Research

Case Report/Case Series

First-line Treatment of Pemphigus Vulgaris

With a Combination of Rituximab and High-Potency
Topical Corticosteroids
Saskia Ingen-Housz-Oro, MD; Laurence Valeyrie-Allanore, MD; Anne Cosnes, MD; Nicolas Ortonne, MD, PhD;
Sophie Hüe, MD, PhD; Muriel Paul, PhD; Pierre Wolkenstein, MD, PhD; Olivier Chosidow, MD, PhD

IMPORTANCE The main component of the first-line treatment of pemphigus vulgaris is high
doses of systemic corticosteroids, but adverse effects of these drugs are frequent and
sometimes severe. Rituximab has shown effectiveness as a corticosteroid-sparing agent or in
case of relapse. To our knowledge, the effectiveness of rituximab as a first-line treatment
without systemic corticosteroids has not been evaluated.

OBSERVATIONS Five women in their 50s, 60s, or 70s with pemphigus vulgaris (Pemphigus
Disease Area Index score, 15-84 at diagnosis) and contraindications to systemic corticosteroid
treatment received rituximab with high-potency topical corticosteroids as first-line
treatment. All patients experienced a favorable response, with a mean time to healing of skin
and mucosal lesions of 15 weeks. Two patients, with 42- and 48-month follow-up evaluations,
did not experience relapse. Three patients developed 2 to 4 relapses, with effective
retreatment achieved using rituximab and topical corticosteroids. No severe adverse effects
were observed.

CONCLUSIONS AND RELEVANCE Considering the high rate of severe adverse effects induced
by prolonged administration of high doses of systemic corticosteroids, new therapeutic
options are warranted in the treatment of pemphigus vulgaris. The combination of rituximab Author Affiliations: Author
and topical corticosteroids could be considered in mild to severe cutaneous disease. Larger affiliations are listed at the end of this
long-term studies are needed to evaluate the optimal treatment strategies according to the article.
severity of the disease and the benefit-risk ratio of rituximab. Corresponding Author: Saskia
Ingen-Housz-Oro, MD, Department
of Dermatology, Henri Mondor
JAMA Dermatol. 2015;151(2):200-203. doi:10.1001/jamadermatol.2014.2421 Hospital, 51 avenue du Maréchal de
Published online October 29, 2014. Lattre de Tassigny, 94000 Créteil,
France (saskia.oro@hmn.aphp.fr).

P
emphigus vulgaris is a rare autoimmune disease char-
acterized by skin and mucous membrane blisters and
erosions due to autoantibodies targeting desmogleins
1 and 3, which are major components of desmosomes. The se-
verity of the disease can be assessed by measures such as the
Harman score1 or by newer scales, such as the Pemphigus Dis-
ease Area Index (PDAI) or Autoimmune Bullous Skin Disorder
Intensity Score.2 To date, except in cases with very limited le-
sions that can be treated by topical corticosteroid mono-
therapy, first-line treatment is based on high-dose systemic cor-
ticosteroids (1.0 or 1.5 mg/kg/d) according to the severity of the
disease,1,3 but this treatment is complicated by a high rate of
severe adverse effects, such as infections, osteoporosis, my-
opathy, and diabetes mellitus. Thus, adjuvant immunosup-
pressive therapies including corticosteroid-sparing agents are
often warranted.
A single cycle of rituximab has shown4-6 excellent effec-
tiveness in patients with refractory pemphigus vulgaris, as
demonstrated by a greater than 80% rate of short-term com-
plete remission, a dramatic corticosteroid-sparing action, and
few severe adverse effects. The mechanism of action of ritux-
imab in pemphigus vulgaris is based on prolonged inhibition
of specific antidesmoglein B-cell response.7
However, to our knowledge, even though rituximab is con-
sidered a major promising treatment of pemphigus vulgaris,
its efficacy in first-line treatment without systemic cortico-
steroids has not been assessed. We report herein a series of 5
patients who received successful treatment with a combina-
tion of rituximab and highly potent topical corticosteroids as
first-line therapy.
Report of Cases
Five women in their 50s, 60s, or 70s had pemphigus vulgaris
with PDAI scores ranging from 15 to 84 (highest possible score,
250) at diagnosis. The patients’ clinical and immunologic char-
acteristics are summarized in the Table. Because of various con-

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 Rituximab and Topical Corticosteroids in Pemphigus Case Report/Case Series Research

Table. Clinical Characteristics, Treatment, and Follow-up of the 5 Patients

Patient Sex (Age, y)

Characteristic F (70s) F (50s) F (70s) F (70s) F (60s)
Site Skin (large folds), oral Skin (trunk, back, Skin (hands, feet, nails, Skin (trunk, face, scalp); Skin (large folds, trunk,
and genital mucosa thighs), oral trunk); oral, epiglottal, oral, conjunctive, thighs), oral and anal
mucosa genital, anal, and conjunctive genital, and anal mucosa
mucosa mucosa
At diagnosis
PDAI score (maximum 15 (skin, 10; mucosa, 5) 19 (skin, 9; 36 (skin, 14; mucosa, 22) 84 (skin, 26; 39 (skin, 17;
score, 250) mucosa, 10) mucosa, 58) mucosa, 22)
Indirect 1:640 1:320 1:320 1:1280 1:80
immunofluorescence
titer
ELISA value, AU/mL Dsg 1, 42; Dsg 3, 172 Dsg 1, 120; Dsg 3, Dsg 1, >100; Dsg 3, >100 Dsg 1, >100; Dsg 3, Dsg 1, 48; Dsg 3, 30
179 >100
Contraindications to Hypertension, glucose Diabetes mellitus Depressive disorder Diabetes mellitus, Depressive disorder,
systemic corticosteroids intolerance hypertension overweight, social
difficulties
Rituximab regimen 375 mg/m2, 4 wk 1 g, 2 doses 1 g, 2 doses 1 g, 2 doses 1 g, 2 doses
Associated topical Clobetasol propionate, Clobetasol Clobetasol propionate, Clobetasol propionate, Clobetasol propionate,
treatment 5 g/d propionate, 20 g/d; methylprednisolone 15 g/d; 10 g/d;
10-20 g/d mouthwashes methylprednisolone methylprednisolone
mouthwashes mouthwashes
Treatment-related adverse None None None None None
effects
Time to disease control Oral mucosa, 6; skin, 12 Skin and mucosa, 2 Skin and mucosa, 4 Skin, 3; mucosa, 5 Skin and mucosa, 1
after first rituximab dose,
wka
Time to complete remission 20 16 12 16 12
after first infusion, wk
At remission
Indirect Negative Negative Negative 1:160 Negative
immunofluorescence
titer
ELISA value, AU/mL Dsg 1, 3; Dsg 3, 72 Dsg 1, <1; Dsg 3, 7 Dsg 1, 10; Dsg 3, 25 Dsg 1, 3; Dsg 3, 80 Dsg 1, 2; Dsg 3, 2
Time to onset and 4 Relapses; time between 2 Relapses; time 3 Relapses; time between (1) 0 0
treatment of relapses, No. (1) 1st rituximab dose between (1) 1st 1st rituximab dose and 1st
and 1st relapse, 12 mo; rituximab dose and relapse, 14 mo; (2) 1st and
(2) 1st and 2nd relapses, 1st relapse, 22 2nd relapses, 15 mo; (3) 2nd
11 mo; (3) 2nd and 3rd mo; (2) 1st and and 3rd relapses, 23 mo;
relapses, 22 mo; (4) 3rd 2nd relapses, 37 each treated with 2 infusions
and 4th relapses, 21 mo; mo; each treated of rituximab, 1 g
each relapse treated with with 2 infusions of
1 infusion of rituximab, rituximab, 1 g
500 mg
Follow-up after the first 78/12; Complete 63/3; Complete 63/1; Partial remission with 48/NA; Complete 42/NA; Complete
rituximab dose/follow-up remission remission clobetasol propionate remission remission
since the last infusion, mo; 10 g/wk
status of disease at last
follow-up
a
Abbreviations: AU, arbitrary unit; Dsg, antidesmoglein; ELISA, enzyme-linked Disease control was the time between the first infusion of rituximab and the
immunosorbent assay; NA, not available; PDAI, Pemphigus Disease Area Index. end of the appearance of new lesions and the beginning of healing.

traindications to use of systemic corticosteroids, such as dia-
betes mellitus, hypertension, obesity, depressive disorder, and
elderly age, a consensual decision of our medical staff was off-
label use of rituximab combined with topical corticosteroids
using a fixed-dose regimen (1-g infusions on day 1 and day 15)
in 4 patients and 4 weekly infusions of 375 mg/m2 in 1 patient.
Premedication included a single infusion of methylpredniso-
lone, 100 mg, as recommended by the manufacturer. All pa-
tients also received daily applications of 5 to 20 g of clobeta-
sol propionate and methylprednisolone mouthwashes (20 mg
2 or 3 times a day) followed by a progressive withdrawal of treat-
ment within a few weeks after significant improvement. The
mean time after the first infusion to achieve complete (n = 4)
or nearly complete (n = 1) healing of the disease (ie, absence
or near absence of active lesions according to a Physician’s
Global Assessment [PGA] score of 0 or 1) was 15 weeks (range,
12-20 weeks). A dramatic decrease of the circulating desmo-
glein autoantibodies identified by indirect immunofluores-
cence and enzyme-linked immunosorbent assay (ELISA) was
observed in all cases during remission. The median follow-up
was 63 months (range, 42-78 months). Two patients did not
experience relapse during 42 and 48 months of follow-up.
Three patients experienced several relapses, with a mean time
to the first relapse of 16 months after the first cycle of ritux-
imab. Relapses were successfully treated with rituximab and
topical corticosteroids, with follow-up evaluations at 1, 3, and
12 months since the last infusion (Table). No adverse effects
related to rituximab occurred during the study period, and no
diabetes mellitus induced or worsened by topical corticoste-
roids was described.

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 Research Case Report/Case Series Rituximab and Topical Corticosteroids in Pemphigus

ment of our patients, but that improvement probably was a mi-

Discussion
Considering the high rate of severe adverse effects induced by
systemic corticosteroids,8 new therapeutic strategies are war-
ranted for treatment of pemphigus vulgaris. As shown in sev-
eral trials and many case reports and series,4,6 rituximab has
emerged as the most effective treatment for pemphigus vul-
garis in refractory cases. Hematologic and rheumatologic regi-
mens have similar effectiveness in autoimmune diseases, in-
cluding pemphigus vulgaris. 8 However, the efficacy of
rituximab as first-line treatment remains to be evaluated. A
French prospective, randomized trial is being conducted to
compare 2 first-line strategies for the treatment of pemphi-
gus vulgaris: the classic high doses of corticosteroids alone vs
lower doses and shorter durations of corticosteroids com-
bined w ith rituximab (clinic altrials.gov identifier:
NCT00784589), but the efficacy of rituximab without con-
comitant systemic corticosteroids has not been assessed.
We report herein a series of 5 patients with pemphigus vul-
garis of moderate severity successfully treated with a combi-
nation of rituximab and high-potency topical corticosteroids
as first-line therapy without use of systemic corticosteroids be-
cause of various comorbidities. In a study conducted by Joly
et al,4 5 of 21 patients received rituximab without corticoste-
roids because of contraindications, and 4 of 5 were in com-
plete remission at 3 months, as were the 16 patients receiving
corticosteroids.
During the time to the initiation of the healing effects of
rituximab in our patients with mild pemphigus vulgaris, we
used short-term topical corticosteroids to limit the extension
of the lesions and promote healing. Topical corticosteroid use
has not been assessed in a blinded manner in the treatment
of pemphigus vulgaris, in contrast with bullous pemphigoid,9
but may be considered in very mild disease with low levels of
autoantibodies.10 In France, topical corticosteroids are avail-
able at a low cost (10 g of clobetasol propionate costs €2.28 [US
$2.95] and 20 tablets of prednisolone for mouthwashes costs
€4.88 [US $6.32]) and are reimbursed at 65% through Social
Security.
In 4 of our patients, the lesions began to heal 1 to 5 weeks
after the first infusion and were in complete remission within
3 to 4 months. This time to achieve complete remission is simi-
lar to that in previously published studies with rituximab4 and
to the time to heal observed with systemic corticosteroids with
or without mycophenolate mofetil.11 Systemic circulation of
topical corticosteroids and methylprednisolone infusion given
as premedication could have played a role in the improve-
nor and short-term effect. Indirect immunofluorescence
showed a dramatic decrease of circulating antibodies in com-
plete remission, with negative results in 4 patients and a low
titer (1:160) in the patient who had the highest titer at diagno-
sis. In contrast, as previously shown, the results of antides-
moglein ELISA did not always parallel the clinical status, with
a persistence of positive ELISA results (especially antidesmo-
glein 3 ELISA) in clinical remission in 3 patients.
In our series, the patients’ tolerance of rituximab was ex-
cellent and no severe treatment-related adverse effects oc-
curred, even in the 3 patients in their 70s. We did not observe
any topical corticosteroid–related diabetes mellitus. This out-
come is in accordance with the good safety profile of ritux-
imab reported4,12 in pemphigus vulgaris, with an incidence of
less than 10% of severe adverse effects. However, a signifi-
cantly higher rate of rituximab-related mortality was re-
cently described13 in patients with autoimmune blistering dis-
eases compared with patients with other autoimmune diseases
(10.4% vs 2.4%), especially in patients receiving systemic cor-
ticosteroids, other immunosuppressive agents, or both given
with rituximab. Furthermore, some unexpected cases of pro-
gressive, multifocal leukoencephalopathy and Pneumocystis
jiroveci pneumonia have been described14,15 in patients with
autoimmune diseases.
In our series, 3 of 5 patients experienced relapses, with a
mean time for the first relapse of 16 months after the first cycle
of rituximab. Our results are similar to those of previously pub-
lished studies4,12 reporting a rate of relapse of 40% to 60% and
a median relapse-free remission of 19 months. A limitation to
our study could be the lack of systematic monitoring of circu-
lating CD19-positive B-cell levels during the treatment, espe-
cially in cases of relapse.
Conclusions
Concomitant use of rituximab and high-potency topical cor-
ticosteroids could be considered as treatment for pemphigus
vulgaris in some patients with contraindications to use of high
doses of systemic corticosteroids. However, larger long-term
studies are needed to evaluate the optimal strategies accord-
ing to the benefit-risk ratio of rituximab and the severity of the
disease. Such studies are especially needed to evaluate which
patients could benefit from rituximab without systemic cor-
ticosteroids and which ones would need short-term systemic
corticosteroids to obtain the most rapid healing possible and
thus reduce the risk of infectious complications.

ARTICLE INFORMATION
Accepted for Publication: July 17, 2014.
Published Online: October 29, 2014.
doi:10.1001/jamadermatol.2014.2421.
Author Affiliations: Department of Dermatology,
Assistance Publique-Hôpitaux de Paris, Henri
Mondor Hospital, Créteil, France (Ingen-Housz-Oro,
Valeyrie-Allanore, Cosnes, Wolkenstein, Chosidow);
Department of Pathology, Assistance Publique-
Hôpitaux de Paris, Henri Mondor Hospital, Créteil,
France (Ortonne); Université Paris-Est Créteil Val de
Marne, Créteil, France (Ortonne, Hüe, Wolkenstein,
Chosidow); Department of Immunology, Assistance
Publique-Hôpitaux de Paris, Henri Mondor
Hospital, Créteil, France (Hüe); Department of
Pharmacy, Assistance Publique-Hôpitaux de Paris,
Henri Mondor Hospital, Créteil, France (Paul);
Institut National de la Santé et de la Recherche
Médicale, Centre d’Investigation Clinique 006,
Assistance Publique-Hôpitaux de Paris, Créteil,
France (Wolkenstein, Chosidow).
Author Contributions: Drs Wolkenstein and
Chosidow contributed equally to the study. Drs
Ingen-Housz-Oro and Valeyrie-Allanore had full
access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Ingen-Housz-Oro, Paul,
Wolkenstein, Chosidow.

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 Rituximab and Topical Corticosteroids in Pemphigus Case Report/Case Series Research

Acquisition, analysis, or interpretation of data:
Ingen-Housz-Oro, Valeyrie-Allanore, Cosnes,
Ortonne, Hüe, Wolkenstein, Chosidow.
Drafting of the manuscript: Ingen-Housz-Oro, Paul.
Critical revision of the manuscript for important
intellectual content: Valeyrie-Allanore, Cosnes,
Ortonne, Hüe, Wolkenstein, Chosidow.
Administrative, technical, or material support:
Cosnes, Ortonne, Hüe, Paul.
Study supervision: Cosnes, Wolkenstein, Chosidow.
Conflict of Interest Disclosures: None reported.
REFERENCES
1. Harman KE, Albert S, Black MM; British
Association of Dermatologists. Guidelines for the
management of pemphigus vulgaris. Br J Dermatol.
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2. Rahbar Z, Daneshpazhooh M, Mirshams-
Shahshahani M, et al. Pemphigus disease activity
measurements: Pemphigus Disease Area Index,
Autoimmune Bullous Skin Disorder Intensity Score,
and Pemphigus Vulgaris Activity Score. JAMA
Dermatol. 2014;150(3):266-272.
3. Joly P, Bernard P, Bedane C, Prost C,
Ingen-Housz-Oro S; Centres de Référence des
Maladies Bulleuses Auto-Immunes, Société
Française de Dermatologie. Pemphigus: guidelines
for the diagnosis and treatment [in French]. Ann
Dermatol Venereol. 2011;138(3):252-258.
4. Joly P, Mouquet H, Roujeau J-C, et al. A single
cycle of rituximab for the treatment of severe
pemphigus. N Engl J Med. 2007;357(6):545-552.
5. Kasperkiewicz M, Shimanovich I, Ludwig RJ,
Rose C, Zillikens D, Schmidt E. Rituximab for
treatment-refractory pemphigus and pemphigoid:
a case series of 17 patients. J Am Acad Dermatol.
2011;65(3):552-558.
6. Cianchini G, Lupi F, Masini C, Corona R, Puddu P,
De Pità O. Therapy with rituximab for autoimmune
pemphigus: results from a single-center
observational study on 42 cases with long-term
follow-up. J Am Acad Dermatol. 2012;67(4):617-622.
7. Colliou N, Picard D, Caillot F, et al. Long-term
remissions of severe pemphigus after rituximab
therapy are associated with prolonged failure of
desmoglein B cell response. Sci Transl Med. 2013;5
(175):175ra30. doi:10.1126/scitranslmed.3005166.
8. Leshem YA, Hodak E, David M, Anhalt GJ,
Mimouni D. Successful treatment of pemphigus
with biweekly 1-g infusions of rituximab:
a retrospective study of 47 patients. J Am Acad
Dermatol. 2013;68(3):404-411.
9. Joly P, Roujeau J-C, Benichou J, et al; Bullous
Diseases French Study Group. A comparison of oral
and topical corticosteroids in patients with bullous
pemphigoid. N Engl J Med. 2002;346(5):321-327.
10. Dumas V, Roujeau JC, Wolkenstein P, Revuz J,
Cosnes A. The treatment of mild pemphigus
vulgaris and pemphigus foliaceus with a topical
corticosteroid. Br J Dermatol. 1999;140(6):1127-1129.
11. Beissert S, Mimouni D, Kanwar AJ, Solomons N,
Kalia V, Anhalt GJ. Treating pemphigus vulgaris with
prednisone and mycophenolate mofetil:
a multicenter, randomized, placebo-controlled trial.
J Invest Dermatol. 2010;130(8):2041-2048.
12. Lunardon L, Tsai KJ, Propert KJ, et al. Adjuvant
rituximab therapy of pemphigus: a single-center
experience with 31 patients. Arch Dermatol. 2012;
148(9):1031-1036.
13. Shetty S, Ahmed AR. Preliminary analysis of
mortality associated with rituximab use in
autoimmune diseases. Autoimmunity. 2013;46(8):
487-496.
14. Carson KR, Focosi D, Major EO, et al.
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multifocal leucoencephalopathy in patients treated
with rituximab, natalizumab, and efalizumab:
a review from the Research on Adverse Drug Events
and Reports (RADAR) project. Lancet Oncol. 2009;
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Clin Rheumatol. 2013;32(11):1677-1681.

NOTABLE NOTES

Dangerous Plants of the Southwestern United States

Walter H. C. Burgdorf, MD; Leonard J. Hoenig, MD; R. Steven Padilla, MD, MBA

The Southwestern United States features a tricultural population (ie, Na-
tive Americans, descendants of early Spanish settlers, and Anglos), pleas-
ant climate, and spectacular scenery ranging from mountains to des-
erts. While everyone is aware of rattlesnakes and scorpions as dangerous
desert denizens, several desert plants also can be hazardous.
Every Western movie fan knows what tumbleweeds are. While many
plants disperse by drying and being blown along the ground, the best
known one is Russian thistle (Kali tragus), which was introduced to the
United States from Russia admixed with flax seeds in the 1870s. Tumble-
weeds, when young, are edible. In the fall, they dry out and start their
rolling journey, dispersing seeds as they go.
When humans handle tumbleweeds, they frequently get an irritant
dermatitis. Injured persons may be gardeners, ranchers, or even handi-
crafters who build tumbleweed snowmen, piling the weeds together and
then spray painting them white. Contact causes a distinctive and easily
recognized clinical pattern—highly pruritic erythematous papules on the
forearms. Treatment is symptomatic with topical corticosteroids or an-
tipruritic agents. Powell and Smith1 identified spiny bracts (modified
leaves associated with flowers) as the main culprit. After testing 13 in-
dividuals, they suggested that there was a type I allergic component to
the reaction, which can be more severe in sensitized individuals, such
as those with allergic rhinitis from tumbleweed pollen.
There are thousands of cacti, and no one needs to be told to avoid
their long spines, which can cause significant traumatic injury.2 But the
chollas (Cylindropuntia) and prickly pears (Opuntia) of the US deserts have
a more refined weaponry. They have areoles featuring both spines and
glochids, which are short-barbed bristles. Slight contact results in the glo-
chids being introduced into the skin, where they are capable of eliciting
a granulomatous response. Often, the injured person is happy to have
avoided the spines and initially scarcely notices the contact with the glo-
chids, which later cause an inflammatory reaction, producing grouped
2- to 4-mm papules with a central dark punctum. Schreiber et al3 stud-
ied 9 patients with cactus granulomas and suggested a possible type I
allergic response based on positive results from intradermal skin tests.
They also dramatically illustrated the tiny glochid barbs within macro-
phages in granulomas. While larger spines can be removed with twee-
zers or glue stripping, the glochids are too small to remove. Symptoms
generally resolve in 10 to 14 days. When they do not, treatment with in-
tralesional or high-potency topical corticosteroids are the best approach.
Both immunologic studies1,3 were done in the 1970s; modern im-
munological techniques have not been applied to better understand the
interplay between traumatic injury, the innate immune response, and
sensitization of victims. But the clinical problems remain; be careful when
handling tumbleweeds or certain cacti.
Author Affiliations: Retired (Burgdorf); private practice (Hoenig); Department
of Dermatology, University of New Mexico, Albuquerque (Padilla).
Corresponding Author: Leonard J. Hoenig, MD, 601 N Flamingo Rd, Ste 201,
Pembroke Pines, FL 33028 (gooddocljh@gmail.com).
1. Powell RF, Smith EB. Tumbleweed dermatitis. Arch Dermatol. 1978;114(5):751-
754.
2. Doctoroff A, Vidimos AT, Taylor JS. Cactus skin injuries. Cutis. 2000;65(5):290-
292.
3. Schreiber MM, Shapiro SI, Berry CZ. Cactus granulomas of the skin: an
allergic phenomenon. Arch Dermatol. 1971;104(4):374-379.

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