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The Cutting Edge |

Mucocutaneous Lichen Planus With Esophageal Involvement:  Successful Treatment With an Anti-CD20 Monoclonal Antibody FREE

Laurent Parmentier, MD, PhD; Blaise-Alain Bron, MD; Christa Prins, MD; Jacky Samson, MD; Isabelle Masouyé, MD; Luca Borradori, MD
[+] Author Affiliations

Assistant Section Editor: Michael P. Heffernan, MD
Assistant Section Editor: Christie Ammirati, MD

More Author Information
Arch Dermatol. 2008;144(11):1427-1430. doi:10.1001/archderm.144.11.1427.
Text Size: A A A
Published online

A 53-year-old woman presented with generalized mucocutaneous lichen planus (LP) with progressive oral and retrosternal burning, accompanied by progressive dysphagia. She had a 9- and 5-year history of buccal and vulvar LP, respectively, both of which were partially controlled by short-term courses of corticosteroids, administered either topically or systemically. Skin examination revealed numerous papules of active LP and postinflammatory hyperpigmented macules on the flexural areas of the arms, axillae, and submammary and inguinal folds, as well as on the umbilical and lumbosacral areas. In the genital area, atrophic changes were evident on the labia minorum. White, reticulated, erosive lesions were observed on the jugal and gingival mucosae, and patchy whitish lesions were seen on the tongue and palate. Esophagoscopy demonstrated lesions consistent with LP spreading downward to the superior sphincter, with focal ulcerations and a moderate circumferential stenosis at the middle portion of the esophagus. Light microscopy of biopsy specimens of esophageal mucosa confirmed the diagnosis of LP, with no evidence of malignant transformation. Serologic tests were negative for hepatitis B and C. In an attempt to quickly alleviate the patient's discomfort, 3 consecutive intravenous pulses of methylprednisolone (500 mg/d) were administered along with a twice-daily topical application of a 0.03% solution of tacrolimus on the buccal and vulvar lesions. The dysphagia and mucocutaneous lesions dramatically improved in the following 2 weeks. Nevertheless, the patient had a relapse within the next 3 months. New lesions appeared on the lower back and inguinal areas, with involvement of the buccal mucosa and the vermilion of the lower lip (Figure 1A). The dysphagia reappeared, and new findings on esophagoscopy confirmed the presence of erosions and white plaques consistent with active LP (Figure 2A). Histologic examination showed a bandlike infiltrate together with an alteration of the dermoepidermal junction and a mild degree of keratinocyte necrosis. The vast majority of the infiltrate consisted of CD8+ T lymphocytes, with smaller numbers of CD4+ T lymphocytes and scarce CD20+ B cells (Figure 3). Direct immunofluorescence microscopy showed no specific deposits.

Place holder to copy figure label and caption
Figure 1.

Before (A) and after (B and C) rituximab therapy. A, Before rituximab treatment, typical lichen planus lesions are present on the buccal mucosa, with erosions and white reticular streaks, as well as on the vermilion of the left part of the lower lip. B, Three months after rituximab treatment, mucosal erosions have completely cleared, while the whitish lesions have regressed and are no longer infiltrated. C, Six months after rituximab treatment, buccal mucosa shows mild residual whitish network, while involvement of the vermilion border of the lower lip has cleared.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Before (A) and after (B) rituximab therapy. A, Widespread erosions with fibrinous layers and bridges partially obstructing the esophagus. There is conspicuous friability. B, Endoscopic follow-up 3 months after treatment with rituximab reveals complete remission with postinflammatory faint, white patches.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Esophagoscopic examination of biopsy specimens. A and B, CD8 and CD20 immunotyping of a superficial esophageal biopsy specimen shows a lymphocytic infiltrate penetrating the inferior part of the mucosal epithelium, with major CD8 proportion and scarce CD20 cells. C and D, The same specimens 3 months after rituximab treatment showing a significant decrease of lymphocytic infiltrate, with almost complete disappearance of CD20 cells and residual CD8 cells.

Graphic Jump Location

Although involvement of the mouth and pharynx is observed in up to 30% to 70% of patients with LP, esophageal disease is very rare and remains frequently unrecognized. In our case, the rapid time to relapse and the risk of esophageal stricture formation prompted us to discuss all possible local and systemic treatment alternatives. Endoscopic dilations of the esophagus were ruled out because if the inflammatory process is not controlled there is a risk of triggering new lesions and strictures by the Koebner phenomenon. Swallowing topical tacrolimus1 was able to control the eosphageal lesions in our patient. Although pulse systemic corticosteroid treatment had a good initial effect, repeated exposures were contraindicated because of marked osteopenia in this middle-aged and overweight woman. The use of cyclosporine2 was contraindicated because of impaired renal function. Systemic retinoid therapy was also not an option because of its limited use in this context and because of insufficient evidence of its efficacy and our desire to limit adverse effects.3 Therefore, an alternative strategy was proposed.

Therapy with rituximab (Rituxan), a chimeric monoclonal antibody that depletes CD20+ B cells, was initiated. The rationale for using this drug in a case of severe mucocutaneous LP was mainly based on previous successes in clinically or physiopathologically related conditions characterized by an interface dermatitis and lymphocytic infiltration. The patient received 4 intravenous courses of rituximab (375 mg/m2), at 1-week intervals, with no significant adverse effects. Systemic corticosteroids were not added to the regimen before or during the perfusion cycle or during the following 6 months. The patient rapidly became symptom free, and her LP showed dramatic improvement at the 3- and 6-month follow-up visits (Figure 1B and C). Control esophagoscopy performed at 3 months did not show evidence of either active LP lesions or stenosis (Figure 2B). Immunohistochemical examination of esophageal mucosal specimens showed disappearance of CD20+ cells, whereas scarce CD8+ lymphocytes were still present (Figure 3C and D). As expected, peripheral blood B cells were undetectable after the fourth rituximab course. After 10 months of follow-up, the patient experienced a very limited relapse of the oral mucosa that was easily controlled with topical tacrolimus, 0.03%.

We report the first case (to our knowledge) of mucocutaneous LP successfully treated with rituximab (Rituxan). We decided to use this treatment in the present case because lichen planus belongs to the group of interface dermatitis diseases, some of which have recently been successfully treated with rituximab. Mucocutaneous LP-like lesions are characteristically found in paraneoplastic pemphigus, which we have also treated successfully with rituximab.4 The successful treatment of paraneoplastic pemphigus was extended to pemphigus vulgaris.5,6 Chronic graft-vs-host disease (C-GVHD) usually presents with LP-like lesions that are associated with sclerodermoid changes and oral lichenoid lesions.7 Histologically, the observed interface dermatitis of C-GVHD with a junctional CD8+ cell infiltrate is very reminiscent of that which is observed in LP.8 The benefit of rituximab therapy for C-GVHD is now well established,9,10 Although less reminiscent of an LP inflammatory infiltrate, an interface dermatitis is usually observed in systemic lupus erythematosus and refractory dermatomyositis, which have also responded to rituximab.11,12

Since the inflammatory infiltrate in LP is composed of T cells (with a predominance of CD8+ over CD4+), the mechanism of action of rituximab, which targets CD20, a B-cell–specific membrane marker, is challenging to explain. CD20+ B cells are very scarce in the typical bandlike CB8+ infiltrate,13 and there is no clear-cut evidence that autoantibodies play a critical role in LP. It is noteworthy that 3 months after treatment, the patient's physical signs had cleared and almost all CD20 cells had disappeared, while the CD8 infiltrate was still present. Also, a mild mucosal LP relapse occurred 9 months after treatment, when the B-cell count had normalized. By contrast, the most recent therapeutic successes in LP have been obtained with T-cell–specific inhibitors, either with a selective anti-CD11a monoclonal antibody that targets the activation of T cells by antigen-presenting cells1416 or with basiliximab, which binds to the high-affinity receptor for interleukin 2α subunit and blocks T-cell activation.17

We hypothesize interdependent B- and T-cell functions in the pathogenesis of LP. B cells could have either a direct and/or an indirect effect on the function of CD8+ cells in the inflammatory cell infiltrate, or interfere critically with T-cell activation at a very early stage of LP. Rituximab therapy has already been proved to be efficacious in the treatment of traditionally T-cell–related diseases such as rheumatoid arthritis.18 In more classic B-cell autoimmune diseases, its effect seems to be related to the alteration of specific T cells, which regulate autoantibody production. In pemphigus vulgaris, the efficacy of rituximab is associated not only with B-cell depletion but also with the selective reduction of antidesmoglein 3 autoreactive T cells.6 In idiopathic thrombocytopenic purpura and systemic lupus erythematosus, the responsiveness to rituximab appears to be directly linked to significant changes in the T-cell in vivo behavior.19,20 While our observations suggest that B cells are also implicated in LP tissue damage, further comprehensive immunologic studies are needed to better explore the interplay between B- and T-cell functions in the pathogenesis of LP.

Box Section Ref ID

Submissions

Clinicians, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Manuscripts should be prepared double-spaced with right margins nonjustified. Pages should be numbered consecutively with the title page separated from the text (see Instructions for Authors [http://archderm.ama-assn.org/misc/ifora.dtl] for information about preparation of the title page). Clinical photographs, photomicrographs, and illustrations must be sharply focused and submitted as separate JPG files with each file numbered with the figure number. Material must be accompanied by the required copyright transfer statement (see authorship form [http://archderm.ama-assn.org/misc/auinst_crit.pdf]). Preliminary inquiries regarding submissions for this feature may be submitted to George J. Hruza, MD (ghruza@aol.com). Manuscripts should be submitted via our online manuscript submission and review system (http://manuscripts.archdermatol.com).

Correspondence: Laurent Parmentier, MD, PhD, Service de Dermatologie, Hôpital de l’Hôtel-Dieu, 1 place de l’Hôpital, 69001 Lyon, France (laurent.parmentier@chu-lyon.fr).

Accepted for Publication: April 17, 2008.

Author Contributions: Drs Parmentier, Bron, Prins, Samson, Masouyé, and Borradori had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of data: Parmentier, Bron, Prins, Samson, Masouyé, and Borradori. Analysis and interpretation of data: Parmentier, Masouyé, and Borradori. Drafting of the manuscript: Parmentier and Borradori. Critical revision of the manuscript for important intellectual content: Parmentier, Bron, Samson, Masouyé, and Borradori. Study supervision: Borradori.

Financial Disclosure: None reported.

Keate  RFWilliams  JWConnolly  SM Lichen planus esophagitis: report of three patients treated with oral tacrolimus or intraesophageal corticosteroid injections or both. Dis Esophagus 2003;16 (1) 47- 53
PubMed
Bobadilla  Jvan der Hulst  RWten Kate  FJTytgat  GN Esophageal lichen planus. Gastrointest Endosc 1999;50 (2) 268- 271
PubMed
Jobard-Drobacheff  CBlanc  DQuencez  E  et al.  Lichen planus of the oesophagus. Clin Exp Dermatol 1988;13 (1) 38- 41
PubMed
Borradori  LLombardi  TSamson  JGirardet  CSaurat  JHHügli  A Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to CD20+ follicular lymphoma–associated paraneoplastic pemphigus. Arch Dermatol 2001;137 (3) 269- 272
PubMed
Joly  PMouquet  HRoujeau  JC  et al.  A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007;357 (6) 545- 552
PubMed
Hertl  MEming  RBorradori  L Rituximab (anti-CD20 monoclonal antibody)—ultimate or first choice in pemphigus? Dermatology 2007;214 (4) 275- 277
PubMed
Aractingi  SChosidow  O Cutaneous graft-versus-host disease. Arch Dermatol 1998;134 (5) 602- 612
PubMed
Sato  MTokuda  NFukumoto  TMano  TSato  TUeyama  Y Immunohistopathological study of the oral lichenoid lesions of chronic GVHD. J Oral Pathol Med 2006;35 (1) 33- 36
PubMed
Zaja  FBacigalupo  APatriarca  F  et al.  GITMO (Gruppo Italiano Trapianto Midollo Osseo): treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant 2007;40 (3) 273- 277
PubMed
Ratanatharathorn  VAyash  LReynolds  C  et al.  Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant 2003;9 (8) 505- 511
PubMed
Eisenberg  RAlbert  D B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus. Nat Clin Pract Rheumatol 2006;2 (1) 20- 27
PubMed
Chung  LGenovese  MCFiorentino  DF A pilot trial of rituximab in the treatment of patients with dermatomyositis. Arch Dermatol 2007;143 (6) 763- 767
PubMed
Abraham  SCRavich  WJAnhalt  GJYardley  JHWu  TT Esophageal lichen planus: case report and review of the literature. Am J Surg Pathol 2000;24 (12) 1678- 1682
PubMed
Cheng  AMann  C Oral erosive lichen planus treated with efalizumab. Arch Dermatol 2006;142 (6) 680- 682
PubMed
Böhm  MLuger  TA Lichen planus responding to efalizumab. J Am Acad Dermatol 2007;56 (5) ((suppl)) S92- S93
PubMed
Heffernan  MPSmith  DIBentley  DTabacchi  MGraves  JE A single-center, open-label, prospective pilot study of subcutaneous efalizumab for oral erosive lichen planus. J Drugs Dermatol 2007;6 (3) 310- 314
PubMed
Rebora  AParodi  AMurialdo  G Basiliximab is effective for erosive lichen planus. Arch Dermatol 2002;138 (8) 1100- 1101
PubMed
Atzeni  FDoria  AMaurizio  TSarzi-Puttini  P What is the role of rituximab in the treatment of rheumatoid arthritis? Autoimmun Rev 2007;6 (8) 553- 558
PubMed
Stasi  RDel Poeta  GStipa  E  et al.  Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura. Blood 2007;110 (8) 2924- 2930
PubMed
Vigna-Perez  MHernández-Castro  BParedes-Saharopulos  O  et al.  Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 2006;8 (3) R83
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Before (A) and after (B and C) rituximab therapy. A, Before rituximab treatment, typical lichen planus lesions are present on the buccal mucosa, with erosions and white reticular streaks, as well as on the vermilion of the left part of the lower lip. B, Three months after rituximab treatment, mucosal erosions have completely cleared, while the whitish lesions have regressed and are no longer infiltrated. C, Six months after rituximab treatment, buccal mucosa shows mild residual whitish network, while involvement of the vermilion border of the lower lip has cleared.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Before (A) and after (B) rituximab therapy. A, Widespread erosions with fibrinous layers and bridges partially obstructing the esophagus. There is conspicuous friability. B, Endoscopic follow-up 3 months after treatment with rituximab reveals complete remission with postinflammatory faint, white patches.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Esophagoscopic examination of biopsy specimens. A and B, CD8 and CD20 immunotyping of a superficial esophageal biopsy specimen shows a lymphocytic infiltrate penetrating the inferior part of the mucosal epithelium, with major CD8 proportion and scarce CD20 cells. C and D, The same specimens 3 months after rituximab treatment showing a significant decrease of lymphocytic infiltrate, with almost complete disappearance of CD20 cells and residual CD8 cells.

Graphic Jump Location

Tables

References

Keate  RFWilliams  JWConnolly  SM Lichen planus esophagitis: report of three patients treated with oral tacrolimus or intraesophageal corticosteroid injections or both. Dis Esophagus 2003;16 (1) 47- 53
PubMed
Bobadilla  Jvan der Hulst  RWten Kate  FJTytgat  GN Esophageal lichen planus. Gastrointest Endosc 1999;50 (2) 268- 271
PubMed
Jobard-Drobacheff  CBlanc  DQuencez  E  et al.  Lichen planus of the oesophagus. Clin Exp Dermatol 1988;13 (1) 38- 41
PubMed
Borradori  LLombardi  TSamson  JGirardet  CSaurat  JHHügli  A Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to CD20+ follicular lymphoma–associated paraneoplastic pemphigus. Arch Dermatol 2001;137 (3) 269- 272
PubMed
Joly  PMouquet  HRoujeau  JC  et al.  A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007;357 (6) 545- 552
PubMed
Hertl  MEming  RBorradori  L Rituximab (anti-CD20 monoclonal antibody)—ultimate or first choice in pemphigus? Dermatology 2007;214 (4) 275- 277
PubMed
Aractingi  SChosidow  O Cutaneous graft-versus-host disease. Arch Dermatol 1998;134 (5) 602- 612
PubMed
Sato  MTokuda  NFukumoto  TMano  TSato  TUeyama  Y Immunohistopathological study of the oral lichenoid lesions of chronic GVHD. J Oral Pathol Med 2006;35 (1) 33- 36
PubMed
Zaja  FBacigalupo  APatriarca  F  et al.  GITMO (Gruppo Italiano Trapianto Midollo Osseo): treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant 2007;40 (3) 273- 277
PubMed
Ratanatharathorn  VAyash  LReynolds  C  et al.  Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant 2003;9 (8) 505- 511
PubMed
Eisenberg  RAlbert  D B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus. Nat Clin Pract Rheumatol 2006;2 (1) 20- 27
PubMed
Chung  LGenovese  MCFiorentino  DF A pilot trial of rituximab in the treatment of patients with dermatomyositis. Arch Dermatol 2007;143 (6) 763- 767
PubMed
Abraham  SCRavich  WJAnhalt  GJYardley  JHWu  TT Esophageal lichen planus: case report and review of the literature. Am J Surg Pathol 2000;24 (12) 1678- 1682
PubMed
Cheng  AMann  C Oral erosive lichen planus treated with efalizumab. Arch Dermatol 2006;142 (6) 680- 682
PubMed
Böhm  MLuger  TA Lichen planus responding to efalizumab. J Am Acad Dermatol 2007;56 (5) ((suppl)) S92- S93
PubMed
Heffernan  MPSmith  DIBentley  DTabacchi  MGraves  JE A single-center, open-label, prospective pilot study of subcutaneous efalizumab for oral erosive lichen planus. J Drugs Dermatol 2007;6 (3) 310- 314
PubMed
Rebora  AParodi  AMurialdo  G Basiliximab is effective for erosive lichen planus. Arch Dermatol 2002;138 (8) 1100- 1101
PubMed
Atzeni  FDoria  AMaurizio  TSarzi-Puttini  P What is the role of rituximab in the treatment of rheumatoid arthritis? Autoimmun Rev 2007;6 (8) 553- 558
PubMed
Stasi  RDel Poeta  GStipa  E  et al.  Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura. Blood 2007;110 (8) 2924- 2930
PubMed
Vigna-Perez  MHernández-Castro  BParedes-Saharopulos  O  et al.  Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 2006;8 (3) R83
PubMed

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