Introduction
Pemphigus vulgaris (PV) affecting the pediatric population is extremely rare, representing
less than 3% of all PV cases.
1
Conventional treatment with systemic steroids with or without adjuvant immunosuppressants
used in adult cases of PV is often employed. However, pediatric cases often present
a therapeutic challenge given their increased susceptibility to systemic therapy’s
associated risks. To date, no specific guidelines regarding treatment strategies in
this patient population exist. We describe a 14-year-old Hispanic female patient with
severe, recalcitrant PV with suboptimal treatment response to systemic steroids and
intravenous immunoglobulin (IVIG) successfully treated with rituximab (RTX), showing
control of disease in as early as 2 weeks after treatment initiation. To our knowledge,
only 45 cases of pediatric PV successfully treated with RTX have been reported in
the literature, highlighting its use as a safe therapeutic option in this patient
population.
1
-17
Case Report
A 14-year-old Hispanic female patient presented to our clinics for evaluation of 1-month
history of multiple scattered flaccid vesicles and erosive lesions involving the trunk,
extremities, and oral mucosa. Lesional and perilesional skin biopsy was obtained,
confirming the diagnosis of PV. At this time, treatment with systemic oral corticosteroids
(0.5 mg/kg/d) was initiated with significant improvement. However, within 1 month
of therapy, the patient had a severe relapse of disease complicated by sepsis requiring
hospitalization (Figure 1). Treatment with intravenous (IV) antibiotics and IV steroids
(methylprednisolone 40 mg) was initiated. After control of disease was achieved approximately
2 weeks following IV steroids, the patient was transitioned to oral prednisone 60
mg and mycophenolate mofetil 500 mg daily. Given suboptimal treatment response and
progressive disease, IVIG treatment (15 g/d [0.4 mg/kg/d]) for 5 days was administered.
Despite the previous treatment regimen, the patient showed minimal improvement. In
addition, the patient developed side effects from the therapy, including recurrent
infections, Cushingoid features, hypertrichosis, and edema. To minimize ongoing prolonged
steroid use, treatment with RTX (4 cycles of 375 mg/m2, 1 week apart) was initiated.
Baseline laboratories prior to initial RTX cycle revealed elevated markers for CD19
and CD20 B cells (25.8%, 25.8%), decreased markers for CD4 T cells (33.4%) and elevated
serum anti-desmoglein (dsg) 1 and 3 antibodies (189 U/mL and 122 U/mL, respectively).
Our patient tolerated RTX therapy well with no adverse effects showing rapid clinical
remission (no new lesions) in as early as 2 weeks after initial infusion (Figure 2).
Following RTX therapy, our patient continued with sustained clinical remission while
on low dose steroids. Following 6 months after RTX infusion, systemic steroids were
successfully discontinued. At the last 18-month follow-up, our patient has remained
disease free off all therapy, with serial serum anti-dsg 1/3 levels persisting below
normal levels and no relapse episodes.
Figure 1.
Note multiple erosions and scattered flaccid bullae involving almost 100% of patient’s
back.
Figure 2.
Significant re-epithelialization 4 weeks after the fourth cycle of rituximab. Note
few scattered erosions and crusted plaques.
Discussion
Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen present
on the cell surface of B cells.
18
Despite its approval in adults with new-onset moderate to severe PV or those with
recalcitrant disease, data regarding its use in pediatric cases of PV currently remain
off-label. Rituximab appears to show promising results for the management of pediatric
PV.
19
In 2019, Bilgic et al reviewed the literature describing a total of 30 cases of pediatric
pemphigus (25 PV; 5 pemphigus foliaceous) successfully treated with RTX.
3
Since then, 21 more pediatric PV cases, including ours, have been described, resulting
in 46 patients
1
-17
(Table 1). At diagnosis and at treatment initiation, mean age was 12.7 (range = 1.5-17)
and 13.9 (range = 4.5-17) years, respectively. Following RTX therapy, patients were
followed up for a mean period of 30 (range = 5-103) months. The most frequently used
RTX dosing regimen in pediatric PV cases was 4 weekly infusions of 500 mg (n = 16),
followed by 2 cycles of 500 mg infusions, 15 days apart (n = 9) and 4 weekly infusions
of 375 mg/m2 body surface area (BSA) (n = 7), respectively.
Table 1.
Summary of Pediatric Cases of Pemphigus Vulgaris Treated With Rituximab.
Total of patients, no.
46
Gender, no
21 F, 25 M
Mean age at diagnosis, years (range)
12.7 (1.5-17)
Mean age at initiation of RTX tx, years (range)
13.9 (4.5-17)
Mean pre-dsg 1/3 levels, U/mL
453.5, 415.2
RTX dosing regimen
Body surface area dosing regimen
500 mg weekly × 4 wks
17
375 mg/m2 BSA weekly × 4 wks
7
Fixed dosing regimen
500 mg ×2, 2 wks apart
8
100 mg × 2, 2 wks apart
4
375 mg/m2 BSA × 2, 2 wks apart
6
375 mg/m2 BSA × 2, 30 days apart
1
300 mg/m2 BSA × 2, 2 wks apart
1
350 mg/m2 BSA × 2, 2 wks apart
2
Mean total follow-up, months (range)
30 (5-103)
Clinical outcome at last follow-up, no
CR off T
21
CR on T
12
PR off T
4
PR on T
3
CR
3
PR
1
Not mentioned
1
Death
1
Reported AE, no
24
Infusion reaction (fever, chills, dyspnea, tachychardia, urticaria)
10
Angioedema
3
HSV
1
Infection (not specific, URI)
2
Sepsis
2
Relapse episodes, no
12
Mean post-dsg 1/3 levels, U/mL
30.4, 101.9
Abbreviations: AE, adverse effects; BSA, body surface area; F, female; M, male; Tx,
treatment; RTX, rituximab; dsg, desmoglein; wks, weeks; CR off T, complete remission
off therapy; CR on T, complete remission on therapy; PR off T, partial remission off
therapy; PR on T, partial remission on therapy; CR, clinical remission; PR, partial
remission; HSV, herpes simplex virus; URI, upper respiratory infection; no, number.
Most cases (78%, n = 36) result in clinical remission following RTX therapy, with
clinical outcome at last follow-up varying from complete remission (CR) requiring
ongoing systemic immunosuppression (n = 12) to CR off all therapy (n = 21). In 2 cases,
CR was reported as treatment outcome, but details regarding ongoing therapies were
unclear.
4,12
Of all pediatric patients treated with RTX therapy, approximately 26% (n = 12) report
a relapse of disease, the majority occurring within a mean period of 13 (range = 8-20)
months after initial RTX therapy. Adverse effects associated with RTX were reported
in approximately 35% of patients (n = 16). Of these, infusion reactions were the most
commonly reported (mild infusion reactions, n = 12; angioedema, n = 3), followed by
infections (n = 5). A summary of the reported cases, including clinical characteristics,
treatment regimen, and outcome, is depicted in Table 2. Although pediatric patients
treated with RTX are thought to have an increased risk of developing severe infections,
sepsis was reported in only 2 cases, one of which resulted in death.
8,12
At 12 months after RTX therapy, our patient has achieved CR off all treatment with
no reported adverse effects or relapse episodes. Whether or not patients benefit from
additional maintenance RTX infusions during follow-up to ensure sustained clinical
remission is still a subject of great debate.
3,4
In this review, a total of 18 patients received additional RTX infusions. In our case,
at 6- and 12-month follow-up evaluations, our patient showed sustained clinical response;
thus, additional maintenance infusions were deferred. Also, follow-up serum anti-dsg
1 and 3 antibody levels remained below normal limits and CD19 B-cell markers remained
<1%, supporting sustained clinical response.
Table 2.
Pediatric Cases of Pemphigus Vulgaris Treated With Rituximab.
Ref.
Case no
Sex/age at onset of PV (yrs)
Previous TX
AE due to previous TX
Age at initiation of RTX (yrs)
Indications for RTX/dosing regimen
Adjuvant TX
Additional RTX doses
AE due to RTX
Clinical outcome at last F/U visit
Total F/U(months)
Relapse
Serum dsg1/3 levels (pre/post RTX)
Our case
1
F/13
CS, TS, MMF, IVIG
Sepsis, CUSH. hirsutism, edema
14
RD375 mg/m2 weekly for 4 wks
TS, PSL (5-60 mg/d)
N
N
CR off T
6
No
189 U/mL and 122 U/mL
25 U/mL and 17 U/mL
Kianfar et al
1
2
M/14
CS, AZT, MMF, ILCS
NR
17
RD500 mg weekly for 4 wks
PSL (0.25 mg/kg/d)
1 cycle (4 infusions)
N
PR off T
103
Yes
NM
NM
3
F/14
CS, AZT
CUSH, hirsutism acne, striae, osteopenia, ↑LFT
17
AE to previous tx/ 500 mg weekly for 4 wks
PSL (0.1 mg/kg/d)
N
Chills and fever
CR on T
18
No
NM
NM
4
F/14
None
NR
14
Severe/500 mg weekly for 4 wks
PSL (1 mg/kg/d)
N
N
CR on T
28.5
Yes
NM
NM
5
F/16
None
NR
16
Severe/500 mg weekly for 4 wks
PSL (1.8 mg/kg/d)
N
Fever
CR off T
58
No
NM
NM
6
M/17
None
Dyspepsia
17
Severe, intolerance to PSL/500 mg weekly for 4 wks
PSL (0.8 mg/kg/d)
1 cycle (4 infusions)
Dyspnea
PR on T
57
Yes
NM
NM
7
F/16
CS, AZT
NR
17
RD/500 mg weekly for 4 wks
PSL (0.5 mg/kg/d)
1 cycle (4 infusions)
Dyspnea, rigor, tachycardia
PR off T
51
Yes
NM
NM
8
F/16
CS, AZT, MMF
↑LFT
17
RD/500 mg weekly for 4 wks
PSL (1.1 mg/kg/d)
N
N
CR on T
102
Yes
NM
NM
9
F/17
None
NR
17
Severe/500 mg weekly for 4 wks
PSL (1.1 mg/kg/d)
2 infusions
N
PR on T
51.5
Yes
NM
NM
10
F/16
CS
NR
17
RD/500 mg weekly, for example, 4 wks
PSL (0.9 mg/kg/d)
N
Dyspnea
CR on T
5
No
NM
NM
11
M/11
CS, AZT
NR
11
RD/500 mg weekly for 2 wks
PSL (2 mg/kg/d)
2 infusions
Fever, infection
CR off T
97
Yes
30 U/mL and 137 U/mL
NM
Broshtilova et al
2
12
F/14
CS, DAP
CUSH, delayed growth, skin atrophy, striae, hirsutism, menstrual irregularity, infections
14
RD and due to AEs of previous therapy/2 dose of 375 mg/m2 30 days apart
NM
NM
N
CR
34
No
270 U/mL and 314 U/mL
255 U/mL and 251 U/mL (first infusion) 202 U/mL and 308 U/mL (second infusion)
Bilgic-Temel et al
3
13
M/16
CS, AZA
Psychosis, OP, wt gain
17
RD and severe adverse events/2 dose 1000 mg 15 days apart
MP (0.5-1 mg/kg/d)
3 cycles of fixed dose (500 mg)
N
CR off T
60
No
NM
NM
14
M/14
CS, AZA, DAP, MMP, IVIG
Cataract, lymphopenia
17
RD and adverse events/2 doses 1000 mg 15 days apart
IVIG
N
N
PR off T
49
No
NM
NM
15
M/13
CS, AZA, DAP
NR
17
RD/2 dose 1000 mg 15 days apart
DAP
N
N
PR off T
60
No
NM
NM
16
F/9
CS, AZA, IVIG, DAP
OP, anemia
13
RD and severe/2 dose 500 mg 15 days apart
MP, AZA
3 cycles of fixed dose (500 mg)
N
CR off T
25
Yes
NM
NM
17
F/10
CS, IVIG, ILS, TS
OP, wt gain, CUSH
11
RD and severe adverse events/375 mg/m2 weekly for 4 weeks
MP, ILS, TS
3 cycles (2 doses of RTX of 375 mg/m2 weekly for 4 wks and 1 prophylactic dose of
RTX of 375 mg/m2 weekly for 2 weeks)
N
CR off T
19
Yes
NM
NM
Gupta et al
4
18
M/12
CS, AZA
NR
12
RD, contraindication to steroids, severe/2 doses of 500 mg 2 wks apart
CS (5-20 mg/d)
N
Infusion reaction (1) HZV (1)
CR off T
12
No
31.8 U/mL and 17.1 U/mL
11.3 U/mL and 3.1 U/mL
19
F/9
CS, AZA
Anemia
9
CS (5-20 mg/d)
N
CR off T
12
No
357 U/mL and 219 U/mL
98 U/mL and 77 U/mL
20
F/11
CS, CP
NR
11
CP (50 mg/d), CS (5-20 mg/d)
N
CR on T
12
No
99.1 U/mL and 103.4 U/mL
3.4 U/mL and 6.7 U/mL
21
M/12
CS, CP
NR
12
CP (50 mg/d), CS (5-20 mg/d)
N
CR on T
12
No
184.6 U/mL and 94 U/mL
80.5 U/mL and 64 U/mL
22
M/9
CS, AZA
NR
9
CS (5-20 mg/d)
N
CR off T
12
No
150 U/mL and 10.8 U/mL
47 U/mL and 1.8 U/mL
Salman et al
5
23
M/14
CS, AZA, IVIG, DAP
Osteopenia, CUSH, ↑LFT
14
RD/2 doses of 375 mg/m2 15 days apart
Low dose CS (0.1-0.2 mg/kg/d)
3 cycles
N
CR on T
24
No
NM
NM
24
M/16
CS, AZA, IVIG, MMF
Cataracts, osteopenia, lymphopenia
16
RD/2 doses of 375 mg/m2 15 days apart
Low dose CS (0.1-0.2 mg/kg/d)
1 cycles
N
CR off T
44
No
NM
NM
Buch JY et al
6
25
F/11
CS, AZA
Hyperglycemia, CUSH
11
RD/2 doses of 300 mg/m2 15 days apart
40 mg PSL
1 cycle
N
CR on T
12
1 patient relapsed (not specific)
20.2 U/mL and 143.4 U/mL
1.8 U/mL and 5.7 U/mL
26
M/11
CS, AZA
CUSH, wt gain, HTN
12
RD/2 doses of 300 mg/m2 15 days apart
40 mg PSL
N
N
CR on T
12
237 U/mL and 194.6 U/mL
64 U/mL and 94 U/mL
27
F/9
CS
CUSH, wt gain
9
RD/2 doses of 300 mg/m2 15 days apart
40 mg PSL
1 cycle
N
CR on T
12
228 U/mL and 229 U/mL
47.3 U/mL and 2.5 U/mL
Kincaid et al
7
28
F/4
CS, IVIG, AZA
HTN, CUSH, delayed growth
4 and 5
RD/2 doses of 375 mg/m2 15 days apart
CS, AZA
2 cycles
Mild infusion reaction, urticaria, low-grade fever
CR off T
24
Yes
320 U/mL
NM
Kong et al
8
29
M/9
CS, MTX, MMF, Cyp, DAP
NR
NM
RD/2 doses of 750 mg/m2 2 wks apart
MTX, CS, MMF
1 cycle
Neutropenia and sepsis
CR on T
25
No
NM
NM
Vinay et al
9
30
M/NS
CS, AZA, DAP
NR
9
RD and severe/2 doses of 375 mg/m2 15 days apart
CS (0.5-1 mg/kg/d)
N
Angioedema
CR off T
36
No
1372.80 U/mL and 888.80 U/mL
0.5 U/mL and 14.22 U/mL
31
M/NS
CS, AZA, DAP
NR
11
Severe/2 doses of 375 mg/m2 15 days apart
CS (0.5-1 mg/kg/d)
N
Infusion reaction
CR off T
8
No
248.52 U/mL and 575.20 U/mL
Lost to F/U
32
M/NS
CS, AZA, DAP, MMF
NR
17
RD and severe/2 doses of 500 mg/m2 15 days apart
AZA (2 mg/kg/d), CS (0.5-1 mg/kg/d)
N
N
CR off T
19
No
67.30 U/mL and 130.33 U/mL
7.56 U/mL and 4.48 U/mL
33
M/NS
CS
CUSH
17
RD and SEs of previous therapy/2 doses of 500 mg/m2 15 days apart
AZA (2 mg/kg/d), CS (0.5-1 mg/kg/d)
1 cycle
Infusion reaction
CR on T
18
No
1148.46 U/mL and 116.09 U/mL
94.04 U/mL and 14.79 U/mL
34
F/NS
CS
NR
17
Severe/2 doses of 500 mg/m2 15 days apart
CS (0.5-1 mg/kg/d)
N
N
CR off T
17
No
1743.74 U/mL and 87.43 U/mL
18.10 U/mL and 0.86 U/mL
35
F/NS
CS, AZA
NR
13
RD/2 doses of 500 mg/m2 15 days apart
CS (0.5-1 mg/kg/d)
N
Upper respiratory tract infection
CR off T
14
No
165.11 U/mL and 340.25 U/mL
1.83 U/mL and 6.26 U/mL
36
M/NS
CS, AZA
NR
12
RD/2 doses of 500 mg/m2 15 days apart
CS (0.5-1 mg/kg/d)
1 cycle
Angioedema
CR off T
12
No
107.11 U/mL and 134.81 U/mL
2.98 U/mL and 274.17 U/mL
Didona et al
10
37
M/11
CS, IVIG
Wt gain, CUSH.
11
RD/2 doses of 375 mg/m2 18 days apart
NM
N
N
CR
10
No
NM
NM
38
M/17
DP, AZA, MMF
NR
NM
RD/2 doses of 500 mg/m2 15 days apart
CS
N
N
NM
12
NM
NM
NM
Chen et al
11
39
M/17
CS, IVIG
NR
17
RD/500 mg/m2 weekly for 4 wks
CS
N
N
CR off T
NS
NM
NM
NM
Kanwar et al
12
40
M/9
CS, DP, AZA
NR
NM
RD and severe/2 doses of 375 mg/m2 15 days apart
PSL (1-1.5 mg/kg/d)
N
Angioedema
CR off T
11.5
NM
1372.80 U/mL and 888.80 U/mL
0.12 U/mL and 742.40 U/mL
41
M/17
CS, CP
NR
NM
RD and severe/2 doses of 1000 mg/m2 15 days apart
PSL (1-1.5 mg/kg/d)
N
Sepsis
Death
N/A
NM
95.73 U/mL and 25.60 U/mL
NA
Reguai et al
13
42
F/14
CS, IVIG
Mood changes, acne, gastric ulcer
14
Severe AEs on previous therapy/375 mg/m2 weekly for 4 wks
NM
2 cycles
N
CR off T
62
Yes
65 U/mL and 160 U/mL
2 U/mL and 44 U/m:
Fuertes et al
14
43
M/1.5
CS, AZA, DAP, Gold
CUSH
14
RD/375 mg/m2 weekly for 4 wks
CS (prednisone 20 mg/d slowly tapered)
N
N
CR
18
No
157 U/mL and 3 U/mL
10 U/mL and 1 U/mL
Schmidt et al
15
44
F/17
CS, IVIG, MTX, AZA, MMF,
NR
NM
RD/375 mg/m2 weekly for 4 wks
MMF and MP
N
N
CR off T
7
NM
NM
NM
Schmidt et al
16
45
M/11.5
CS, AZA, DAP, MMF, CP, IVIG, MMF
Osteopenia, infections, CUSH, growth delay
14
RD/375 mg/m2 weekly for 4 wks
MMF (1-5 g/d), MP (12 mg/d), IVIG (10 g after 1st and 4th infusion)
N
N
CR off T
24
No
NM
NM
Kong et al
17
46
F/10
CS, AZA, MMF, IVIG, plasmapheresis
Myelosuppression, infections
17
RD/375 mg/m2 weekly for 4 wks, then every 4 or 8 wks
CS
Y, 375 mg/m2/wk × 4 every 4-8 weeks
N
CR on T
17
NM
2079 U/mL and 4616 U/mL
33 U/mL and 564 U/mL
Abbreviations: AE, adverse effects; AZA, azathioprine; CS, systemic corticosteroids;
CP, cyclophosphamide; Cys, cyclosporine; CR off T, complete remission off therapy;
CR on T, complete remission on therapy; CR, complete remission; CUSH, cushingoid;
DAP, dapsone; Dsg, desmoglein; F/U, follow-up; IVIG, intravenous immunoglobulin; ILCS,
intralesional steroids; LFT, liver function tests; MMF, mycophenolate mofetil; MTX,
methotrexate; MP, methylprednisolone; NR, not reported; NM, not mentioned; OP, osteoporosis;
PR on T, partial remission on therapy; PSL, prednisolone; Ref, references; RTX, rituximab;
RD, refractory disease to conventional therapy; TS, topical steroids; wt, weight;
wks, weeks.
Conclusion
We describe a 14-year-old Hispanic female patient who achieved sustained CR off treatment
with no adverse effects or relapses reported at 18-month follow-up evaluation after
successfully being treated with RTX. To our knowledge, CR off therapy has also been
reported in 22 other cases. Given the vulnerability of this patient population, there
is an increasing need for new therapeutic options. Our case is relevant because it
supports the growing number of cases reporting successful treatment for pediatric
PV using RTX. Physicians treating pediatric PV should be aware of the use of RTX as
a therapeutic option in cases of recalcitrant pediatric PV, achieving prompt control
of the disease. However, the need for randomized clinical trials to assess the role
and efficacy of RTX on pediatric patients with PV remains.
Author Contributions
OCY and FC conceptualized and proposed the case report, edited the report, and provided
guidance throughout. OYC, MS, VJG and FMR completed the literature review, wrote the
first draft of the manuscript, and edited the report. MS, VJG, and FMR created the
tables. All authors approved the final manuscript as submitted and agree to be accountable
for all aspects of the work.