+ All Categories
Home > Documents > Manage OCP

Manage OCP

Date post: 03-Jun-2018
Category:
Upload: tickky-tick-tickky
View: 237 times
Download: 0 times
Share this document with a friend

of 13

Transcript
  • 8/12/2019 Manage OCP

    1/13

    The management of mucousmembrane pemphigoid

    and pemphigus dth_1323 268..280Richelle M. K nudson , A mer N. K alaaji & A lison J. BruceDepartment of Dermatology, Mayo Clinic/Mayo Clinic College of Medicine,Rochester, Minnesota

    ABSTRACT: Mucous membrane pemphigoid and pemphigus vulgaris are autoimmune blistering dis-orders in which many similar drugs and therapeutic strategies are utilized. In general, localized diseasecan be treated with topical agents. In contrast, patients with more severe and progressive diseaseusually require a combination of systemic corticosteroids and immunosuppressive medications. Oralcorticosteroids, adjuvant immunosuppressive agents, antibiotics such as dapsone and immunomodu-latory procedures like intravenous immunoglobulin are the main therapeutic agents used in treating these two disorders. Much of the morbidity and mortality associated with these disorders are related tothe sites involved and to the drugs used for therapy. Treatment should be individualized based onseverity, extent, and rate of progression of disease, comorbidities, and age of the patient. Serum levelsof specic autoantibodies and indirect immunouorescence titers, in certain cases, can be used tomonitor response to therapy.

    KEYWORDS: cicatricial pemphigoid, mucous membrane pemphigoid, pemphigus vulgaris, therapy

    Introduction

    Mucous membrane pemphigoid (MMP) and pem-phigusvulgaris (PV) areautoimmuneblisteringdis-orders that can have a signicant impact on apatients quality of life. Both are characterized by autoantibodies directed at different regions of theepithelium. Many of the same drugs and therapeu-ticstrategiesare utilizedinthese twodiseases.Thereare some differences, however, that arise due to

    their different characteristics. We review the impor-tant characteristics of MMP and PV and providetreatment recommendations. Treatment of MMPand PV utilizes both topical and systemic therapy.Treatment should be individualized based on

    severity, extent, andrate of progression ofdisease as well as patient comorbidities including age.

    MMP

    MMP is a chronic inammatory subepithelial blis-tering disease. The incidence of MMP is estimatedto be between 1 in 12,000 and 1 in 20,000 in thegeneral population with a predilection for theelderly (60 to 80 years, mean age 62 to 66 years)(13). However, children may also be affected (4,5).MMP is characterized by the linear deposition of IgG, IgA, and/or C3 along the epidermal basementmembrane zone in mucosal and/or cutaneousbiopsy specimens (6). Numerous target antigens inthe hemidesmosome have been associated withMMP. These include bullous pemphigoid (BP)antigen 180 (also known as collagen XVII andbullous pemphigoid antigen [BPAG]2), BP antigen230 (also known as BPAG1), laminin 5 (laminin332), laminin 6 (laminin 311), and integrin b4subunit. The most commonly affected areas are the

    Address correspondence and reprint requests to: Alison J.Bruce, MD, Mayo Clinic, Department of Dermatology,200 First Street SW, Rochester, MN 55905, or email:[email protected] authors have no conict of interest.

    268

    Dermatologic Therapy, Vol. 23, 2010, 268280 Printed in the United States All rights reserved

    2010 Wiley Periodicals, Inc.

    DERMATOLOGIC THERAPY ISSN 1396-0296

  • 8/12/2019 Manage OCP

    2/13

    oral and ocular mucosa, but the nasopharynx,esophagus, larynx, and anogenital mucosa may also be involved (FIGS. 13). The consequences of this disease can be severe, including airway con-striction secondary to laryngeal webs, change invision and blindness secondary to ocular scarring,

    and urinary and sexual dysfunction (6). The skin of the face, scalp, extremities, and umbilicus can alsobe involved. Mucous membrane lesions can occurin 10 to 40% of patients with bullous pemphigoid,but it is not usually a presenting symptom. In con-trast, oral involvement is often the presenting

    symptom of PV (7).MMP can be localized or extensive and canaffect both cutaneous and mucosal surfaces.Depending on the area most affected, pemphigoidcan broadly be divided into cutaneous (bullous)pemphigoid and mucosal pemphigoid, with someoverlap between these two entities. Historically,mucosal disease has been given many namesdepending on the region involved (e.g., gingival,oral, and ocular, etc.). Further classication hasbeen based on the tendency to scar hence theterm cicatricial pemphigoid. This latter term isoften used interchangeably with ocular pemphig-oid as ocular involvement classically leads to scarformation. However, cutaneous involvement can,on occasion, produce scarring, as seen with a local-ized form of pemphigoid involving the head andneck region known as Brunsting-Perry pemphig-oid. Furthermore, on rare occasions, oral involve-ment may also produce scarring, usually at thecommissures of the mouth, although this is nottypical.

    As mentioned previously, there are numeroustarget antigens that have been associated withMMP. It is now recognized that MMP has several

    subsets based on the target antigen involved and,in reality, likely represents a heterogeneous groupof disorders characterized by a similar subepithe-lial blistering pathogenesis. Regardless of targetantigen, the clinical result is blister formation. Onmucosal surfaces, this is usually appreciated as asloughing or desquamative process. The location(depth) of the target antigen within the basementmembrane zone may explain why some subsetsportend greater scarring.

    On a practical level, therefore, the authors preferthe term mucosal pemphigoid to include all themucosal subtypes, with further descriptors of loca-tion used in individual patients. The authors alsoavoid using the term cicatricial pemphigoid andprefer to classify disease based on the location, rec-ognizing that certain regions of involvement have agreater tendency for scar formation.

    Because of the variability in presentation, theextent of mucosal pemphigoid determines theapproach to therapy. Localized disease may beeasier to control. However, it can progress to exten-sive disease, which is typically more difcult tocontrol. Extensive disease can progress rapidly,

    FIG. 1. Erythematous,swollenattachedgingiva. Note areaof desquamation characteristic of desquamative gingivostoma-titis in a patient with MMP.

    FIG. 2. H&E, MMP: Subepithelial separation.

    FIG. 3. Direct immunouorescence, MMP: Linear deposi-tion of C3 and IgG along the dermoepidermal junction.

    Mucous membrane pemphigoid and pemphigus

    269

  • 8/12/2019 Manage OCP

    3/13

    necessitating more aggressive therapy. Topicaltherapy with corticosteroids and/or tacrolimus, with occasional use of systemic corticosteroidsduring exacerbations, is often the appropriatetherapy for those with limited disease. Such diseasehas often been termed benignmucous membrane

    pemphigoid, but this terminology is not favored,as the disease is not benign in its potentialsequelae. For example, severemouth pain can limitoral intake, adversely affecting nutritional well-being. Patients with extensive disease require acombination of systemic corticosteroids andimmunosuppressive or anti-inammatory medi-cations (7).

    PV

    Pemphigus is a group of autoimmune intraepithe-lial blistering diseases that affect the skin andmucous membranes. Subtypes include PV, pem-phigus foliaceus, pemphigus vegetans, pemphiguserythematosus, and paraneoplastic pemphigus.The various subtypes are associated with differenttarget antigens. In mucosal-dominant PV, thetarget antigen is desmoglein 3, whereas in themucocutaneous type, the target antigen is bothdesmoglein 1 and desmoglein 3. In contrast, thetarget antigen is desmoglein 1 in pemphigus folia-ceus and pemphigus erythematosus. Numeroustarget antigens have been described with paraneo-plastic pemphigus. These include desmoglein 3,

    desmoglein 1, plectin, desmoplakin I, desmoplakinII, BPAG1, envoplakin, and periplakin.The incidence of PV is estimated to range from

    one to six new cases per million per year, with themean age of onset being 50 to 60 years. The diseaseis precipitated by IgG autoantibodies binding todesmoglein 3 and/or desmoglein 1. PV is the mostcommon subtype, frequently presenting with oralinvolvement including desquamative gingivosto-matitis or cheilitis due to the erosion of the fragilemucosal surface (FIGS. 47). Seventy to ninety percent of patients with PV develop erosions of theoral mucosa; oral involvement is the presenting sign in 50% of patients with PV. Other mucosal sur-faces include the throat, esophagus, conjunctivae,nasal mucosa, vagina, vulva, penis, and anus (8).More than half of patients develop skin involve-ment with accid bullae or erosions. In patients with pemphigus foliaceus, blisters are limited tocutaneous surfaces, without mucosal involvement.Pemphigus erythematosus, a localized form of pemphigus foliaceus, is characterized by involve-ment of the malar area of the face and seborrheicregions. Pemphigus vegetans is a rare variant of PV

    characterized by vegetative granulating plaquesinvolving intertriginous areas. Paraneoplasticpemphigus usually presents with severe stomatitisthat extends onto the vermilion lip (FIGS. 89).

    Before corticosteroids were introduced in the1950s, the mortality of PV was approximately 75%

    FIG. 4. Erythema and desquamation of the attached gingiva and lips typical of PV.

    FIG. 5. Erythema, ulceration and erosions of the palate in a patient with PV.

    FIG. 6. H&E, PV: Acantholysis and intraepithelial separation with tombstoning of basal keratinocytes.

    Knudson et al.

    270

  • 8/12/2019 Manage OCP

    4/13

    (9).Today, themortalityis around10% andis mostly secondary to complications of therapy, especially high dosesof corticosteroidsused over long periodsof time to maintain disease control (913).

    Overview of therapy of MMP and PV

    Topical therapy may be minimally effective, andalthough adequate for mild disease, control of more severe disease frequently requires systemictherapies. Systemic corticosteroids may be neededfor optimal disease control, with or withoutthe addition of adjuvant systemic medications(Tables 1 and 2).

    Systemic corticosteroids are the rst line of therapy for extensive and rapidly progressive MMPas well as for more severe PV. Adjuvant drugs areoften used for their steroid-sparing effects and may be used alone to maintain remission. Immunosup-pressive agents such as azathioprine, mycopheno-late mofetil (14,15), cyclophosphamide (6,16,17),and methotrexate (18) have been used in MMP fortheir steroid-sparing effects. These four drugsalong with cyclosporine have also been used in PV (1931). Antibiotics such as dapsone (7,17,32) andcombinations of tetracycline and nicotinamide(13,33,34) have demonstrated efcacy in both

    FIG. 7. Direct immunouorescence, PV: cell surface deposi-tion of IgG and C3.

    FIG. 8. Erosionsand crusting of thelips in patient with para-neoplastic pemphigus.

    FIG. 9. Direct immunouorescence, paraneoplastic pem-phigus: cell surface deposition of IgG and C3 in combination with linear or granular deposition of IgG and C3 at the base-ment membrane zone.

    Table 1. Recommendations for the treatment of mucous membrane pemphigoid

    Mild, local oral disease1. Moderate to high potency topical corticosteroids

    can be used initially (two to three times daily).2. If the response to topical therapy is not adequate,

    dapsone therapy can be initiated (125 to 150 mg daily, gradually titrated upward).

    3. Alternatively, tetracycline (1 to 2 g per day) andnicotinamide (2 to 3 g per day) can be used.

    4. If disease is not adequately controlled with theabove regimens, oral corticosteroids (prednisone1 to 2 mg/kg per day) +/ - an adjuvantimmunosuppressive agent can be used.

    Ocular involvement, severe involvement a, and/orrapidly progressive disease

    1. Initial treatment with oral corticosteroids(prednisone 1 to 2 mg/kg per day) plus adjuvantimmunosuppressive therapy (azathioprine 1 to2 mg/kg per day, mycophenolate mofetil 2 to2.5 g per day divided into two doses, orcyclophosphamide 12 mg/kg per day) isrecommended.

    2. When the disease becomes adequately controlled,prednisone is tapered while continuing adjuvantimmunosuppression.

    3. IVIg can be used in resistant disease and in rapidly progressive ocular disease which threatens vision.

    4. Other modalities of therapy, such as the biologics,can be considered in disease that has beenrefractory to all other treatment options.

    aSevere involvement includes laryngotracheal, esophageal,and/or anogenital disease.

    Mucous membrane pemphigoid and pemphigus

    271

  • 8/12/2019 Manage OCP

    5/13

    MMP andPV. Gold, an anti-inammatory drug, hasbeen used in PV but not in MMP (13,3538). Immu-nomodulatory procedures such as intravenous

    immunoglobulin (IVIg) therapy (3949) and plas-mapheresis (5052) may be effective in MMP or PV.Extracorporeal photopheresis, another immuno-modulatory procedure, has been used in PV (5357). More recently, biologic agents, such asrituximab (5862), etanercept (63,64), and inix-imab (65), have been reported to be effective in thetreatment of either MMP or PV. Thalidomide (66)and subconjunctival mitomycin C injections (67)have been used with limited evidence in MMP. Ingeneral, most patients with extensive diseaserequire long-term therapy.

    Oral and ocular care

    Excellent oral care has been emphasized as being an important part of the treatment of both MMPand PV. This consists of brushing the teeth twicedaily using a soft-bristle brush and gentle tech-nique, ossing on a daily basis, and professionalteeth cleaning performed every 3 to 6 months. Ahmed et al. have recommended gentle debride-ment of necrotic mucosal tissue to prevent in-fection (68). Thus, having a dentist involved in

    the patients care is vital. Topical analgesics oranesthetics and antiseptic mouthwashes arerecommended as further treatment. Variouselixirs containing combinations of viscous lido-caine (Xylocaine Viscous), diphenhydramine(Benadryl) and antacids such as Maalox can

    be used as an oral rinse to decrease mouth pain(68,69). Oral trauma can lead to the formation of new erosions and should be avoided. Poorly tting dentures are commonly associated with trauma tothe mucosal surface as are dry crackers or hardcandies. Patients should be evaluated to ensurethat all dental appliances t properly.

    Ocular care plays a very important role in themanagement of ocular MMP. Frequent lubricationto prevent drying is recommended. This can beachieved with preservative-free articial tears if used more than four times daily or with any type of articial tears if used less frequently. More viscoussolutions, such as Refresh Celluvisc or GentealGel, can be used when the eyes becomeextremely dry. A petrolatum-based ointment, suchas Refresh PM, can be used at bedtime. Place-ment of lacrimal punctal plugs is recommendedif the patients do not already have occludedpuncta secondary to conjunctival scarring. Topicalcyclosporine, also known as Restasis, can be con-sidered in patients with dry eyes, but burning canlimit compliance. It is also important to clean thedebris and exudate that can accumulate aroundthe eyes in order to prevent secondary infection.

    Articial tears are often adequate, but if furthercleaning is necessary, buffered preserved salinesolutions, such as EyeWash or Dacriose, can beused. Eye involvement may result in scarring andmechanical obstruction, potentially progressing toblindness. Thus, even with limited or local disease,aggressive therapy is warranted. Hence, systemictherapies are always indicated for ocular disease.

    Involving a dentist and ophthalmologist in themanagement of patients with MMP and PV is very important. Often, those with ocular MMP arereferred to dermatology by an ophthalmologist forconsideration of systemic therapy. It may also beimportant to involve otolaryngology and/or gas-troenterology if there is development of symptomssuspicious for upper airway or esophageal involve-ment. Patients should undergo endoscopy if symp-toms develop and to monitor the response totherapy.

    Topical corticosteroid therapy

    The rst-line therapy for MMP localized to the oralcavity, or the oral cavity and the skin, has been

    Table 2. Recommendations for the treatment of mucous membrane pemphigus vulgaris

    Mild, nonprogressive oral disease1. Moderate to high potency topical corticosteroids

    can be used initially (two to three times daily).2. Dapsone therapy (125 to 150 mg daily, gradually

    titrated upward) can be introduced early.3. Alternatively, tetracycline (2 g per day) and

    nicotinamide (1500 mg per day) can be considered.Severe mucous membrane involvement or concurrent

    cutaneous involvement1. Initial treatment with oral corticosteroids

    (prednisone 0.5 to 1 mg/kg per day) plus adjuvantimmunosuppressive therapy (azathioprine 1.5 to3 mg/kg per day, mycophenolate mofetil 2 to 2.5 g daily divided into two doses, cyclophosphamide 50to 200 mg per day, cyclosporine 5 mg/kg per day,or methotrexate 10 to 17.5 mg per week) isrecommended.

    2. When the disease becomes adequately controlled,prednisone is tapered while continuing adjuvantimmunosuppression.

    3. IVIg is helpful in refractory cases and is usedconcurrently with corticosteroids and animmunosuppressant.

    4. Plasmapheresis and rituximab can be considered inrefractory cases.

    Knudson et al.

    272

  • 8/12/2019 Manage OCP

    6/13

    topical corticosteroids. A conservative approachhas been recommended because there is less risk of scarring in these regions (6). Some patients withPV may have mild disease with limited inamma-tion and erosion of the mucosal surfaces. If thedisease appears nonprogressive and restricted to

    one body area such as the mouth, topical therapy alone may be adequate. There are a few recognizedadverse effects associated with the use of topicalcorticosteroids in the oral cavity. These include oralcandidiasis and reactivation of herpes simplex virus. Oral candidiasis can be treated with anti-fungal agents such as clotrimazole lozenges(Mycelex), nystatin swish and swallow (Mycosta-tin), or oral uconazole (Diucan). Clotrima-zole lozenges are used ves times per day for 7 to 14days. Nystatin swish and swallow is dosed at 5 mLfour times per day until the patient is asymptom-atic for 48 hours. Oral uconazole, 100 to 200 mg daily, is used for 7 to 14 days. If the patient hasfrequent recurrent episodes of oral candidiasis,oral uconazole 100 mg can be used twice weekly for prophylaxis.

    Corticosteroid gels or ointments, such as uoci-nonide 0.05% (Lidex), desoximetasone 0.25%ointment or 0.05% gel (Topicort), or clobetasol0.05% (Temovate), can be used two or three timesper day (7). Gels are often more easily applied andbetter tolerated within the oral cavity. Corticoster-oids can be compounded in an adhesive base, suchas Orabase, to improve adherence (70). Some

    patients nd this base too granular to apply effec-tively. Thus, the authors prefer gels. Patients shouldbe advised to apply the topical therapy two to threetimes per day initially when symptoms are severeand to gradually taper the frequency of applicationonce relative improvement occurs.We recommendusing either a Q-tip or ngertip for application,rubbing the gel or ointment into affected areasgently for 30 seconds, and then abstaining fromeating or drinking for 30 minutes. Patients shouldbe made aware that such applications are typically off-label and the products often stipulate forexternal use only. A prosthetic device (such as adental tray) that ts over the teeth and gingiva canbe fashioned by a dentist to make application of acorticosteroid preparation easier. When corticos-teroids are applied under dentures or such anappliance, their potency is increased (71). Intrale-sional corticosteroid injections can be used in thetreatment of MMP and PV with some success.Injection of triamcinolone acetonide (Kenalog), 5to 10 mg/mL, every 2 to 4 weeks, is recommended(68). Corticosteroid injections have also been usedfor ocular MMP, but this usually only produces

    short-term results and there is signicant risk of cataract formation. Subconjunctival injectionsshould only be performed by an ophthalmologistbut are rarely used in practice. Topical corticoster-oids should not be used alone and are not effectivein controlling disease progression in ocular MMP

    (72).

    Other agents used as topical therapy

    Signicant response to the use of topical tacroli-mus (Protopic) twice daily has been reported forthe treatment of MMP (7376). We have foundtopical corticosteroids to be more efcacious. Fur-thermore, a black box warning associated with tac-rolimus states that although a causal relationshiphas not been established, rare cases of malignancy (e.g., skin cancer and lymphoma), have beenreported in patients treated with topical cal-cineurin inhibitors. The risks of this medicationshould be reviewed with the patient.

    Systemic corticosteroids

    Systemic corticosteroids are the rst-line therapy for the treatment of extensive MMP, rapidly pro-gressive MMP, or in patients with ocular, laryngeal,esophageal, severe anogenital, or severe gingivalinvolvement causing loosening of the teeth (7).Systemic corticosteroids can prevent severe com-plications such as loss of vision, airway obstruc-

    tion, urinary dysfunction, sexual dysfunction, andloss of teeth. An initial dose of 0.75 to 1 mg/kg perday is recommended, and this dose is continueduntil the disease is brought under control.

    Systemic corticosteroids are the rst-linetherapy for the treatment of severe PV. Before theadvent of corticosteroid therapy in the 1950s, PV was uniformly fatal. Since then, the mortality of PV has dropped signicantly, with current rates of 0to 10% (912,25). The authors typically use 0.75to 1 mg/kg of oral prednisone given as a singlemorning dose. On occasion, higher doses of pred-nisone may be required to achieve control.

    A rapid response is usually noted once treat-ment is initiated. Even so, treatment may be nec-essary for an extended period of time and may beassociated with many adverse effects (77). In bothdisorders, the initial dose is continued until no new lesions develop and all lesions have healed. Oncethis control is achieved, we recommend a gradualtaper of systemic corticosteroids, 5 to 10 mg incre-ments per week, over the course of several weeks.Consideration can be given to using alternate day corticosteroids. However, the authors do not use

    Mucous membrane pemphigoid and pemphigus

    273

  • 8/12/2019 Manage OCP

    7/13

    this approach when tapering corticosteroids.Whenthe dose is reduced to 2025 mg daily, we taperfurther in smaller increments usually 1 mg every other week as long as disease remains quiescent.

    Should the disease are at any point along thecorticosteroid taper, we return to the dose used

    prior to the disease are and maintain that dose forapproximately 4 weeks before proceeding with aslower taper thereafter. We have found thatpatients with PV will require many months of high-dose systemic corticosteroid therapy before a tapercan be attempted, whereas patients with MMP canbe weaned more rapidly, irrespective of whetheradjuvant therapy is administered. Patients shouldtherefore be advised that systemic corticosteroidsmay need to be used for several months and toanticipate a protracted course of therapy untiladequate disease control is achieved. Furthermore,patients should also be advised that bisphospho-nates, calcium, and vitamin D are necessary evenearly in treatment (see below).

    The many side effects and the risk of long-termcorticosteroid use in older MMP and PV patientsmandate that the lowest effective dose of corticos-teroids be used and that adjuvant therapy beinitiated early. When treatment with systemic cor-ticosteroids is commenced, it is recommended thatan immunosuppressive agent such as azathio-prine, cyclophosphamide, or mycophenolatemofetil should also be started. These immunosup-pressive agents are continued long-term, whereas

    corticosteroids are tapered over 6 to 12 months.The eventual goal is monotherapy with the immu-nosuppressive agent.

    Adjuvant management strategies are recom-mended to protect against many of the recognizedsequelae of prolonged corticosteroid treatment.These include use of an H2-blocker or protonpump inhibitor for ulcer prophylaxis, as well as abisphosphonate (daily, weekly, or monthly), andcalcium (1000 to 1500 mg daily) and vitamin D (800to 1000 IU daily) supplementation for osteoporosisprophylaxis (78).

    Close clinical monitoring is necessary in allpatients while on therapy. Prior to initiating any systemic immunosuppressive agent, a completephysical examination and age-appropriate malig-nancy screening should be performed. Baselinelaboratory data that may be helpful in selecting asteroid-sparing immunosuppressive agent andmonitoring for potential adverse effects includecomplete blood count (CBC) with differential,renal function tests, liver function tests (LTF),fasting lipid prole, urinalysis, tuberculin skin test,QuantiFERON-TB Gold test, hepatitis panel,

    glucose-6-phosphate dehydrogenase (G6PD)enzyme level (for dapsone), and TPMT enzymelevel (for azathioprine). Bone densitometry is indi-cated for patients on a daily dose of prednisone5 mg or more for greater than 6 months (78).Blood pressure, blood glucose, and stool guaiac

    should also be monitored (13). Prophylaxis forPneumocystis carinii should be considered in thoseon long-term oral corticosteroids or other immu-nosuppressives with the exception of dapsone (79).Patients should be followed closely for signs orsymptoms of infection or malignancy. If eitheroccurs, treatment should be instituted early andaggressively.

    Adjuvant corticosteroid pulse therapy

    Corticosteroid pulse therapy can be used to induceremission in patients with severe or recalcitrant PV (51). Corticosteroid pulse therapy involves the useof discontinuous intravenous infusions of very high doses of corticosteroids over a short period of time (80). It was originally used for PV in the 1980s. With this type of therapy, intravenous infusions of 500 to 1000 mg of methylprednisolone acetate or100 to 200 mg infusions of dexamethasone aregiven in divided doses on three consecutive daysper month as pulse therapy, in combination withmaintenance scheduled prednisone and otherimmunosuppressants such as azathioprine (81).Pulse therapy can be administered orally rather

    than intravenously, with dexamethasone 100 mg given on 3 consecutive days on a monthly basis.Tothet al. report success of monthly glucocorticoidpulses as monotherapy in patients with mild orallesions in the early stage of PV (13).

    Pulse corticosteroid therapy is associated withmany side effects including mood changes, weightgain, hypertension, severe electrolyte abnormali-ties, myocardial infarction, cardiac arrhythmia,and pancreatitis (82).

    Antibiotics

    Antibiotics such as dapsone, other sulfonamides,and tetracycline with or without nicotinamide areeffective in the treatment of both MMP and PV.

    Dapsone can be used as rst-line therapy inlocalized MMP or slowly progressing, extensiveMMP as it may take 10 to 12 weeks before produc-ing benet (17). Dapsone can be instituted aloneor with concurrent systemic corticosteroids. If the benet of dapsone is suboptimal, then otherimmunosuppressive agents can be added. Onceremission has been achieved and maintained for

    Knudson et al.

    274

  • 8/12/2019 Manage OCP

    8/13

    several months to years, the more aggressiveimmunosuppressive agent can be tapered whilecontinuing dapsone, which has a more favorableside effect prole. Although some studies haveshown no statistically signicant difference inremission when dapsone was compared to

    placebo, the authors have found dapsone to beextremely useful in controlling mild-to-moderatePV or MMP if introduced early in disease evolution.

    Dapsone is contraindicated in patients with low G6PD levels. In patients with normal G6PD levels,the degree of hemolytic anemia and associatedsymptoms may be reduced by gradually increasing the dose of dapsone. Begin dapsone at 25 to 50 mg per day for 3 days. Thereafter, the dose can beincreased by 25 mg per day every third day up to100 mg per day. The patient should then take 100mg per day for 7 days before increasing to a targetmaintenance dose of 125 to 150 mg daily (17). Thisgradual titration allows for the bone marrow toadapt to the hemolytic insult. Doses higher than150 mg daily usually do not produce incrementalbenet.

    The main side effects of dapsone include meth-emoglobinemia, hemolytic anemia, agranulocyto-sis, and hypersensitivity syndrome. Patients shouldbe counseled that dapsone causes hemolysis, anda1- to 2-g drop in hemoglobin should be antici-pated. Most patients tolerate this mild anemia, andthis drop in hemoglobin is not a reason to discon-tinue therapy. Decreases in hemoglobin greater

    than 2 g may necessitate discontinuation of dapsone. A CBC with differential and reticulocytecount should be monitored every week for the rst4 to 6 weeks, every 2 weeks until week 12, and every 3 months thereafter once stable dosing is achieved.Frequent monitoring of the CBC with differentialis also necessary because agranulocytosis canoccur in approximately 1 in 400 patients andoccurs most often after 8 to 12 weeks of therapy (83,84). Dapsone hypersensitivity syndrome is anidiosyncratic reaction characterized by fever,generalized eruption, hepatitis, and peripheraleosinophilia; dapsone should be immediately discontinued. Dapsone also causes a distal motorperipheral neuropathy, which is usually reversibleupon discontinuation. Therefore, patients shouldbe monitored for hand and/or leg weakness ormuscle atrophy (7).

    Tetracycline, along with nicotinamide, has beenused with some success in patients with minimalor localized MMP ata dose of 1 to 2 g oftetracyclineper day and 2 to 3 g of nicotinamide per day (33,34). For mild PV, 2 g per day of tetracycline and1500 mg per day of nicotinamide are used (13).

    This regimens minimal side effect prole is ideally suited for elderly patients. The adverse effects of tetracycline include gastrointestinal upset andphototoxicity. It should notbe used in patients withrenal impairment or in children less than 9 yearsold. The adverse effects of nicotinamide include

    ushing and pruritus.

    Immunosuppressive adjuvant therapy

    Numerous immunosuppressive agents have beenused as an adjunct to oral corticosteroids in thetreatment of MMP and PV, particularly in moreseveredisease, or when disease extends beyond theoral cavity. Adjuvant medications are used formany reasons. In those patients requiring the ini-tiation of systemic corticosteroids, an immuno-suppressive agent should be started concurrently with the systemic corticosteroid. Adjuvant drugsdecrease the dose of systemic corticosteroidsneeded to achieve disease control and facilitatetapering. Adjuvant therapies may permit betterdisease control and maintenance as corticoster-oids are tapered. Once disease control is achieved,the corticosteroids can be discontinued while theimmunosuppressive drug is continued. Azathio-prine, mycophenolate mofetil, cyclophosphamide,and methotrexate are used in the treatment of MMP and PV. Cyclosporine is also used in the treat-ment of PV.

    Combination adjuvant immunosuppressive

    and/or anti-inammatory therapies can be used without corticosteroids. Azathioprine or mycophe-nolate mofetil may each be used with dapsone if use of the latter alone fails to achieve control.

    Azathioprine. Azathioprine (1 to 2 mg/kg per day)is the rst choice of adjuvant therapy in MMP,provided the disease is not rapidly progressive orthreatening vision. Azathioprine (1.5 to 3 mg/kg per day) is used in patients with PV (13,28). Whenazathioprine and systemic corticosteroids areused, remission rates of 2845% and mortality ratesof 1.47% have been reported (9,19,85,86). Azathio-prine has been used alone; however, its long latency of onset (up to 8 weeks) limits its initial useas monotherapy (19,87). Despite the recom-mended doses mentioned above, azathioprinedosing should be individualized based on thepatients thiopurine methyltransferase (TPMT)enzyme activity level (13). The TPMT assay may notbe widely available but is available at many refer-ence labs. The main side effects of azathioprineinclude hepatotoxicity, hypersensitivity syndrome,and neutropenia. Patients with low levels of TPMT

    Mucous membrane pemphigoid and pemphigus

    275

  • 8/12/2019 Manage OCP

    9/13

    are at greater risk of developing neutropenia. Inpatients with high TPMT levels, doses of up to 3.5to 4 mg/kg may be needed to achieve clinical effect(88). Regular laboratory monitoring should includeLFTs and CBC with differential.

    Mycophenolate mofetil. Mycophenolate mofetil (2to2.5 grams per day in two divided doses) is used incombination with systemic corticosteroids in bothMMP and PV (14,15,22,88,89). Like azathioprine, itmay take6 to 8 weeks to achieve clinical effect but isless hepatotoxic (89). Laboratory parameters (CBC with differential, LFTs) must be monitored regu-larly. Bothazathioprine andmycophenolatemofetilcan be used in conjunction with dapsone shouldthe latter provide only partial control.

    Cyclophosphamide. Cyclophosphamide (1 to2 mg/kg per day) is used in MMP when the diseaseis aggressive, as it achieves efcacy sooner thanazathioprine or mycophenolate mofetil (6). Con-current use of cyclophosphamide and systemiccorticosteroids is indicated in patients with severeesophageal or laryngotracheal lesions, anogenitallesions, or progressive ocular disease is to preventesophageal stenosis, asphyxiation, urinary andsexual dysfunction, and blindness (16,17).

    In patients with PV who cannot tolerate the oralroute, intravenous administration is used. Cyclo-phosphamide has a steroid-sparing effect at dosesof 50 to 200 mg per day in numerous case series

    (20,23,27,29,31). Cyclophosphamide has typically been used along with systemic corticosteroids asan adjuvant immunosuppressive medication.

    Cyclophosphamide has a higher incidence of adverse effects when compared to azathioprine ormycophenolate mofetil. The side effects includehemorrhagic cystitis, infertility, and bladder cancer(20,90). Because of its potential toxicity, cyclophos-phamide should be used as short-term therapy andtransitioned to an alternate adjuvant immunosup-pressive agent once disease control is achieved.Regular laboratory monitoring includes CBC withdifferential as well as urinalysis. Oral cyclophos-phamide is an alternative adjuvant therapy inpatients who have previously been recalcitrant toazathioprine or mycophenolate mofetil (51).

    Methotrexate. Although the use of methotrexate isfairly straightforward and dermatologists are famil-iar with its administration, it is not commonly usedas adjuvant therapy in MMP and PV. However, ithas been found to be helpful in some patients(18,26,30).Methotrexate(10 to17.5 mg weekly)may be considered in patients in whom other adjuvant

    medications have failedor arecontraindicated.Themajor side effect of methotrexate is hepatotoxicity which is related to total cumulative dose.Additionalsideeffectsinclude anemia, leukopenia,pulmonary toxicity, mucositis, and nausea.

    Cyclosporine. Cyclosporine (5 mg/kg per day) isused concomitantly with prednisone in the treat-ment of PV (25). Nephrotoxicity, hypertension,hepatitis, and neurologic changes are known sideeffects. Thus, cyclosporine should not be consid-ered as rst-line adjuvant therapy, but it may beused to achieve rapid initial control.

    Immunomodulatory procedures

    IVIg. IVIg may be necessary in patients with rapidly progressive, extensive, or treatment-resistant MMPor PV (39,40,44,47,48). There are many theories asto the mechanism of action of IVIg including selec-tivelydecreasingserum autoantibody levels, block-ing the function of Fc receptors, increasing thecatabolism of immune complexes, and inhibiting complement-mediated damage (10,91).

    IVIg has a very rapid onset of action, and it hasbeen found to be especially helpful in patients withprogressive ocular MMP in whom vision has dete-riorated and is threatened (39,40,43,44,47,48). Insome patients, IVIg arrests the progression of eyedisease, maintains vision, and prevents blindness

    (44). IVIg is used with oral corticosteroids and animmunosuppressant drug in patients with refrac-tory PV. However, efcacy of IVIg in PV is contro-versial (4143,49).

    Indications for IVIg, as determined by consen-sus, include: failure of conventional therapy withprednisone at a maximum dose of 60 mg per day orhigher for6 weekswith a concurrently administeredimmunosuppressant agent for 10 to 12 weeks; sig-nicant adverse effects from the use of conven-tional therapy; contraindications to high-doselong-term corticosteroids or immunosuppressantagents; and life-threatening or severely debilitating disease despite maximum conventional systemictherapy (40). The suggested dose is 2 grams/kg percycle.A cycle consists of thetotaldose given in threeequal doses over a period of 3 days. Initially, onecycle is administered every 3 to 4 weeks, but inpatients with aggressive ocular MMP, the cycleinterval may be shortened to 2 weeks (44). Once thedisease is effectively controlled, the intervalbetween cycles can be gradually increased with aproposed end point of two cycles given 16 weeksapart (40).

    Knudson et al.

    276

  • 8/12/2019 Manage OCP

    10/13

    Treatment with IVIg is extremely expensive. Adverse events occur in less than 1% of patientsbeing treated for autoimmune diseases (46). Fever,chills, ushing, myalgias, nausea, vomiting, andheadache occur during infusion and are related tothe infusion rate. Many of these side effects are

    mild and may be managed by slowing the rate of,or temporarily discontinuing, the infusion. Rare,serious side effects include acute renal failure,hemolysis, neutropenia, anaphylactic reactions (inthose with IgA deciency), congestive heart failure(in those with heart disease), cerebrovascular acci-dents, and aseptic meningitis (45,46).

    Plasmapheresis. Plasmapheresis plays a limitedrole in the management of MMP and PV but can beconsidered in difcult cases. Plasmapheresis is notrecommended as initial therapy but is best consid-ered as a short-term bridging therapy to decreaseautoantibody levels while a longer-term therapeu-tic option is sought (9, 5052).

    Extracorporeal photopheresis. Extracorporeal pho-topheresis has been used in patients with PV; butoutcomes are variable, and results are difcult tointerpret overall (5357).

    Other treatment modalities

    An increase in tumor necrosis factor alfa (TNF- a )has been found in the serum and blister uid of

    patients with immunobullous disorders (92,93).Thus, there is rationale for the use of anti-TNF- aagents (etanercept, iniximab, and thalidomide) inthese conditions. Other less commonly usedagents include subconjunctival mitomycin C, gold,and rituximab. Rituximab, an anti-CD20 mono-clonal antibody, is emerging as an effective treat-ment of immunobullous diseases.

    Biologics. Etanercept (25 mg subcutaneously twice weekly) and iniximab (5 mg/kg given by infusion at 0, 2, and 6 weeks, then every 8 weeksthereafter), have been reported to be successful forMMP in single case reports and small case series(6365).

    Rituximab, a humanized monoclonal IgG anti-body against theB cell-speciccell-surface antigenCD20, binds to and depletes CD20-expressing Bcells from the circulation for 6 to 12 months (94).Rituximab has been reported to be successful inthree cases of recalcitrant MMP (59,61,62). In thetreatment of PV, rituximab (375 mg per metersquared given weekly for 4 weeks) is administeredto patients resistant to or intolerant of standard

    regimens (oral corticosteroids and another immu-nosuppressant drug). Rituximab has also beenused concomitantly with IVIg, other immunosup-pressants, and oral corticosteroids. After the4-week induction cycle, long-term therapy withinfusions every 4 or 12 weeks may be continued

    (60). It has been noted that most patients respond within 3 months after starting rituximab, but therehave been reports of delayed response after a yearof treatment (58).

    Serious adverse events associated with ritux-imab, including death and infection, occurred in13% of patients with immunobullous diseases (PV,pemphigus foliaceus, and paraneoplastic pemphi-gus) (60). Rituximab is contraindicated in preg-nancy, and patients of childbearing age must useeffective contraception during its use and for 12months thereafter (60).

    Thalidomide. Thalidomide has well-known anti-TNF- a effects. A single case of thalidomide use(100 mg daily) in refractory MMP has beenreported (66). Thalidomide may be considered asan alternative treatment option in those notresponding to conventional therapy (66).

    Subconjunctival mitomycin C. Subconjunctivalmitomycin C injections have been used by oph-thalmologists in the treatment of ocular MMP (67).They are used as a last option in patients in whomdisease is progressing rapidly and not responding

    to oral agents, or in those in whom oral agentscannot be used due to side effects. The effects of subconjunctival mitomycin C are not permanent,and injections cannot be given more than one tothree times. If used more often, scleral and con- junctival ischemia and necrosis may occur. Thiscan result in permanent damage to the eye.

    Gold. Gold (50 mg intramuscularly per week) hasbeen used in mild-to-moderate cases of PV as monotherapy or with oral glucocorticoids(13,36,38). Because of its delayed onset of action,side effect prole, and relative ineffectiveness, it isseldom used today. Two early studies reportedcomplete remission in 15 to 44% in a total of 44 PV patients. In 15 to 28%, gold was considered to beineffective, and 17 to 35% of patients discontinuedthe drug because of side effects (35,37).

    Diagnosis and response to treatment

    Microscopy and appropriate laboratory testing areused to diagnose and monitor the response totherapy for MMP and PV. Direct immunouores-

    Mucous membrane pemphigoid and pemphigus

    277

  • 8/12/2019 Manage OCP

    11/13

    cence (DIF) of perilesional skin in MMP showslinear deposition of IgG, IgA, and/or C3 along theepithelial basement membrane zone. Indirectimmunouorescence (IIF) reveals serum autoanti-bodies binding to the epidermal or dermal side of salt-split skin. Serum levels of autoantibodies to

    BP230 and the NC16 domain of BP180 can beobtained by enzyme-linked immunosorbent assay (ELISA). Autoantibodies to BP180 and BP230 may be absent as other target antigens may be involved.In MMP, IIF titers do not correlate with diseaseactivity. However, the serum level of autoantibod-ies to the NC16 domain of BP180 does correlate with disease activity and can be used to monitorresponse to treatment in cases where BP180 is thetarget antigen (95).

    DIF microscopy of perilesional skin in PV showsintercellular deposits of IgG and C3 (96). Serumlevels of autoantibodies to desmoglein 1 and/ordesmoglein 3 can be obtained by ELISA, and thepresence of circulating autoantibodies that bind tointercellular junctions of keratinocytes in sub-strates such as monkey esophagus can be detected with the use of IIF microscopy (97). In PV, diseaseactivity correlates with both IIF titers and serumlevels of desmoglein 1 and/or desmoglein 3autoantibodies. These tests can therefore be usedto monitor a patients response to treatment (98).

    The serologic tests mentioned above should beobtained at diagnosis. Once therapy is initiated,these tests can be monitored every few months to

    determine the efcacy of treatment. Serologictesting can be extremely helpful in making treat-ment decisionsaboutmanagement ofMMPandPV,inconjunctionwiththeclinicalstatusofthepatient.

    Conclusion

    MMP and PV are disorders that can be mild andlimited, or severe and progressive with devastating effects on patients. Similar drugs and therapeuticstrategies are used in both disorders. For localizednon-ocular disease, topical therapy is the mainstay of treatment, whereas more severe and progressivedisease requires systemic therapies. Treatmentshould be individualized based on severity andextent of disease, rate of disease progression,comorbidities, and age of the patient as well asphysician preference and experience.

    References1. Mondino BJ, Sutart IB. Ocular cicatricial pemphigoid. Oph-

    thalmology 1981: 88 : 95100.

    2. Ahmed AR, Hombal SM. Cicatricial pemphigoid. Int J Der-matol 1986: 25: 9096.

    3. Laskaris G, Sklavounou A, Stratigos J. Bullous pemphigoid,cicatricial pemphigoid and pemphigus vulgaris: a com-parative clinical survey of 278 cases. Oral Surg Oral MedOral Pathol Oral Radiol Endod 1982: 54 : 656662.

    4. Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young girl. Clin Exp Dermatol 1977: 2: 281284.

    5. Rogers M, Painter D. Cicatricial pemphigoid in a 4-year-oldchild. Australas J Dermatol 1981: 22 : 2123.

    6. Chan LS,Ahmed AR,Anhalt GF, et al.The rst internationalconsensus on mucous membrane pemphigoid. Arch Der-matol 2002: 138 : 370379.

    7. Fleming TE, Korman NJ. Cicatricial pemphigoid. J Am AcadDermatol 2000: 43 : 571591.

    8. Bystryn JC, Rudolph JL. Pemphigus. Lancet 2005: 366 :6173.

    9. Bystryn JC, Steinman NM. The adjuvant therapy of pem-phigus. An update. Arch Dermatol 1996: 132 : 203212.

    10. Bystryn JC, Rudolph JL. IVIg treatment of pemphigus: how it works and how to use it. J Invest Dermatol 2005: 125 :10931098.

    11. Herbst A, Bystryn JC. Patterns of remission in pemphigusvulgaris. J Am Acad Dermatol 2000: 42 : 422427.

    12. Kanwar J, Dhar S. Factors responsible for death in patients with pemphigus. J Dermatol 1994: 21 : 655659.

    13. Toth GG, Jonkman MF. Therapy of pemphigus. Clin Der-matol 2001: 19: 761767.

    14. Megahed M, Schmiedeberg S, Becher J, Ruzicka T. Treat-ment of cicatricial pemphigoid with mycophenolatemofetil as a steroid-sparing agent. J Am Acad Dermatol2001: 45 : 256259.

    15. Saw VPJ, Dart JKG, Rauz S, et al. Immunosuppressivetherapy for ocular mucous membrane pemphigoid:strategies and outcomes. Ophthalmology 2008: 115 : 253261.

    16. Korman NJ. Update on the use of cyclophosphamide in themanagement of pemphigus, bullous pemphigoid and cica-tricial pemphigoid. Med Surg Dermatol 1998: 5: 16.

    17. Rogers RS, Mehregan DA. Dapsone therapy of cicatricialpemphigoid. Semin Dermatol 1988: 7: 201205.

    18. McCluskey P, Chang JH, Singh R, Wakeeld D. Methotrex-ate therapy for ocular cicatricial pemphigoid. Ophthalmol-ogy 2004: 111 : 796801.

    19. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathio-prine in the treatment of pemphigus vulgaris: a long-termfollow-up. J Am Acad Dermatol 1987: 16 : 527533.

    20. Ahmed AR, Hombol SM. Cyclophosphamide. J Am AcadDermatol 1984: 11 : 11151126.

    21. Bredlich RO, Grundmann-Kollman M, Behrens S. Myco-phenolate mofetil monotherapy for pemphigus vulgaris. BrJ Dermatol 1999: 141 : 934.

    22. Enk AH, Knop J. Mycophenolate is effective in the treat-ment of pemphigus vulgaris. Arch Dermatol 1999: 135 :5456.

    23. Fellner MJ, Katz JM, McCabe JB. Successful treatment of cyclophosphamide and prednisolone for initial treatmentof pemphigus vulgaris. Arch Dermatol 1978: 114 : 889894.

    24. Grundmann-Kollmann M, Kaskel P, Leiter U. Treatment of pemphigus vulgaris and bullous pemphigoid with myco-phenolate mofetil monotherapy. Arch Dermatol 1999: 135 :724725.

    25. Ioannides D, Chrysomallis F, Bystryn JC. Ineffectivenessof cyclosporine as an adjuvant to corticosteroids in the

    Knudson et al.

    278

  • 8/12/2019 Manage OCP

    12/13

    treatment of pemphigus. Arch Dermatol 2000: 136 : 868872.

    26. Ryan JG. Pemphigus. A 20-year survey of experience with 70cases. Arch Dermatol 1971: 104 : 1420.

    27. Krain LS, LandauJW, Newcomer VD. Cyclophosphamide inthe treatment of pemphigus vulgaris andbullous pemphig-oid. Arch Dermatol 1972: 106 : 657661.

    28. Mimouni D, Nousari CH, Cummins DL, Kouba DJ,David M, Anhalt GJ. Differences and similaritiesamong expert opinions on the diagnosis and treatment of pemphigus vulgaris. J Am Acad Dermatol 2003: 49 : 10591062.

    29. Pasricha JS, Sood VD, Minocha Y. Treatment of pemphigus with cyclophosphamide. Br J Dermatol 1975: 93 : 573576.

    30. Smith TJ, Bystryn JC. Methotrexate as an adjuvant treat-ment for pemphigus vulgaris. Arch Dermatol 1999: 135 :12751276.

    31. Piamphongsant T. Treatment of pemphigus with corticos-teroids and cyclophosphamide. J Dermatol 1979: 6: 359363.

    32. Werth VP, Fivenson D, Pandya AG, et al. Multicenter ran-domized, double-blind, placebo-controlled, clinical trialof dapsone as a glucocorticoid-sparing agent inmaintenance-phase pemphigus vulgaris. Arch Dermatol2008: 144 : 2532.

    33. Poskitt K, Wojnarowska F. Treatment of cicatricial pem-phigoid with tetracycline and nicotinamide. Clin Exp Der-matol 1995: 20 : 258259.

    34. Reiche L, Wojnarowska F, Mallon E. Combination therapy with nicotinamide and tetracycline for cicatricial pemphig-oid: further support forits efcacy. Clin ExpDermatol1998:23 : 254257.

    35. Pandya AG, Dyke C. Treatment of pemphigus with gold. Arch Dermatol 1998: 134 : 11041107.

    36. Penneys NS, Eaglstein WH, Indgin S, Frost P. Gold sodiumthiomalate treatment of pemphigus. Arch Dermatol 1973:108 : 5660.

    37. Penneys NS, Eaglstein WH, Frost P. Management of pem-phigus with gold compounds. A long-term follow-upreport. Arch Dermatol 1976: 112 : 185187.

    38. Sutej PG, Jorizzo JL, White W. Intramuscular gold therapy for young patients with pemphigus vulgaris: a prospective,open, clinical study utilizing a dermatologist/rheumatologist team approach. J Eur Acad Dermatol Venereol 1995: 5: 222228.

    39. Ahmed AR, Colon JE. Comparison between IVIG and con-ventional immunosuppressive therapy regimens inpatients with severe oral pemphigoid. Arch Dermatol 2001:137 : 11811189.

    40. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatmentof autoimmune mucocutaneous blistering diseases. Arch

    Dermatol 2003: 139 : 10511059.41. Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus.J Am Acad Dermatol 2009: 60 : 595603.

    42. Baum S, Scope A, Barzilai A, Azizi E, Trau H. The role of IVIg treatmentin severepemphigus vulgaris. J Eur Acad Derma-tol Venereol 2006: 20 : 548552.

    43. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus withintravenous immunoglobulin. J Am Acad Dermatol 2002:47 : 358363.

    44. Ahmed AR Foster CS. IVIG therapy for ocular cicatricialpemphigoid: a preliminary study. Ophthalmology 1999:106 : 21362143.

    45. Jolles S, Hughes J, Whittaker S. Dermatological uses of high-dose intravenous immunoglobulin. Arch Dermatol1998: 134 : 8086.

    46. MobiniN, Sarela A, Ahmed AR. Intravenous immunoglobu-lins in the therapy of autoimmune and systemic inamma-tory disorders. Ann Allergy Asthma Immunol 1995: 74:119128.

    47. Sami N, Bhol KC, Ahmed AR. IVIG therapy in patients withmultiple mucosal involvement in mucous membrane pem-phigoid. Clin Immunol 2002: 102 : 5967.

    48. SamiN, Bhol KC, Ahmed AR. Treatment of oral pemphigoid with IVIG as monotherapy long-term follow-up: inuenceof treatment on autoantibody titers to human alpha 6 inte-grin. Clin Exp Immunol 2002: 129 : 533540.

    49. Segura S, Iranzo P, Pablo IM, et al. High-dose intravenousimmunoglobulins for the treatment of autoimmune muco-cutaneous blistering diseases: evaluation of its use in 19cases. J Am Acad Dermatol 2007: 56: 960967.

    50. Guillaume JC, Roujean JC, Morel P. Controlled study of plasma exchange in pemphigus. Arch Dermatol 1988: 124 :16591663.

    51. Harman KE, Albert S, Black MM. Guidelines for the man-agement of pemphigus vulgaris. Br J Dermatol 2003: 149 :926936.

    52. Hashimoto Y, Suga Y, Yoshiike T, Hashimoto T, Takamori K. A case of antiepiligrin cicatricial pemphigoid successfully treated by plasmapheresis. Dermatology 2000: 201 : 5860.

    53. Azana JM, de Misa RF, HartoA. Severepemphigus foliaceustreated with extracorporealphotochemotherapy. Arch Der-matol 1997: 133 : 287289.

    54. Gollnick HPM, Owsianowski M, Taube KM, Orfanos CE.Unresponsive severe generalized pemphigus vulgaris suc-cessfully controlled by extracorporeal photophoresis. J Am Acad Dermatol 1993: 28 : 122124.

    55. Liang G, Nahass G, Kerdel FA. Pemphigus vulgaris treated with photopheresis. J of the Am Acad Dermatol 1992: 26 :779780.

    56. Rook AH, Heald PW,Nahass GT, et al.Treatment of autoim-mune disease with extracorporeal photochemotherapy:pemphigus vulgaris: preliminary report. Yale J Biol Med1989: 62 : 647652.

    57. Wollina U, Lange D, Looks A. Short-time extracorporealphotochemotherapy in the treatment of drug-resistantautoimmune bullous diseases. Dermatology 1999: 198 :140144.

    58. Niedermeier A. Delayed response of oral pemphigus vul-garis to rituximab treatment. Eur J Dermatol 2006: 16: 266270.

    59. Ross A, Jaycock P, Cook S, Dick A, Tole D. The use of ritux-imab in refractory mucous membrane pemphigoid withsevere ocular involvement. Br J Ophthalmol 2009: 93: 421

    422.60. Schmidt E, Goebeler M, Zillikens D. Rituximab in severepemphigus. Ann N Y Acad Sci 2009: 1173 : 683691.

    61. Schumann T, Schmidt E, Booken N, Goerdt S, Goebeler M.Successful treatment of mucous membrane pemphigoid with the anti-CD20 antibody rituximab. Acta Derm Venereol 2009: 89 : 101102.

    62. Taverna JA, Lerner A, Bhawan J, Demierre MF. Successfuladjuvant treatment of recalcitrant mucous membranepemphigoid with anti-CD20 antibody rituximab. J DrugsDermatol 2007: 6: 731732.

    63. Canizares MJ, Smith DI, Conners MS, Maverick KJ, Hef-fernan MP. Successful treatment of mucous membrane

    Mucous membrane pemphigoid and pemphigus

    279

  • 8/12/2019 Manage OCP

    13/13

    pemphigoid with etanercept in 3 patients. Arch Dermatol2006: 142 : 14571461.

    64. Sacher C, Rubbert A, Konig C, Scharffetter-Kochanek K,Krieg T, Hunzelmann N. Treatment of recalcitrant cicatri-cial pemphigoid with the tumor necrosis factor alphaantagonist etanercept. J Am Acad Dermatol 2002: 46 : 113115.

    65. Hefferman MP, Bentley DD. Successful treatment of mucous membrane pemphigoid with iniximab.Arch Der-matol 2006: 142 : 12681270.

    66. Duong DJ, Moxley RT, Kellman RM, Pincus SH, Gaspari A.Thalidomide therapy for cicatricial pemphigoid. J Am AcadDermatol 2002: 47 : S193S195.

    67. Donnenfelt ED, Perry HD, Wallerstein A, et al. Subconjunc-tival mitomycin C for the treatment of ocular cicatricialpemphigoid. Ophthalmology 1999: 106 : 7278.

    68. Ahmed AR, Kurgis BS, Rogers RS. Cicatricial pemphigoid.J Am Acad Dermatol 1991: 24 : 9871001.

    69. Muzyka BC, Greenberg MS, Glick MG. Management of oralmanifestations of mucous membrane pemphigoid. JGeriatr Dermatol 1994: 2: 105109.

    70. Lozada-Nur F, Huang MZ, Zhou G. Open preliminary clini-cal trial of clobetasol propionate ointment in adhesivepaste for treatment of chronic oral vesiculo-erosive dis-eases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod1991: 71: 283287.

    71. Lee MS, Wakeeld PE, Lonzelman JL, James WD. Oralinsertable prosthetic device as an aidin treatingoral ulcers. Arch Dermatol 1991: 127 : 479480.

    72. Foster CS. Cicatricial pemphigoid. Trans Am OphthalmolSoc 1986: 85 : 527663.

    73. Assman T, Becker J, Ruzicka T, Megahed M. Topical tacroli-mus for oral cicatricial pemphigoid. Clin Exp Dermatol2004: 29: 674676.

    74. Gunther C, Wozel G, Meurer M, Pfeiffer C. Topical tacroli-mus treatment for cicatricial pemphigoid. J Am Acad Der-matol 2004: 50 : 325326.

    75. Hall VC, Liesegang TF, Kostick DA, Lookingbill DP. Ocularmucous membrane pemphigoid and ocular pemphigusvulgaris treated topically with tacrolimus ointment. ArchDermatol 2003: 139 : 10831084.

    76. Lebeau S, Mainetti C, Masouye I, Saurat JH, Borradori L.Localized childhood vulval pemphigoid treated with tac-rolimus ointment. Dermatology 2004: 208 : 273275.

    77. Vincent SD, Lilly GE, Baker KA. Clinical, historic, andtherapeutic features of cicatricial pemphigoid. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1993: 76: 453459.

    78. Khan YK, Kalaaji AN, Clarke BL. Prevention and treatmentof glucocorticoid-induced osteoporosis in dermatologicpractice: a review. J Drugs Dermatol 2008: 7: 28.

    79. Gerhart J, Kalaaji A. Development of Pneumocystis carinii pneumonia in patients with immunobullous and connec-

    tive tissue disease receiving immunosuppressive medica-tions. J Am Acad Dermatol 2009.80. The big shot. Lancet 1977: 309 : 633634.81. Mentink LF, Mackenzie MW, Toth GG, et al. Randomized

    controlled trial of adjuvant oral dexamethasone pulsetherapy in pemphigus vulgaris. Arch Dermatol 2006: 142 :570576.

    82. Chrousos GA, Kattah JC, Beck RW, Cleary PA. Side effects of glucocorticoid treatment: experience of the optic neuritistreatment trial. JAMA 1993: 269 : 21102112.

    83. Hornsten P, Keisu M, Wiholm B. The incidence of agranu-locytosis during treatmentof dermatitis herpetiformis withdapsone as reported in Sweden, 1972 through 1988. ArchDermatol 1990: 126 : 919922.

    84. Raizman MB, Fay AM, Weiss JS. Dapsone-induced neutro-penia in patients treated for ocular cicatricial pemphigoid.Ophthalmology 1994: 101 : 18051807.

    85. Carson PJ, Hameed A, Ahmed AR. Inuence of treatmenton the clinical course of pemphigus vulgaris. J Am AcadDermatol 1996: 34 : 645652.

    86. Wolf R, Landau M, Tur E, Brenner S. Early treatment of pemphigus does not improve the prognosis: a review of 53patients. J Eur Acad Dermatol Venereol 1995: 4: 131136.

    87. Roenigk HH, Deodhar S. Pemphigus treatment with aza-thioprine. Arch Dermatol 1973: 107 : 353357.

    88. Nousari HC, Anhalt GJ. The role of mycophenolate mofetilin the management of pemphigus. J Am Acad Dermatol1999: 135 : 853854.

    89. Kirtschig G, Khumalo NP. Management of bullous pem-phigoid: recommendations for immunomodulatory treat-ments. Am J Clin Dermatol 2004: 5: 319326.

    90. Beissert S, Werfel T, Frieling U, et al. A comparison of oralmethylprednisolone plus azathioprine or mycophenolatemofetil for the treatment of pemphigus. Arch Dermatol2006: 142 : 14471454.

    91. Rutter A, Luger TA. High-dose intravenous immunoglobu-lins: an approach to treat severe immune-mediated andautoimmune diseases of the skin. J Am Acad Dermatol2001: 44 : 10101024.

    92. Ameglio F, DAuria L, Bonifati C, Ferraro C, Mastroianni A,Giacalone B. Cytokine pattern in blister uid and serum of patients with bullous pemphigoid: relationships withdisease intensity. Br J Dermatol 1998: 138 : 611614.

    93. Lee SJ, Zhengzhi L, Sherman B, Foster CS. Serum levels of tumor necrosis factor alpha and interleukin-6 in ocularcicatricial pemphigoid. Invest Ophthalmol Vis Sci 1993: 34:35223525.

    94. Browning JL. B cells move to centre stage: novel opportu-nities for autoimmune disease treatment. Nat Rev Drug Discov 2006: 5: 564576.

    95. Schmidt E, Obe K, Brocker EB, Zillikens D. Serum levels of autoantibodies to BP180 correlate with disease activity inpatients with bullous pemphigoid. Arch Dermatol 2000:136 : 174178.

    96. Beutner EH, Lever WF, Witebsky E. Autoantibodies in pem-phigus vulgaris. Response to an intercellular substance of epidermis. JAMA 1965: 92 : 682688.

    97. Beutner EH, Jordon RE. Demonstration of skin antibodiesin serum of pemphigus vulgaris patients by indirect immu-

    nouorescence staining. Proc Soc Exp Biol Med 1964: 117 :505510.98. Ishii K, Amagai M, Hall RP, et al. Characterization of

    autoantibodies in pemphigus using antigen-specicenzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol 1997: 159 :20102017.

    Knudson et al.


Recommended