Immunoglobulin A vasculitis (IgAV) is a systemic small-vessel vasculitis. Although corticosteroids (CS) are the primary treatment for gastrointestinal manifestations associated with IgAV, some patients develop refractory or recurrent symptoms such as vomiting and abdominal pain despite CS treatment. Dapsone, a synthetic sulfone antimicrobial, has been used to treat cutaneous purpura in IgAV, but few authors have reported its use for refractory gastrointestinal symptoms. In this retrospective observational study, we describe results in 7 children with IgAV who were treated with dapsone for abdominal pain resistant to CS. Dapsone rapidly relieved abdominal pain in all 7 patients, who then were tapered off CS without relapse. Side effects of mild methemoglobinemia and hemolysis appeared to be manageable with planned monitoring and dose adjustment; a single patient who discontinued dapsone had fatigue and hypoxia associated with methemoglobinemia. No side effects were life-threatening. Dapsone may be considered as a therapeutic option for gastrointestinal symptoms refractory to CS in children with IgAV.

Immunoglobulin A vasculitis (IgAV), or Henoch-Schönlein purpura, is a systemic small-vessel vasculitis characterized by perivascular IgA deposition.1  IgAV, the most common small-vessel vasculitis in children, mainly affects skin, the gastrointestinal tract, joints, and kidneys. ∼65% of patients with IgAV have gastrointestinal symptoms such as vomiting and abdominal pain; 30% experience gastrointestinal bleeding.2  Corticosteroids (CS), commonly given to treat patients with IgAV who manifest gastrointestinal manifestations, frequently reduce the severity of these symptoms and shorten the duration of illness.3,4  In some patients, however, gastrointestinal symptoms become resistant to CS or recur during attempts to taper the dose of CS. Other limitations of CS in children are potentially severe side effects such as growth retardation and cushingoid features.5  Reported alternative treatments include coagulation factor XIII replacement and immunosuppressive agents.6,7  However, no treatment has emerged as standard therapy for children with refractory gastrointestinal symptoms of IgAV.

Dapsone is a synthetic sulfone antimicrobial first used for leprosy in the 1940s. In addition to antimicrobial effects, dapsone has shown antiinflammatory properties in a wide range of inflammatory diseases.8  Several studies have revealed that dapsone demonstrated efficacy in treating cutaneous purpura in IgAV, but there are few reports of dapsone treatment for refractory gastrointestinal symptoms.9  Although methemoglobinemia and hemolysis have been reported as common side effects of dapsone, their severity and incidence in children with IgAV have not been well documented. Here we report the efficacy and safety outcomes of dapsone treatment for refractory gastrointestinal symptoms in 7 children with IgAV.

Seven children 16 years old or younger diagnosed with IgAV were treated with dapsone for refractory gastrointestinal symptoms at Saitama Children’s Medical Center or Kurume University Hospital between December 2018 and March 2021. We identified eligible patients by searching the patient database at each institution, using keywords such as IgA vasculitis, gastrointestinal symptoms, and dapsone. All eligible patients were included. All patients met the diagnostic criteria for IgAV.10  Patient characteristics, clinical and laboratory features, imaging findings, treatment regimens, and efficacy and side effects of dapsone were retrieved retrospectively from electronic medical records. We defined CS resistance in these patients as a lack of improvement in gastrointestinal symptoms at CS doses ≥2 mg prednisolone/kg/day. We defined CS dependence as the recurrence of gastrointestinal symptoms after a reduction in CS dose to <1 mg/kg/day, or the inability to discontinue CS within 3 months because of persistent symptoms. We judged that abdominal pain had resolved if the electronic medical record noted that pain was minimal or absent. Relapse after discontinuation of dapsone was defined as the reemergence of gastrointestinal symptoms that required the resumption of treatment for IgA vasculitis within the observation period. Methemoglobinemia after dapsone administration was defined as a relative methemoglobin concentration of 3% or more in venous blood gas specimens, and we presumed that hemolytic anemia had occurred if hemoglobin had decreased by ≥2 g/dL compared with the patient’s baseline before treatment. Laboratory evaluations to monitor for side effects of dapsone treatment were performed according to clinicians' individual judgment.

The Wilcoxon rank test was used for the analysis of side effects. We considered P values <.05 to be indicative of statistical significance. Statistical analyses were performed by using GraphPad Prism version 8.0 (San Diego, CA), which also was used to produce related figures.

Patient data acquisition for this report complied with the ethical guidelines of the Declaration of Helsinki of 1975 as revised in 2004 and was approved by the Ethical Committee of Saitama Children’s Medical Center and Kurume University. This retrospective study was conducted by an opt-out method.

Data from the 7 Japanese patients in this report (4 girls, 3 boys) who met inclusion criteria for statistical analyses are summarized in Table 1 and Supplemental Table 2. The median age at initiation of dapsone was 7 years (range, 5–13). In 6 patients, IgAV was in the acute phase (within 3 months after onset), and a seventh patient who had experienced recurrent disease over 5 years was in the chronic phase. All patients had purpura and gastrointestinal symptoms, and 5 reported joint pain. Abdominal pain had persisted in all patients until the initiation of dapsone, whereas bloody stools and/or vomiting in 4 patients had resolved with CS treatment. Patients underwent abdominal ultrasonography and/or computed tomography; in this imaging, all patients showed duodenal or jejunal wall thickening typical of IgAV. Patients undergoing upper gastrointestinal endoscopy or small bowel capsule endoscopy showed mucosal erosion and ulceration (Fig 1). Complications of IgAV occurred in 2 patients, including encephalopathy in 1 and epididymitis in the other. All patients were treated with CS for abdominal pain before dapsone treatment; 2 (cases 1 and 2) were CS-resistant and 5 were CS-dependent. The median follow-up period after initiation of dapsone was 337 days (120–880). No nephritic complications of IgAV requiring treatment occurred in any patient during the follow-up period.

FIGURE 1

Imaging of abdominal lesions in enrolled subjects. Wall thickening involving duodenum (arrow) and gallbladder (triangle) (A) and duodenal mucosal eruption and ulceration (B) in case 2, duodenal wall thickening in case 5 (C), and mucosal eruption and multiple ulcers involving jejunum in case 7 are demonstrated by computed tomography and esophagogastroduodenoscopy, ultrasonography, and capsule endoscopy, respectively.

FIGURE 1

Imaging of abdominal lesions in enrolled subjects. Wall thickening involving duodenum (arrow) and gallbladder (triangle) (A) and duodenal mucosal eruption and ulceration (B) in case 2, duodenal wall thickening in case 5 (C), and mucosal eruption and multiple ulcers involving jejunum in case 7 are demonstrated by computed tomography and esophagogastroduodenoscopy, ultrasonography, and capsule endoscopy, respectively.

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TABLE 1

Patient Characteristics

CaseSexAgeaSymptoms and ComplicationsbCS ResponsePrevious TherapyDapsone TreatmentInterval From Dapsone Initiation to CS Withdrawal, dRelapse After Dapsone WithdrawalSide Effects
VomitingBloody StoolJoint PainDose (mg/kg/d)Duration to Response, dDuration of Use, dPeak Value of MetHb (%)Change in Hemoglobin (g/dL)c
— — — 1.4 80 75 No 3.2 −3.2 
— XIII 1.2 56 35 No 3.5 −0.4 
— XIII 1.5 N/A 70 60 Yes 6.4 −3.2 
— — — 1.4 79 70 No 4.2 −3.4 
10 — 0.9 190 14 No 5.0 −2.7 
13 — XIII, CLC 1.6 130 60 Yes 3.1 −2.1 
13 — XIII, AZA, MMF 1.3 N/A 520 67 N/A 5.0 −4.2 
Median (range) — 7 (5 to 13) — — — — — 1.4 (0.9 to 1.6) 1 (1 to 5) 80 (56 to 520) 60 (14 to 75) — 4.2 (3.1 to 6.4) −3.2 (−4.2 to −0.4) 
CaseSexAgeaSymptoms and ComplicationsbCS ResponsePrevious TherapyDapsone TreatmentInterval From Dapsone Initiation to CS Withdrawal, dRelapse After Dapsone WithdrawalSide Effects
VomitingBloody StoolJoint PainDose (mg/kg/d)Duration to Response, dDuration of Use, dPeak Value of MetHb (%)Change in Hemoglobin (g/dL)c
— — — 1.4 80 75 No 3.2 −3.2 
— XIII 1.2 56 35 No 3.5 −0.4 
— XIII 1.5 N/A 70 60 Yes 6.4 −3.2 
— — — 1.4 79 70 No 4.2 −3.4 
10 — 0.9 190 14 No 5.0 −2.7 
13 — XIII, CLC 1.6 130 60 Yes 3.1 −2.1 
13 — XIII, AZA, MMF 1.3 N/A 520 67 N/A 5.0 −4.2 
Median (range) — 7 (5 to 13) — — — — — 1.4 (0.9 to 1.6) 1 (1 to 5) 80 (56 to 520) 60 (14 to 75) — 4.2 (3.1 to 6.4) −3.2 (−4.2 to −0.4) 

MetHb, methemoglobin; R, refractory; D, dependent; XIII, coagulation factor XIII; CLC, colchicine; AZA, azathioprine; MMF, mycophenolate mofetil; N/A, data not available; —, not applicable.

a

Age at dapsone initiation

b

All patients had purpura and abdominal pain related to IgA vasculitis, whereas cases 1 and 3 had a dapsone-related complication, epididymitis and encephalopathy, respectively.

c

Hemoglobin concentration during dapsone treatment minus hemoglobin concentration before.

The efficacy of dapsone treatment is summarized in Table 1. The median steady-state dose of dapsone was 1.4 mg/kg/day (0.8–1.6) and the median duration of treatment was 80 days (56–520). In 5 patients, abdominal pain resolved soon after initiation of dapsone, usually within 1 day. In the other 2 patients (cases 3 and 7), abdominal pain had already lessened when the CS dose was increased before the initiation of dapsone. In all 6 patients who had purpura at the time of dapsone initiation, lesions resolved after a median time of 6 days (2–48). CS were tapered and discontinued in all patients without immediate relapse; the median interval from initiation of dapsone to discontinuation of CS was 60 days (14–75). The one patient with chronic IgAV disease relapsed 3 months after discontinuation of CS. Four of the 6 patients in the acute phase did not relapse after withdrawal of dapsone during the postwithdrawal observation period, which had a median duration of 184 days (41–600) among all acute-phase patients. Two acute-phase patients (cases 3 and 6) relapsed at 121 and 55 days, respectively, after discontinuation of dapsone. Both rapidly improved after reinitiation of CS with or without dapsone.

Side effects of dapsone treatment are summarized in Table 1 and Supplemental Table 2. Methemoglobinemia and hemolysis were almost universal. All patients had methemoglobinemia; the median methemoglobin value significantly increased from 0.4% (0.2–0.7) before initiation of dapsone to 4.2% (3.1–6.4; P = .0223) during dapsone treatment (Fig 2A). The median time from initiation of dapsone to the peak methemoglobin value was 14 days (5–70). Hemolysis occurred in 6 patients. The median hemoglobin value significantly decreased from 13.7 g/dL (9.6–15.1) before initiation of dapsone to 10.5 g/dL (9.2–12.5; P = .0156) during dapsone treatment (Fig 2B). The median time from initiation of dapsone for the hemoglobin concentration to reach a nadir was 65 days (7–135). Case 3 developed fatigue and hypoxia in association with methemoglobinemia, leading to discontinuation of dapsone. Case 7 had a significant drop in hemoglobin (-4.2 g/dL) but was managed by reducing the dose of dapsone from 1.8 to 1.3 mg/kg/day. The other 5 patients with methemoglobinemia and/or hemolysis were asymptomatic and continued on their prescribed dose of dapsone. Leukopenia, thrombocytopenia, the elevation of liver enzymes, and impairment of kidney function were not observed in any patient.

FIGURE 2

Methemoglobin and hemoglobin before and after dapsone treatment. The median methemoglobin value (A) significantly increased from 0.4% before dapsone treatment (range, 0.2–0.7) to 4.2% after dapsone treatment (3.1–6.4; P = .0223), whereas median hemoglobin concentration, (B) significantly decreased from 13.7 g/dL (9.6–15.1) to 10.5 g/dL (9.2–12.5; P = .0156).

FIGURE 2

Methemoglobin and hemoglobin before and after dapsone treatment. The median methemoglobin value (A) significantly increased from 0.4% before dapsone treatment (range, 0.2–0.7) to 4.2% after dapsone treatment (3.1–6.4; P = .0223), whereas median hemoglobin concentration, (B) significantly decreased from 13.7 g/dL (9.6–15.1) to 10.5 g/dL (9.2–12.5; P = .0156).

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The current study provides evidence for potential efficacy and details the safety profile of dapsone administration for refractory gastrointestinal symptoms in 7 Japanese children with IgAV. In all patients, abdominal pain resolved soon after initiation of dapsone, and CS could be tapered and discontinued without relapse in 6 of the 7 patients. Methemoglobinemia and hemolysis were common side effects of dapsone.

Although the immunopathogenesis of IgAV remains uncertain, interleukin-8 (IL-8) has been suggested to contribute importantly to the inflammatory process.11  Dapsone has been found to inhibit IL-8 release and suppress IL-8- mediated chemotaxis of neutrophils,12  suggesting that dapsone might reduce excessive IL-8 in IgAV.

Dapsone was first used to treat cutaneous purpura in patients with IgAV in 1983.13  Several studies of dapsone treatment in IgAV have followed, usually without mentioning efficacy against gastrointestinal symptoms. Volejnikova et al14  reported successful treatment for 3 children with dapsone for refractory purpura and gastrointestinal symptoms without side effects. Our study revealed dapsone to be effective against refractory abdominal pain as well as purpura in IgAV. Although abdominal pain is a risk factor for IgAV nephritis,15  no patient in this study developed nephritis. The effect of dapsone on IgAV nephritis awaits future evaluation.

In our case series, methemoglobinemia occurred in all and hemolytic anemia in most patients but did not require specific treatment. Dapsone has been previously reported to cause local and systemic side effects affecting various organs, including hematologic, dermatologic, neurologic, gastrointestinal, hepatic, and renal reactions as well as hypersensitivity syndrome.16  Dapsone-hydroxylamine, a metabolite produced by cytochrome P-450 enzymes, is considered to mediate hematologic effects including methemoglobinemia and hemolysis. Adam et al17  reported the occurrence of methemoglobinemia in nearly 20% of pediatric oncology patients receiving dapsone for Pneumocystis jiroveci prophylaxis. With respect to hemolysis, Byrd et al18  reported that 83% of leprosy patients receiving dapsone experienced a decrease in hemoglobin concentration by ≥1 g/dL.

Previous reports that did monitor for methemoglobinemia may have failed to detect this side effect because patients with <10% methemoglobin are generally asymptomatic. All patients in our report were monitored from the initiation of dapsone, with particular attention to methemoglobinemia. By monitoring, we provided a higher degree of safety for patients treated with dapsone. Wozel et al19  recommended monitoring of laboratory tests such as complete blood count, liver enzymes, urinalysis, serologic tests for hepatitis, and glucose-6-phosphate dehydrogenase determinations in addition to methemoglobin assays. We suggest monitoring methemoglobin and hemoglobin levels once or twice weekly for 2 to 4 weeks after initiation of dapsone to confirm maintenance of a hematologic steady state. After that, we suggest repeat laboratory evaluation at least every 2 weeks for the first 2 to 3 months, and then every 1 to 2 months.

Although our present case series presents important novel findings, it is limited by its retrospective nature and small number of subjects and institutions, as well as the lack of a concurrent control group treated only with CS and of fully uniform details of dapsone therapy. This case series is also limited by variability in routine clinical observation and monitoring and by variability in the detailing of outcomes in the medical record. However, our case series supports a prospective multicenter controlled study of a larger population to evaluate more rigorously the potential efficacy and safety profile of dapsone treatment for a wide range of symptoms in patients with IgAV.

In conclusion, all children with IgAV and refractory abdominal pain in this report experienced resolution of abdominal pain soon after initiating dapsone treatment. Side effects of dapsone, including methemoglobinemia and hemolysis, were well tolerated or able to be managed by dose adjustment due to careful monitoring. Dapsone may be an important therapeutic option for gastrointestinal symptoms refractory to CS treatment in children with IgAV, particularly during the acute phase of the disease.

The authors thank the patients and their parents for their cooperation. We also thank Drs Ryo Ebana at Saitama Children’s Medical Center and Ken Kato at Kurume University for their collaboration.

Dr Yoshida collected data, analyzed and interpreted data, validated the results, and drafted the initial manuscript; Dr Nambu conceptualized and designed the study, collected data, analyzed and interpreted data, validated the results, drafted the initial manuscript, and coordinated and supervised data collection; Drs Yasuda and Sakaguchi collected data and validated the results; Dr Hara analyzed and interpreted data and validated the results; Dr Iwama validated the results; Dr Mizuochi conceptualized and designed the study, coordinated and supervised data collection, analyzed and interpreted data, validated the results, and drafted the initial manuscript; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

CS

corticosteroids

IgAV

immunoglobulin A vasculitis

IL-8

interleukin-8

1
Ozen
S
,
Marks
SD
,
Brogan
P
, et al
.
European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative
.
Rheumatology (Oxford)
.
2019
;
58
(
9
):
1607
1616
2
Saulsbury
FT
.
Clinical update: Henoch-Schönlein purpura
.
Lancet
.
2007
;
369
(
9566
):
976
978
3
Ronkainen
J
,
Koskimies
O
,
Ala-Houhala
M
, et al
.
Early prednisone therapy in Henoch-Schönlein purpura: a randomized, double-blind, placebo-controlled trial
.
J Pediatr
.
2006
;
149
(
2
):
241
247
4
Weiss
PF
,
Klink
AJ
,
Localio
R
, et al
.
Corticosteroids may improve clinical outcomes during hospitalization for Henoch-Schönlein purpura
.
Pediatrics
.
2010
;
126
(
4
):
674
681
5
Aljebab
F
,
Choonara
I
,
Conroy
S
.
Systematic review of the toxicity of long-course oral corticosteroids in children
.
PLoS One
.
2017
;
12
(
1
):
e0170259
6
Lamireau
T
,
Rebouissoux
L
,
Hehunstre
JP
.
Intravenous immunoglobulin therapy for severe digestive manifestations of Henoch-Schönlein purpura
.
Acta Paediatr
.
2001
;
90
(
9
):
1081
1082
7
Crayne
CB
,
Eloseily
E
,
Mannion
ML
, et al
.
Rituximab treatment for chronic steroid-dependent Henoch-Schonlein purpura: 8 cases and a review of the literature
.
Pediatr Rheumatol Online J
.
2018
;
16
(
1
):
71
8
Zhu
YI
,
Stiller
MJ
.
Dapsone and sulfones in dermatology: overview and update
.
J Am Acad Dermatol
.
2001
;
45
(
3
):
420
434
9
Lee
KH
,
Hong
SH
,
Jun
J
, et al
.
Treatment of refractory IgA vasculitis with dapsone: a systematic review
.
Clin Exp Pediatr
.
2020
;
63
(
5
):
158
163
10
Ozen
S
,
Pistorio
A
,
Iusan
SM
, et al;
Paediatric Rheumatology International Trials Organisation (PRINTO)
.
EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria
.
Ann Rheum Dis
.
2010
;
69
(
5
):
798
806
11
Lee
KH
,
Park
JH
,
Kim
DH
, et al
.
Dapsone as a potential treatment option for Henoch-Schönlein Purpura (HSP)
.
Med Hypotheses
.
2017
;
108
:
42
45
12
Booth
SA
,
Moody
CE
,
Dahl
MV
,
Herron
MJ
,
Nelson
RD
.
Dapsone suppresses integrin-mediated neutrophil adherence function
.
J Invest Dermatol
.
1992
;
98
(
2
):
135
140
13
Ledermann
JA
,
Hoffbrand
BI
.
Dapsone in allergic vasculitis: its use in Henoch-Schönlein disease following vaccination
.
J R Soc Med
.
1983
;
76
(
7
):
613
614
14
Volejnikova
J
,
Horacek
J
,
Kopriva
F
.
Dapsone treatment is efficient against persistent cutaneous and gastrointestinal symptoms in children with Henoch-Schönlein purpura
.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
.
2018
;
162
(
2
):
154
158
15
Jauhola
O
,
Ronkainen
J
,
Koskimies
O
, et al
.
Renal manifestations of Henoch-Schonlein purpura in a 6-month prospective study of 223 children
.
Arch Dis Child
.
2010
;
95
(
11
):
877
882
16
Wozel
G
,
Blasum
C
.
Dapsone in dermatology and beyond
.
Arch Dermatol Res
.
2014
;
306
(
2
):
103
124
17
Esbenshade
AJ
,
Ho
RH
,
Shintani
A
,
Zhao
Z
,
Smith
LA
,
Friedman
DL
.
Dapsone-induced methemoglobinemia: a dose-related occurrence?
Cancer
.
2011
;
117
(
15
):
3485
3492
18
Byrd
SR
,
Gelber
RH
.
Effect of dapsone on haemoglobin concentration in patients with leprosy
.
Lepr Rev
.
1991
;
62
(
2
):
171
178
19
Wozel
VE
.
Innovative use of dapsone
.
Dermatol Clin
.
2010
;
28
(
3
):
599
610

Supplementary data