Successful use of rituximab in the treatment

of childhood and juvenile pemphigus

Keshavamurthy Vinay, MD,a Amrinder J. Kanwar, MD, FRCP,a Gitesh U. Sawatkar, MD,a
Sunil Dogra, MD, FRCP,a Norito Ishii, MD,b and Takashi Hashimoto, MDb
Chandigarh, India, and Fukuoka, Japan

Background: There is a lack of data on outcomes of management of pemphigus in children.

Objective: We sought to evaluate rituximab treatment in childhood and juvenile pemphigus.

Method: All cases of pemphigus treated with rituximab in patients younger than 18 years were included.
Clinical and epidemiologic data and details of rituximab administration were recorded. Response
to treatment was assessed as control of disease activity, partial remission, complete remission, and
relapse/flare.

Results: Ten patients aged 9 to 17 years received rituximab treatment. After therapy, they were followed
up for a median period of 16 months (range 8-36 months). Complete remission without concomitant
therapy was achieved in 7 patients by a mean of 21 weeks. One patient each achieved complete remission
(on immunosuppressant therapy), control of disease activity, and partial remission (on immunosuppressant
therapy) by 15, 8, and 14 weeks, respectively. Relapse/flare occurred in 6 patients by a mean period of
13 months. Two patients received a second cycle of rituximab infusions with good clinical response.
Infusion reactions were the most common adverse event. There were no long-term complications.

Limitation: Small sample size and retrospective study design are limitations.

Conclusion: The current data suggest that rituximab is useful in treating childhood and juvenile
pemphigus. ( J Am Acad Dermatol 2014;71:669-75.)

Key words: autoimmune bullous diseases; childhood pemphigus vulgaris; juvenile pemphigus vulgaris;
rituximab.

P emphigus is rare in children and adolescents.

In a study of pemphigus from North India,
children younger than 15 years accounted for
3.7% of total cases.1 Pemphigus in children younger
Abbreviations used:
CR:
Dsg:
ELISA:
complete remission
desmoglein
enzyme-linked immunosorbent assay
than 12 years is known as childhood pemphigus, PF: pemphigus foliaceus
and in those aged 12 to 18 years as juvenile PR: partial remission
PV: pemphigus vulgaris
pemphigus.2 A recent review of the English-
language literature found 33 cases of childhood
pemphigus vulgaris (PV) and 47 cases of juvenile
PV.3,4 Most reports are of sporadic cases and corticosteroids, azathioprine, dapsone, mycopheno-
small series, and lack data on treatment late mofetil, cyclophosphamide, and intravenous
outcomes. Treatment modalities include systemic immunoglobulin.3,4 Reported adverse events such

From the Department of Dermatology, Venereology, and Reprint requests: Amrinder J. Kanwar, MD, FRCP, Department of
Leprology, Postgraduate Institute of Medical Education and Dermatology, Venereology, and Leprology, Postgraduate
Research, Chandigarha; and Department of Dermatology, Institute of Medical Education and Research, Sector 12,
Kurume University School of Medicine, and Kurume University Chandigarh 160012, India. E-mail: [email protected].
Institute of Cutaneous Cell Biology, Fukuoka.b Published online July 9, 2014.
Funding sources: None. 0190-9622/$36.00
Conflicts of interest: None declared. Ó 2014 by the American Academy of Dermatology, Inc.
Accepted for publication May 31, 2014. http://dx.doi.org/10.1016/j.jaad.2014.05.071

669
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OCTOBER 2014

as infections, weight gain, Cushing disease, with prednisolone (1.5 mg/kg/d) or its equivalent
menstrual irregularity, hypertension, acne, cataract, and concurrent use of cyclophosphamide (2 mg/
growth retardation, osteopenia, conduct disorder, kg/d) or azathioprine (2.5 mg/kg/d) for 12 weeks.10
diabetes mellitus, and avascular necrosis may have Patients were also considered to have resistant
profound effects on the physical growth, social disease if new lesions continued to appear and/or
interactions, and psychosocial health of children old lesions failed to heal with 6 pulses of
and adolescents. intravenous dexamethasone (100-mg dose), admi-
Rituximab, a monoclonal antibody directed to nistered monthly.
CD20 antigen on the cell sur- At every visit, the disease
face of B lymphocytes, has was assessed according to
shown promising results in CAPSULE SUMMARY the revised severity index
the treatment of pemphigus. for pemphigus described by
dData on treatment outcomes of
It acts by inducing apoptosis Ikeda et al11 (Ikeda severity
1
of CD20 cells. 5,6
Data on childhood and juvenile pemphigus are
score). Each item in the
rituximab use in childhood limited.
severity index was scored
and juvenile PV are limited to dWe report a positive clinical and from a minimum of 0 to a
individual case reports.7 Our immunologic outcome in 10 cases of maximum of 3. Thus: (I) the
study presents data on childhood/juvenile pemphigus treated ratio of the affected area to
10 patients with childhood/ with rituximab. the total skin surface as a
juvenile pemphigus treated dRituximab is a promising treatment percentage (0, none; 1,
with rituximab. option for severe/refractory pemphigus \5%; 2, 5%-15%; and 3,
in children and adolescents. [15%); (II) the presence or
METHODS absence of the Nikolsky phe-
Patients nomenon (0, none; 1, only
This was a retrospective analysis of clinical focal; 2, positive; and 3, distinct); (III) the number of
records of patients with pemphigus treated and newly developed blisters per day (0, none; 1,
followed up at the Postgraduate Institute of occasional blisters; 2, 1-5 blisters; and 3, [5 blisters);
Medical Education and Research, Chandigarh, and (IV) the presence or absence of oral lesions as a
India, from October 2010 to June 2013. As this was percentage (0, none; 1, \5%; 2, 5%-30%; and 3,
a retrospective analysis of the patient treatment [30%). The severity of each case was rated by the
records, institutional review board approval was total sum of the scores. Disease was assessed to be
not required. mild, moderate, and severe, if the scores were less
Ten patients younger than 18 years with than 5, 5 to 7, or higher than 7, respectively.
pemphigus who received rituximab treatment with
at least 6 months of posttreatment follow-up were Follow-up and response to treatment
identified. Clinical and epidemiologic data extracted After rituximab infusions, the patients were
included age at rituximab administration, gender, followed up for a variable time period. At each visit,
and disease duration. The clinical diagnosis and response to treatment was assessed as per standard
previous therapies were evaluated. definitions, including control of disease activity,
partial remission (PR), complete remission (CR),
Rituximab treatment and relapse/flare, as defined by the consensus
All 10 patients were treated with either of 2 statement from the International Pemphigus
regimens: (1) a fixed-dose regimen, where rituximab Committee.10 PR and CR were further defined
(500 mg) was administered twice, 15 days apart; depending on intake of concomitant immunosup-
and (2) a body-weight regimen, where rituximab pressant therapy: on therapy [CR (on) and PR (on)] or
(375 mg/m2 body surface area) was administered off therapy [CR (off) and PR (off)].10
twice, 15 days apart. In every patient the
pre-rituximab evaluation and treatment followed a Immunologic evaluation
protocol described previously.8,9 At baseline, skin biopsy specimens were taken
Indications for treatment were resistant disease, from all patients, and the specimens were submitted
severe disease, or contraindications to conventional for histopathologic assessment using hematoxylin-
therapies. Resistant disease was defined as the eosin staining and for direct immunofluorescence for
continued extension of old lesions, continued IgG, IgA, IgM, and C3. Enzyme-linked immunosor-
development of new lesions, or failure of established bent assay (ELISA) for IgG anti-desmoglein (Dsg)1
lesions to begin to heal, despite 3 weeks of therapy and Dsg3 antibodies was performed as described
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VOLUME 71, NUMBER 4

previously.12 Cut-off index value was 20. Index respectively. Relapse/flare was seen in 6 patients
values between 10 and 20 and below 10 were during the follow-up period. The mean period to
considered to be indeterminate and negative value, relapse/flare was 13 months with a range of 8 to
respectively. For sera with index values more than 20 months. Relapse was mild in 4 patients,
150 in 1:100 serum dilution, ELISA was repeated in who achieved CR again with a short course of
1:1600 serum dilution and true index values were corticosteroids and azathioprine. The other 2
calculated. ELISA was also performed at the end of patients had moderate to severe relapse, 1 of
follow-up period. whom was intolerant of conventional therapies.
These 2 patients were administered a second cycle
RESULTS of rituximab infusions (2 doses of 500 mg, 15 days
Patients apart) with good clinical response. At the final visits,
Among the 10 patients (8 boys and 2 girls), 7 of 7 patients were in CR, 1 patient had PR, and 2 patients
10 were given the diagnosis of PV and 3 of 10 of had control of disease activity (Table I).
pemphigus foliaceus (PF), based on clinical and
immunologic features. All patients with PV had both Immunologic evaluation of patients with PV
mucosal and cutaneous lesions. Their age at By ELISA, both anti-Dsg1 and Dsg3 index values
rituximab infusion ranged from 9 to 17 years. Two were raised in all 7 patients with PV at baseline,
patients had childhood pemphigus and 8 patients which correlated well with the clinical diagnosis.
had juvenile pemphigus. The median disease ELISA was repeated in 6 patients at the final visit,
duration before rituximab administration was 33 except for 1 patient who was lost to follow-up.
months, ranging from 6 to 84 months. Most patients Immunologic response to treatment was evidenced
had received various immunosuppressant agents in by negative anti-Dsg index values in 4 patients who
the past, including azathioprine, dexamethasone had achieved CR (off) at the final visit (Table I).
pulse therapy, methotrexate, and mycophenolate
mofetil, in addition to systemic corticosteroids. Immunologic evaluation of patients with PF
Three patients received corticosteroids as sole Only anti-Dsg1 index values were raised in 3
therapy. The Ikeda severity score at rituximab patients with PF at baseline, which correlated well
administration ranged from 3 to 11: 3 of 10 patients with the clinical diagnosis. A decrease in index
had mild disease, 2 of 10 had moderate disease, and values of anti-Dsg 1 antibodies was seen in all 3
5 of 10 had severe disease (Table I). patients. The index value of anti-Dsg 1 antibodies
became negative in only 1 patient who achieved CR
Rituximab treatment at the final visit (Table I).
Eight patients (5 PV, 3 PF) received fixed-dose
rituximab and 2 patients (both PV) received Adverse events
rituximab based on body surface area. Seven patients Infusion reaction at rituximab administration was
had resistant disease, which had failed to respond to the most common immediate adverse event. Two
multiple immunosuppressant agents. Three of patients developed mild infusion reactions,
these 7 patients also had severe disease (Ikeda including uneasiness, chills, and rigors. Severe
severity score [7). Two patients with iatrogenic complications, including angioedema, were seen in
Cushing disease were given rituximab to reduce 2 patients. Infusion reactions were managed by
the steroid requirement. One patient had severe lowering the infusion rate and administrating
mucocutaneous PV. All patients received daily oral systemic corticosteroids and antihistamines. The
prednisolone (0.5-1 mg/kg/d, depending on the remaining 6 patients tolerated the infusion well.
response) in tapering doses, after rituximab Upper respiratory infection developed in 1 patient,
treatment. Four patients who relapsed were also a month after rituximab administration, which
treated with azathioprine (2 mg/kg/d) (Table I). responded to oral antibiotics. No serious late-onset
adverse events were noted (Table I).
Follow-up and response to treatment
After rituximab treatment, patients were followed DISCUSSION
up for a median period of 16 months (range 8-36 Treatment of pemphigus has evolved with use
months). All patients showed a clinical response. CR of targeted therapies and immunomodulators,
(off) was achieved in 7 patients by a mean time of 21 including rituximab and intravenous immunoglo-
weeks (range 16-28 weeks) (Figs 1 and 2). One bulin. Many long-term studies of rituximab treatment
patient each achieved CR (on), control of disease in adult patients with pemphigus have shown good
activity, and PR (on) by 15, 8, and 14 weeks, therapeutic outcomes.13-15 The data in childhood
 672 Vinay et al
Table I. Disease characteristics and treatment response in individual patients
Relapse Baseline
or flare/ Clinical ELISA* ELISA at last visit*
Age at Disease Follow-up Late end post- status
Patient rituximab duration, Previous ISS Rituximab Indication for Concomitant duration, point rituximab, during Anti- Anti- Anti- Anti-
No. therapy, y Gender Diagnosis mo therapy (baseline) dose therapy therapies mo Adverse effects achieved/wk mo last visit Dsg1 Dsg3 Dsg1 Dsg3

1 9 Male PV (MC) 6 AZA, CS, 9 375 mg/m2 RD 1 severe CS 36 Angioedema CR (off)/18 Yes/18 CR (off) 1372.80 888.80 0.5 14.22
DP 32 disease
2 11 Male PV (MC) 12 AZA, CS, 11 375 mg/m2 Severe disease CS 8 Infusion CR (off)/18 No CR (off) 248.52 575.20 Lost to follow-up
DP 32 reaction
3 16 Male PF 36 AZA, CS, 5 500 mg 3 2 RD AZA, CS 20 None CR (off)/24 Yes/20 CD 811.1 0 42.07 1.43
DP, MTX
4 17 Male PV (MC) 12 AZA, CS, 10 500 mg 3 2 RD 1 severe AZA, CS 19 None CR (off)/16 Yes/8 CR (off) 67.30 130.33 7.56 4.48
DP, MMF disease
5 17 Male PV (MC) 84 CS 7 500 mg 3 2 RD 1 iatrogenic AZA, CS 18 Infusion CR (on)/15 Yes/12y CR (on) 1148.46 116.09 94.04 14.79
Cushing reaction
6 17 Female PV (MC) 36 CS 9 500 mg 3 2 Severe disease CS 17 None CR (off)/22 No CR (off) 1743.74 87.43 18.10 0.86
7 13 Male PF 36 AZA, CS, 8 500 mg 3 2 RD 1 severe AZA, CS 15 None CR (off)/28 Yes/9 CR (on) 131.87 1.27 0.53 1.24
DP disease
8 13 Female PV (MC) 12 AZA, CS 4 500 mg 3 2 RD CS 14 URTI CR (off)/20 No CR (off) 165.11 340.25 1.83 6.26
9 12 Male PV (MC) 30 AZA, CS 3 500 mg 3 2 RD CS 12 Angioedema CD/8 Yes/11y CD 107.11 134.81 2.98 274.17
10 12 Male PF 36 CS 4 500 mg 3 2 Contraindication CS 8 None PR (on)/14 No PR (on) 1333.70 2.9 146.33 3.05
to conventional
therapy,
iatrogenic
Cushing

AZA, Azathioprine; CD, control of disease activity; CR (off), complete remission off treatment; CR (on), complete remission on treatment; CS, corticosteroids; DP, dexamethasone pulse; Dsg,
desmoglein; ELISA, enzyme-linked immunosorbent assay; ISS, Ikeda severity score; MC, mucocutaneous type; MMF, mycophenolate mofetil; MTX, methotrexate; PF, pemphigus foliaceus; PR (on),
partial remission on treatment; PV, pemphigus vulgaris; RD, refractory to conventional therapy; URTI, upper respiratory tract infection.
*ELISAs of recombinant baculoprotein of Dsg1 and Dsg3 for IgG antibodies.
y
Treated with repeated rituximab infusions (500 mg 3 2).

J AM ACAD DERMATOL
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Fig 1. Juvenile pemphigus vulgaris (patient 4). A, Raw erosions over the back before
treatment. B, Areas of postinflammatory hyperpigmentation at 19 months posttreatment.

Fig 2. Juvenile pemphigus foliaceus (patient 7). A, Crusted erosions over scalp before
treatment. B, Complete healing of the lesions at 15 months posttreatment.

pemphigus are limited but rituximab has been surface areaedependent dosing is associated
widely used to treat other pediatric autoimmune with possible dosing errors, and a higher
disorders, including nephrotic and nephritic pharmacokinetic variability.20 All responded to
syndromes,16 antineutrophil cytoplasmic antibodye rituximab treatment, with 8 patients achieving CR
associated vasculitis,17 autoimmune thrombo- after a single infusion cycle. These results are similar
cytopenia,18 and juvenile dermatomyositis.19 Cases to long-term treatment outcomes in adults reported
of childhood and juvenile pemphigus treated with by Heelan et al15 and Cianchini et al,14 in which
rituximab were reviewed by us previously and we CR was achieved in 80% and 86% of patients,
reported 2 of the 10 patients in the current study.7,8 respectively, after a single infusion cycle. In our
These patients were followed up further and study, among the 7 patients with resistant disease, CR
long-term data are presented here. (off) was achieved in 5 patients, and CR (on) and
The majority of our cases were treated with control of disease activity was achieved in 1 patient
the fixed-dose regimen, because fixed-dose each, substantiating its usefulness in resistant cases.
administration of monoclonal antibody is advisable In patients achieving PR and control of disease
for drugs with a wide therapeutic window. The body activity, rituximab treatment dramatically reduced
674 Vinay et al J AM ACAD DERMATOL
OCTOBER 2014

the corticosteroid requirement. After initial response, 3. Mabrouk D, Ahmed AR. Analysis of current therapy and clinical
6 patients relapsed during the follow-up period at a outcome in childhood pemphigus vulgaris. Pediatr Dermatol
2011;28:485-93.
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those reported by Heelan et al,15 with a relapse rate pemphigus vulgaris: analysis of data on clinical outcomes.
of 61% at a median of 15 months. Two patients who Am J Clin Dermatol 2010;11:21-33.
relapsed received a second cycle of rituximab with 5. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R,
good response. Some authors propose additional et al. Depletion of B cells in vivo by a chimeric mouse human
monoclonal antibody to CD20. Blood 1994;83:435-45.
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maintain clinical remission.14,21 A recent study by Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody
Gregoriou et al22 found no additional benefit from sensitizes a B cell lymphoma cell line to cell killing by cytotoxic
prophylactic infusions of rituximab. As in our study, drugs. Cancer Biother Radiopharm 1997;12:177-86.
most relapses after rituximab treatment are mild 7. Kanwar AJ, Sawatkar GU, Vinay K, Hashimoto T. Childhood
pemphigus vulgaris successfully treated with rituximab. Indian
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suppressant agents. Overuse of rituximab might Efficacy and safety of rituximab treatment in Indian
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cells in protected niches, generation of na€ıve bone Borradori L, et al. Consensus statement on definitions of
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autoreactive plasma cells and T cells, circulating CD20 J Am Acad Dermatol 2008;58:1043-6.
11. Ikeda S, Imamura S, Hashimoto I, Morioka S, Sakuma M,
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to CD20.23 Colliou et al24 reported differences in for pemphigus in Japan. Arch Dermatol Res 2003;295(Suppl):
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