 |
|
Serum Levels of Autoantibodies to BP180 Correlate With Disease Activity in Patients With Bullous Pemphigoid
Enno Schmidt, MD;
Karin Obe;
Eva-Bettina Bröcker, MD;
Detlef Zillikens, MD
Arch Dermatol. 2000;136:174-178.
ABSTRACT
| |
Objective To investigate the possible correlation of levels of circulating anti-BP180 autoantibodies with disease activity in bullous pemphigoid (BP).
Design Diagnostic study.
Setting Regional referral center at a university dermatology department.
Patients Fifteen patients with typical clinical, histologic, and immunofluorescence findings of BP who had not received prior systemic treatment.
Interventions Initially, 6 consecutive patients with BP were treated with oral doxycycline and niacinamide. Subsequently, 9 consecutive patients with BP received a combination of oral dapsone and prednisolone.
Main Outcome Measures Disease activity, serum levels of autoantibodies to BP180, and titers of anti–basement membrane zone autoantibodies were assayed before initiation of treatment and 4 and 8 weeks later. Reactivity to BP180 was analyzed by enzyme-linked immunosorbent assay using a recombinant form of BP180 NC16A. Titers of anti–basement membrane zone autoantibodies were assayed by indirect immunofluorescence on 1-mol/L sodium chloride–split human skin.
Results In both treatment groups, disease activity correlated with serum levels of autoantibodies to BP180 NC16A (P = .004 [dapsone-prednisolone] and .007 [doxycycline-niacinamide]). No correlation was seen between disease activity and indirect immunofluorescence reactivity (P= .18 and .16, respectively). In patients receiving dapsone plus prednisolone, the dose of corticosteroids necessary to suppress new blister formation correlated with anti-BP180 reactivity ( P= .002).
Conclusions In contrast to indirect immunofluorescence reactivity that reflects reactivity to both BP180 and BP230, serum levels of autoantibodies to BP180 correlate with disease activity in BP. Assaying reactivity to BP180 should be a helpful guide for the therapeutic management of patients with this disease. Our results underline the pathogenic relevance of autoantibodies to human BP180.
INTRODUCTION
BULLOUS pemphigoid (BP) is a subepidermal blistering disease of the elderly that is characterized by linear deposits of IgG and/or C3 at the basement membrane zone (BMZ).1 Circulating autoantibodies label the epidermal side of 1-mol/L sodium chloride–split human skin and are directed against 2 hemidesmosomal antigens designated BP1802-3 and BP230.4-5 BP230 is restricted to the intracellular hemidesmosomal plaque,6 and thus, autoantibodies to this antigen are thought not to be involved in the initiation of the disease. BP180, on the other hand, is a transmembrane glycoprotein with a long, collagenous extracellular tail domain that spans the lamina lucida of the BMZ.7-9 A noncollagenous stretch of the BP180 ectodomain (designated NC16A) has recently been shown to harbor several major antigenic sites recognized by BP serum samples.10-11 Using the NC16A domain as the antigenic target, a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) for the detection of autoantibodies to BP180 has recently been developed.12 In a passive transfer animal model, it has been demonstrated that antibodies to the murine homolog of BP180 NC16A induce a BP-like disease in neonatal mice. These data suggest that antibodies to human BP180 may play a key role in the pathogenesis of human BP.13-14
Thus far, no clinical or immunologic indicators have been identified that would aid in predicting the clinical course in patients with BP.15 Although it is clear that BP is an autoantibody-mediated disease, the titers of circulating autoantibodies detected by indirect immunofluorescence do not parallel the clinical activity in BP.16-17 This is thought to be due to the fact that indirect immunofluorescence reveals the presence of antibodies to both BP180 and BP230. Based on the hypothesis that autoantibodies to the BP180 NC16A domain are directly involved in the pathogenesis of BP, we investigated the correlation between serum levels of antibodies to BP180 and disease activity. Fifteen patients with BP were followed up during their therapy, which involved either a combination of dapsone and prednisolone or doxycycline plus niacinamide. During the first 8 weeks of treatment, we monitored disease activity, titers of autoantibodies to the BMZ by indirect immunofluorescence, and serum levels of autoantibodies to BP180 NC16A by ELISA. In contrast to indirect immunofluorescence titers, we observed a direct relation between disease severity and levels of autoantibodies to BP180 NC16A.
PATIENTS AND METHODS
PATIENTS
The study included 15 patients treated at the Department of Dermatology, University of Würzburg, Würzburg, Germany, between April 1997 and May 1998. All patients had widespread bullous disease, and no systemic treatment had been initiated. Direct immunofluorescence of perilesional skin revealed linear deposits of IgG and/or C3 along the BMZ in all patients. By indirect immunofluorescence on 1-mol/L sodium chloride–split normal human skin, all sera exclusively stained the epidermal side of the artificial split. Titers ranged from 1:10 to 1:640. Reactivity against recombinant BP180 NC16A was positive by immunoblot and ELISA in all patients. Between April 1997 and September 1997, 6 consecutive patients with BP were treated with a combination of doxycycline and niacinamide. Between October 1997 and May 1998, 9 consecutive patients with BP received a combination of dapsone and prednisolone. Nine patients were included in the dapsone-prednisolone group and 6 in the doxycycline-niacinamide group. In the dapsone-prednisolone group, 4 patients were men and 5 were women. The median age was 71 years (range, 50-90 years), and the mean (±SD) age was 69 ± 13 years. The doxycycline-niacinamide group consisted of 3 men and 3 women between 68 and 92 years of age. The median age was 77 years, and the mean (±SD) age was 79 ± 10 years.
The doxycycline-niacinamide regimen followed a modification of a previously reported protocol.18 Doxycyline, 100 mg orally, was given 2 times daily in combination with niacinamide, 400 mg orally, 3 times daily, and topical 0.5% clobetasol propionate. After cessation of new blister formation and healing of pre-existing lesions, topical treatment was changed to a moisturizing emollient. The mean (±SD) duration of topical clobetasol treatment was 12 ± 8 days for the doxycycline-niacinamide group. Doxycycline dosage was then reduced to 100 mg/d orally and the niacinamide dosage to 600 mg/d orally. Finally, niacinamide and then doxycycline were omitted completely. Dapsone was given at 1.0 to 1.5 mg/kg of body weight in combination with prednisolone, 0.5 to 1.0 mg/kg of body weight orally daily (dapsone-prednisolone group). When no new blisters had developed for 1 week, prednisolone was tapered in 10-mg steps to 20 mg/d, then in steps of 5 mg until a dose of 10 mg/d, then in 2.5-mg steps. After discontinuation of use of the corticosteroid, dapsone was reduced by 25 mg every 4 weeks. In both treatment groups, blister fluid was aspirated, and lesions were treated with 0.5% crystal violet solution; all patients received Candida prophylaxis with oral nystatin. Patients in the dapsone-prednisolone group were also treated orally with daily doses of ranitidine, 150 mg, vitamin E, 600 mg, cholecalciferol, 0.025 mg, and calcium tablets, 500 mg.
Patients were seen weekly until lesions had cleared completely and then monthly for 1 year. On each visit, the number of blisters and erosions was recorded. More than 10 blisters and/or erosions corresponded to an activity score of 3, 1 to 10 blisters and/or erosions to a score of 2, and when no blister or erosion was detected, the score was 1. When skin lesions healed completely and no further medical treatment was required to control lesion formation, the score was 0. In addition, blood samples were taken for ELISA and indirect immunofluorescence analysis on each visit.
IMMUNOBLOT
Glutathione S-transferase (GST)–NC16A fusion proteins and recombinant GST were expressed in Escherichia coli.11 Sodium dodecyl sulfate–polyacrylamide gel electrophoresis and immunoblotting were performed as described.19 To eliminate reactivity with the GST portion of the fusion protein, serum samples of patients and controls were preadsorbed with bacterial cell lysate containing recombinant GST.11
ENZYME-LINKED IMMUNOSORBENT ASSAY
To determine ELISA reactivity with BP180 NC16A, we used a previously reported protocol.12 Briefly, each well of a standard 96-well microtiter plate was coated with purified recombinant GST-NC16A1-5 or the same amount of recombinant GST. Wells were then incubated with 50 µL of BP or control serum in a 1:100 dilution with assay buffer (phosphate-buffered saline, pH 7.2, containing 1% bovine serum albumin and 0.05% Tween-20; all Sigma, Deisenhofen, Germany). As detection antibody, a horseradish peroxidase–labeled goat anti–human IgG (Kirkegaard and Perry, Gaithersburg, Md), diluted 1:10,000 in assay buffer, was used. After substrate addition, the optical density was measured at 492 nm. Each serum was analyzed in triplicate for reactivity with both GST-NC16A and recombinant GST alone. The mean optical density reading obtained with GST was substracted from the mean optical density reading for GST-NC16A. To minimize plate-to-plate variability, each ELISA plate included the same 4 internal controls.12
STATISTICAL ANALYSIS
To analyze the correlation between disease activity, titers of anti-BMZ autoantibodies by indirect immunofluorescence, serum reactivity to BP180 NC16A, and prednisolone doses during the first 8 weeks of treatment, the AR(1) Serial Correlation test was applied.20 Analysis was done seperately for patients in the dapsone-prednisolone group (n = 9) and doxycycline-niacinamide group (n = 6). P values of .01 or less were considered statistically significant.
RESULTS
After 1 month of treatment, a good response was seen in both the dapsone-prednisolone and the doxycycline-niacinamide groups. Eight of 9 patients in the dapsone-prednisolone group and 5 of 6 in the doxycycline-niacinamide group were free of blisters and erosions. After 8 weeks, however, in 2 patients in the doxycycline-niacinamide group, blisters recurred. One of the 2 patients had deliberately stopped taking the medication. In contrast, all patients in the dapsone-prednisolone group had a complete response after 8 weeks of therapy. In most cases in both groups, indirect immunofluorescence reactivity of IgG anti-BMZ antibodies did not markedly change after 4 and 8 weeks of treatment compared with indirect immunofluorescence titers before initiation of therapy. In 3 patients in the dapsone-prednisolone group, a negative indirect immunofluorescence stain was seen after 8 weeks of treatment, and in the doxycycline-niacinamide group, no patient had a negative stain by this time. In contrast, at the 8-week time point, IgG antibodies to BP180 NC16A were negative in 4 of 9 patients in the dapsone-prednisolone group, and in another 4 patients in this group, NC16A reactivity was just slightly above the cutoff of the assay (optical density, 0.22). After 8 weeks of treatment with doxycycline-niacinamide, on the other hand, 3 patients still had markedly elevated levels of anti-BP180 NC16A antibodies, and the remaining 3 patients had levels close to the cutoff. The results of this analysis are summarized in the Table 1.
|
|
|
|
Patient Demographics, Disease Activity, Serum Levels of Autoantibodies to BP180 NC16A, and Levels of Anti–Basement Membrane Zone (BMZ) Autoantibodies in the Clinical Course of 15 Patients With Bullous Pemphigoid
|
|
|
We observed a significant correlation between disease activity and serum levels of antibodies to BP180 NC16A during the first 8 weeks of treatment. This correlation was found for both the dapsone-prednisolone (P = .004) and the doxycycline-niacinamide (P = .007) groups. In contrast, in both groups, no correlation was found between disease activity and titers of anti-BMZ antibodies by indirect immunofluorescence (P = .18 and .16, respectively). The Figure 1 shows a representative example of a patient treated with dapsone-prednisolone. A correlation was also observed between levels of autoantibodies to BP180 NC16A and the prednisolone dose necessary to suppress new blister formation in the dapsone-prednisolone group (P = .002).
|
|
|
|
In bullous pemphigoid (BP), disease activity correlates with serum levels of antibodies to BP180 NC16A but not with indirect immunofluorescence titers of anti–basement membrane zone (BMZ) antibodies. Results of a representative patient of the dapsone-prednisolone group are shown. Disease activity (columns) was scored according to the number of blisters and/or erosions: 3, more than 10 fresh lesions; 2, 1 to 10 lesions; 1, no fresh lesions; and 0, no skin lesions and no further treatment required to suppress new lesion formation. The patient did not reach the activity score 0 during the observation period shown here. Serum reactivity to BP180 NC16A (solid circles) was assayed by enzyme-linked immunosorbent assay. Samples were analyzed in triplicates, and results are expressed as optical density (OD) (measured at 492 nm). Error bars indicate mean ± SD. The cutoff of the assay (optical density, 0.22) aligns with the reading for negative indirect immunofluorescence titers. Titers of anti-BMZ antibodies were analyzed by indirect immunofluorescence on sodium chloride–split human skin (squares). Although anti-BP180 antibodies paralleled disease activity and decreased to normal values within a few weeks after blister formation has ceased, the anti-BMZ antibody titer decreased only by 1 step during the observation period.
|
|
|
COMMENT
The clinical course of BP is heterogenous, and periods of remission may be followed by 1 or more relapses.21 Indirect immunofluorescence titers of anti-BMZ antibodies do not parallel activity of this disease.16-17 Recently, it has been established that most BP serum samples react with the NC16A domain of BP180.12, 22-23 The purpose of this study was to test the hypothesis that the level of IgG reactivity to NC16A reflected disease severity in patients with BP. Fifteen consecutive patients were analyzed: 9 patients were treated with dapsone-prednisolone, and 6 patients received doxycycline-niacinamide. Consistent with our hypothesis, disease activity correlated with levels of autoantibodies to BP180 NC16A in both treatment groups. One patient deliberately stopped taking the medication; subsequently, blisters recurred, and levels of antibodies to BP180 NC16A increased. In agreement with previous findings, no correlation between disease severity and titers of anti-BMZ autoantibodies as detected by indirect immunofluorescence was found. Recently, it has become evident that indirect immunofluorescence staining of BP autoantibodies mainly reflects reactivity to BP230 and, to a lesser extent, BP180.24-25 This may explain the finding that indirect immunofluorescence reactivity does not correlate with the clinical course of BP, whereas reactivity to BP180 reflects disease severity well.
Serum levels of various other inflammatory mediators, including tumor necrosis factor  , interleukin (IL) 1 , IL-2, soluble IL-2 receptor, IL-5, IL-8, soluble E-selectin, and IgE antibodies to BP230 have been reported to be related to disease intensity in BP.17, 26-29 In contrast to antibodies to BP180, which are thought to be directly linked to the pathogenesis of BP, some of these other factors may instead reflect the general inflammatory response in patients with BP.
The pathogenic role of rabbit antibodies to the murine homolog of BP180 NC16A has been demonstrated in a passive transfer mouse model.13-14 Since the murine homolog of BP180 lacks the epitopes recognized by autoantibodies in patients with BP,13 this experimental model is not suitable to test for the pathogenic relevance of antibodies to human BP180. Using organ culture or cryostat sections of normal human skin, autoantibodies from patients with BP induced subepidermal blisters when accompanied by complement activation and infiltration of inflammatory cells.30-31 The specificity of autoantibodies in these in vitro models, however, was not further characterized. In the present study, we demonstrate that levels of autoantibodies to human BP180 reflect disease activity and further support the concept that these autoantibodies are pathogenically relevant in patients with this disease.
Levels of BP180 NC16A autoantibodies decreased at a slower rate in patients in the doxycycline-niacinamide group compared with the dapsone-prednisolone group. This difference may be explained by the stronger effect of prednisolone on lymphocyte functions compared with doxycycline-niacinamide.32-33 After 8 weeks of treatment, in 2 patients in the doxycycline-niacinamide group, only a slight decrease in levels of antibodies to BP180 NC16A was observed while these patients were free of blisters. To suppress new blister formation, these 2 patients still required the initial dose of doxycycline-niacinamide. This observation suggests that the regimen of doxycycline-niacinamide may exert its effects, at least in part, by modulation of the local inflammatory response in BP lesions. In fact, doxycycline and niacinamide were shown to exhibit their anti-inflammatory actions by interfering with neutrophil and eosinophil functions and, to a lesser extent, by suppression of antibody production.32-33 In the dapsone-prednisolone group, we found a direct correlation between the corticosteroid dose necessary to suppress blister formation and serum levels of antibodies to BP180 NC16A. The NC16A ELISA should, therefore, prove to be a helpful tool in guiding treatment of patients with BP, especially in those patients who are free of skin lesions yet still receive systemic treatment.
In summary, this study demonstrates that serum levels of antibodies to BP180, in contrast to indirect immunofluorescence titers of anti-BMZ antibodies, correlate with disease activity in BP. The BP180 NC16A ELISA is, therefore, helpful in guiding treatment decisions in this disease. In addition, our data substantiate the pathogenic relevance of autoantibodies to BP180.
AUTHOR INFORMATION
Accepted for publication June 9, 1999.
This work was supported by grant 98.073.1 from Wilhelm Sander-Stiftung, Munich (Dr Zillikens), and grant Z1 from the Interdisciplinary Center for Clinical Research at the University of Würzburg (Dr Schmidt), Germany.
Presented in part at the 40th meeting of the German Dermatological Society, Hamburg, Germany, May 15, 1999.
We are grateful to Heike Krenig and Karin Herzele, MS, Department of Dermatology, University of Würzburg, for technical assistance. We also acknowledge George Giudice, PhD, and Luis Diaz, MD, Medical College of Wisconsin, Milwaukee, for providing the recombinant BP180 and for helpful advice on this project.
Reprints: Detlef Zillikens, MD, Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany (e-mail: zillikens-d.derma{at}mail.uni-wuerzburg.de).
From the Department of Dermatology, University of Würzburg, Würzburg, Germany.
REFERENCES
| |
1. Zillikens Z, Giudice GJ, Diaz LA. Bullous pemphigoid: an autoimmune blistering disease of the elderly. J Geriatr Dermatol. 1996;4:35-41.
2. Labib RS, Anhalt GJ, Patel HP, Mutasim DF, Diaz LA. Molecular heterogeneity of the bullous pemphigoid antigens as detected by immunoblotting. J Immunol. 1986;136:1231-1235.
ABSTRACT
3. Giudice GJ, Emery DJ, Diaz LA. Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180. J Invest Dermatol. 1992;99:243-250.
FULL TEXT
|
ISI
| PUBMED
4. Stanley JR, Hawley-Nelson P, Yuspa SH, Shevach EM, Katz SI. Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell. 1981;24:897-903.
FULL TEXT
|
ISI
| PUBMED
5. Stanley JR, Tanaka T, Mueller S, et al. Isolation of complementary DNA for bullous pemphigoid antigen by use of patients' autoantibodies. J Clin Invest. 1988;82:1864-1870.
6. Tanaka T, Korman NJ, Shimizu H, et al. Production of rabbit antibodies against carboxy-terminal epitopes encoded by bullous pemphigoid cDNA. J Invest Dermatol. 1990;94:617-623.
FULL TEXT
|
ISI
| PUBMED
7. Bedane C, McMillan JR, Balding SD, et al. Bullous pemphigoid and cicatricial pemphigoid autoantibodies react with ultrastructurally separable epitopes on the BP180 ectodomain: evidence that BP180 spans the lamina lucida. J Invest Dermatol. 1997;108:901-907.
FULL TEXT
|
ISI
| PUBMED
8. Masunaga T, Shimizu H, Yee C, et al. The extracellular domain of BPAG2 localizes to anchoring filaments and its carboxyl terminus extends to the lamina densa of normal human epidermal basement membrane. J Invest Dermatol. 1997;109:200-206.
FULL TEXT
|
ISI
| PUBMED
9. Zillikens D, Giudice GJ. BP180/type XVII collagen: its role in acquired and inherited disorders of the dermal-epidermal junction. Arch Dermatol Res. 1999;291:187-194.
FULL TEXT
|
ISI
| PUBMED
10. Giudice GJ, Emery DJ, Zelickson BD, Anhalt GJ, Liu Z, Diaz LA. Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain. J Immunol. 1993;151:5742-5750.
ABSTRACT
11. Zillikens D, Rose PA, Balding SD, et al. Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies. J Invest Dermatol. 1997;109:573-579.
FULL TEXT
|
ISI
| PUBMED
12. Zillikens D, Mascaro JM, Rose PA, et al. A highly sensitive enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid. J Invest Dermatol. 1997;109:679-683.
FULL TEXT
|
ISI
| PUBMED
13. Liu Z, Diaz LA, Troy JL, et al. A passive transfer mouse model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest. 1993;92:2480-2488.
14. Liu Z, Diaz LA, Swartz SJ, Troy JL, Fairley JA, Giudice GJ. Molecular mapping of a pathogenically relevant BP180 epitope associated with experimentally induced murine bullous pemphigoid. J Immunol. 1995;155:5449-5454.
ABSTRACT
15. Venning VA, Wojnarowska F. Lack of predictive factors for the clinical course of bullous pemphigoid. J Am Acad Dermatol. 1992;26:585-589.
ISI
| PUBMED
16. Ahmed AR, Maize JC, Provost TT. Bullous pemphigoid: clinical and immunologic follow-up after successful therapy. Arch Dermatol. 1977;113:1043-1046.
ABSTRACT
17. Zillikens D, Ambach A, Schuessler M, Dummer R, Hartmann AA, Burg G. The interleukin-2 receptor in lesions and serum of bullous pemphigoid. Arch Dermatol Res. 1992;284:141-145.
FULL TEXT
|
ISI
| PUBMED
18. Hornschuh B, Hamm H, Wever S, et al. Treatment of 16 patients with bullous pemphigoid with oral tetracycline and niacinamide and topical clobetasol. J Am Acad Dermatol. 1997;36:101-103.
FULL TEXT
|
ISI
| PUBMED
19. Zillikens D, Kawahara Y, Ishiko A, et al. A novel subepidermal blistering disease with autoantibodies to a 200-kDa antigen of the basement membrane zone. J Invest Dermatol. 1996;106:1333-1338.
FULL TEXT
| PUBMED
20. Jones RH, Boadi-Boateng F. Unequally spaced longitudinal data with AR(1) serial correlation. Biometrics. 1991;47:161-175.
FULL TEXT
|
ISI
| PUBMED
21. Lever WF. Pemphigus and pemphigoid: a review of the advances made since 1964. J Am Acad Dermatol. 1979;1:2-31.
ISI
| PUBMED
22. Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16A domain of the 180 kDa bullous pemphigoid antigen. Arch Dermatol Res. 1996;288:507-509.
ISI
| PUBMED
23. Nakatani C, Muramatsu T, Shirai T. Immunoreactivity of bullous pemphigoid autoantibodies against the NC16A and C-terminal domains of the 180 kDa BP antigen (BP180): immunoblot analysis and enzyme-linked immunosorbent assay using BP180 recombinant proteins. Br J Dermatol. 1998;139:365-370.
FULL TEXT
|
ISI
| PUBMED
24. Pas HH, de Jong MCJM, Jonkman MF, Heeres K, Slijper-Pal IJ, van der Meer JB. Bullous pemphigoid: serum antibody titre and antigen specificity. Exp Dermatol. 1995;4:372-376.
FULL TEXT
| PUBMED
25. Ghohestani RF, Cozzani E, Kanitakis J, Nicolas JF, Faure M, Claudy AL. BPAg2 antibodies are present at lower levels than BPAg1 antibodies in serum from patients with bullous pemphigoid. Eur J Dermatol. 1996;6:491-494.
26. Schaller J, Giese T, Ladusch M, Haustein UF. Interleukin-2 receptor expression and interleukin-2 production in bullous pemphigoid. Arch Dermatol Res. 1990;282:223-226.
FULL TEXT
|
ISI
| PUBMED
27. Delaporte E, Dubost-Brama A, Ghohestani R, et al. IgE autoantibodies directed against the major bullous pemphigoid antigen in patients with a severe form of pemphigoid. J Immunol. 1996;157:3642-3647.
ABSTRACT
28. D'Auria L, Fei PC, Pietravalle M, et al. The serum levels of sE-selectin are increased in patients with bullous pemphigoid or pemphigus vulgaris: correlation with the number of skin lesions and recovery after corticosteroid therapy. Br J Dermatol. 1997;137:59-64.
FULL TEXT
|
ISI
| PUBMED
29. Ameglio F, D'Auria L, Bonifati C, Ferraro C, Masrtroiani A, Giacalone B. Cytokine pattern in blister fluid and serum of patients with bullous pemphigoid: relationships with disease intensity. Br J Dermatol. 1998;138:611-614.
FULL TEXT
|
ISI
| PUBMED
30. Gammon WR, Merrit CC, Lewis DM, et al. An in vitro model of immune complex–mediated basement membrane zone separation caused by pemphigoid antibodies, leukocytes, and complement. J Invest Dermatol. 1982;78:285-290.
FULL TEXT
|
ISI
| PUBMED
31. Naito K, Morioka S, Ogawa H. The pathogenic mechanisms of blister formation in bullous pemphigoid. J Invest Dermatol. 1982;79:303-306.
FULL TEXT
|
ISI
| PUBMED
32. Humbert P, Treffel P, Chapuis J-F, et al. The tetracyclines in dermatology. J Am Acad Dermatol. 1991;25:691-697.
ISI
| PUBMED
33. Burger DR, Vandenbark AA, Daves D, Anderson WA, Vetto RM, Finke P. Nicotinamide: suppression of lymphocytic transformation with a component identified in human transfer factor. J Immunol. 1976;117:797-801.
FREE FULL TEXT
RELATED ARTICLES
Levels of Antibodies to BP180 Correlate With Disease Activity in Bullous Pemphigoid
Diya F. Mutasim
Arch Dermatol. 2000;136(2):253-254.
EXTRACT
| FULL TEXT
Archives of Dermatology Reader's Choice: Continuing Medical Education
Arch Dermatol. 2000;136(2):280-281.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Childhood Bullous Pemphigoid: Clinical and Immunological Findings in a Series of 4 Cases
Martinez-De Pablo et al.
Arch Dermatol 2007;143:215-220.
ABSTRACT
| FULL TEXT
Urticarialike Plaques on the Breasts of a 72-Year-Old Woman--Diagnosis
Arch Dermatol 2005;141:1161-1166.
FULL TEXT
Usefulness of BP180 NC16a Enzyme-Linked Immunosorbent Assay in the Serodiagnosis of Pemphigoid Gestationis and in Differentiating Between Pemphigoid Gestationis and Pruritic Urticarial Papules and Plaques of Pregnancy
Powell et al.
Arch Dermatol 2005;141:705-710.
ABSTRACT
| FULL TEXT
Bullous Pemphigoid Associated With Mantle Cell Lymphoma
Iranzo et al.
Arch Dermatol 2004;140:1496-1499.
ABSTRACT
| FULL TEXT
Evaluation of Recombinant Antigen-Based Assays for Diagnosis of Bullous Autoimmune Diseases
D'Agosto et al.
CVI 2004;11:762-765.
ABSTRACT
| FULL TEXT
Immunoblotting and Enzyme-Linked Immunosorbent Assay for the Diagnosis of Pemphigoid Gestationis
Sitaru et al.
Obstet Gynecol 2004;103:757-763.
ABSTRACT
| FULL TEXT
Risk Factors for Lethal Outcome in Patients With Bullous Pemphigoid: Low Serum Albumin Level, High Dosage of Glucocorticosteroids, and Old Age
Rzany et al.
Arch Dermatol 2002;138:903-908.
ABSTRACT
| FULL TEXT
Annual Trainee Award for 2000
Orlow
Arch Dermatol 2001;137:948-948.
FULL TEXT
Pemphigoid: Clinical, Histologic, Immunopathologic, and Therapeutic Considerations
Yancey and Egan
JAMA 2000;284:350-356.
ABSTRACT
| FULL TEXT
Bullous Pemphigoid of Childhood: Autoantibodies Target the Same Epitopes Within the NC16A Domain of BP180 as Autoantibodies in Bullous Pemphigoid of Adulthood
Chimanovitch et al.
Arch Dermatol 2000;136:527-532.
ABSTRACT
| FULL TEXT
Levels of Antibodies to BP180 Correlate With Disease Activity in Bullous Pemphigoid
Mutasim
Arch Dermatol 2000;136:253-254.
FULL TEXT
|
