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Acta Derm Venereol 93

CLINICAL REPORT

Acta Derm Venereol 2013; 93: 346349

2013 The Authors. doi: 10.2340/00015555-1471Journal Compilation 2013 Acta Dermato-Venereologica. ISSN 0001-5555

High-dose intravenous immunoglobulin (IVIG) therapy

is used in patients with severe autoimmune blistering di-

seases that are refractory to standard immunosuppres-

sive therapy. To determine the efcacy and frequency

of adverse events of IVIG therapy, we retrospectively

analysed data for 16 patients with pemphigus vulgaris,

pemphigus foliaceus, paraneoplastic pemphigus, bullous

pemphigoid and paraneoplastic bullous pemphigoid.

Frequency of adverse reactions and efcacy of IVIG

were analysed over time with a scoring system for every 6months of IVIG therapy. Headache (43.8%) and fatigue

(43.8%) were the most common side-effects recorded;

serious adverse reactions did not occur. There was good

overall efcacy, as measured by clinical response rates

using a clinical score, as well as indicated by a mean re-

duction of 75.8% in the starting steroid dose.Key words:

high-dose intravenous immunoglobulin therapy; autoim-

mune mucocutaneous blistering disease; pemphigus vul-

garis; pemphigus foliaceus; bullous pemphigoid.

Aepted Jul 23, 2012; Epub ahead of print Ot 16, 2012

Ata Derm Venereol 2013; 93: 346349.Eva Hadashi, Department of Dermatology, University

Hospital, Vostreet 2, DE-69115 Heidelberg, Germany.

E-mail: Eva.hadashi@med.uni-heidelberg.de

High-dose intravenous immunoglobulins (IVIG) haveimmunomodulatory apaity and have been shown to beeffetive in treating severe autoimmune disease (15). Indermatology, autoimmune blistering diseases and on-netive tissue diseases, inluding dermatomyositis (6)and lupus erythematodes (6, 7), are the main diseasestreated with IVIG after failure of standard immunosup-

pressive therapy.Autoimmune muoutaneous blistering diseases,

inluding pemphigus vulgaris (PV) and bullous pemphi-goid (BP), are rare, potentially life-threatening diseases.Standard treatment onsists of a ombination regimen ofortiosteroids and different immunosuppressive agents,inluding methotrexate, azathioprine, myophenolatemofetil, ylosporine and dapsone (8).

However, some patients fail to respond to standardtherapy or show relapses under immunosuppressiveombination regimens. For these patients, high-doseIVIG are used to ontrol disease ativity (2, 6).

Even though IVIG therapy is onsidered to be effe-tive and safe in treating autoimmune blistering diseases(9), lear evidene for the therapeuti effet of IVIG

besides ase reports and ase series is missing. Thepauity of randomized ontrolled trials on IVIG therapyan partially be explained by the high osts of IVIG(10). In addition, autoimmune blistering diseases arerare, thus recruitment for larger study cohorts is difcult.

There are only a few published double-blind plaebo-

ontrolled randomized trials for the use of IVIG inpemphigus that show the efcacy of IVIG in PV andpemphigus foliaeus (PF). One Japanese study showeda redution in disease severity and autoantibody titres asmeasured by enzyme-lined immunoassay (ELISA) in

patients who reeived a single dose of IVIG (11). Theseond study showed a redution in autoantibody titresand improvement in subjetive disease sores after asingle yle of IVIG (12).

In the present study we retrospetively analysedpatient data for a relatively large ohort of 16 patientswith severe or refratory autoimmune blistering diseases

under IVIG therapy. We investigated the efcacy andfrequeny of adverse events during a 24-month periodand conclude that IVIG therapy is efcient and safe forrefratory autoimmune blistering diseases.

MATERIALS AND METHODS

Patients

We retrospetively investigated data for 16 patients who reeivedtreatment with high-dose IVIG for severe autoimmune blistering di-seases at the Department of Dermatology, University of Heidelberg,between January 2004 and July 2011. Eligibility riteria were: (i)diagnosis of PV, PF, paraneoplasti pemphigus (Pn P), BP or para-

neoplasti bullous pemphigoid (PnBP); (ii) refratory or relapsingdisease under immunosuppressive ombination therapy with at least2 immunosuppressive drugs; and (iii) IVIG therapy for at least 6full yles between January 2004 and July 2011. Refratory diseasewas dened as time without control of disease activity under a givenimmunosuppressive ombination therapy. Relapsing disease wasdened as appearance of 3 new lesions/month, which do not healspontaneously within one wee, or by the extension of establishedlesions in a patient who has ahieved disease ontrol in aordanewith the consensus denitions (16). Sixteen patients were eligibleaording to the above-mentioned riteria (10 patients with PV, 3with PF, 1 with PnP, 1 with BP, and 1 with PnBP).

The following data were retrospetively retrieved from patientreords for analysis: gender, height, weight, age at diagnosis,

Analysis of High-dose Intravenous Immunoglobulin Therapy in 16Patients with Refractory Autoimmune Blistering Skin Disease: HighEfcacy and No Serious Adverse Events

Vera SEIDLING, Johen H. O. HOFFMANN, Alexander H. ENk and Eva N. HADAScHIkDepartment of Dermatology, University Hospital Heidelberg, Heidelberg, Germany

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347High-dose IVIG for autoimmune blistering skin disease

immunosuppressive therapy before IVIG, time from diagnosisto start of IVIG therapy, duration of IVIG therapy, numberof IVIG yles and umulative dose of IVIG. The study wasapproved by the local ethics committee (S-188/2010).

Intravenous immunoglobulins therapy

Prior to initiation of IVIG therapy a omplete physial exami-nation and blood tests were performed, and ontraindiations,inluding IgA defiieny, were ruled out. Patients gave writteninformed onsent to IVIG therapy. The majority of patients re-eived Intratet (Biotest Pharma GmbH, Dreieih, Germany),2 patients (patient numbers 4 and 12) reeived Intraglobin(Biotest Pharma GmbH) for < 4 yles at the beginning of thetherapy and then were swithed to Intratet and one patient(patient number 6) reeived Intratet at the beginning ofhis therapy and after relapse was swithed to Privigen (cSLBehring GmbH, Hattersheim am Main, Germany). High-doseIVIG were administered at a total dose of 2 g/kg body weightintravenously (i.v.) per yle over 2 days. Some patients reei-ved the total dose per yle frationated over 3 or 4 days due toonomitant diseases. Patients reeived IVIG every 4 wees,and prior to disontinuation of IVIG the time between yleswas extended to 5 or 6 wees.

Tolerability of intravenous immunoglobulins therapyData on the following adverse events were retrospetivelyretrieved from patient reords for analysis: headahe, fatigue,back pain, increase/decrease in blood pressure, nausea, circula-tory problems (vertigo/sweating), thoracic discomfort, blurredvision, sin symptoms (petehiae), allergi reations (urtiaria,anaphylaxis). Blood pressure was monitored before and every60 min during administration of IVIG. Inrease in blood pres-sure was defined as systolic pressure 180 mmHg, decreasedblood pressure as systoli pressure < 100 mmHg.

Efcacy of intravenous immunoglobulins therapy

The following riteria were used to measure effiay of IVIGtherapy: hanges in sin symptoms, hanges in autoantibody

titres, and tapering of steroid dose.The treating physiian doumented linial status after

physial examinat ion prior to administration of IVIG. Sinsymptoms were reorded at eah infusion yle; the following3 possible options regarding sin status (in omparison with theprevious yle) were onsidered to generate the effiay sore:1) sin symptoms ameliorated, 2) sin symptoms unhanged,and 3) sin symptoms deteriorated.

Aording to our standard operating proedures, laboratoryblood tests inluding anti-basement-membrane antibodies andanti-interellular epidermal antibodies are routinely performed inpatients on IVIG therapy. Blood is drawn before administrationof IVIG, thus representing the situation at the end of the previousinfusion yle. Both types of auto-antibodies are determined bystandardized indirect immunouorescence, and results are given

as titres. To measure efcacy of IVIG therapy we developed asore for eah 6 months during the total period of 24 months:1 (very good): no sin symptoms, autoantibody titre: no hange

or lower titre,2 (good): sin symptoms ameliorated, autoantibody titre: no

hange or lower titre,3 (satisfatory): sin symptoms unhanged, autoantibody titre:

no hange or higher titre,4 (unsatisfatory): sin symptoms deteriorated, autoantibody

titre: no hange or higher titre.The levels of autoantibodies against desmoglein (Dsg) 3

and Dsg 1 in patient sera were measured by speifi ELISA,as desribed in the manufaturers instrutions (MESAcUP,MBL, Nagoya, Japan).

Statistics

Data are shown in absolute numbers and perentage of indiatedtotal entity. Values are given as means and standard deviations.

RESULTS

Patient harateristis are summarized in Table I. Of the

16 patients with autoimmune blistering diseases treatedwith IVIG, the majority had pemphigus, inluding PV, PFand Pn P, whereas only two patients had BP. The meanage at time of diagnosis was 50.4 years and the meanduration from diagnosis to initiation of IVIG therapy was40.8 months. Patients had a mean of 2.9 immunosuppres-sive drugs prior to initiation of IVIG therapy (Table SI;available from http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1471). By the end of the24-month observational period of the present study mostof the patients were still reeiving IVIG. Until this ut-offthe mean total number of yles per patient was 38.6.

Table SII (available from http://www.medicaljour-nals.se/acta/content/?doi=10.2340/00015555-1471)details the immunosuppressive therapies prior to ini-tiation of IVIG therapy, the reasons for starting IVIG,including non-response, relapse as dened in the con-sensus statement for pemphigus (13) and side-effetsto immunosuppressive drugs for eah patient.

The adverse events during IVIG therapy are listed inTable SIII (available from http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1471). Adverseevents were reorded in 87.5% of patients and in 56.3%of total infusion yles. However, adverse events weremild, with no ases of severe side-effets, suh as ana-

phylaxis, meningitis or emboli events inluding deepvein thrombosis, ardia infartion or stroe. The mostommon adverse events were headahe and fatigue (bothin 43.8% of patients), followed by ba pain (in 31.3%of patients) and hanges in blood pressure (in 25% of

patients either inrease or derease in blood pressure).In addition, we analysed hanges in the prevalene ofadverse events for every 6 months during the 24-month

period in a given patient under IVIG therapy. However,there was no derease or adaptation over time onerningany of the analysed side-effets (data not shown).

Headahe, whih was by far the most ommon adverseevent, was treated with non-steroidal anti-inammatorydrugs (NSAIDs). In addition, patients were advised to

Table I. Patient characteristics

Disease (total No. of patients)

Sex

M/F

Age at diag-

nosis, years

IVIG

cycles, n

Pemphigus vulgaris (n =10), meanSD 4/6 49.913.6 40.922.7

Paraneoplastic pemphigus (n = 1) 1/0 72 42

Pemphigus foliaceus (n =3), meanSD 1/2 38.711.9 29.722.4

Bullous pemphigoid (n =1) 1/0 58 32

Paraneoplastic bullous pemphigoid (n =1) 1/0 61 45

Overall (n = 16), meanSD 8/8 50.414.1 38.620.0

IVIG: intravenous immunoglobulins.

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348 V. Seidling et al.

ensure a uid intake of 23 l/day. Using these measures,headahes were effetively treated in most patients. In

patients with more severe headahes, preventive intaeof NSAIDs helped to redue the severity of headahes.

Fatigue as the seond most ommon side-effet usu-ally showed onset during/after the rst day of infusionand lasted for several days. However, fatigue usually didnot hinder patients in their everyday life, nor did it havea negative inuence on their working life. There wasno specic therapeutic measure applied to treat fatigue.

Inrease in blood pressure ourred in all ases in pa-tients with pre-existing elevated blood pressure and waseffetively treated with standard antihypertensive drugs(alium-hannel bloer) without the need for any furtherintervention. Dereased blood pressure also ourredin patients displaying low blood pressure before IVIGtherapy and was resolved by letting patients wal, indi-ating that immobilization during infusion was the mainause.

Thorai disomfort was reported in one patient and

immediately led to further evaluation. cardiologialexamination did not reveal any pathologial results;therefore no therapeuti intervention was neessary.

Blurred vision ourred in 2 patients, one of whomhad a history of ytomegalovirus retinitis. He had pre-viously reported blurred vision; however, the symptomswere aggravated during IVIG infusion. After hangingthe administration of infusion to 3 days, the symptomsdisappeared. In the other patient blurred vision ourredduring several yles but did not last longer than theIVIG infusions themselves and was not aompanied

by any pathologial oular hanges.

As the only sin symptoms, only one patient reportedpetehiae after a single infusion yle. These symptomswere not aompanied by any hanges in blood ounts,resolved spontaneously within one day without furthertreatment, and did not our again thereafter. There wasno ase of allergi reation or anaphylaxis in any of theanalysed infusion yles.

Efcacy of IVIG therapy was measured by deve-lopment of linial symptoms, autoantibody titres anddegree of tapering of ortiosteroids under ontinuousIVIG therapy. First we analysed the development oflinial sin symptoms during the full 24 months ofIVIG therapy and found that in 62.5% of patients there

was amelioration of sin symptoms, in 25% of patientsthere was no hange, and 12.5% of patients showed aninitial response, followed by relapse of disease underIVIG (Table II). In addition to the linial symptoms, weanalysed the degree of tapering ortiosteroids, whihwas possible under ontinuous IVIG therapy. A meandose redution of 75.8% in the original steroid dose atinitiation of IVIG therapy was ahieved over the total

period of 24 months (Table II).The autoantibodies in sera of patients with PV or-

relate better with disease ativity than patients with BP.

Dsg 3 is the major auto-antigen in PV and Dsg 1 for PF.Fig. 1 shows the redution in autoantibody titres in asubgroup of patients with PV and PF, where results wereavailable before and during therapy, the rst data-pointrepresents the amount of autoantibody before initiationof IVIG and the seond one under IVIG treatment, bothas measured by specic ELISA.

To analyse the efcacy of IVIG therapy in more detail

we developed a sore, whih ombines linial hangesin sin symptoms as well as hanges in autoantibodytitres. We applied this sore for eah half-year periodwithin the total time-frame of 24 months. The majorityof patients had a very good sore (43.8%, 75%, 61.5%and 58.3%, respetively) in all of the 4 half-year periods,indiating a onstant therapeuti effet of IVIG over time(Table SIV; available from http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1471). Themean efcacy score over the total time of 24 monthswas 1.6, thus conrming the therapeutic effect of IVIGin severe autoimmune blistering diseases.

DIScUSSION

The ohort of patients treated with IVIG onsists ofpatients with severe autoimmune blistering diseaseswho were either resistant to, or experiened relapseunder, onventional immunosuppressive therapy. Thelong duration of 40.8 months from diagnosis to ini-tiation of IVIG reects the difculties in controllingdisease ativity and underlines disease severity in thisohort of patients. In addition, the mean number of 2.9immunosuppressive drugs outlines the need for doubleor even triple ombination regimens during the ourse

of disease before initiation of IVIG therapy.The adverse events reported in our ohort of patients

during the total period of 24 months of IVIG therapywere all mild to moderate. No severe adverse eventswere reorded, emphasizing the aepted fat that IVIGis a relatively safe therapy (3, 14). The results of ourstudy with only mild to moderate adverse events, suhas headahe and fatigue, being by far the most ommonside-effets, are in line with another observational studyanalysing side-effets of IVIG therapy (14). Most ofthe other adverse events appeared either only during a

Table II. Efcacy of intravenous immunoglobulins (IVIG) in therst 24 months of treatment

Disease

(n)

Skin symptoms, n (%) Dose reduction

of corticosteroid

(% initial dose)

MeanSD

Amelioration

under IVIG No change

Relapse

under IVIG

PV (10) 5 (50) 3 (30) 2 (20) 76.013.7

Pn P (1) 1 (100) 85.0

PF (3) 3 (100) 74.727.7BP (1) 1 (100) 62.5

Pn BP (1) 1 (100) 81.3

Overall (16) 10 (62.5) 4 (25) 2 (12.5) 75.815.3

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349High-dose IVIG for autoimmune blistering skin disease

single yle or disappeared without further intervention(petehiae and thorai disomfort both in one patient)or an be related to a onomitant disease (e.g. blurredvision in a patient with nown ytomegalovirus retinitis).

One initiated, the majority (62.5%) of patients sho-wed amelioration under IVIG therapy and this effetwas onsistent during all 4 half-year periods analysed(Table SIV). Remarably, at the same time tapering ofsteroids up to a mean redution of 75.8% in starting dosewas possible without relapse in most patients. However,4 patients only showed stable disease with no hange insin symptoms. One patient had PnPV with underlyingrefratory malignant lymphoma, whih made it impos-sible to ontrol disease ativity. The other 3 patientshad severe realitrant disease, whih did not showimprovement under therapy. Two patients experiened

a relapse during IVIG therapy; in both ases the om-bination of IVIG with rituximab, whih was reported asan effetive regimen for patients with relapsing diseaseunder IVIG therapy (15), nally achieved remission.

In summary, this study showed, for a ohort of 16patients with refratory autoimmune blistering disease,that the administration of high-dose IVIG an learlinial symptoms and result in onstant ameliorationover time, while tapering of ortiosteroids is possible atthe same time. This high efcacy of IVIG is not hampe-red by severe side-effets, as is often the ase for othereffetive treatment regimens, suh as hemotherapy.

AckNOWLEDGEMENT

Funding by cSL Behring was reeived for parts of data analysis.

The authors report no conflicts of interest.

REFERENcES

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4. Levy Y, Sherer Y, George J, Langevitz P, Ahmed A, Bar-Dayan Y, et al. Serologi and linial response to treatmentof systemi vasulitis and assoiated autoimmune diseasewith intravenous immunoglobulin. Int Arh Allergy Im-munol 1999; 119: 231238.

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a bPV / PnP ELISA

0

50

100

150

200

250

Dsg1 Dsg3

PF ELISA

0

100

200

300

400

500

600

700

Dsg1 Dsg3

(U/ml)

(U/ml)

Fig. 1. Levels of desmoglein 1 (Dsg 1) and 3 (Dsg 3) autoantibodies in sera of

patients with (a) pemphigus vulgaris (PV) and paraneoplastic pemphigus (PnP)

and (b) pemphigus foliaceus (PF). The rst data-point represents the level of

autoantibody before initiation of intravenous immunoglobulins (IVIG), the

second during IVIG therapy. Data are shown as means standard deviations

(SD) in U/ml as determined by specic enzyme-linked immunoassay (ELISA)

(n = 7 for PV; n= 2 for PF).

Acta Derm Venereol 93