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Treatment of Pemphigus Vulgaris with
Rituximab and Intravenous Immune Globulin
A. Razzaque Ahmed, M.D., Zachary Spigelman, M.D., Lisa A. Cavacini, Ph.D.,
and Marshall R. Posner, M.D.

A bs t r ac t

Background
From the Center for Blistering Diseases
(A.R.A.), Parker Hill Oncology and Hematology (Z.S.), and the Department of Medicine (A.R.A., Z.S.), New England Baptist
Hospital; the Department of Oral Medicine, Infection, and Immunity, Harvard
School of Dental Medicine (A.R.A.); the
Waltham Cancer Center and Harvard Medical School (Z.S.); the Human Monoclonal
Antibody Laboratory, Beth Israel Deaconess Medical Center (L.A.C., M.R.P.); and
Dana–Farber Cancer Institute and Harvard
Medical School (M.R.P.) — all in Boston.
Address reprint requests to Dr. Ahmed at
the Center for Blistering Diseases, New
England Baptist Hospital, 70 Parker Hill
Ave., Suite 208, Boston, MA 02120.
N Engl J Med 2006;355:1772-9.

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous blistering disease. Conventional therapy consists of high-dose corticosteroids, immunosuppressive
agents, and intravenous immune globulin.
Methods

We studied patients with refractory pemphigus vulgaris involving 30% or more of
their body-surface area, three or more mucosal sites, or both who had inadequate
responses to conventional therapy and intravenous immune globulin. We treated
the patients with two cycles of rituximab (375 mg per square meter of body-surface
area) once weekly for 3 weeks and intravenous immune globulin (2 g per kilogram
of body weight) in the fourth week. This induction therapy was followed by a monthly
infusion of rituximab and intravenous immune globulin for 4 consecutive months.
Titers of serum antibodies against keratinocytes and numbers of peripheral-blood
B cells were monitored.

Copyright © 2006 Massachusetts Medical Society.

Results

Of 11 patients, 9 had rapid resolution of lesions and a clinical remission lasting 22
to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone,
could be discontinued before ending rituximab treatment in all patients. Two patients
were treated with rituximab only during recurrences and had sustained remissions.
Titers of IgG4 antikeratinocyte antibodies correlated with disease activity. Peripheral-blood B cells became undetectable shortly after initiating rituximab therapy
but subsequently returned to normal values. Side effects that have been associated
with rituximab were not observed, nor were infections.
Conclusions

The combination of rituximab and intravenous immune globulin is effective in patients with refractory pemphigus vulgaris.

1772

n engl j med 355;17

www.nejm.org

october 26, 2006

The New England Journal of Medicine
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Copyright © 2006 Massachusetts Medical Society. All rights reserved.

17 lack of response to long-term.11 We assessed the response to treatment. For personal use only. and the ruling out of coexisting illnesses on the basis of normal findings for blood counts. was given. or both. In the fourth week.rituximab and intr avenous immune globulin for pemphigus vulgaris P emphigus vulgaris is a potentially fatal blistering mucocutaneous autoimmune disease that affects the skin and the oral cavity and other mucosal surfaces. at the time of initiation of rituximab therapy. 5. In months 3. Immunologic Responses Serum samples were collected from all patients before each infusion of rituximab and intravenous immune globulin. All patients gave written informed consent. serum chemical measurements. We treated these patients with rituximab (Rituxan. deposition of the IgG of the patient on the surface of keratinocytes in perilesional tissue as shown by direct immunofluorescence. Copyright © 2006 Massachusetts Medical Society. We report a study of 11 patients with severe pemphigus vulgaris that was resistant to corticosteroids plus immunosuppressive agents and intravenous immune globulin. abdomen. seven additional infusions of intravenous immune globulin were given. the consequences of which are now the most common cause of death in patients with pemphigus vulgaris. oral methotrexate. 1773 . and an institutional review board of New England Baptist Hospital approved the study. urinalysis. or other immunosuppressive agents used in combination with intravenous immune globulin to induce a sustained remission. and an intact basal layer. with complete reepithelialization.5 Current therapy consists of high doses of corticosteroids plus immunosuppressive agents. and pelvis.org on November 1.7 Patients who do not have a response to corticosteroids plus immunosuppressive agents or who have severe side effects from this therapy have been successfully treated with intravenous immune globulin. 2 g per kilogram of body weight. a failure of dapsone. Thus. and the presence. each patient received a total of 10 infusions of rituximab and 6 infusions of intravenous immune globulin. as determined by indirect immunofluorescence with the use of monkey esophagus. 2015. toxic effects. 2006 The New England Journal of Medicine Downloaded from nejm. Therapy Patients were treated with an infusion of rituximab (375 mg per square meter of body-surface area) once a week for 3 weeks. or acute relapse whenever intervals between intravenous infusions of immune globulin were increased9.org october 26.9 which can be used as monotherapy and can produce long-term remissions. The time to discontinuation of all systemic immunosuppressive therapy after the start of rituximab therapy was recorded. No other uses without permission.nejm. the duration of clinical remission.2-4 The risk of death in patients with pemphigus vulgaris has been substantially reduced by treatment with systemic corticosteroids. chest. The duration of follow-up was the time between the start of treatment and the last office visit.6 This combination frequently causes long-term immunosuppression. The lesion is characterized by intraepidermal vesicles with acantholysis and an intact basal layer. Me thods Patients Patients were eligible for the study if they met the following criteria: pathological findings of a lesion showing intraepidermal vesicles. This treatment was repeated for a second cycle. suprabasilar acantholysis.10. and computed tomographic scans of the neck. and immune correlates of the response. of antibodies that bind to the surface of keratinocytes.8. plus intravenous immune globulin. 4. and 6. All rights reserved.9 The time to first improvement was defined as the time from the start of therapy to the healing of earlier lesions and the cessation of the development of new lesions.1 Serum samples from patients with pemphigus vulgaris contain antibodies against desmoglein 3. involvement by pemphigus vulgaris of at least 30% of the body surface. If by then the patient was clinically free of disease. patients received a single infusion of rituximab plus a single infusion of 2 g of intravenous immune globulin per kilogram at the start of the month. The titers of antibodies against keratinocyte cell-surface antigen were measured www. Complete improvement was defined as the time from the start of therapy to complete clearing or clinical resolution and healing of all lesions. high-dose prednisone plus at least three or more immunosuppressive agents and a minimal response to intravenous immune globulin when given as described below. Additional eligibility criteria were a n engl j med 355. during a 6-month period. intravenous immune globulin. which have been shown to be pathogenic. Genentech). three or more mucosal surfaces. a humanized monoclonal antibody against the B-cell antigen CD20 that depletes antibody-producing B cells.

No other uses without permission. and CD20 (IF5. Attempts to prolong the intervals between cycles resulted in a recurrence in seven patients.12 The secondary antibodies in this assay were fluorescein-conjugated goat antihuman IgG. one patient received one additional course of rituximab. including intravenous immune globulin. Complete clearance of lesions was achieved between the seventh and ninth infusions.2). all patients with relapses received dapsone with methotrexate and intravenous immune globulin. including 1.org october 26. All patients had improvement between the third and sixth infusions of rituximab (mean. four). All rights reserved.7). Copyright © 2006 Massachusetts Medical Society. 2015. www.org on November 1. All patients had a clinical response to subsequent therapy with intravenous immune globulin. Characteristic Male sex (no.5 to 2.6). CD32 (Coulter Immunotech). For personal use only. .17 m e dic i n e between the fourth and fifth infusions). 68. Characteristics of the Patients. All patients had been and were being treated with conventional therapy. IgG1. consisting of high-dose corticosteroids and immunosuppressive agents. This triple therapy was used for 12 to 36 months (mean. halfway n engl j med 355.) 30–48 mo 49–96 mo >96 mo Response to Therapy with Rituximab and Intravenous Immune Globulin 1774 of Patients (N = 11) 5 38 15–68 5 5 11 3 3 2 11 7 8 5 11 11 10 9 9 6 1 1 1 1 1 5 4 2 3 6 2 * The affected body-surface area of one patient was not recorded.) Prednisone Mycophenolate mofetil Azathioprine Dapsone Methotrexate Cyclophosphamide Thalidomide Gold Colchicine Tacrolimus Cyclosphorine Intravenous immune globulin (no. The duration of conventional therapy ranged from 20 to 132 months (mean.) Age at onset (yr) Median Range Involvement (no. Of the 11 patients.) Skin* 30 to 40% of body-surface area 41 to 60% of body-surface area Oral cavity Penis Vagina Conjunctiva Pharynx Larynx Nose Anus Drug therapy before intravenous immune globulin therapy (no.) 10–20 cycles 21–60 cycles >60 cycles Duration of disease before rituximab therapy (no. 125). 9 received 10 infusions of rituximab and had a sustained remission. Initially.3). intravenous immune globulin was used as monotherapy for 4 to 22 months (mean. Four patients had recurrences during treatment with intravenous immune globulin.1.The n e w e ng l a n d j o u r na l with the use of an indirect immunofluorescence assay with monkey esophagus.5). CD8 (OKT8). and the other reTable 1. 2006 The New England Journal of Medicine Downloaded from nejm. The duration of all systemic therapy before study entry. and IgG4 antibodies.nejm. CD19 (Exalpha). The phenotypes of peripheral-blood mononuclear cells were determined by flow cytometry with the use of murine monoclonal antibodies (10 μg per milliliter) against CD4 (SIM4). 55. The highest dose of prednisone ranged from 60 to 240 mg daily (mean. and none had a remission. The total previous duration of therapy with intravenous immune globulin ranged from 18 to 81 months (mean. 16. followed by fluorescein-conjugated goat antimouse IgG.0 mg of cyclophosphamide per kilogram per day for at least 6 months (6 patients) and 2 to 3 g of mycophenolate mofetil per kilogram per day for at least 6 months (11 patients).13 R e sult s characteristics of the Patients Eleven patients were enrolled and treated (Table 1). Two patients had a relapse after initial therapy. 12. ranged from 31 to 219 months (mean. Since relapses occurred with intravenous immune globulin. CD16 (B73.8).1). All patients had received four to eight immunosuppressive agents (mean. 32.

with a return to normal breast morphology. and a complete clinical resolution of disease was observed. A B C Table 2. cytokine-release syndrome. Results of Therapy with Rituximab. Panel C shows breast involvement.org october 26. the inframammary area. These patients discontinued all conventional immunosuppressive therapy and were free of pemphigus lesions during the period of remission. the patient remained disease-free and received no systemic therapy. Variable Value Time to first improvement No. Patient 10 had a recurrence 6 months after the 10th infusion of rituximab. www. a second. Five patients who had been unable to work because of the disease and the treatment were able to resume full employment. Panel B shows complete involvement of the lower lip and partial involvement of the upper lip and gingivae with pemphigus vulgaris before treatment. All patients were observed for the following side effects that have been associated with rituximab and intravenous infusions of immune globulin: allergic reactions. and the adjoining abdomen. wide- spread recurrence developed. 2006 The New England Journal of Medicine Downloaded from nejm. Twenty-four months later. rigors. The duration of follow-up after the discontinuation of rituximab therapy was 15 to 37 months (mean.1) (Table 2) for nine patients. The patient again was given an infusion of rituximab once a week for 3 consecutive weeks. Panel A shows the back of a patient with extensive confluent erosions and denuded epithelium before treatment with rituximab and complete healing. of patients 9 Median — wk (range) 9 (7–9) Duration of complete remission No. with a substantial loss of the epithelium of the breast. The patient was given an infusion of rituximab once a week for 3 consecutive weeks and had a complete clinical resolution. with return to normal skin. of patients 2 Time to first recurrence — mo Patient 10 12 Patient 11 12 Duration of most recent remission — mo Patient 10 24 Patient 11 15 n engl j med 355. Tapering of immunosuppressive therapy was begun as soon as rituximab therapy had been initiated and was discontinued by the end of the second cycle in all patients.rituximab and intr avenous immune globulin for pemphigus vulgaris ceived two additional courses. The patient remained free of disease and received no systemic therapy for 15 months. Eight months later.17 Figure 1. chills. complete reepithelialization of the skin occurred. 2015. Patient 11 also had a recurrence 6 months after the 10th infusion of rituximab. Photographs of Patients with Pemphigus Vulgaris before (Left) and after (Right) Treatment with Rituximab. 31. After treatment with rituximab. fever. Complete recovery from mucocutaneous lesions to normal morphology is shown after treatment with rituximab. None of these side effects were observed in any of the patients. of patients 9 Median — mo (range) 31 (22–37) Recurrence No.nejm. of patients 11 Median — wk (range) 4 (3–6) Time to complete remission No. Copyright © 2006 Massachusetts Medical Society. after treatment. All rights reserved. 32. The patient was given an additional infusion of rituximab once a week for 3 consecutive weeks without any added drugs. For personal use only. Sustained clinical remissions lasted for 22 to 37 months of observation (mean. vomiting. nausea. A complete resolution was observed within 6 weeks. and infections. 1775 .5). No other uses without permission.org on November 1. Figure 1 shows representative photographs documenting the disease at baseline and after treatments.

All rights reserved. there was a rapid decrease in the levels of IgG4 antibodies. who had one relapse. The levels returned to 13 percent in 9 months and remained at that level thereafter. Hence. who had two relapses. . levels became undetectable within a mean of 4. and Panel C shows the titers in Patient 11.2) after the discontinuation of rituximab treatment. Dis cus sion We report the clinical course of 11 patients with refractory. No other uses without permission. the percentage of B cells rapidly declined to undetectable levels after the infusions of rituximab but returned to 14 percent of peripheral-blood mononuclear cells at the time of recurrence (Fig. IgG4 is pathogenic. For personal use only. Panel B shows the titers in Patient 10. and prolonged pemphigus vulgaris who were treated with rituximab and intravenous immune globulin. The total IgG levels decreased more slowly.The n e w e ng l a n d j o u r na l Titers of Antikeratinocyte Cell-Surface Autoantibodies Autoantibodies to keratinocyte cell-surface antigen. The increases and decreases in titers of IgG and IgG4 antikeratinocyte cell-surface antibodies in the two patients with recurrences (Fig. whereas IgG1 is nonpathogenic.org october 26. 1:5120 to 1:320) before the start of rituximab A Patients 1– 9 Mean Antibody Titer 1:2560 1:800 1:640 IgG 1:320 IgG4 0 0 5 10 15 20 25 30 20 25 30 25 30 Months B Patient 10 Antibody Titer 1:2560 1:1280 1:800 IgG 1:640 IgG4 1:320 0 0 5 10 15 Months C Patient 11 Antibody Titer m e dic i n e treatment (Fig. There were no significant changes from baseline in CD4+ or CD8+ T cells or Fc-receptor–positive cells. 2015.3). In Patient 10. 2B and 2C) correlated directly with disease activity.6 months (range. Log scales are used. The percentage of B cells in peripheral blood was lower than normal because all patients were receiving multiple immunosuppressive agents before rituximab therapy. reaching a mean titer of 1:40 by 7 months and remaining at that level in all patients who had a sustained response.2-4. 2006 The New England Journal of Medicine Downloaded from nejm. A return to normal levels was observed 8 to 18 months (mean. total IgG titers are reported. A similar relationship between the two recurrences of disease and B-cell levels was observed in Patient 11. In nine of the patients. and B cells remained at normal levels during the follow-up period in the nine patients with sustained remission (Fig. can be of the IgG1 or IgG4 subclass. and they remained at undetectable levels for the subsequent 6 months. 2.5 to 5. The IgG4 titers remained undetectable during the follow-up period after the final discontinuation of rituximab. Subgroup Analysis of Peripheral-Blood Lymphocytes 1:1280 1:2560 1:2240 1:1920 1:1600 1:1280 1:800 1:640 1:320 0 IgG IgG4 0 5 10 15 20 Months Figure 2. 11.12 The titers of IgG1 and total IgG antikeratinocyte cell-surface antibodies were identical in our patients (data not shown). Within 2 weeks after the start of rituximab therapy.org on November 1. widespread. CD20+ B cells were undetectable in all patients and remained so throughout the treatment. Before treatment was www. 2A). Copyright © 2006 Massachusetts Medical Society. Panel A shows the mean titer of total IgG and IgG4 antikeratinocyte cellsurface antibodies at various intervals in nine patients who were treated according to the study protocol and had no recurrences. 3A). The mean titer of total IgG and IgG4 antikeratinocyte cell-surface antibodies in the 11 patients was 1:1280 (range. 1776 of n engl j med 355. 3B).17 Lymphocytes from patients were analyzed longitudinally for the expression of specific T-cell and B-cell markers and Fc receptors. or desmoglein. Treatment of this recurrence with rituximab resulted in a rapid decline in CD20+ B-cell levels. Relationship between Titers of Serum Antikeratinocyte Antibodies and Rituximab Therapy in Patients with Pemphigus Vulgaris.nejm.

We speculate that these relapses were due to the reappearance of pathogenic memory B cells. and therapy with these two agents resulted in sustained and complete remission in 9 of 11 patients and eventually in complete control of the disease in all 11 patients. For personal use only. all patients had limited or incomplete responses to conventional treatment and had had numerous relapses and remissions associated with multiple side effects and hospitalizations.2-4.12 Previous experience with rituximab therapy for patients with pemphigus vulgaris is limited.17 www. The patient was given a second cycle of rituximab.9 However. to eliminate pathogenic B cells and the production of pathogenic autoantibodies. these cells returned to normal levels within 10 to 12 months but without the reappearance of pathogenic autoantibodies in most patients. Panel A shows the mean number of B cells in the peripheral blood at various time intervals in the nine patients with no recurrences. 2006 The New England Journal of Medicine Downloaded from nejm. 1777 . All patients ultimately were able to discontinue all treatment.rituximab and intr avenous immune globulin for pemphigus vulgaris initiated. Sev- Mean CD20+ B-Cell Count (%) A Patients 1– 9 16 12 8 4 0 0 3 6 9 12 15 18 21 24 15 18 21 24 Months B Patient 10 CD20+ B-Cell Count (%) 16 12 8 4 0 0 3 6 9 12 Months Figure 3. The regimen of two induction cycles followed by consolidation therapy was designed to eliminate pathogenic antibody-producing B cells and then to destroy memory B cells that might have escaped the induction treatment. Relationship between Peripheral-Blood B-Cell Counts and Rituximab Therapy in Patients with Pemphigus Vulgaris. 2015.org on November 1.14-17 which rituximab can cause. Our finding that the levels of antikeratinocyte IgG4 antibodies correlated with disease activity better than did the levels of IgG antibodies is consistent with published reports that IgG4 antibodies against keratinocyte cell surfaces are pathogenic in pemphigus vulgaris. Panel B shows B-cell counts in Patient 10. Copyright © 2006 Massachusetts Medical Society. n engl j med 355.10 Intravenous immune globulin alone can produce long-term clinical and serologic remissions in patients with pemphigus vulgaris. along with long-term follow-up. which were subsequently eliminated by rituximab monotherapy. two patients had recurrences. We treated the patients with a combination of intravenous immune globulin and rituximab to provide protection from reduced immunoglobulin levels. it did not do so in our patients. and to try to reconstitute normal immunity. B-cell counts after the second cycle are presented. we believe that the dramatic and rapid clinical responses we observed can be attributed to rituximab and possibly to synergistic effects of intravenous immune globulin. No other uses without permission. No observable side effects were associated with the use of rituximab and intravenous immune globulin. All rights reserved. Control of the pemphigus was correlated with a reduction in titers of pathogenic IgG4 antikeratinocyte antibodies. For this reason. who had one relapse 12 months after initial treatment with rituximab.org october 26.nejm. Although rituximab reduced peripheral-blood CD20+ B cells to undetectable levels within 2 weeks. The long- term remissions in these patients could be due in part to the transient elimination of B cells by rituximab in combination with the regulatory effects of intravenous immune globulin. Despite aggressive treatment.

Correlation of subclasses of IgG with disease activity in pemphigus vulgaris. Panizo C. the rapid and lasting responses seen in our study have not been observed in most other studies. Blank M. Bhol K. Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation. A case for regulatory B cells. Anwar Khurshid. which is limited to infusions of rituximab once a week for 4 consecutive weeks.39 Although none of the patients in our study had these serious side effects. Duval M. Furthermore.8:117-30. Viguier M. 2. Ahmed AR. Hacker MK. Truhan AP. Hunzelmann N.26-37 although these studies did not involve a combination of intravenous immune globulin and rituximab or a planned regimen of induction and consolidation with rituximab that was similar to ours. Lazarus HM. All rights reserved. Treatment of refractory pemphigus vulgaris with rituximab (anti-CD20 monoclonal antibody). cancer. (In German. Healy E. Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalci- october 26. Tredget EE. Ahmed AR.nejm. Emes CL. 18. Immunomodulatory effects of intravenous immunoglobulins as a treatment for autoim- n engl j med 355. Power J. Kong HH. 11. 23. Janson M. Ahmed AR. et al. Mohimen A. Sami N. Salopek TG. Most acute side effects of rituximab are mild. Rituximab: expanding role in therapy for lymphomas and autoimmune diseases.11 In addition.176: 705-10. White CA. Dupuy A.51:817-9. Bedane C. Ahmed RA. Bhol K. The cytokine-release syndrome can develop in patients receiving rituximab for lymphoma and is most common in patients with bulky adenopathy or bone marrow involvement. Ann N Y Acad Sci 2005.) 15. and Eli Choufani for their assistance in the care of the patients. Lehrnbecher T. 2006 The New England Journal of Medicine Downloaded from nejm. 20. Effect of antibody valency on interaction with cell-surface expressed HIV-1 and viral neutralization. Fernandez-Galar M. Arch Dermatol 2004. Ware RE. 120:68-75. 2015.50: 974-6. Am J Clin Dermatol 2005. Intravenous immunoglobulins in the prevention of infection in children with hematologic-oncologic diseases. N Engl J Med 1990. For personal use only. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment 1778 of autoimmune mucocutaneous blistering diseases. Treatment of pemphigus vulgaris: current and emerging options. Cavacini LA. Yeh SW. No other uses without permission.323:705-12.189:Suppl 1:85-9. conventional immunosuppressive therapy was used concomitantly with rituximab and was maintained in most patients. and infusion-related. 4. Ahmed AR. Pathogenic human monoclonal antibody against desmoglein 3. J Immunol 2006. Correlation of peptide specificity and IgG subclass with pathogenic and nonpathogenic autoantibodies in pemphigus vulgaris: a model for autoimmunity.22:461-4. Yeh SW. Proc Natl Acad Sci U S A 1995. Aoki V. 8. 14.The n e w e ng l a n d j o u r na l enteen patients have been reported to have received rituximab therapy for refractory pemphigus. Steinman NM. of m e dic i n e There were no clinically significant side effects of therapy in our study. Cooper HL. Bhol KC. Natarajan K. Clin Exp Dermatol 2003. 17. Molina A.132:203-12. Treatment of resistant pemphigus vulgaris with an anti-CD20 monoclonal antibody (rituximab).55:477-503. Clin Immunol 2002. Engert A. Copyright © 2006 Massachusetts Medical Society.org mune diseases.139:1051-9. Pemphigus: current concepts. the long-term consequences of rituximab therapy in patients with autoimmune diseases are unknown. 19. 105:64-74. 7.153:620-5. Arch Dermatol 1996. 21. Isotypes and antigenic profiles of pemphigus foliaceus and pemphigus vulgaris autoantibodies. References 1. Hall RP III. Nine of the 17 patients (53%) were disease-free at a 6-month follow-up.28:366-8. transient. Kopecky KJ. We conclude that refractory pemphigus vulgaris can respond to a regimen of intravenous immune globulin and 10 infusions of rituximab during a 6-month period. Treatment with rituximab has been used for other autoimmune diseases. Intravenous immune globulin and rituximab were provided through the insurance plans of the patients or donated by the Center for Blistering Diseases at New England Baptist Hospital. Arin MJ. Expert Opin Investig Drugs 2004.38. and to George and Judith Revelas for their inspiration. No potential conflict of interest relevant to this article was reported. Friedmann PS. et al. 5.152:2538-45. Theaker JM. Rastetter W. and recurrent pregnancy loss.92:5239-43. Biol Blood Marrow Transplant 2002. 3.6:327-42. . Sokos DR. Therapy of refractory pemphigus vulgaris with monoclonal antiCD20 antibody (rituximab).13:1019-32. Nagarwalla N. Clin Immunol 2006. Treatment of autoimmune mucocutaneous blistering diseases with intravenous immunoglobulin therapy. Ahmed AR. 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