Modern Rheumatology Case Reports

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A case of rheumatoid arthritis complicated with

mucous membrane pemphigoid

Ryosuke Hanaoka , Toshiko Haginoya & Masami Koike

To cite this article: Ryosuke Hanaoka , Toshiko Haginoya & Masami Koike (2020): A case of
rheumatoid arthritis complicated with mucous membrane pemphigoid, Modern Rheumatology Case
Reports, DOI: 10.1080/24725625.2020.1839196

To link to this article: https://doi.org/10.1080/24725625.2020.1839196

Accepted author version posted online: 21

Oct 2020.

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TMCR-2020-0103 Received: 17-Aug-2020; Accepted: 15-Oct-2020

Case Report

A case of rheumatoid arthritis complicated with mucous membrane pemphigoid

Ryosuke Hanaoka1, Toshiko Haginoya1, Masami Koike2

1
Department of Rheumatology, Kamitsuga General Hospital, Kanuma, Tochigi, Japan

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2
Department of Dermatology, Koike-clinic, Kanuma, Tochigi, Japan

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Corresponding author: Ryosuke Hanaoka,

Department of Rheumatology, Kamitsuga General Hospital,

1-1033 Shimodamachi, Kanuma, Tochigi 322-8550, Japan us

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TEL: +81-289-64-2161; FAX: +81-289-64-2468, E-mail: hanaoka@kamituga-hp.or.jp
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Abstract

Rheumatoid arthritis (RA) is a disease of unknown etiology that causes irreversible joint destruction and has been
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known to present with not only various extra-articular symptoms, but also various autoimmune disorders. Mucous

membrane pemphigoid (MMP) is a chronic autoimmune disease characterized by inflamed and eroded mucosa.
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The prognosis of MMP can be poor, so early diagnosis and prompt initiation of therapy are necessary for optimal
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management. Here, we report a rare case of RA complicated with MMP involving a 68-year-old woman admitted

to our hospital because of hoarseness and symmetrical narrowing of the eye fissures. She presented with bilateral
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coxalgia and had been diagnosed with RA 24 years earlier. Oral methotrexate was prescribed, but subsequently

discontinued, and this was followed by treatment with tocilizumab 3 years earlier. Tocilizumab was discontinued

because of financial distress 5 months earlier, after which her RA disease activity worsened. She presented to our

hospital after further worsening of her eye-opening difficulty. Physical and laboratory examinations led to a

diagnosis of MMP. Her sputum, cough, throat discomfort, conjunctival congestion, mucous erosion, and blistering

promptly disappeared after treatment with rituximab (500 mg per week for 4 weeks). She subsequently recovered

her vocalization ability, and her hoarseness, dysphagia, and eye-opening difficulty gradually improved, but not
completely. This case suggests that that RA and MMP share common immunological mechanisms. Therefore,

MMP should be considered when encountering patients with RA who present with systemic membrane mucous

disorders.

Keywords: rheumatoid arthritis; mucous membrane pemphigoid; HLA-DR4; autoimmunity

Introduction

Rheumatoid arthritis (RA) is a disease of unknown etiology that causes irreversible joint destruction due to a

chronic synovial inflammatory process via autoimmunity. It is well known that RA can present with not only

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various extra-articular symptoms, but also various autoimmune disorders [1]. Mucous membrane pemphigoid

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(MMP) is a chronic, autoimmune, inflammatory, and blistering disease characterized by inflamed and eroded

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mucosa involving any or all of the oral cavity, ocular conjunctiva, nose, pharynx, larynx, esophagus, anus, and

genital mucous membranes. The prognosis of MMP can be poor because of consequent symblepharon,

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ankyloblepharon, eventual blindness, or progressive laryngeal and tracheal involvement leading to asphyxiation.
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Therefore, early diagnosis and prompt initiation of therapy are essential for optimal management [2]. Here, we

report a rare case of RA complicated with MMP.

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Case presentation
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A 68-year-old woman was admitted to our hospital because of hoarseness and symmetrical narrowing of the eye

fissures. She presented with bilateral coxalgia and had been diagnosed with RA 24 years earlier. Oral methotrexate
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was prescribed, but subsequently discontinued because of resultant dry cough. She had not been prescribed a

dipeptidyl peptidase-4 inhibitor or diuretic. RA had improved to low disease activity since starting treatment with
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tocilizumab 3 years earlier. One year earlier, she had complained of hoarseness and discomfort in her throat, cough,

and sputum, which gradually worsened. Eight months earlier, she started to experience appetite loss, body weight
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loss, conjunctival congestion, and difficulty opening the eyes. Tocilizumab had been discontinued because of

financial distress 5 months earlier. Since that time, her RA disease activity had also worsened. She decided to be

admitted to the hospital after further worsening of her eye-opening difficulty.

Physical examinations revealed symmetrical narrowing of the eye fissures, symblepharon, palpebral

edema, conjunctival congestion due to cicatrizing conjunctivitis (Figure 1A). Adhesion between the palpebral and

bulbar conjunctivae resulted in eversion of the eyelid and eyelashes. The corneas in both eyes were partially
covered by granulation tissue. Extensive mucus erosion was observed in her oral cavity (Figure 1B). Laryngeal

endoscope showed erosion and blistering of the mucosa around the epiglottis (Figure 1C). Vocalization was almost

impossible. Mutilans deformity was seen in her bilateral fingers.

Laboratory examinations revealed mild leukocytosis, neutrophilia, hypoalbuminemia, elevated serum

immunoglobulin G (IgG), a mildly elevated erythrocyte sedimentation rate, and mildly elevated serum C-reactive

protein. Although rheumatoid factor was positive (149 IU/mL), it remained at a similar level compared with that

before the onset of mucosal lesions. Anti-circular citrullinated peptide antibody was positive. Anti-desmoglein 1,

anti-desmoglein 3, and anti-BP180 antibodies were negative. Plain radiography of the hands showed bone erosion

in the 1st, 4th, and 5th proximal interphalangeal joints of the right hand, and marked bone erosion and subluxation

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in the metatarsophalangeal joints of most fingers. Lytic bone lesions and ankylosis were also seen in both wrists

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(Figure 2).

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Biopsy of the oral mucosa revealed epidermal exfoliation, perhaps because the biopsy sample was taken

from the base of the ulcer (Figure 3A). Lymphatic vessels located directly below the epidermis were enlarged and

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contained numerous neutrophils and few eosinophils centered around the capillaries, accompanied by severe

infiltration of lymphoid and other small round cells (Figure 3B, C). Severe fibrosis of the dermis was also
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observed. The direct fluorescent antibody method was applied to a sample of the patient’s lip tissue. Complement
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component 3 (Figure 3D) and IgG (Figure 3E) deposits were seen in the epidermal basement membrane. The

indirect fluorescent antibody method was also applied to a sample of the patient’s lip tissue. Normal mucosa was
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treated in 1 M saline for 48 h, and the dermis and epidermis were removed before adding serum from the patient,

resulting in the appearance of linear deposits on the epidermis side (Figure 3F). Based on these findings, MMP was
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diagnosed.

Despite the administration of prednisolone (20 mg daily) and azathioprine (50 mg daily), improvement of
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the mucous erosion was inadequate. After the administration of rituximab (500 mg per week for 4 weeks), sputum,

cough, discomfort in the throat, conjunctival congestion, mucous erosion, and blistering promptly disappeared.
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She subsequently recovered her vocalization ability, and her hoarseness, dysphagia, and eye-opening difficulty

gradually improved, but not completely. Six months later, we confirmed that no new mucosal lesion had appeared,

and thus restarted tocilizumab carefully for treatment of RA flare. Remission of MMP has been sustained since

restarting tocilizumab.

Discussion
 Pemphigoid is an epidermal autoimmune inflammatory disorder characterized by autoantibodies against

hemidesmosomes, which bind epidermal cells to the epidermal basement membrane. MMP is a rare type of

pemphigoid that specifically attacks the mucous membranes.

To our knowledge, there have been few reports of patients with RA complicated by MMP. However,

MMP is a rare condition, and although the prevalence of MMP among RA patients is extremely low, the

prevalence of RA among MMP patients may not be so uncommon. Olsen et al. [3] and Foster et al. [4] reported

that 10 (18.6 %) of 53 patients and 19 (14.6 %) of 130 patients had MMP complicated by RA.

A PubMed search identified 10 such patients (50% female, mean age, 67.7 years) in five case reports

(Table 1) [5–9]. Every case showed an extensive duration of RA. D-penicillamine was prescribed in four patients,

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and thus, the authors discussed the association between D-penicillamine and MMP, as the present case had never

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been prescribed D-penicillamine. In addition, seven of 10 patients needed immunosuppressants in addition to

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glucocorticoids.

We speculated that RA and MMP may share common immunological mechanisms. It is well known that

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HLA-DR4 antigen is strongly associated with the etiology of RA [10]. On the other hand, it has been also reported

that a significantly higher incidence of HLA-DR4 genotype was found in the MMP patients when compared with
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a control population [11].
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We selected the use of rituximab because it is effective for both RA and MMP. Rituximab is a promising

treatment for patients with RA who do not respond sufficiently to disease-modifying antirheumatic drugs [12].
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Moreover, rituximab appears to have rapid and dramatic efficacy in patients with severe, refractory MMP. Le

Roux-Villet et al. [13] treated 25 patients with severe refractory MMP and reported a complete responses rate of
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88%.

In resuming treatment for RA, we avoided the use of tumor necrosis factor (TNF) inhibitors because
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some cases of RA complicated by bullous pemphigoid while using TNF inhibitors have been reported [14,15].

Repeated use of rituximab seemed difficult because it has never been covered by insurance for RA. The patient had
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previously used tocilizumab without any problems. The only reason she stopped the use of tocilizumab

temporarily was economic difficulties. Moreover, to our knowledge, no case of RA complicated by pemphigoid

during the use of tocilizumab has been reported. Therefore, we selected tocilizumab to restart treatment for RA

flare.
 In conclusion, here, we described a case of RA complicated by MMP. Our findings suggest that this

comorbidity needs to be considered when dealing with patients with RA who present with systemic membrane

mucous disorders.

Patient Consent

The patient provided informed written consent prior to inclusion of her data in this report.

Funding

The authors received no specific grant from any funding agency in the public, commercial, or not-for-profit

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sectors.

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Conflict of Interest

None

Ethical approval
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Not applicable
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References
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1. Wasserman AM. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2011;84:1245–52.

2. Murrell DF, Marinovic B, Caux F, et al. Definitions and outcome measures for mucous membrane
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pemphigoid: recommendations of an international panel of experts. J Am Acad Dermatol. 2015;72:168–74.

3. Olsen KE, Holland EJ. The association between ocular cicatricial pemphigoid and rheumatoid arthritis.
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Cornea. 1998;17:504–7.

4. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc. 1986;84:527–663.

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5. Spigel GT, Winkelmann RK. Cicatricial pemphigoid and rheumatoid arthritis. Arch Dermatol.

1978;114:415–7.

6. Shuttleworth D, Graham-Brown RA, Hutchinson PE, et al. Cicatricial pemphigoid in D-penicillamine

treated patients with rheumatoid arthritis--a report of three cases. Clin Exp Dermatol. 1985;10:392–7.

7. Wu D, Zhang LM, Jiang Y. Cicatricial pemphigoid in accompany with rheumatoid arthritis: a case report.

Chin Med Sci J. 2010;25:182–4.

8. Peyrí J, Servitje O, Ribera M, Henkes J, Ferrandiz C. Cicatricial pemphigoid in a patient with rheumatoid

arthritis treated with D-penicillamine. J Am Acad Dermatol. 1986;14:681.

9. Cytryn E, Laduron JC, Colebunders R, Dony A. Oesophageal stenosis caused by benign mucous membrane

pemphigoïd in a patient with an inactive rheumatoïd arthritis. Rofo. 1985;142:469–70.

10. Gibert M, Balandraud N, Touinssi M, Mercier P, Roudier J, Reviron D. Functional categorization of

HLA-DRB1 alleles in rheumatoid arthritis: the protective effect. Hum Immunol. 2003;64:930–5.

11. Tavakolpour S, Alesaeidi S, Darvishi M, et al. A comprehensive review of rituximab therapy in rheumatoid

arthritis patients. Clin Rheumatol. 2019;38(11):2977–94.

12. Zaltas MM, Ahmed R, Foster CS. Association of HLA-DR4 with ocular cicatricial pemphigoid. Curr Eye

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Res. 1989;8(2):189–93.

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13. Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, et al. Rituximab for patients with refractory mucous

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membrane pemphigoid. Arch Dermatol. 2011;147(7):843–9.

14. Boussemart L, Jacobelli S, Batteux F, et al. Autoimmune bullous skin diseases occurring under anti-tumor

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necrosis factor therapy: two case reports. Dermatology. 2010;221(3):201–5.

15. Bordignon M, Belloni-Fortina A, Pigozzi B, et al. Bullous pemphigoid during long-term TNF-alpha blocker
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therapy. Dermatology. 2009;219(4):357–8.
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Figure legends

Figure 1. (A) Right ocular findings. The palpebral and bulbar conjunctivae were adherent, which caused the

eyelid and eyelashes to be everted. In addition, granulation tissue covered the cornea. (B) Oral findings. Soft

palate erosion was observed, as was severe and widespread gingival erosion. (C) Laryngeal fiberscope findings.

Blistering and erosion of the mucous membrane around the epiglottis were observed.

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Figure 2. Plain radiography of the hands. Bone erosion in the 1st, 4th, and 5th proximal interphalangeal joints of
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the right hand, and marked bone erosion and subluxation in the metatarsophalangeal joints of most fingers were

observed. Lytic bone lesions and ankylosis were also seen in both wrists.
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Figure 3. Histopathologic analysis of the oral mucosa. (A) The epidermis was detached from the basement

membrane. Marked infiltration of small round cells from just below the basement membrane to the upper layer
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of the dermis was seen (hematoxylin and eosin staining, 10 objective). (B) Interstitial edema and dilatation of

the lymphatic vessels were observed in the dermis just below the basement membrane. Marked fibrosis was
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observed in the dermal interstitium. Infiltration of small round cells consisted of mainly lymphoid cells, and

neutrophils and eosinophils were partially distributed around the capillaries (hematoxylin and eosin staining, 20
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objective). (C) Infiltration of eosinophils (stained with eosin) was noticeable (hematoxylin and eosin staining,

40 objective). (D, E) Direct immunofluorescence study of lip tissue. (D) Linear deposits of complement
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component 3 on the epidermal basement membrane were seen (40 objective). (E) Linear deposits of
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immunoglobulin G on the epidermal basement membrane were seen. (F) Indirect immunofluorescence study of

biopsied lip tissue (40 objective). Linear deposits were observed on the epidermis side after normal mucosa
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was treated in 1 M saline for 48 h and the dermis and epidermis were removed before adding serum from the

patient.
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Table 1. Previous reports of rheumatoid arthritis complicated with mucous membrane

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pemphigoid
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Preceding Durati
Distribution Treatment
treatment on of
Durat
A muco
Refere Se ion of Outco
ge us
nce x arthrit DP G Oth Sk Ey Mou G me
(y) lesion Others
is (y) C C ers in es th C
(mont
hs)
N N Survi
5 56 M 30 NA 36 - + + - -
A A ved
5 67 F 4 N N NA 5 - + + + AZA Survi
 A A ved
AS Blepharop Survi
5 80 M 2 - - 12 - + - -
A lasty ved
5 78 M 50 - - - 48 + + + + - Died
Survi
6 55 F 9 + + - 0.5 + + + + AZA
ved
Chloramb
6 71 M 16 + + - 1.5 + + + + Died
ucil
6 69 M 7 + + - 5 - + + + AZA Died
MT IVCYC, Survi
7 72 F 19 - - 7 - + + +
X CsA ved
Survi
8 55 F 18 + - - 2 + + + + Oral CYC
ved
Survi
9 74 F 20 - - - 12 + + + + SASP

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ved

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Our AZA, Survi
68 F 24 - - TCZ 12 + + + +
case RTX ved

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ASA, acetylsalicylic acid; AZA, azathioprine; CsA, ciclosporin A; CYC, cyclophosphamide;

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DPC, D-penicillamine; F, female; GC, glucocorticoid; IVCYC, intravenous

cyclophosphamide; M, male; MTX, methotrexate; NA, not available; PSL, prednisolone;

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RTX, rituximab; SASP, sulphasalazine; TCZ, tocilizumab
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