REVIEW

Ocular Mucous Membrane Pemphigoid: Current Stateof Pathophysiology, Diagnostics and Treatment

Panagiotis Georgoudis . Francesco Sabatino . Nora Szentmary .

Sotiria Palioura . Eszter Fodor . Samer Hamada . Hendrik P. N. Scholl .

Zisis Gatzioufas

Received: December 3, 2018 / Published online: January 29, 2019� The Author(s) 2019

ABSTRACT

Mucous membrane pemphigoid (MMP) is asystemic cicatrizing autoimmune disease thatprimarily affects orificial mucous membranes,

such as the conjunctiva, the nasal cavity, theoropharynx, and the genitalia. Ocular involve-ment occurs in about 70% of all MMP cases.Ocular MMP (OcMMP) also encompasses theconditions linear immunoglobulin A disease,mucosal dominated epidermolysis bullosaacquisita, and anti-laminin 332/anti-epiligrin/anti-laminin 5 pemphigoid. It is a complexclinical entity that may lead to ocular surfacefailure and result in inflammatory and infec-tious complications, as well as potentially dev-astating visual loss. Early diagnosis andappropriate treatment are of paramount impor-tance and require a high level of expertise as thiscondition can be extremely challenging todiagnose and treat even for experienced clini-cians. In this review we provide an up-to-dateinsight on the pathophysiology of OcMMP, withan emphasis on the current state of its diagnos-tics and therapeutics. Our the aim is to increaseour understanding of OcMMP and highlightmodern diagnostic and therapeutic options.

Keywords: Diagnostics; Mucous; Ocularpemphigoid; Pathophysiology; Treatment

INTRODUCTION

Mucous membrane pemphigoid (MMP) is a sys-temic cicatrizing autoimmune disease that pri-marily affects orificial mucous membranes, such

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P. GeorgoudisWhipps Cross University Hospital, Barts Health NHSTrust, London, UK

F. SabatinoMoorfields Eye Hospital, London, UK

N. SzentmaryDepartment of Ophthalmology, Saarland UniversityMedical Center, Homburg/Saar, Germany

N. Szentmary � E. FodorDepartment of Ophthalmology, SemmelweisUniversity, Budapest, Hungary

S. PaliouraAthens Vision Eye Institute, Athens, Greece

S. HamadaCorneo-Plastic Unit, Queen Victoria Hospital, EastGrinstead, UK

H. P. N. Scholl � Z. Gatzioufas (&)Department of Ophthalmology, Basel UniversityHospital, Basel, Switzerlande-mail: zisisg@hotmail.com

H. P. N. SchollInstitute of Molecular and Clinical OphthalmologyBasel (IOB), Basel, Switzerland

Ophthalmol Ther (2019) 8:5–17

https://doi.org/10.1007/s40123-019-0164-z

as the conjunctiva, the nasal cavity, theoropharynx, and the genitalia. In some cases theesophagus, the trachea, and the skin may also beinvolved.Theeyes are affected inabout 70%ofallMMP cases. The progressive inflammatory andscarring nature of MMP leads to severe visualimpairment in 30% of affected eyes and bilateralblindness in 20% [1–4]. Systemic immunomod-ulatory therapy is often required to limit diseaseprogression. The older term ocular cicatricialpemphigoid (OCP)hasnow largely been replacedby ocularMMP (OcMMP) after publication of the2002 international consensus document [5].OcMMP also encompasses the conditions linearimmunoglobulin (Ig) A disease, mucosal domi-nated epidermolysis bullosa acquisita, and anti-laminin 332/anti-epiligrin/anti-laminin 5 pem-phigoid [6]. This article is based on previouslyconducted studies and does not contain anystudies with human participants or animals per-formed by any of the authors.

EPIDEMIOLOGY

Ocular MMP is the leading cause of cicatrizingconjunctivitis in developed countries [4, 7, 8].Its incidence in the UK is estimated as 0.8 permillion, with MMP currently representingabout 60% of cicatrizing conjunctivitis cases [8].Similar incidences have been estimated France(1.13 per million) and Germany (0.87 per mil-lion) [4]. MMP may affect any race, but it seemsto be more common in Caucasians than inIndians and Chinese. Expression of the HLA-DR4, HLA-DQw3, and HLA-DQb*10301 alleles,which are involved in antigen presentation to Tcells, is associated with development of OcMMP[9–13]. For most patients, however, no identifi-able predisposing factor is found.

PATHOPHYSIOLOGY

The underlying pathophysiological mechanismof this mucocutaneous disease—which is rarelyassociated with the blistering cutaneous form—is a type 2 hypersensitivity reaction against thebasal epithelial membrane of the conjunctiva[14]. Like most autoimmune diseases,

environmental factors and genetic susceptibil-ity are each believed to play a role to initiate aloss of tolerance to one or more components ofthe basal membrane zone.

The conjunctiva is composed of a superficialepithelium and an underlying connective tissuestroma (substantia propria). The conjunctivalepithelium is a stratified, non-keratinized,secretory epithelium. This non-keratinized stateof the conjunctival epithelium is crucial to itshealth, which is lost in keratinized ocular sur-face disorders, such as OcMMP. In OcMMP, thenormal conjunctival epithelium undergoessquamous metaplasia and is transformed to anon-secretory, keratinized epithelium. Addi-tional changes include loss of goblet cells,increased cellular stratification, enlargement ofsuperficial cells, keratinization, and limbal stemcell deficiency [14].

The basement membrane zone (BMZ) of theconjunctival epithelium is between the epithe-lial cells and the superficial layer of the sub-stantia propria. The basement membrane (BM)is composed of two layers: the lamina lucida,which is closer to the basal epithelial cells, andthe lamina densa, which lies closer to the sub-stantia propria. The BM is mainly composed oftype IV collagen, laminin, and fibronectin.Desmosomes hold conjunctival epithelial cellstightly together, while hemidesmosomes,intracytoplasmatic cytokeratin filaments andanchorage fibers, and plaques facilitate theadherence of the conjunctival epithelium to thelamina lucida of the BM [14, 15]. A majorcomponent of the hemidesmosome proteincomplex is integrin a6b4. The ligands of thisintegrin (a6 integrin, b4 integrin, laminin 5[laminin 332], collagen VII, BP180 [bullouspemphigoid 180-kDa antigen; also known as BPantigen 2], and BP230 [bullous pemphigoid230-kDa antigen; also known as BP antigen 1])are the main target antigens of OcMMP [15, 16].

BP230 is a cytoskeletal linker protein thatconnects hemidesmosomes with keratin inter-mediate filaments. It is not thought to beinvolved in the initiation of the inflammatoryresponse due to its intracellular localization.BP180 is a transmembrane protein that spansthe lamina lucida and projects to the laminadensa. The most important epitope of BP180 is

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the non-collagenous 16A domain (NC16A),which is located at the membrane–proximalregion. Circulating autoantibodies (IgG and IgE)prefer to recognize the phosphorylatedBP180–NC16A ectodomain [17]. Anotherimportant target antigen is laminin 332 (lami-nin 5), which connects the transmembraneproteins of the epithelial cells to the anchoringfilaments of the basement membrane. Anti-bodies against laminin 332 (laminin 5) arethought to induce subepidermal blisters [17].

Deep in the BMZ lies the fibrovascular con-nective tissue referred to as the stroma (sub-stantia propria). The stroma contains blood andlymphatic vessels, fibroblasts, nerve fibers,melanocytes, accessory lacrimal glands, andnumerous immune cells. In normal conjunc-tiva, dendritic antigen-presenting cells(Langerhans cells) and CD8 suppressor T cellsare in the epithelium, and CD8 suppressor Tcells, CD4 helper cells, and Langerhans cells arein the substantia propria. This diffuse layer ofnumerous subepithelial lymphocytes forms theconjunctival associated lymphoid tissue(CALT), which in turn is part of the mucosa-associated lymphoid tissues (MALT) [14].

The immunopathological progression ofOcMMP has three distinct phases: the injuryphase, the acute inflammation and proliferationphase, and the fibrosis phase. The trigger for theonset of the OcMMP is unknown.

In the injury phase, autoantibodies are direc-ted against conjunctival BM antigens, such asBP180, laminin 332 (laminin 5), collagen VII,and a6b4 integrin [17]. The activated T cellsgenerate specific B-cell clones, and these clonesproduce circulating autoantibodies (IgG andIgA) that bind to the specific BMZ component,initiate a type 2 hypersensitivity reaction, andactivate the complement cascade (C3) [15].

In the acute inflammation and proliferationphase, damage to the complement-mediatedepithelial, BMZ, and connective tissue leads tovasodilatation and consecutive inflammatorycell infiltration. Neutrophils, macrophages,antigen-presenting cells, mast cells, platelets,and T cells accumulate in the substantia propriaand initiate a destructive inflammatory cascade.Activated neutrophils play a major role in col-lateral tissue damage by releasing

proinflammatory cytokines, proteinases, andreactive oxygen species. The acute inflamma-tory cytokines, such as interleukin-1 (IL-1), IL-17, and tumor necrosis factor-alpha (TNFa),that are released stimulate conjunctival fibrob-lasts and promote further inflammatory cellinfiltration [15]. In cases of mild conjunctivalinflammation, the ratio of CD4:CD8 T cells is\ 0.5, while in severe forms it increases to 1.0[18]. Type 1 helper T cells produce interferongamma and IL-2, and type 2 helper T cellsrelease IL-4, IL-5, and IL-13. IL-13. The afore-mentioned cytokines have a strong proinflam-matory and profibrotic effect on conjunctivalfibroblasts. Macrophages secrete profibroticcytokines, transforming growth factor-beta(TGFb), and platelet-derived growth factor,which leads to the fibrosis phase [15].

In the fibrosis phase, conjunctival fibroblastsare activated, proliferate, and produce extracel-lular matrix (ECM), connective tissue growthfactor, TGFb, and other (detected but unexam-ined) cytokines. Consecutively, vascularendothelial cells proliferate to form fibrovascu-lar granulation tissue and subconjunctivalscarring. Proteolytic enzymes, such as matrix-metalloproteases (MMP-2, 9, 13) and theirinhibitors (tissue inhibitors of metallopro-teinases; TIMPs), vascular endothelial growthfactor and fibrovascular growth factor, and IL-1b, -2, -4, -5, -6, -8, -10, -15, and -16 play a rolein the tissue remodeling that occurs, althoughtheir exact role remains to be elucidated [17]. Aneurotrophic growth factor-driven mechanismof fibroblast proliferation has recently beenproposed, which may also be a target in thetreatment of OcMMP [19]. Phenotypic changesin fibroblasts isolated from OcMMP patientsinclude increased motility, contractile function,ECM synthesis, and myofibroblast transforma-tion, and it has been speculated that conjunc-tival fibroblasts may be activated independentlyof cytokines in OcMMP [20]. Recently, it hasbeen shown that the aldehyde dehydrogenase 1subfamily (ALDH 1) plays a role in immune-mediated ocular mucosal scarring and thatALDH inhibition has an antifibrotic action [21].

In summary, circulating autoantibodies havea key role in the pathogenesis of OcMMP asthey bind to antigens within the epithelial BMZ

Ophthalmol Ther (2019) 8:5–17 7

of the conjunctiva and activate the complementcascade, with C3 complement fragmentsdepositing within the lamina lucida [16].Immune cells are recruited secondarily and leadto fibroblast activation and ECM remodeling viacytokine release.

DIFFERENTIAL DIAGNOSIS

A wide range of ocular surface diseases associ-ated or not with systemic conditions may resultsecondarily in cicatricial conjunctivitis [22].Cicatricial conjunctivitis can be broadlycatagorized as (1) static/slow, when the under-lying disease is controlled or when withdrawingthe drug inducing the disease the halts its pro-gression, and (2) progressive with sight-threat-ening potential [23]. Recognizing causes andassociated clinical signs is of paramountimportance for the management of diseaseprogression.

The differential diagnosis of OcMMPincludes other causes of cicatrizing conjunc-tivitis, such as drug-induced progressive con-junctival cicatrization [24], Stevens–Johnsonsyndrome (SJS)/toxic epidermal necrolysis(TEN) [25, 26], mucosal-predominant epider-molysis bullosa acquisita, linear IgA disease,dermatitis herpetiformis, anti-laminin 332pemphigoid [4, 6], ocular surface squamousneoplasia (OSSN) [27], sebaceous cell carcinoma(SCC) [28], atopic keratoconjunctivitis[7, 29, 30], ocular rosacea [7, 31], adenoviralconjunctivitis [32, 33], trachoma [34], con-junctival trauma (chemical, thermal, surgical,or radiation-induced) [4, 35], paraneoplasticpemphigus [36, 37], pemphigus vulgaris[38, 46], graft-versus-host disease [39], and thecongenital disease ectodermal dysplasia [40], asdepicted in Table 1.

Although several of the aforementioned eti-ologies of cicatrizing conjunctivitis have a sim-ilar clinical appearance, careful examination ofthe patient and careful clinical history takingcan aid in making the correct diagnosis. Thefollowing five clinical pearls can be used todistinguish MMP from the above-mentionedconditions.

Is the Disease Unilateral or Bilateral? AlthoughOcMMP can be asymmetric, with one eye sig-nificantly more affected than the other, it israrely unilateral [4, 41]. In a series of 115 casesof OcMMP only 6% were unilateral [1]. Unilat-eral cases of conjunctival scarring should alertthe clinician that a tumor, either OSSN or SCC,may be masquerading as OcMMP [42]. More-over, if topical drugs with preservatives havebeen used unilaterally, then toxic conjunctivitisrather than OcMMP may be the correctdiagnosis.

Is There Involvement of Other Mucous Mem-branes or the Skin? Distinguishing the ocularfeatures of OcMMP from the chronic conjunc-tivitis observed in the aforementioned muco-cutaneous and immunobullous disorders can bechallenging given that the clinical phenotype isoften identical [22]. A useful pointer is thatocular involvement is preceded by cutaneous or

Table 1 Differential diagnosis of ocular mucous mem-brane pemphigoid

Causes of cicatrizing conjunctivitis

Stevens–Johnson syndrome (SJS)/toxic epidermal

necrolysis (TEN)

Paraneoplastic pemphigus

Graft-versus-host disease

Mucosal-predominant epidermolysis bullosa acquisita

Linear immunoglobulin A disease

Dermatitis herpetiformis

Pemphigus vulgaris

Ocular surface squamous neoplasia (OSSN)

Sebaceous cell carcinoma (SCC)

Trachoma

Adenoviral conjunctivitis

Conjunctival trauma (chemical, thermal, surgical, or

radiation-induced)

Atopic keratoconjunctivitis

Ocular rosacea

Ectodermal dysplasia

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oral involvement in mucocutaneous andimmunobullous disorders and the severity ofthe ocular signs is generally milder in theseconditions [22], except for a small number ofpatients affected by SJS and TEN who can alsosuffer from progressive cicatricial conjunctivitis[22].

A medical history of a skin ‘‘rash’’ or ‘‘blisters’’may indicate MMP skin involvement while ahistory of ‘‘difficulty swallowing’’ may suggestesophageal involvement. The oral mucosashould be examined for signs of gingival orpalatal inflammation and scarring in all patientswith progressive conjunctival cicatrization. Thiscan be easily done during a routine appoint-ment using a penlight. Skin and other mucosalinvolvement may precede any ocular signs andsymptoms. Alternatively, the eyes may be thefirst—or the only—tissue to be affected; in32–48% of MMP cases the eyes are the onlytissue affected [2, 8]. These intricacies of MMPmake diagnosis even more challenging for theophthalmologist, and it is therefore not surpris-ing that the mean diagnostic delay for patientswith OcMMP is about 2.5 years, with a range ofup to 10 years [8].

Is There an Associated Systemic Disease?Other than MMP, systemic diseases associatedwith conjunctival scarring include SJS/TEN,graft-versus-host disease, paraneoplastic pem-phigus, pemphigus vulgaris, graft-versus-hostdisease, and ectodermal dysplasia. Of these,MMP, paraneoplastic pemphigus, pemphigusvulgaris, and sarcoid can manifest in the eyesbefore there is any other systemic manifestation[2, 8, 36, 38, 43]. This presents an additionaldiagnostic challenge for the ophthalmologistwho should have a high index of suspicion incases of progressive cicatrization that do not fitinto any other disease category.

Is There Meibomitis, Eyelid Margin Telangiec-tasias, and/or Facial Rosacea? Chronic mei-bomitis, often accompanied by eyelid marginkeratinization, is a typical chronic manifesta-tion of patients with history of SJS/TEN or graft-versus-host disease. In such cases, the etiologyof the progressive conjunctival cicatrization isevident by the patient’s clinical history. Mei-bomian gland inflammation, inspissation, or

dropout associated with eyelid margin telang-iectasias is seen in ocular rosacea, which canalso cause some bilateral conjunctival scarring[4].

Is There Chronic Use of Topical Medica-tions? Chronic use of topical glaucoma drops,and rarely of other topical medications, can leadto progressive conjunctival inflammation andscarring. Although preservatives play a role,even non-preserved glaucoma medications havebeen associated with drug-induced conjunctivalcicatrization [44]. Upon withdrawal of the cul-prit medication, in most cases the inflammationquiets down and progression of scarring haltswithin 2–6 weeks [24]. In rare cases, however, asmall subset of patients develops progressivescarring that is indistinguishable from OcMMP,even after withdrawal of the offending medica-tion [24].

Other clues from the patient’s historyinclude history of being born or raised in aregion where trachoma is endemic, history ofacute severe viral conjunctivitis, history ofconjunctival trauma, and history of atopy(eczema, allergic rhinitis, asthma).

CLINICAL PRESENTATION

Ocular MMP can affect both young and adultpatients (reported age ranges of patients instudies 20–91 years), but the median age in twoof the largest studies conducted to date is over65 years [2, 8]. When young patients are affec-ted, the disease is typically more severe andmore rapidly progressive despite treatment.Gender preponderance of OcMMP is unclear[45]. Involvement of the medial canthus withloss of the caruncle and plica semilunaris maybe the initial clinical sign of OcMMP and occursmore frequently in this disease than in othercicatrizing disorders [22]. Chronic and low-grade subconjunctival inflammation in OcMMPinduces feltwork-like reticular fibrosis andinfiltration of the tarsal and bulbar conjunctiva,which leads to forniceal foreshortening, sym-blepharon formation (i.e., fibrotic adhesionsbetween the bulbar and the palpebral conjunc-tiva), secondary cicatricial entropion, and

Ophthalmol Ther (2019) 8:5–17 9

ankylopblepharon (i.e., fibrotic adhesionsbetween the lids) [22, 46].

Tear film instability occurs in the moreadvanced stages of OcMMP due to impairmentof all three layers of the tear film. Inflammationand fibrosis of the main and accessory lacrimalglands are responsible for aqueous tear defi-ciency. Conjunctival goblet cell loss leads toimpairment of the mucin layer, whereas scar-ring at the orifices of the meibomian glandsaccounts for the lipid deficiency [47]. Ulti-mately, conjunctival keratinization secondaryto severe dry eye confers a skin-like appearanceto the ocular surface [4].

Corneal involvement includes punctateepithelial keratitis (secondary to chronic con-junctivitis, toxicity induced by topical medica-tions, and blepharitis), filamentary keratitis(due to the combination of aqueous tear filmdeficiency and blepharitis), corneal irritation(promoted by cicatricial entropion and trichia-sis), exposure keratitis (subsequent to poor lidclosure from eyelid cicatrization), persistentepithelial defects, corneal ulceration, and per-foration (due to the resultant limbal stem celldeficiency) [4].

Clinical presentation can vary markedly.Patients can present either with slowly pro-gressive chronic conjunctivitis that failed torespond to topical treatments (often with sym-blepharon due to misdiagnosis and inappropri-ate treatment) or with acute conjunctivitis andlimbitis that can rapidly progress towards con-junctival cicatrization and ocular surface failureif not promptly and adequately treated [22].Recurrent entropion and trichiasis after surgicalcorrection should also alert physicians, espe-cially if associated with conjunctival fibrosis[22].

In 1986, Foster proposed a staging system inwhich subconjunctival scarring and fibrosisrepresented stage 1; foreshortening of the for-nix, stage 2; symblepharon, stage 3; and anky-loblepharon, stage 4 [46]. Mondino and Brownproposed four stages for the loss of inferior for-nix depth, in which 0–25% loss was defined asstage 1; 25–50% loss, stage 2; 50–75% loss, stage3; and 75–100% loss, stage 4 [48]. Other stagingsystems were subsequently proposed by Tauber

et al. [49], Rowsey et al. [50], and Reeves et al.[51], respectively.

DIAGNOSTIC STUDIES

Indirect immunofluorescence (IIF) microscopytesting of salt-split skin can be used to identifyserum autoantibodies in OcMMP (a6b4 inte-grin, BP180, BP230, laminin 332, laminin c1,and type VII collagen), but this method haspoor sensitivity and specificity [4]. Bulbar per-ilesional conjunctival biopsy allows forhistopathological investigation and confirma-tion of the MMP diagnosis through directimmunofluorescence (DIF) testing [4, 52]; theformer is crucial to rule out OSSN, atopic kera-toconjunctivitis, and sarcoid, whereas the latterhelps to confirm OcMMP [4]. However, itshould be remembered that other disorders,such as some cases of SJS, TEN, and drug-in-duced scarring, pemphigus vulgaris, lichen pla-nus, ectodermal dysplasia, and lupus, also testpositive for DIF and that the result may beindistinguishable from that for bullous pem-phigoid. DIF testing is not mandatory for diag-nosing OcMMP when the biopsy result fromother mucosal/skin tissues is positive and theocular phenotype is characteristic of OcMMP[4].

Although the first international consensuson OcMMP strongly recommended thatOcMMP diagnosis requires clinical findings andpositive immunopathology, DIF is neither asensitive nor specific marker of OcMMP [4, 5];moreover, DIF is often negative or can becomenegative with remission of the disease. There-fore, it has been proposed that OcMMP can bediagnosed even if DIF is negative when IIF ispositive or—in cases of negative IIF—whenother causes of cicatricial conjunctivitis havebeen ruled out [4, 53, 54]. The diagnostic crite-ria of OcMMP are summarized in Table 2.

TREATMENT

Management of OcMMP is aimed at controllingthe immune-mediated inflammatory disease,

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preventing fibrosis, and managing the ocularsurface disease.

Management of the Inflammatory Disease

Occular MMP requires systemic immunosup-pression to control the inflammatory process,halt the fibrotic process, and prevent progres-sion to more advanced stages. Secondary ocularsurface inflammation needs to be identified andmanaged as well, as it contributes to progressivedamage. The patients requiring systemic treat-ment need to be properly identified. A quarterof patients with OcMMP do not require sys-temic treatment if the disease is very mild andnon-progressive [55]. Moreover, end-stage dis-ease patients with total surface failure will notbenefit from systemic immunosuppression. Forthis group of patients, efforts should be directedtowards managing the symptoms and sequalae.Topical treatment is not effective in controlling

the immune-mediated disease and preventingprogression, but it is employed for symptomaticrelief. When topical steroids are used, patientsshould be monitored for the development ofcataract and glaucoma.

A stepladder approach is used to selectimmunosuppressive agents and to escalatetreatment, depending on disease severity (mild,moderate, severe; see Table 3). The medicationsused are dapsone, sulphapyridine, sul-phasalazine, azathioprine (AZA), methotrexate(MTX), mycophenolate mofetil (MMF),cyclophosphamide, and short courses of oralsteroids. CD20 monoclonal antibodies, TNFainhibitors, and intravenous immunoglobulin(IVIg) are used to treat disease non-responsiveto conventional immunosuppressants. Dap-sone, sulfapyridine, and sulfasalazine are sulfadrugs used to treat mild to moderate disease,

Table 2 Diagnostic criteria of ocular mucous membranepemphigoid

Diagnostic criteria of ocular mucous membranepemphigoid

Chronic conjunctivitis

Conjunctival fibrosis

Conjunctival keratinization

Loss of plica semilunaris and/or caruncle

Fornix shortening

Symblephara

Cicactricial entropion

Punctate keratitis

Filamentary keratitis

Exposure keratopathy

Persistent epithelial defects

Corneal ulceration

Limbal stem cell deficiency

(?) or (-) direct immunofluorescence

Extraocular involvement

Table 3 Step-by-step treatment used to select immuno-suppressive agents and escalate treatment according todisease severity

Step-by-step treatment

Mild disease

Dapsone

Sulfapyridine/sulfasalazine

Moderate disease

Mycophenolate mofetil

Methotrexate

Azathioprine

Severe disease

Cyclophosphamide

Oral or IV steroids are used only for acute control of

very severe disease; no role for long-term control

IVIg, Anti-TNFa, rituximab, or a combination

thereof—in cases of resistance to conventional

treatment, poorly controlled disease, or adverse

reactions to conventional treatment

A combination of the above-mentioned agents can be

used; refer to the text and references for details

IV Intravenous, IVIg intravenous immunoglobulin, TNFatumor necrosis factor-alpha

Ophthalmol Ther (2019) 8:5–17 11

but they are contraindicated in patients withglucose-6-phosphate dehydrogenase deficiencyand those allergic to sulpha drugs. Their mostcommon side effect is hemolytic anemia; otherside effects include skin rash and gastrointesti-nal problems. The treatment dose for dapsone is1 mg/kg/day (with a maximum dose of200 mg/day). If there is intolerance to dapsone,it can be substituted by sulphasalazine or sul-phapyridine. The doses for sulfasalazine andsulfapiridine are 1–4 g/day and 500 mg once ortwice/day, respectively [4, 55].

MMF, AZA and MTX can be used to treatmoderate disease. Of these agents, MMF has thebest safety profile and is very well tolerated,having the lowest drop-out rate among theagents used. The recommended dose is 1 g twicedaily, and this treatment achieves control of thedisease in 59% of patients [1, 56]. In cases ofintolerance to MMF, AZA or MTX can be used asalternative agents. AZA achieves control in 47%of patients as monotherapy [1]. MTX can also beconsidered in the treatment of moderateOcMMP (10–15 mg once/week). McCluskey andcolleagues reported a success rate in 83% ofpatients receiving MTX [57]. The most commonside effects seen with MTX use are gastroin-testinal problems, fatigue, and alopecia,although long-term use of MTX is associatedwith pulmonary and hepatic fibrosis.

In cases of severe or poorly controlledinflammatory disease, the use of cyclophos-phamide is indicated (1–2 mg/kg/day)[1, 58–60]. Cyclophosphamide has serious sideeffects with prolonged use, such as bladdercarcinoma, so it should be used for a maximumduration of 12–18 months. If cyclophos-phamide needs to be substituted, one of the lesstoxic drugs is then used. Oral steroids may needto be used in the acute phase of the disease toachieve control until the immunomodulatoryagents begin to have effect, at which point theyare then tapered [4, 57]. For acute control ofvery severe disease, oral or intravenous corti-costeroids may need to be used. There is no rolefor long-term oral corticosteroids.

There are different approaches to the choiceof immunomodulatory agent and the mode ofescalation of the stepladder approach proposedin the literature. The choice of agents used to

control the disease depends on physicianexperience, hospital setting, and availability ofthe medication. Our review is not meant toserve as a guide for treatment but rather as anoverview of the existing treatment strategies.The two stepladder approaches presented hereare from Sobolewzca et al. [56] and Saw et al. [1],respectively.

Saw et al. [1] and Dart et al. [4] reported theuse of a step–up and step–down treatmentstrategy for the choice of drugs depending ondisease severity and patient response to treat-ment, using monotherapy or combination ofmedications. In cases of partial success in con-trolling the disease, a combination of the above-mentioned agents should be used. Sulfa drugs(dapsone, sulfasalazine, sulphapyridine) can becombined with myelosuppressive agents (MMF,AZA, MTX, cyclophosphamide). In the case offailure of conventional immunosuppressivetreatment, anti-TNFa [61–63], the anti-CD20monoclonal antibody rituximab [64–66], IVIgtreatment [67, 68], or a combination of theabove has been described [69]. Once the diseasehas been controlled, immunosuppressionshould continue for 1 year and can then betapered and discontinued if the disease is ofmild or moderate severity. Lifelong monitoringis needed, however, as one-third of patients willrelapse [70].

It is crucial for the clinical monitoring to bestandardized in order to properly assess pro-gression of the disease process. Forniceal fore-shortening has been described as a quantifiablemeans of objectively measuring the extent ofthe fibrosis [71]. The normal depth of the con-junctival fornix has been documented forhealthy South Asian [72] and Caucasian [73]populations. Fornix depth measurers have beenused and validated for the measurement offornix depth, providing reproducible results andfacilitating the monitoring of conjunctivalscarring [74].

Management of the Ocular Surface Disease

Conjunctival fibrosis causes a number of prob-lems, including dry eyes, punctate epitheliopa-thy, blepharitis, lid disease, trichiasis,entropion, and lagophthalmos. All of these

12 Ophthalmol Ther (2019) 8:5–17

conditions contribute to secondary ocular sur-face inflammation, ocular surface failure,epithelial breakdown, and persistent epithelialdefects (PED) and predispose to corneal ulcera-tion, infective keratitis, corneal melt, andperforation.

The severity of dry eyes in OcMMP varies andranges from mild to very severe. In case of mildto moderate dry eyes, artificial tears should beused. The preparations should be preservativefree to avoid ocular surface toxicity. In cases ofsevere tear deficiency, NaCl 0.9% can also beused as it does not cause blurring of vision [1].In cases of keratinization, paraffin-based eyeointments can provide great symptomatic relief[1]. Autologous serum can also be used in casesof severe ocular surface dryness. The lacrimalpuncta may be occluded by conjunctival fibro-sis; if not, then permanent punctal occlusionshould be considered once the ocular surfaceinflammation is controlled.

Blepharitis is common in OcMMP and can bemanaged with lid hygiene and use of oraltetracyclines. Secondary dry eye-induced ocularinflammation may require the short-term use oftopical preservative-free steroid drops. Topicalciclosporin, although not beneficial for thesuppression and control of the systemicimmune-mediated disease, can be of help inmanaging the secondary ocular surface inflam-mation. Mucous filamentary keratitis due topoor-quality tear film can be managed with theuse of topical mucolytics, such as acetylcysteine5% used 3–4 times/day.

The cicatrizing disease causes conjunctivalfibrosis, resulting in shortening of the fornices.Although occasionally this requires no inter-vention, if this condition is associated with acompromised Bell’s phenomenon, cicatricialentropion, and lagophthalmos resulting inexposure keratopathy, then fornix reconstruc-tion with oral mucosa grafts is indicated [75, 76].Fornix reconstruction may also be required inpatients who need to use contact lenses.

Trichiasis can be managed with epilation ofaberrant lashes, which is a short-term manage-ment option as the lashes grow back within4–6 weeks. A more permanent solution is elec-trolysis or trephination of the lash follicle andcauterization. Gray line split and anterior

lamellar repositioning may be needed for upperlid cicatricial entropion [77], and gray line splitwith inferior retractor plication may be neededfor lower lid entropion [78].

Keratinization occurs most frequently on thelid margin and tarsal conjunctiva. It can beremoved manually, although it tends to recurvery soon, causing irritation. The use of topicalvitamin A preparations is reported to be ofbenefit; however it may be difficult to source[1]. In these cases, scleral contact lenses canhelp alleviate the symptoms.

Dry eyes, punctate epitheliopathy, poorblink, lagophthalmos, and ocular surface dis-ease predispose eyes with OcMMP to epithelialbreakdown, risk of persistent epithelial defects(PEDs), risk of perforation, and risk of infectiouskeratitis. Any epithelial defect may harbor acorneal infection, bacterial or viral (such asherpetic keratitis). However, it must be notedthat due to systemic and topical immunosup-pression, the clinical presentation may beatypical. If infection is suspected or confirmed,it is treated with fortified or broad-spectrumtopical antibiotics (for bacterial keratitis) or oralantiviral agents (for herpetic keratitis).

Tarsoraphy may be needed for the manage-ment of PEDs. An amniotic membrane graft asan inlay in the area of the PED supplemented byan onlay amniotic membrane graft to cover thewhole cornea is effective in reducing ocularsurface inflammation and in promotingepithelial healing. Use of autologous serum isalso useful in cases of PED.

Corneal perforation should be managed withcorneal gluing. A lamellar or patch graft may berequired although corneal grafting in OcMMPhas a very poor prognosis due to poor epithelialhealing, melt, and infection and may need to becombined with a conjunctival or amnioticmembrane graft.

Summarizing the treatment strategy forOcMMP, a stepladder approach is used tochoose medications and escalate treatmentaccording to disease severity and activity. Astep–up and step–down approach and combi-nation of immunosuppressive agents is effectivein achieving and maintaining control of theimmune-mediated disease. Secondary ocularsurface disease, lid disease, trichiasis, and other

Ophthalmol Ther (2019) 8:5–17 13

factors that predispose to corneal exposure,ulceration and risk of keratitis, and corneal meltmust be managed promptly and aggressively.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Hendrik P.N. Scholl is supportedby the Foundation Fighting Blindness ClinicalResearch Institute (FFBCRI); Shulsky Foundation,NewYork, NY;National Centre of Competence inResearch (NCCR) Molecular Systems Engineering(University of Basel and ETH Zurich), SwissNational Science Foundation, Wellcome Trust.Hendrik P. N. Scholl is a member of the ScientificAdvisory Board of the Astellas Institute forRegenerative Medicine; Gensight Biologics;Intellia Therapeutics, Inc.; Ionis Pharmaceuticals,Inc.; ReNeuron Group Plc/Ora Inc.; PharmaResearch & Early Development (pRED) of F.Hoffmann-La Roche Ltd; and Vision Medicines,Inc. Hendrik P. N. Scholl is member of the DataMonitoring and Safety Board/Committee of thefollowing entities: Genentech Inc./F. Hoffmann-La Roche Ltd; and ReNeuron Group Plc/Ora Inc.Hendrik P. N. Scholl is member of the SteeringCommittee of the following entities: Novo Nor-disk (FOCUS trial). Hendrik P. N. Scholl is co-di-rector of the Institute of Molecular and ClinicalOphthalmology Basel (IOB) which is constitutedas a non-profit foundation and receives fundingfrom the University of Basel, the UniversityHospital Basel, Novartis, and the government ofBasel-Stadt. These arrangements have beenreviewed and approved by the Johns HopkinsUniversity in accordance with its conflict ofinterest policies. Johns Hopkins University andBayer Pharma AG have an active research

collaboration and option agreement. Thesearrangements have also been reviewed andapproved by the University of Basel (Univer-sitatsspital Basel, USB) in accordance with itsconflict of interest policies. Hendrik P. N. Scholl isprincipal investigator of grants at the USB spon-sored by the following entities: Acucela Inc.;Aegerion Pharmaceuticals (Novelion Therapeu-tics); Kinarus AG; NightstaRx Ltd.; OphthotechCorporation; Spark Therapeutics England, Ltd.Grants atUSB are negotiated and administered bythe institution (USB) which receives them on itsproper accounts. Individual investigators whoparticipate in the sponsored project(s) are notdirectly compensated by the sponsor but mayreceive salary or other support from the institu-tion to support their effort on the project(s).Hendrik P. N. Scholl is a paid consultant of thefollowing entities: Boehringer Ingelheim PharmaGmbH & Co. KG; Gerson Lehrman Group;Guidepoint. Panagiotis Georgoudis, FrancescoSabatino, Nora Szentmary, Sotiria Palioura, EszterFodor and Samer Hamada have nothing to dis-close. Zisis Gatzioufas is a member of the Oph-thalmology and Therapy Editorial Board.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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