dysplasia membrane autoantibodies in ectodermal Cicatrising

Document Sample
dysplasia membrane autoantibodies in ectodermal Cicatrising Powered By Docstoc
					                                    Downloaded from bjo.bmj.com on 25 September 2008

                                Cicatrising conjunctivitis with anti-basement
                                membrane autoantibodies in ectodermal
                                V P J Saw, J K G Dart, C Sitaru and D Zillikens

                                Br. J. Ophthalmol. 2008;92;1403-1410

                                Updated information and services can be found at:

                                These include:
         References             This article cites 27 articles, 6 of which can be accessed free at:

Rapid responses                 You can respond to this article at:

     Email alerting             Receive free email alerts when new articles cite this article - sign up in the box at
           service              the top right corner of the article

Topic collections               Articles on similar topics can be found in the following collections

                                  Ocular surface (4 articles)
                                  Neurology (8 articles)
                                  Vision (4 articles)
                                  Conjunctiva (2 articles)
                                  Cornea (3 articles)


To order reprints of this article go to:

To subscribe to British Journal of Ophthalmology go to:
                                                 Downloaded from bjo.bmj.com on 25 September 2008

                                                                                                                                  Clinical science

                                    Cicatrising conjunctivitis with anti-basement
                                    membrane autoantibodies in ectodermal dysplasia
                                    V P J Saw,1 J K G Dart,1 C Sitaru,2 D Zillikens2
 Cornea and External Diseases       ABSTRACT                                                       circulating or mucosa-deposited anti-basement
Service, Moorfields Eye Hospital,   Aims: To report circulating and mucosa-deposited anti-         membrane autoantibodies associated with bilateral
London, UK; 2 Department of                                                                        cicatrising conjunctivitis in these patients has not,
Dermatology, University of
                                    basement membrane zone autoantibodies in a series of
Lubeck, Lubeck, Germany
         ¨                          six ectodermal dysplasia patients with severe bilateral        to our knowledge, been previously reported.
                                    cicatrising conjunctivitis and blindness due to both corneal      This article presents new findings regarding the
Correspondence to:                  disease and intractable surface inflammation. We also          immunopathology of chronic bilateral cicatrising
Dr V P J Saw, Moorfields Eye                                                                       conjunctivitis in ectodermal dysplasia, and dis-
Hospital, 162 City Road, London
                                    report clinical improvement with steroid-sparing systemic
EC1V 2PD, UK; v.saw@ucl.ac.         immunosuppression combined with clearance of bacterial         cusses insights that this reveals about the potential
uk                                  colonisation.                                                  triggers for autoimmune conjunctivitis. We also
                                    Methods: Conjunctival and buccal immunohistopathol-            report a new approach of combined steroid-sparing
Accepted 26 April 2008              ogy, and serological analysis using a panel of epithelial      immunosuppression and clearance of bacterial
                                    basement membrane zone proteins including the bullous          colonisation to treat these patients, who are blind
                                    pemphigoid antigen 180 (BP180) were carried out as part        from both the corneal disease and intractable
                                    of an ocular pemphigoid work-up in each patient. The           surface inflammation, and present significant
                                    degree of photophobia, conjunctival inflammation and           difficulties in management.
                                    visual acuity were monitored to evaluate the response to
                                    immunosuppression. The mean duration of follow-up was          PATIENTS AND METHODS
                                    31 (SD 6) months.                                              Patients and investigations
                                    Results: Four of the six patients showed positive              All six ectodermal dysplasia patients had been
                                    immunopathology: direct immunofluorescence testing of          referred to the External Disease Service at
                                    the conjunctiva in one patient demonstrated linear IgA         Moorfields Eye Hospital between March 2003
                                    deposition along the basement membrane zone, and IgG           and September 2004 with disabling bilateral con-
                                    and IgM in the buccal mucosa of another patient.               junctivitis unresponsive to topical therapy and
                                    Circulating autoantibodies to BP180 were detected in two       poor vision.
                                    other patients. Treatment with systemic immunosup-                Upper and lower conjunctival fornix depth was
                                    pression, combined with clearance of bacterial colonisa-       measured with a fornix gauge.11 As part of the
                                    tion, reduced the severity of photophobia and degree of        work-up for cicatrising conjunctivitis clinically
                                    conjunctival inflammation in 5/6 (83%) patients.               resembling ocular mucous membrane pemphigoid
                                    Conclusions: Systemic immunosuppression, used as               (MMP), conjunctival and buccal mucosal biopsies
                                    steroid-sparing therapy, combined with clearance of            for direct immunofluorescence12 and histopathol-
                                    bacterial colonisation can control inflammation and            ogy (conjunctival only) were taken. Serological
                                    disabling photophobia, and allow improvement in vision, in     testing for circulating anti-epithelial basement
                                    a subgroup of ectodermal dysplasia patients who have           membrane autoantibodies was carried out by
                                    severe cicatrising conjunctivitis which shares clinical and    indirect immunofluorescence on monkey oesopha-
                                    immunopathological features with ocular mucous mem-            gus and human salt split skin for IgG and IgA, as
                                    brane pemphigoid.                                              well as by non-conventional diagnostic techniques
                                                                                                   including an IgG ELISA for reactivity with recom-
                                                                                                   binant BP180 NC16A (bullous pemphigoid antigen
                                    The ectodermal dysplasias are a large group of                 180 kDa, 16th non-collagenous domain A), and
                                    disorders which include ectrodactyly, ectodermal               immunoblotting studies testing for reactivity to a
                                    dysplasia, cleft lip and palate (EEC) syndrome, and            panel of cell-derived and recombinant proteins
                                    are characterised by dry skin, sparse hair, dys-               reported as target antigens in mucous membrane
                                    trophic nails, hypoplastic teeth, and sweat gland              pemphigoid,13–15 including the soluble ectodomain
                                    anomalies.1 Recognised ophthalmic features of                  of BP180 (also known as LAD-1, first described as a
                                    ectodermal dysplasias include absence of meibo-                target antigen in Linear IgA Disease), laminin 5 and
                                    mian glands,2 3 lacrimal drainage abnormalities,4              type VII collagen. Serological screening for auto-
                                    corneal vascularisation and perforations,5–7 dry               immune connective tissue diseases was also carried
                                    eye symptoms3 and conjunctivitis.4 7 8                         out. Lid and conjunctival microbiological cultures
                                       Conjunctivitis in ectodermal dysplasia has pre-             and sensitivities were taken at each clinic visit. The
                                    viously been attributed to infection secondary to              mean duration of follow-up was 31 (SD 6) months.
                                    lacrimal drainage problems,7 or to blepharocon-
                                    junctivitis.8 In other cases, the aetiology of the             Immunosuppressive and antibiotic therapy strategy
                                    keratoconjunctivitis      has      been    obscure.2           The criterion for treatment with systemic therapy
                                    Conjunctival scarring, along with entropion and                was when severe photophobia and conjunctival
                                    secondary trichiasis, are recognised features of the           inflammation did not respond to at least 8 weeks
                                    subtype EEC syndrome,2 7 9 10 but the presence of              of local therapy with topical steroids, antibiotics

Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583                                                                                       1403
                                                                                                                                                                                                                                                                                                                                     Clinical science

                                                                 Table 1 Ocular examination at presentation, immunofluorescence and serology results
                                                                                                                                                         Upper          Lower
                                                                                                                         Visual acuity    Conjunctival   conjunctival   conjunctival   Upper            Lower            Corneal           Location of
                                                                                Age (years),                             with preferred   inflammation   fornix depth   fornix depth   cicatrisation    cicatrisation    vascularisation   corneal           Schirmer     Conjunctival
                                                                 Case no        sex            Diagnosis         Eye     correction       (grade 0–4)    (mm)           (mm)           stage (Tauber)   stage (Tauber)   (quadrants 0–4)   vascularisation   test* (mm)   DIF                   Buccal DIF          Serology

                                                                 1              49, M          EEC               OD      HM               2               11            11 normal      IIb              I                3                 Superior 270u       1          Negative              Negative            IgG
                                                                                                                                                                                                                                                                                                                    to BP180-
                                                                                                                 OS      CF               4               16                    9      IIbIIIb(2)       IIa              4                 360u                2          Negative
                                                                 2              39, M          EEC               OD      3/60, CL 6/12    3              .18 normal             4      I                IIcIIIb(2)       2                 Superior          .10          Negative              Linear BMZ          Negative
                                                                                                                                                                                                                                                                                                staining with IgG
                                                                                                                 OS      6/9              3               16                    2.5    IIa              IIcIIIb(2)       1.5               Superior          .10          Negative
                                                                 3              28, F          EEC               OD      6/60             3              .18 normal             9      I                IIa              2                 Superior          .10          Linear BMZ fibrin     Negative            Negative
                                                                                                                 OS      HM               3               11                   10      IIcIIIc(1)       I                2                 Superior          .10          Linear BMZ fibrin
                                                                 4              37, M          Hypohydrotic ED   OD      CF               3              .18 normal             9      I                IIa              4                 360u                5          Linear BMZ staining   Negative            Negative
                                                                                                                                                                                                                                                                          with IgA
                                                                                                                 OS      3/60 ph 6/60     3              .18 normal             9      I                IIa              4                 360u               10          Linear BMZ staining
                                                                                                                                                                                                                                                                          with IgA
                                                                 5              42, M          EEC               OD      6/24, ph 6/9     4                 9                   6      IIc              IIbIIIb(3)       4                 360u              .10          Linear BMZ fibrin     Negative            IgA autoanti-
                                                                                                                                                                                                                                                                          staining                                  bodies to
                                                                                                                                                                                                                                                                                                                    BP180 soluble
                                                                                                                 OS      6/9              3               13            11 normal      IIb              IIIa(1)          1                 Superior          .10          Linear BMZ fibrin
                                                                 6              39, F          Hypohydrotic ED   OD      CF               2                 9                   8      IIcIIIa(1)       IIbIIIa(1)       2.5               Superior            4          Linear BMZ fibrin     Negative            Negative
                                                                                                                                                                                                                                                                                                                                                        Downloaded from bjo.bmj.com on 25 September 2008

                                                                                                                 OS      2/60             2                 7                   7      IIcIIIa(1)       IIbIIIa(1)       3.5               Superior            0          Linear BMZ fibrin

                                                                     *Schirmer test without anaesthesia, at 5 min.
                                                                     {Detected by ELISA to a recombinant NC16A (16th non-collagenous domain A) portion of BP180.
                                                                     BMZ, basement membrane zone; BP180, bullous pemphigoid antigen 180 kDa; CF, count fingers; CL, contact lens; DIF, direct immunofluorescence; EEC, ectrodactyly, ectodermal dysplasia, cleft lip and palate; HM, hand movements; LAD-1, linear
                                                                     IgA dermatosis antigen-1; OD, right eye; OS, left eye; ph, pinhole; VA, visual acuity.

Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583
                                               Downloaded from bjo.bmj.com on 25 September 2008

                                                                                                                    Clinical science

Figure 1 (A) Conjunctival direct
immunofluorescence from case 4
showing linear basement membrane IgA
deposition. (B) Buccal mucosal direct
immunofluorescence from case 2
showing linear basement membrane IgG

selected according to the lid and conjunctival cultures, and             (bullous pemphigoid antigen of 180 kDa) in case 1, and IgA
unpreserved lubricants. A stepladder strategy for steroid-sparing        autoantibodies reacting against the soluble ectodomain of
immunosuppression was employed, as described previously,16 17            BP180 (also known as LAD-1 (linear IgA dermatosis antigen-
consisting of a 4–6 week course of oral corticosteroids combined         1)) in case 5. Indirect immunofluorescence on human salt split
with one or more immunosuppressive agents. The least toxic               skin and monkey oesophagus, and autoimmune connective
agents were used first, and therapy was stepped up to more               tissue disease tests were negative in all patients. Conjunctival
toxic agents if the conjunctival inflammation did not respond            histopathology showed goblet cell depletion in thickened
after 6–8 weeks. Blood pressure, weight, urinalysis and blood            irregular epithelium, and a chronic inflammatory mononuclear
tests were evaluated regularly to screen for drug-related side           infiltrate and scarring in the substantia propria in all cases.
effects. The degree of photophobia (graded 0–4), conjunctival               Immunosuppression reduced conjunctival inflammation in 9/
inflammation (graded 0–4)18 and visual acuity were monitored.            12 eyes (table 2, figs 2–4). Photophobia was markedly reduced in
                                                                         all patients during the course of treatment, but this deteriorated
                                                                         when the inflammation rebounded, or corneal perforations
Literature-review strategy
                                                                         occurred. Improvement of visual acuity, including the ability to
The authors conducted a comprehensive search to identify all
                                                                         tolerate a contact lens for best vision, occurred in 4/12 eyes. Of
previous reports describing the immunopathological manifesta-
                                                                         the remaining eight eyes, visual acuity remained stable in five,
tions of ectodermal dysplasia and cicatrising conjunctivitis.
                                                                         and deteriorated in three eyes. Recurrent epithelial defects,
English and non-English language articles were retrieved using a
                                                                         corneal perforations and frequent corneal and conjunctival
keyword and thesaurus search of MEDLINE (1966 onwards),
                                                                         infections punctuated the treatment course in 5/12 eyes.
EMBASE (1966 onwards) and the Web of Science Citation
                                                                            Immunosuppressive drugs were given according to the
Index. The search terms included: ectodermal dysplasia and
                                                                         stepladder strategy previously described,16 17 and included
(Boolean) immunoglobulin, basement membrane immunoglobulin,
                                                                         prednisolone 1–1.5 mg/kg/day as a tapering course over 6 weeks
fluorescent antibody test, cicatrix and (Boolean) conjunctivitis,
                                                                         (six patients), ciclosporin 3–5 mg/kg/day (five patients), dap-
cicatrising conjunctivitis. This was supplemented by manually
                                                                         sone 50–100 mg/day (four patients), azathioprine 1–2.5 mg/kg/
searching the reference lists of all included studies. Reference
                                                                         day (three patients), mycophenolate 0.5–1 g twice daily (six
books searched included major dermatological and ophthalmo-
                                                                         patients) and cyclophosphamide 1–2 mg/kg/day (three
logical texts.
                                                                         patients) (table 2). A combination of two or more drugs was
   The study was conducted with approval of the local research
                                                                         necessary to control inflammation in all patients. Changes in
governance committee and with the informed consent of the
                                                                         treatment were due to either intolerance or inadequate control
                                                                         of inflammation. For details, see Case Reports (available online).
                                                                            Bacterial infection and colonisation were treated with
RESULTS                                                                  4 weeks of topical antibiotics to which the organisms were
The mean age was 39 (7) years (range 28–49) with a                       sensitive, followed by topical chlorhexidine 0.02% or polyhex-
male:female ratio of 2:1. There was shortening of the upper              amethylbiguanide (PHMB) if organisms were still cultured.
conjunctival fornix in 8/12 (67%) eyes and of the lower fornix in
10/12 (83%) eyes (table 1). Advanced scarring and contracture
with symblephara were present in 8/12 (83%) eyes. Entropion
                                                                         Anti-basement membrane zone autoantibodies were detected in
was present in 4/12 and trichiasis in 4/12 (33%) eyes.
                                                                         four of the six ectodermal dysplasia patients with bilateral
Meibomian gland orifices were absent in all eyelids, and no
                                                                         chronic cicatrising conjunctivitis in this series. The inflamma-
meibomian gland tissue could be detected by lid eversion at the
                                                                         tion, photophobia and blepharospasm appeared to respond to
slit lamp. Tear-film break-up time was reduced in all eyes.
                                                                         steroid-sparing systemic immunosuppression combined with
Schirmer’s I test without anaesthetic was reduced in both eyes
                                                                         topical antibiotics, when it had failed to respond to topical
of three patients.
                                                                         steroids, antibiotics and lid hygiene alone.
   Direct immunofluorescence testing (direct IF) showed linear
immunoglobulin staining on the conjunctival biopsies (IgA)
from case 4 (fig 1A), and the buccal biopsy (IgG, IgM) from case         Significance of the anti-basement membrane zone
2 (fig 1B). Circulating autoantibodies were detected in the              autoantibodies
serum of two additional patients: IgG autoantibodies reacting            Conjunctival cicatrisation is a recognised feature of the EEC
with the NC16A (16th non-collagenous A) domain of BP180                  syndrome, but to our knowledge the presence of anti-basement

Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583                                                                         1405
                                                                 Table 2 Immunosuppressive therapy and treatment course

                                                                                              Conjunctival                                                                                       Conjunctival
                                                                                              inflammation at   Photophobia at                                                                   inflammation    Photophobia
                                                                          Visual acuity* at   presentation      presentation                                                 Visual acuity* at   at last visit   at last visit                                        Follow-up
                                                                 Case     presentation        (grade 0–4)       (grade 0–4)      Immunosuppressive treatment                 last visit          (grade 0–4)     (grade 0–4)     Events occurring during follow-up    duration (m)   Microbial cultures

                                                                 1        OD HM               OD 2              OD 3             3/2003{ ciclosporin+short course            OD 1/36             OD 1            OD 1            9/2003{OS ECCE/IOL/vitrectomy; 8/ 38                3/2003{ eyelids: S aureus, Conj:
                                                                                                                                 prednisolone reduced inflammation                                                               2004 OS microbial keratitis                         no growth
                                                                          OS CF               OS 4              OS 4             9/2003 dapsone+ciclosporin after OS         OS CF, CL 6/18      OS 2            OS 2            11/2004 OD phacoemulsification/IOL                  8/2004 cornea-negative cultures
                                                                                                                                                                                                                                                                                                                          Clinical science

                                                                                                                                 cataract surgery controlled inflammation
                                                                                                                                 for 7 months then rebound OD
                                                                                                                                 4/2004 dapsone+mycophenolate                                                                    12/2004 OD corneal perforation                      9/2004 eyelids: mixed skin flora
                                                                                                                                 controlled inflammation for 24 months
                                                                                                                                                                                                                                 6/2005 OS ocutome capsulotomy                       12/2004 cornea-negative cultures
                                                                                                                                                                                                                                                                                     8/2005 eyelids: no growth
                                                                                                                                                                                                                                                                                     8/2005 conj: S aureus, S
                                                                 2        OD 3/60, CL 6/12    OD 3              OD 3             1/2004 dapsone reduced inflammation to      OD CL 6/18 ph 6/9 OD 0              OD 0            8/2004 L corneal ulcer               34             7/2006 conj: S viridans
                                                                                                                                 grade 1 OS, grade 2 OD
                                                                          OS 6/9              OS 3              OS 3             8/2004 dapsone+azathioprine+short           OS CL 6/18 ph 6/9 OS 1              OS 1                                                                9/2006 conj: no growth
                                                                                                                                 course prednisolone reduced inflammation
                                                                                                                                 to grade 1 for 9 months then rebound
                                                                                                                                 5/2005 dapsone+mycophenolate poor
                                                                                                                                 10/2005 dapsone+cyclophosphamide+
                                                                                                                                 short course prednisolone controlled
                                                                                                                                 inflammation for 9 months
                                                                 3        OD 6/60             OD 3              OD 4             5/2004 azathioprine+short course            OD 6/36             OD 0            OD 0            5/2004 OS upper fornix MMG           34             10/2005 cornea: S aureus, b haem-
                                                                                                                                 prednisolone for fornix reconstruction;                                                         reconstruction                                      strep
                                                                                                                                 nausea due to azathioprine
                                                                          OS HM               OS 3              OS 4             6/2004 mycophenolate                        OS LP               OS 1            OS 1            8/2005 OS ex-vivo amplified allo-                   11/2005 conj: skin flora, Candida
                                                                                                                                                                                                                                 LSCGraft                                            albicans
                                                                                                                                 8/2005 mycophenolate+ciclosporin+short                                                          10/2005 OS perforated microbial                     12/2005 Cornea: S pneumoniae
                                                                                                                                 course prednisolone for ex vivo amplified                                                       keratitis, suprachoroidal
                                                                                                                                 LSCGraft                                                                                        haemorrhage, emergency tectonic
                                                                                                                                                                                                                                 corneoscleral graft
                                                                                                                                 2/2006 mycophenolate alone                                                                      11/2005 2nd OS ex-vivo amplified                    5/2006 conj: no growth
                                                                                                                                 5/2006 stopped medication as                                                                    12/2005 OS microbial keratitis in
                                                                                                                                 inflammation controlled                                                                         persistent defect
                                                                                                                                                                                                                                 1/2006 OS conjunctival flap
                                                                 4        OD CF               OD 3              OD 3             2/2004 azathioprine+short course            OD CF               OD 0            OD 0            1/2005 Elevated creatinine           29             1/2004 conj: MRSA, S pneumoniae
                                                                                                                                                                                                                                                                                                                                             Downloaded from bjo.bmj.com on 25 September 2008

                                                                                                                                 prednisolone controlled inflammation for                                                        ciclosporin ceased
                                                                                                                                 5 months then rebound
                                                                          OS 3/60 ph 6/60     OS 3              OS 3             7/2004 mycophenolate did not control        OS 6/60 ph 6/36     OS 0            OS 0
                                                                                                                                 9/2004 mycophenolate+ciclosporin+
                                                                                                                                 prednisolone controlled inflammation for
                                                                                                                                 5 months then rebound
                                                                                                                                 2/2005 mycophenolate+dapsone
                                                                                                                                 controlled inflammation for 14 months
                                                                 5        OD 6/24 ph 6/9      OD 4              OD 4             3/2004 azathioprine—did not tolerate        OD 6/24 ph 6/12     OD 0            OD 0            5/2004 OS Pseudomonas keratitis      32             5/2004 cornea: M catarrhalis,
                                                                                                                                 nausea, insomnia                                                                                with corneal perforation and                        Pseudomonas
                                                                                                                                                                                                                                 deterioration of OS vision to 1/60
                                                                          OS 6/9              OS 3              OS 3             4/2004 dapsone did not control              OS CF               OS 1            OS 1                                                                10/2005 eyelids: CN Staph; Conj:
                                                                                                                                 inflammation                                                                                                                                        Pseudomonas
                                                                                                                                 5/2004 dapsone+mycophenolate+short                                                                                                                  12/2005 conj: no growth
                                                                                                                                 course oral prednisolone controlled for
                                                                                                                                 21 months then rebound


Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583
                                                                                                                                                                                                                           Downloaded from bjo.bmj.com on 25 September 2008

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                Clinical science

                                                                                                                                                                                                                                                                                                                allo-LSCGraft, allogeneic limbal stem cell graft; b haem-strep, beta haemolytic Streptococcus; CF, count fingers; CL, when tolerating contact lens correction; conj, conjunctiva; CN Staph, coagulase negative Staphylococcus; ECCE, extracapsular
                                                                                                                                                             11/2005 conj and eyelids: S aureus
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     membrane zone autoantibodies has not previously been

                                                                                            10/2006 conj: no growth, eyelids:

                                                                                                                                                                                                                                                                             8/2006 conj: no growth, eyelids:
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     reported. The finding of basement membrane autoantibodies

                                                                                                                                10/2004 eyelids: no growth
                                                                 3/2006 conj: Pseudomonas
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     in four of the six patients with cicatrising conjunctivitis

                                                                                                                                                                                                                                                   4–7/2006 conj: S aureus
                                                                                                                                                                                                  1/2006 conj: no growth

                                                                                                                                                                                                                                                                             11/2006 conj: S aureus
                                                                                                                                                                                                                           3/2006 conj: S aureus

                                                                                                                                                                                                                                                                                                                cataract extraction; HM, hand movements; IOL, intraocular lens; LP, light perception; m, months; MMG, mucous membrane graft; MRSA, methicillin-resistant Staphylococcus aureus; OD, right eye; OS, left eye; ph, pinhole; Phaco,
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     suggests that the pathogenesis may be similar to that occurring
                             Microbial cultures

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     in mucous membrane pemphigoid (MMP), or may indicate a
                                                                                            CN Staph                                                                                                                                                                                                                                                                                                                                                                                                                                                                 predisposition to developing a mucous membrane pemphigoid-

                                                                                                                                                                                                                                                                             S aureus
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     like disease where the mucosal injury acts as a trigger. No
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     symptoms or signs of ulceration or scarring of extraocular
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     mucous membranes or skin were detected in any of the patients
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     in this series. Ectodermal dysplasia may be associated with
                    duration (m)

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     autoimmune disease,19 as in case 3 who had Addison disease, but

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     there may also be no evidence of immunological dysfunction in

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     other EEC patients.20
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        In addition to immunofluorescence techniques, we used
                             Events occurring during follow-up

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     serological diagnostic techniques, including immunoblot assay
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     and ELISA to detect circulating autoantibodies to basement
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     membrane zone antigens which have been reported to contain
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     target epitopes in mucous membrane pemphigoid (MMP), as
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     part of our work-up for cicatrising conjunctivitis resembling
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     ocular mucous membrane pemphigoid. When indirect immuno-
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     fluorescence microscopy is used, circulating antibodies against
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     the epithelial basement membrane zone are detected in only
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     about 50% of MMP sera.14 In comparison, when immunoblot-

               (grade 0–4)
               at last visit

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     ting assays are used, autoantibodies can be detected in 75–100%
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     of MMP sera.13 14 These assays are not currently used outside the
                                                                                                                                OD 3

                                                                                                                                                             OS 3

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     research setting due to the costs involved.
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        Finding autoantibodies in these four patients may provide a

            (grade 0–4)
            at last visit

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     rationale for the use of systemic immunosuppression, but
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     steroid-sparing immunosuppression may also be helpful in
                                                                                                                                OD 3

                                                                                                                                                             OS 3

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     patients in whom no immunoglobulin deposition is detected,
                    Visual acuity* at

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     as in case 3 in our series. Longitudinal follow-up of these cases,
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     including those treated with immunosuppression and those not
                    last visit

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     treated with immunosuppression, will help assess whether and
                                                                 9/2004 minimal conjunctival inflammation, OD CF

                                                                                                            OS CF

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     how quickly cicatrisation progresses. Repeat fornix depth
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     measurements in Case 5, whose conjunctival inflammation
                                                                 +short course prednisolone did not control
                                                                 +ciclosporin controlled inflammation for

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     has been overall well controlled with systemic immunosuppres-
                                                                 3/2006 ciclosporin+cyclophosphamide
                                                                 12 months then flare of inflammation

                                                                 11/2005 ciclosporin+mycophenolate
                                                                 4/2006 dapsone+cyclophosphamide

                                                                 no immunosuppression required for

                                                                 2/2006 ciclosporin+mycophenolate

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     sion, have showed no change over the last 24 months.
                                                                 2/2006 dapsone+mycophenolate+

                                                                 9/2005 ciclosporin+short course
                             Immunosuppressive treatment

                                                                 prednisolone poor response
                                                                 ciclosporin poor response

                                                                 +dapsone poor response

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     Previous treatments reported
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     Conventional ocular treatment for patients with ectodermal
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     dysplasia has addressed lid margin colonisation8 10 and the
                                                                 poor response

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     characteristic blepharitis, where the eyelids become thickened
                                                                 7 months

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     and inflamed despite the absence or paucity of meibomian
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     glands. Lid hygiene, topical antibiotics and topical steroids or
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     anti-inflammatory agents have had variable effects.7 10 21
               Photophobia at

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     Monitoring for glaucoma in these patients is not easy. The
               (grade 0–4)

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     severe photophobia and blepharospasm makes examination
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     very difficult, and in some cases examinations under anaesthesia
                                                                                                                                OD 2

                                                                                                                                                             OS 2

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     are necessary. For this reason, we have avoided all but short-
                                                                                                                                                                                                                                                                                                                *Visual acuity with preferred correction. {Month/year.

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     term use (ie, less than 1 month) of topical steroids in these
            inflammation at

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        Topical vitamin A therapy has been reported to reduce

            (grade 0–4)

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     photophobia in a patient with hidrotic ectodermal dysplasia and
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     corneal erosions.6 Systemic ciclosporin, topical mycophenolate
                                                                                                                                OD 2

                                                                                                                                                             OS 2

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     and oral steroids have been used to prevent graft rejection
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     following penetrating keratoplasty and keratolimbal allograft-
                    Visual acuity* at

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     ing in two ectodermal dysplasia patients, but their effect on

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     photophobia or conjunctival inflammation in these patients
                                                                                                                                                             OS 2/60

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     was not described.5
                                                                                                                                OD CF

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     Effectiveness and safety of systemic immunosuppression
Table 2

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     Systemic immunosuppression combined with topical antibiotic

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     or antiseptic therapy appeared to reduce disabling photophobia

Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     1407
                                              Downloaded from bjo.bmj.com on 25 September 2008

 Clinical science

Figure 2 (A) Right and (B) left eyes of
case 2, at presentation with grade 3
conjunctival inflammation. Meibomian
gland orifices are absent, and there are
right inferonasal symblephara associated
with fornix contraction. There is left
superior corneal pannus, and epithelial
opacity, indicating focal limbal stem cell
deficiency. Corneal impression cytology
showed central cytokeratin 19,
supporting the clinical findings of stem
cell deficiency.5

Figure 3 (A) Right and (B) left eyes of
case 3 at presentation. (C) Right and (D)
left eyes of case 3 after 8 months of
treatment with mycophenolate. The
conjunctiva and eyelids appear
significantly less inflamed.

Figure 4 Case 5 (A) right and (B) left
eyes at presentation. There is a
contracted right inferior fornix with sheet
scarring and grade 4 conjunctival
inflammation. Case 5 (C) right and (D) left
eyes after 7 months of immuno-
suppression with mycophenolate and
dapsone. The conjunctiva is less
inflamed, with less congested vessels.
Note that the superior corneal opacity has
progressed in the left eye following
Pseudomonas keratitis and corneal
perforation in this area of recurrent
epithelial breakdown associated with
limbal stem cell deficiency.

1408                                                                                Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583
                                               Downloaded from bjo.bmj.com on 25 September 2008

                                                                                                                                   Clinical science

and conjunctival inflammation in 5/6 (83%) of patients in this           lacrimal drainage abnormalities; (3) lack of lipid and mucin in
series. The chief rationale for systemic immunosuppression was           the tear film due to absent meibomian glands and reduced
the clinical dilemma of a prolonged active inflammatory state            goblet cells. Goblet cells may be reduced as a consequence of
with poor response to topical therapy. Given the prolonged               inherent defects in the conjunctival epithelium as well as
course of inflammation, immunosuppression was commenced                  secondary to conjunctival fibrosis. In severe cases (eg, case 1),
as steroid-sparing therapy, to avoid the significant morbidity           lacrimal ductule obstruction from conjunctival fibrosis leads to
associated with long-term high-dose systemic corticosteroids.            further instability of the tear film and surface epithelial
This is an uncontrolled case series, however, so the true value of       destruction. Meibomian lipid may also function to trap and
the combined treatment approach cannot be assessed.                      enfold micro-organisms, pollen or other organic matter, thereby
Furthermore, topical immunosuppression using ciclosporin or              rendering the entity isolated and harmless, and a lack of
tacrolimus could be considered. In the UK, our locally available         meibomian lipid may enable such particles to injure the
preparation of ciclosporin is poorly tolerated (2% in oil), and          mucosa;26 and (4) a primary defect of ectodermally derived
topical tacrolimus is not available for ophthalmic use.                  conjunctival epithelium. Recent evidence from a mouse model
   Recurrent corneal and conjunctival infections and colonisa-           of X linked anhydrotic ectodermal dysplasia supports the latter
tion by pathogenic organisms despite prophylactic topical                notion of ocular surface health being dependent on proteins
antibiotics or antiseptic therapy was a recalcitrant problem for         such as ectodysplasin, which regulates and maintains ectoderm-
all patients, and was responsible for rebounds in conjunctival           derived tissues.27
inflammation. Systemic immunosuppression appeared to be                     Major visual disability in ectodermal dysplasia patients is
effective for several months, but then corneal perforations or a         attributed to severe photophobia and blepharospasm,21 along
flare-up of conjunctival inflammation led to a change in                 with blindness secondary to corneal vascularisation.7 Our
medication. Most patients required two agents to control                 patients were most improved when they were taking immuno-
photophobia and inflammation, and three of the six have                  suppression, and their conjunctival and eyelid cultures showed
required the most toxic agent, cyclophosphamide. Systemic                no growth. For this reason, we postulate that the ongoing
immunosuppression did not appear to impair the ability to                conjunctival inflammation and associated conjunctival scarring
overcome corneal or conjunctival infections, as all acute                in these patients may be due to an abnormal host response to
infections in this series of patients resolved. Whether immuno-          bacterial colonisation or infection. Ongoing surface inflamma-
suppressive therapy had any effect on increasing the predisposi-         tion and limbitis may play a role in the pathogenesis of ocular
tion to developing such infections could not be evaluated in this        surface failure and corneal vascularisation, which is the other
study.                                                                   major cause of visual impairment.
   Adverse effects encountered during immunosuppression in                  In conclusion, anti-basement membrane zone autoantibodies
our patients, all of which were reversible upon cessation of             are detectable in a subgroup of ectodermal dysplasia patients
therapy, included renal impairment due to ciclosporin, nausea            with cicatrising conjunctivitis. We propose that clearance of
due to azathioprine and liver-function abnormalities due to              bacterial colonisation, combined with suppression of the
mycophenolate and azathioprine. Although the sample size and             excessive inflammatory response by immunosuppressive ther-
duration of follow-up are not great enough to know how safe              apy administered by experienced physicians, can improve the
immunosuppressive treatment is in this group of patients, some           visual disability caused by intractable conjunctival inflamma-
information on the safety and risks associated with the                  tion and photophobia, and provide an opportunity for carrying
treatment can be gained from our report of use of a similar              out ocular surface reconstructive surgery to treat the blindness
immunosuppressive strategy in 115 patients with mucous                   due to corneal disease.
membrane pemphigoid, where the duration of follow-up was
up to 14 years.17 Furthermore, it is unknown how long the
                                                                         Funding: This study was supported by the Special Trustees of Moorfields Eye
immunosuppressive therapy will be maintained for in these                Hospital, a Royal Australian & New Zealand College of Ophthalmologists/Advanced
patients. In case 3, immunosuppression was stopped after                 Medical Optics Scholarship and a University College London Graduate School
3 years as the ocular surface inflammation had been quiescent            Scholarship (VPJS).
for 6 months.                                                            Competing interests: None.
                                                                         Ethics approval: Ethics approval was obtained from the local research governance
Proposed pathogenesis of the cicatrising conjunctivitis                  committee.
Patients developing conjunctival scarring as part of their disease       Patient consent: Obtained.
process can be divided into two categories, and the patients
with ectodermal dysplasia presented here may fit both of these:
in the first category, chronic ocular mucosal injury precipitates         1.   Lamartine J. Towards a new classification of ectodermal dysplasias. Clin Exp
conjunctival cicatrisation that may be progressive, as in atopic               Dermatol 2003;28:351–5.
keratoconjunctivitis, rosacea and trachoma22 (cases 3, 6 in this          2.   Bonnar E, Logan P, Eustace P. Absent meibomian glands: a marker for EEC
report). In the second category, conjunctival cicatrisation may                syndrome. Eye 1996;10:355–61.
                                                                          3.   Kaercher T. Ocular symptoms and signs in patients with ectodermal dysplasia
be associated with antibodies directed at the basement                         syndromes. Graefes Arch Clin Exp Ophthalmol 2004;242:495–500.
membrane, as in mucous membrane pemphigoid,12 which may                   4.   McNab AA, Potts MJ, Welham RA. The EEC syndrome and its ocular
be a final common pathway for a subset of patients with                        manifestations. Br J Ophthalmol 1989;73:261–4.
progressive conjunctival cicatrisation, including those with              5.   Anderson NJ, Hardten DR, McCarty TM. Penetrating keratoplasty and keratolimbal
                                                                               allograft transplantation for corneal perforations associated with the ectodermal
Stevens–Johnson syndrome23 and drug-induced ocular pemphi-                     dysplasia syndrome. Cornea 2003;22:385–8.
goid24 25 (cases 1, 2, 4, 5 in this report).                              6.   Donahue JP, Shea CJ, Taravella MJ. Hidrotic ectodermal dysplasia with corneal
  Possible factors involved in chronic mucosal injury in these                 involvement. J AAPOS 1999;3:372–5.
                                                                          7.   Mawhorter LG, Ruttum MS, Koenig SB. Keratopathy in a family with the ectrodactyly-
patients with ectodermal dysplasia include: (1) recurrent lid and
                                                                               ectodermal dysplasia-clefting syndrome. Ophthalmology 1985;92:1427–31.
conjunctival infection due to microbial colonisation of the               8.   Kasmann B, Ruprecht KW. Ocular manifestations in a father and son with EEC
ocular surface; (2) recurrent conjunctival infection due to                    syndrome. Graefes Arch Clin Exp Ophthalmol 1997;235:512–16.

Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583                                                                                             1409
                                                           Downloaded from bjo.bmj.com on 25 September 2008

 Clinical science

 9.    Ireland IA, Meyer DR. Ophthalmic manifestations of ectrodactyly-ectodermal                   18.   Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroid in
       dysplasia-clefting syndrome. Ophthal Plast Reconstr Surg 1998;14:295–7.                            ocular cicatricial pemphigoid. Br J Ophthalmol 1995;79:264–6.
10.    Kaiser-Kupfer M. Ectrodactyly, ectodermal dysplasia, and clefting syndrome.                  19.   Hung SO, Patterson A. Ectodermal dysplasia associated with autoimmune disease.
       Am J Ophthalmol 1973;76:992–8.                                                                     Br J Ophthalmol 1984;68:367–9.
11.    Schwab IR, Linberg JV, Gioia VM, et al. Foreshortening of the inferior conjunctival fornix   20.   Obel N, Hansen B, Black FT. Normal immunological status in four patients with
       associated with chronic glaucoma medications. Ophthalmology 1992;99:197–202.                       ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC-syndrome). Clin Genet
12.    Chan LS, Ahmed AR, Anhalt GJ, et al. The first international consensus on mucous                   1993;43:146–9.
       membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical            21.   Baum JL, Bull MJ. Ocular manifestations of the ectrodactyly, ectodermal dysplasia,
       treatment, and prognostic indicators. Arch Dermatol 2002;138:370–9.                                cleft lip-palate syndrome. Am J Ophthalmol 1974;78:211–16.
13.    Oyama N, Setterfield JF, Powell AM, et al. Bullous pemphigoid antigen II (BP180)             22.   Bernauer W, Elder MJ, Dart JK. Introduction to cicatrising conjunctivitis. Dev
       and its soluble extracellular domains are major autoantigens in mucous membrane                    Ophthalmol 1997;28:1–10.
       pemphigoid: the pathogenic relevance to HLA class II alleles and disease severity.           23.   Chan LS, Soong HK, Foster CS, et al. Ocular cicatricial pemphigoid occurring as a
       Br J Dermatol 2006;154:90–8.                                                                       sequela of Stevens–Johnson syndrome. JAMA 1991;266:1543–6.
14.    Schmidt E, Skrobek C, Kromminga A, et al. Cicatricial pemphigoid: IgA and IgG                24.   Leonard JN, Hobday CM, Haffenden GP, et al. Immunofluorescent studies in ocular
       autoantibodies target epitopes on both intra- and extracellular domains of bullous                 cicatricial pemphigoid. Br J Dermatol 1988;118:209–17.
       pemphigoid antigen 180. Br J Dermatol 2001;145:778–83.                                       25.   Patten JT, Cavanagh HD, Allansmith MR. Induced ocular pseudopemphigoid.
15.    Sitaru C, Zillikens D. Mechanisms of blister induction by autoantibodies. Exp                      Am J Ophthalmol 1976;82:272–6.
       Dermatol 2005;14:861–75.                                                                     26.   McCulley JP, Shine WE. Meibomian gland and tear film lipids: structure, function
16.    Rauz S, Maddison PG, Dart JK. Evaluation of mucous membrane pemphigoid with                        and control. Adv Exp Med Biol 2002;506:373–8.
       ocular involvement in young patients. Ophthalmology 2005;112:1268–74.                        27.   Cui CY, Smith JA, Schlessinger D, et al. X-linked anhidrotic ectodermal dysplasia
17.    Saw VP, Dart JK, Rauz S, et al. Immunosuppressive therapy for ocular mucous                        disruption yields a mouse model for ocular surface disease and resultant blindness.
       membrane pemphigoid strategies and outcomes. Ophthalmology 2008;115:253–61.                        Am J Pathol 2005;167:89–95.

1410                                                                                                                 Br J Ophthalmol 2008;92:1403–1410. doi:10.1136/bjo.2007.130583