had pompholyx alone or a combination of pompholyx on the hands or feet and two or fewer additional body surfaces involved. The majority of reported cases (75%) experienced the eczematous reaction after their first IVIG treatment. Neurologic conditions were the most common (85.9%) diseases for which IVIG was used. Most patients responded well to topical steroids or did not require treatment. Limitations: Some reported cases had insufficient descriptions to be included in this review. A literature review may underestimate the frequency of eczematous reactions to IVIG because these reactions are often limited and may not be reported. Conclusions: With the use of IVIG increasing, it is important for dermatologists to recognize this cutaneous side effect of IVIG. ( J Am Acad Dermatol 2012;66:312-6.) Key words: adverse skin reactions; dyshidrotic eczema; eczema; intravenous immunoglobulin; pompholyx.
I
ntravenous immunoglobulin (IVIG) was developed more than 30 years ago and is currently used on- and off-label for several dermatologic, neurologic, hematologic, and immunologic disorders.1 As From the Department of Dermatology, Johns Hopkins School of Medicine. Funding sources: None. Conflicts of interest: None declared. Presented at the Gross and Microscopic Symposium at the Annual American Academy of Dermatology Meeting in March 6, 2009, San Francisco, California (Abstract #261). Reprint requests: Meg R. Gerstenblith, MD, Department of Dermatology, Case Western Reserve University, Lakeside 3500, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: meg. [email protected]. Published online May 23, 2011. 0190-9622/$36.00 Ó 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.12.034
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a blood product consisting of only IgG antibodies pooled from at least 1000 different human donors, IVIG must be manufactured using viral inactivation measures and screened for infections to ensure its safety. Minor adverse effects occur in about 30% to 40% of patients and include headache, chills, fatigue, nausea, arthralgias, myalgias, and back pain.1,2 Rarely, more serious reactions may occur, including aseptic meningitis, renal failure, anaphylactic shock, hemolytic anemia, and thromboembolic complications.1-7 Although minor adverse effects may be related to the rate of infusion, some of the serious reactions may be related to the particular osmotic and sodium loads of the IVIG preparation, the rate of infusion, and host factors.2 For example, the risk of renal failure with IVIG is related not only to the sucrose content of the IVIG preparation and rate of infusion, but also host factors such as pre-existing renal disease, diabetes,
Gerstenblith et al 313
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and hypertension. Cutaneous adverse effects may were obtained in only 13 patients; therefore, eczeoccur and vary in presentation from localized to matous reactions were classified largely on a morgeneralized reactions and are estimated to occur in phologic basis. Typical findings of pompholyx are 0.4% to 6% of treated patients.6,8,9 There are several shown in Fig 1, A and B, with multiple, grouped reports of urticaria and isolated reports of alopecia, pinpoint clear and erythematous vesicles occurring erythema multiforme, lichenoid dermatitis, purpuric on the palms and soles bilaterally. Representative erythema, vasculitis, and morbilliform eruptions histopathology reveals a loculated, spongiotic vesiassociated with IVIG10-16; cle, typical of dyshidrosis; a however, an underappreciperivascular infiltrate conCAPSULE SUMMARY ated cutaneous reaction is ecsisting of lymphocytes and zema, often localized to the eosinophils; and exocytosis The use of intravenous immunoglobulin palms and soles as the vesicof lymphocytes into the epi(IVIG) to treat multiple inflammatory and ular variant, pompholyx. dermis (Fig 1, C ). autoimmune disorders is increasing. Forty of the reported cases Pompholyx is an important cutaneous METHODS (62.5%) presented with pomside effect of IVIG. We conducted a literature pholyx alone or a combinareview using the PubMed and tion of pompholyx (hands or Pompholyx occurring after IVIG MEDLINE databases and the feet) and fewer than two treatment typically wanes over time but search terms ‘‘intravenous imbody surfaces involved; 8 can recur and become more extensive munoglobulin pompholyx,’’ (12.5%) had pompholyx in with subsequent IVIG treatments. ‘‘intravenous immunoglobuassociation with a generalDermatologists should recognize this lin eczema,’’ ‘‘intravenous ized, widespread eczematous cutaneous side effect of IVIG. immunoglobulin cutaneous eruption; 3 (4.7%) had wideadverse effects,’’ ‘‘intravenous spread eczematous erupimmunoglobulin cutaneous effects,’’ ‘‘intravenous imtions; and 13 (29.7%) had other unspecified munoglobulin skin effects,’’ and ‘‘intravenous immueczematous reactions. The majority of eczematous noglobulin adverse effects,’’ for English-language reactions occurred during the first IVIG treatment articles. Relevant English-language articles or articles course (75.0%). Most patients (85.9%) were being in other languages cited in English-language articles treated with IVIG for neurologic conditions. were included. We reviewed the titles and abstracts Interestingly, only 3 cases are reported of pompholyx identified in the literature searches. We also reviewed occurring in patients treated with IVIG for dermatoreferences from bibliographies of pertinent articles. logic conditions, including one patient with StevensJohnson syndrome and two patients with chronic urticaria.31,40 Another patient with Stevens-Johnson RESULTS syndrome developed vesicles on the palms after IVIG We identified 64 cases to date of eczematous treatment, with histopathology showing an intracorreactions associated with IVIG therapy, including a neal vesicle without inflammatory cells in the epiderpatient treated on our inpatient consult service.17-40 mis or dermis, findings not entirely consistent with Two articles were non-English-language articles; one pompholyx.29 could be translated and one included a table in There are no known risk factors for developing English with enough detail to be included in our cutaneous adverse effects with IVIG therapy. When analysis.26,36 Few additional cases were reported but assessed, the majority of affected individuals did not without the demographic and clinical data needed to have a personal history of atopy, eczema, allergic be included.41,42 reactions, or another dermatologic condition Table I summarizes the clinical characteristics of (83.0%). In our review, eczematous reactions and the identified patients, including age; sex; history of pompholyx were reported with multiple IVIG prepatopy, including hand eczema, childhood asthma, arations but occurred most frequently with and seasonal allergies; the underlying disease being Sandoglobulin (Novartis, East Hanover, NJ), which treated with IVIG; the type of IVIG preparation and may reflect its widespread use. Interestingly, switchits dose and treatment course if reported; the type of ing the type of IVIG in 5 patients resulted in variable eczematous reaction; the time for the reaction to responses. One patient with pompholyx developed appear and resolve; the treatments for the reaction an identical reaction, one patient with pompholyx if any; and the response to subsequent IVIG courses. developed noneczematous skin eruptions of inNoneczematous skin reactions or reactions not specreased severity (Baboon syndrome and a morbillicifically described as pompholyx or eczematous form rash),17 one patient with no prior cutaneous were excluded from our analysis. Biopsy specimens d
d
d
d
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Table I. Reported cases to date of pompholyx and eczematous reactions occurring in association with intravenous immunoglobulin treatment Demographic information Age (n = 33) Mean, y Median, y Range, y Male:female (n = 42) Underlying disease and atopic history information Underlying disease Neurologic diseases Multiple sclerosis Chronic inflammatory demyelinating polyneuropathy Guillain-Barre syndrome Multifocal motor neuropathy Other neurologic Dermatologic diseases Chronic urticaria Stevens-Johnson syndrome Hematologic diseases* Immunologic diseasesy Ophthalmologic diseasesz History of atopy (n = 23) Hand eczema Childhood asthma Seasonal allergies Not specified IVIG treatment information Initial IVIG type (n = 38) Sandoglobulin Gammagard Tegelin IVIG dose (n = 53) 0.4-0.5 g/kg/d 3 3-5 d 1 g/kg/d 3 2 d 2 g/kg/d 3 1 d Days to first eruption (n = 44) \8 8-14 >14 Skin reaction characteristics (n = 64) Pompholyx primarily with # 2 body surfaces involved in addition to hands/feet Pompholyx with simultaneous, preceding, or subsequent generalized eczema (>2 body surfaces involved in addition to hands/feet) Widespread, generalized eczematous eruption Other, unspecified eczematous eruptions Biopsy specimens taken
50.6 55 7-75 33:9 N (%) (n = 64) 55 (85.9) 14 (25.5) 9 (16.4) 9 8 15 3 2 1 3 2 1 4 1 1 1 1
(16.4) (14.5) (27.3) (4.7) (66.7) (33.3) (4.7) (3.1) (1.6) (17.4) (25) (25) (25) (25)
18 (47.4) 11 (28.9) 9 (23.7) 35 (66.0) 16 (30.2) 2 (3.8) 34 (77.3) 6 (13.6) 4 (9.1) 40 (62.5) 8 (12.5)
3 (4.7)
Table I. Cont’d Time to resolution, wk (n = 27) \3 $3 Treatment for first or subsequent reaction (n = 45)x Topical steroids Spontaneous resolution Antihistamines Systemic steroids Hospitalization Subsequent IVIG courses (n = 29) No. of patients with subsequent reaction Improved reaction Same reaction Worse reaction IVIG preparation changed after rash development (n = 5) No further reaction Same reaction Worse reaction Morphology of reaction changed
7 (26.0) 20 (74.1)
27 11 7 6 2
(60.0) (24.4) (15.6) (13.3) (4.4)
24 3 5 16
(82.8) (12.5) (20.8) (66.7)
2 1 1 1
(40) (20) (20) (20)
Available data were extracted from reported cases for this table; therefore, numbers used vary for categories presented. IVIG, Intravenous immunoglobulin. *There were two cases of thrombocytopenic purpura and one case of idiopathic systemic capillary leak syndrome. y Includes one patient with dermatomyositis and the patient we treated who had an initial diagnosis of immunodeficiency that was not confirmed on subsequent testing. z Birdshot retinochoroidopathy. x Total number and percentages do not add up to 45 and 100%, respectively, because some individuals received more than one treatment.
reaction developed a new vesicular facial eruption,20 and two patients with pompholyx or eczema improved with no subsequent reaction after a change in IVIG formulation.20 Most of the patients responded well to topical steroids or did not require therapy, although oral steroids were occasionally necessary. In 74.1% of reported cases, the reaction subsided in 3 or more weeks. For all reported cases, the eczematous reactions improved, although in one case, pruritus occurred for several months after IVIG treatment.20 There were no mortalities reported in these patients with eczematous reactions to IVIG; however, for many patients, IVIG was not continued because of these eczematous reactions.
13 (29.7) 13 Continued
DISCUSSION IVIG use is becoming more widespread as the numbers of both indications and patients with autoimmune and inflammatory disorders increase. IVIG has several proposed mechanisms of action;
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Fig 1. A and B, Multiple grouped pinpoint vesicles, which were present on palms and soles bilaterally. C, Biopsy specimen from foot demonstrating dyshidrotic intraepidermal spongiotic vesicle with eosinophils and lymphocytes. (Hematoxylin and eosin stain; original magnification: 310.)
however, there is no clear mechanism that can explain the association with eczema. Interestingly, we were unable to identify any cases of pompholyx or eczematous reactions occurring in patients being treated with IVIG for an underlying immunodeficiency. There are two potential hypotheses to explain the near absence of eczematous reactions in the immunodeficient population treated with IVIG. First, this type of reaction may not occur in association with IVIG in individuals with true immune deficiency. Alternatively, the dose used to treat immunodeficiency is typically lower than that used in neurologic, hematologic, and dermatologic conditions described here (0.4 and 2 g/kg, respectively), which could suggest that pompholyx and eczematous reactions occur only when high-dose IVIG is used. This may reflect a possible dose response for eczematous reactions. Although eczematous reactions to IVIG are reported to wane over time, in our review we found that the reaction was likely to recur with subsequent treatments, and, in the majority of patients, the reaction worsened. Because pompholyx is treatable,
the general recommendation is for IVIG treatment to be continued for patients experiencing clinical benefit. In the case of severe cutaneous reactions, IVIG should be discontinued. Dermatologists should be aware that pompholyx and eczema are common cutaneous adverse effects of IVIG that can occur alone or in combination, and that these effects may worsen upon subsequent IVIG treatments. However, these effects can be successfully treated, allowing continuation of IVIG therapy if warranted. REFERENCES 1. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55. 2. Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev 2007;6:257-9. 3. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121:259-62. 4. Brox AG, Cournoyer D, Sternbach M, Spurll G. Hemolytic anemia following intravenous gamma globulin administration. Am J Med 1987;82:633-5.
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5. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-6. 6. Misbah SA, Chapel HM. Adverse effects of intravenous immunoglobulin. Drug Saf 1993;9:254-62. 7. Tan E, Hajinazarian M, Bay W, Neff J, Mendell JR. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol 1993;50:137-9. 8. Brannagan TH III, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology 1996;47:674-7. 9. Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol 2005;29:173-84. 10. Chan-Lam D, Fitzsimons EJ, Douglas WS. Alopecia after immunoglobulin infusion. Lancet 1987;1:1436. 11. Hamdalla HH, Hawkes CH, Spokes EG, Bamford JM, Goulding PJ. Intravenous immunoglobulin in the Guillain-Barre syndrome may cause severe adverse skin reactions. BMJ 1996;313:1399-400. 12. Howse M, Bindoff L, Carmichael A. Facial vasculitis rash associated with intravenous immunoglobulin. BMJ 1998;317: 1291. 13. Rodeghiero F, Castaman G, Vespignani M, Dini E, Bertazzoni M. Erythema multiforme after intravenous immunoglobulin. Blut 1988;56:145. 14. Yockey SM, Ahmed I. Intravenous immunoglobulin-induced lichenoid dermatitis: a unique adverse reaction. Mayo Clin Proc 1997;72:1151-2. 15. Schiavotto C, Ruggeri M, Rodeghiero F. Adverse reactions after high-dose intravenous immunoglobulin: incidence in 83 patients treated for idiopathic thrombocytopenic purpura (ITP) and review of the literature. Haematologica 1993;78(Suppl): 35-40. 16. Smith KJ, Dutka AL, Skelton HG. Lichenoid/interface cutaneous eruptions to IVIG with the primary infusion may be related to the re-regulation of anti-idiotype network. J Cutan Med Surg 1998;3:96-101. 17. Barbaud A, Tr echot P, Granel F, Lonchamp P, Faure G, Schmutz JL, et al. A baboon syndrome induced by intravenous human immunoglobulins: report of a case and immunological analysis. Dermatology 1999;199:258-60. 18. Barucha C, McMillan JC. Eczema after intravenous infusion of immunoglobulin. Br Med J (Clin Res Ed) 1987;295:1141. 19. Catteau B, Delaporte E, Piette F. Meningitis and skin reaction after intravenous immune globulin therapy. Ann Intern Med 1997;127:1130. 20. Cohen Aubart F, Barete S, Amoura Z, Frances C, Lyon-Caen O, Lebrun-Vignes B. Intravenous immunoglobulins-induced eczematous eruption: a long-term follow-up study. Eur J Intern Med 2009;20:70-3. 21. Dalakas MC. Intravenous immune globulin therapy for neurologic diseases. Ann Intern Med 1997;126:721-30. 22. Dalakas MC. Meningitis and skin reaction after intravenous immune globulin therapy [reply]. Ann Intern Med 1997;127:1130. 23. Guillet MH, Wierzbicka E, Guillet S, Dagregorio G, Guillet G. A 3-year causative study of pompholyx in 120 patients. Arch Dermatol 2007;143:1504-8. 24. Iannaccone S, Sferrazza B, Quattrini A, Smirne S, Ferini-Strambi L. Pompholyx (vesicular eczema) after IV immunoglobulin therapy for neurologic disease. Neurology 1999;53:1154-5. 25. Ikeda K, Iwasaki Y, Ichikawa Y, Kinoshita M. Pompholyx after IV immunoglobulin therapy for neurologic disease. Neurology 2000;54:1879.
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26. Leclech C, Maillard H, Penisson-Besnier I, Laine-Cessac P, Verret JL. Unusual skin reaction after intravenous infusion of polyvalent immunoglobulins: 3 case reports [in French]. Presse Med 1999;28:531. 27. LeHoang P, Cassoux N, George F, Kullmann N, Kazatchkine MD. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm 2000;8: 49-57. 28. Llombart M, Garcıa-Abujeta JL, Sanchez-Perez RM, Hernando de Larramendi C. Pompholyx induced by intravenous immunoglobulin therapy. J Investig Allergol Clin Immunol 2007;17: 277-8. 29. Lin WL, Lin WC, Chang YC, Yang LC, Hung SI, Hong HS, et al. Intravenous immunoglobulin-induced, non-eczematous, vesiculobullous eruptions in Stevens-Johnson syndrome. Am J Clin Dermatol 2009;10:339-42. 30. Maetzke J, Sperfeld AD, Scharffetter-Kochanek K, Sunderk€ otter C. Vesicular and bullous eczema in response to intravenous immunoglobulins (IVIG). Allergy 2006;61:145-6. 31. O’Donnell BF, Barr RM, Black AK, Francis DM, Kermani F, Niimi N, et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol 1998;138:101-6. 32. P€ ohlau D, Przuntek H, Sailer M, Bethke F, Koehler J, K€ onig N, et al. Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicenter study. Mult Scler 2007;13:1107-17. 33. Rhee DY, Park GH, Chang SE, Lee MW, Choi JH, Moon KC, et al. Pompholyx after intravenous immunoglobulin therapy for treatment of Guillain-Barre syndrome. J Eur Acad Dermatol Venereol 2009;23:602-4. 34. Sarmiento E, Micheloud D, Carbone J. Complement consumption associated with eczematous cutaneous reaction during infusions of high doses of intravenous immunoglobulin. Br J Dermatol 2004;151:721. 35. Sorensen PS, Wanscher B, Jensen CV, Schreiber K, Blinkenberg M, Ravnborg M, et al. Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998;50: 1273-81. 36. Tada M, Tada M, Ishiguro H, Yagi E, Hirota K. Eczematous reactions after intravenous immunoglobulin therapy in two patients with Guillain-Barre syndrome and a patient with Miller Fisher syndrome [in Japanese]. No To Shinkei 2003;55: 401-5. 37. Uyttendaele H, Obadiah J, Grossman M. Dyshidrotic-like spongiotic dermatitis after intravenous immunoglobulin therapy. J Drugs Dermatol 2003;2:337-41. 38. Vecchietti G, Kerl K, Prins C, Kaya G, Saurat JH, French LE. Severe eczematous skin reaction after high-dose intravenous immunoglobulin infusion: report of 4 cases and review of the literature. Arch Dermatol 2006;142:213-7. 39. Whittam LR, Hay RJ, Hughes RA. Eczematous reactions to human immune globulin. Br J Dermatol 1997;137:481-2. 40. Young PK, Ruggeri SY, Galbraith S, Drolet BA. Vesicular eczema after intravenous immunoglobulin therapy for treatment of Stevens-Johnson syndrome. Arch Dermatol 2006;142:247-8. 41. Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Brain 2001;124:145-53. 42. Stangel M, Kiefer R, Pette M, Smolka MN, Marx P, Gold R. Side effects of intravenous immunoglobulins in neurological autoimmune disordersea prospective study. J Neurol 2003;250: 818-21.
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ntravenous immunoglobulin (IVIG) was developed more than 30 years ago and is currently used on- and off-label for several dermatologic, neurologic, hematologic, and immunologic disorders.1 As From the Department of Dermatology, Johns Hopkins School of Medicine. Funding sources: None. Conflicts of interest: None declared. Presented at the Gross and Microscopic Symposium at the Annual American Academy of Dermatology Meeting in March 6, 2009, San Francisco, California (Abstract #261). Reprint requests: Meg R. Gerstenblith, MD, Department of Dermatology, Case Western Reserve University, Lakeside 3500, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: meg. [email protected]. Published online May 23, 2011. 0190-9622/$36.00 Ó 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.12.034
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a blood product consisting of only IgG antibodies pooled from at least 1000 different human donors, IVIG must be manufactured using viral inactivation measures and screened for infections to ensure its safety. Minor adverse effects occur in about 30% to 40% of patients and include headache, chills, fatigue, nausea, arthralgias, myalgias, and back pain.1,2 Rarely, more serious reactions may occur, including aseptic meningitis, renal failure, anaphylactic shock, hemolytic anemia, and thromboembolic complications.1-7 Although minor adverse effects may be related to the rate of infusion, some of the serious reactions may be related to the particular osmotic and sodium loads of the IVIG preparation, the rate of infusion, and host factors.2 For example, the risk of renal failure with IVIG is related not only to the sucrose content of the IVIG preparation and rate of infusion, but also host factors such as pre-existing renal disease, diabetes,
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and hypertension. Cutaneous adverse effects may were obtained in only 13 patients; therefore, eczeoccur and vary in presentation from localized to matous reactions were classified largely on a morgeneralized reactions and are estimated to occur in phologic basis. Typical findings of pompholyx are 0.4% to 6% of treated patients.6,8,9 There are several shown in Fig 1, A and B, with multiple, grouped reports of urticaria and isolated reports of alopecia, pinpoint clear and erythematous vesicles occurring erythema multiforme, lichenoid dermatitis, purpuric on the palms and soles bilaterally. Representative erythema, vasculitis, and morbilliform eruptions histopathology reveals a loculated, spongiotic vesiassociated with IVIG10-16; cle, typical of dyshidrosis; a however, an underappreciperivascular infiltrate conCAPSULE SUMMARY ated cutaneous reaction is ecsisting of lymphocytes and zema, often localized to the eosinophils; and exocytosis The use of intravenous immunoglobulin palms and soles as the vesicof lymphocytes into the epi(IVIG) to treat multiple inflammatory and ular variant, pompholyx. dermis (Fig 1, C ). autoimmune disorders is increasing. Forty of the reported cases Pompholyx is an important cutaneous METHODS (62.5%) presented with pomside effect of IVIG. We conducted a literature pholyx alone or a combinareview using the PubMed and tion of pompholyx (hands or Pompholyx occurring after IVIG MEDLINE databases and the feet) and fewer than two treatment typically wanes over time but search terms ‘‘intravenous imbody surfaces involved; 8 can recur and become more extensive munoglobulin pompholyx,’’ (12.5%) had pompholyx in with subsequent IVIG treatments. ‘‘intravenous immunoglobuassociation with a generalDermatologists should recognize this lin eczema,’’ ‘‘intravenous ized, widespread eczematous cutaneous side effect of IVIG. immunoglobulin cutaneous eruption; 3 (4.7%) had wideadverse effects,’’ ‘‘intravenous spread eczematous erupimmunoglobulin cutaneous effects,’’ ‘‘intravenous imtions; and 13 (29.7%) had other unspecified munoglobulin skin effects,’’ and ‘‘intravenous immueczematous reactions. The majority of eczematous noglobulin adverse effects,’’ for English-language reactions occurred during the first IVIG treatment articles. Relevant English-language articles or articles course (75.0%). Most patients (85.9%) were being in other languages cited in English-language articles treated with IVIG for neurologic conditions. were included. We reviewed the titles and abstracts Interestingly, only 3 cases are reported of pompholyx identified in the literature searches. We also reviewed occurring in patients treated with IVIG for dermatoreferences from bibliographies of pertinent articles. logic conditions, including one patient with StevensJohnson syndrome and two patients with chronic urticaria.31,40 Another patient with Stevens-Johnson RESULTS syndrome developed vesicles on the palms after IVIG We identified 64 cases to date of eczematous treatment, with histopathology showing an intracorreactions associated with IVIG therapy, including a neal vesicle without inflammatory cells in the epiderpatient treated on our inpatient consult service.17-40 mis or dermis, findings not entirely consistent with Two articles were non-English-language articles; one pompholyx.29 could be translated and one included a table in There are no known risk factors for developing English with enough detail to be included in our cutaneous adverse effects with IVIG therapy. When analysis.26,36 Few additional cases were reported but assessed, the majority of affected individuals did not without the demographic and clinical data needed to have a personal history of atopy, eczema, allergic be included.41,42 reactions, or another dermatologic condition Table I summarizes the clinical characteristics of (83.0%). In our review, eczematous reactions and the identified patients, including age; sex; history of pompholyx were reported with multiple IVIG prepatopy, including hand eczema, childhood asthma, arations but occurred most frequently with and seasonal allergies; the underlying disease being Sandoglobulin (Novartis, East Hanover, NJ), which treated with IVIG; the type of IVIG preparation and may reflect its widespread use. Interestingly, switchits dose and treatment course if reported; the type of ing the type of IVIG in 5 patients resulted in variable eczematous reaction; the time for the reaction to responses. One patient with pompholyx developed appear and resolve; the treatments for the reaction an identical reaction, one patient with pompholyx if any; and the response to subsequent IVIG courses. developed noneczematous skin eruptions of inNoneczematous skin reactions or reactions not specreased severity (Baboon syndrome and a morbillicifically described as pompholyx or eczematous form rash),17 one patient with no prior cutaneous were excluded from our analysis. Biopsy specimens d
d
d
d
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Table I. Reported cases to date of pompholyx and eczematous reactions occurring in association with intravenous immunoglobulin treatment Demographic information Age (n = 33) Mean, y Median, y Range, y Male:female (n = 42) Underlying disease and atopic history information Underlying disease Neurologic diseases Multiple sclerosis Chronic inflammatory demyelinating polyneuropathy Guillain-Barre syndrome Multifocal motor neuropathy Other neurologic Dermatologic diseases Chronic urticaria Stevens-Johnson syndrome Hematologic diseases* Immunologic diseasesy Ophthalmologic diseasesz History of atopy (n = 23) Hand eczema Childhood asthma Seasonal allergies Not specified IVIG treatment information Initial IVIG type (n = 38) Sandoglobulin Gammagard Tegelin IVIG dose (n = 53) 0.4-0.5 g/kg/d 3 3-5 d 1 g/kg/d 3 2 d 2 g/kg/d 3 1 d Days to first eruption (n = 44) \8 8-14 >14 Skin reaction characteristics (n = 64) Pompholyx primarily with # 2 body surfaces involved in addition to hands/feet Pompholyx with simultaneous, preceding, or subsequent generalized eczema (>2 body surfaces involved in addition to hands/feet) Widespread, generalized eczematous eruption Other, unspecified eczematous eruptions Biopsy specimens taken
50.6 55 7-75 33:9 N (%) (n = 64) 55 (85.9) 14 (25.5) 9 (16.4) 9 8 15 3 2 1 3 2 1 4 1 1 1 1
(16.4) (14.5) (27.3) (4.7) (66.7) (33.3) (4.7) (3.1) (1.6) (17.4) (25) (25) (25) (25)
18 (47.4) 11 (28.9) 9 (23.7) 35 (66.0) 16 (30.2) 2 (3.8) 34 (77.3) 6 (13.6) 4 (9.1) 40 (62.5) 8 (12.5)
3 (4.7)
Table I. Cont’d Time to resolution, wk (n = 27) \3 $3 Treatment for first or subsequent reaction (n = 45)x Topical steroids Spontaneous resolution Antihistamines Systemic steroids Hospitalization Subsequent IVIG courses (n = 29) No. of patients with subsequent reaction Improved reaction Same reaction Worse reaction IVIG preparation changed after rash development (n = 5) No further reaction Same reaction Worse reaction Morphology of reaction changed
7 (26.0) 20 (74.1)
27 11 7 6 2
(60.0) (24.4) (15.6) (13.3) (4.4)
24 3 5 16
(82.8) (12.5) (20.8) (66.7)
2 1 1 1
(40) (20) (20) (20)
Available data were extracted from reported cases for this table; therefore, numbers used vary for categories presented. IVIG, Intravenous immunoglobulin. *There were two cases of thrombocytopenic purpura and one case of idiopathic systemic capillary leak syndrome. y Includes one patient with dermatomyositis and the patient we treated who had an initial diagnosis of immunodeficiency that was not confirmed on subsequent testing. z Birdshot retinochoroidopathy. x Total number and percentages do not add up to 45 and 100%, respectively, because some individuals received more than one treatment.
reaction developed a new vesicular facial eruption,20 and two patients with pompholyx or eczema improved with no subsequent reaction after a change in IVIG formulation.20 Most of the patients responded well to topical steroids or did not require therapy, although oral steroids were occasionally necessary. In 74.1% of reported cases, the reaction subsided in 3 or more weeks. For all reported cases, the eczematous reactions improved, although in one case, pruritus occurred for several months after IVIG treatment.20 There were no mortalities reported in these patients with eczematous reactions to IVIG; however, for many patients, IVIG was not continued because of these eczematous reactions.
13 (29.7) 13 Continued
DISCUSSION IVIG use is becoming more widespread as the numbers of both indications and patients with autoimmune and inflammatory disorders increase. IVIG has several proposed mechanisms of action;
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Fig 1. A and B, Multiple grouped pinpoint vesicles, which were present on palms and soles bilaterally. C, Biopsy specimen from foot demonstrating dyshidrotic intraepidermal spongiotic vesicle with eosinophils and lymphocytes. (Hematoxylin and eosin stain; original magnification: 310.)
however, there is no clear mechanism that can explain the association with eczema. Interestingly, we were unable to identify any cases of pompholyx or eczematous reactions occurring in patients being treated with IVIG for an underlying immunodeficiency. There are two potential hypotheses to explain the near absence of eczematous reactions in the immunodeficient population treated with IVIG. First, this type of reaction may not occur in association with IVIG in individuals with true immune deficiency. Alternatively, the dose used to treat immunodeficiency is typically lower than that used in neurologic, hematologic, and dermatologic conditions described here (0.4 and 2 g/kg, respectively), which could suggest that pompholyx and eczematous reactions occur only when high-dose IVIG is used. This may reflect a possible dose response for eczematous reactions. Although eczematous reactions to IVIG are reported to wane over time, in our review we found that the reaction was likely to recur with subsequent treatments, and, in the majority of patients, the reaction worsened. Because pompholyx is treatable,
the general recommendation is for IVIG treatment to be continued for patients experiencing clinical benefit. In the case of severe cutaneous reactions, IVIG should be discontinued. Dermatologists should be aware that pompholyx and eczema are common cutaneous adverse effects of IVIG that can occur alone or in combination, and that these effects may worsen upon subsequent IVIG treatments. However, these effects can be successfully treated, allowing continuation of IVIG therapy if warranted. REFERENCES 1. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55. 2. Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev 2007;6:257-9. 3. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121:259-62. 4. Brox AG, Cournoyer D, Sternbach M, Spurll G. Hemolytic anemia following intravenous gamma globulin administration. Am J Med 1987;82:633-5.
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