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complete remission and no adverse events were observed.
However, 5 patients experienced grade 3 or 4 adverse events
(1 patient had sepsis; 2, diabetes; 1, hypertension; and 2, en-
docrine disorders) between the initial cycle and the first ritux-
imab maintenance infusion. At their last follow-up visit (me-
dian [range], 78 [42-147] months after the first cycle of
rituximab), all 11 patients remained in complete remission,w ith
10 patients having discontinued rituximab maintenance
therapy. Serum anti–desmoglein 1 and 3 antibody levels, which
had been high before rituximab treatment, decreased mark-
edly and remained below 14 U/mL during rituximab mainte-
nance therapy (Table 2).
Discussion |The results of this case series indicated that rituximab
can be used as single maintenance therapy, without a systemic
corticosteroid, with good efficacy and tolerance in patients hav-
ing severe pemphigus requiring long-termtherapy for preven-
tion of relapse. This study supplements a previous one show-
ing the efficacy of rituximab alone in the treatment of relapse
to pemphigus initially controlled with a combination of ritux-
imab and corticosteroid.
6
We found that treatment with ritux-
imab alone, even at a low dose, not only prevented relapsebut
also maintained complete remission with a better benefit to risk
ratio than treatment with corticosteroids. The maintenance
therapy was shown to be effective for preventing relapse despite
shortcomings inherent in retrospective studies (eg, heteroge-
neity of patient pemphigus history and variable length of ritux-
imab maintenance therapy), highlightingthe feasibility of such
an approach. A progressive decrease in serum anti-desmoglein
autoantibody levels to less than 14 U/mL occurred in all cases
along with clinical complete remission even after maintenance
therapy cessation.
Practical questions remain about the rituximab treatment
regimen, including the optimal dose (500 mg or 1 g), frequency
of administration (every 6 months or 1 year), and immunologic
criteria enabling treatment withdrawal (negativedirec t immu-
nofluorescence results or low serum autoantibody levels), and
the cost-effectiveness of this maintenance therapy in patients
with pemphigus. The criteria we used to discontinue rituximab
maintenance therapy were persistent complete clinical remis-
sion and serum anti–desmoglein 1 and 3 autoantibody levels less
than 14 U/mL for at least 1 year. Further prospective studies are
warranted to identify patients for treatmentw ithmaintenance
rituximab therapy and to optimize long-term management of
difficult-to-treat pemphigus.
Julia Sanchez, MD
Saskia Ingen-Housz-Oro, MD
Olivier Chosidow, MD, PhD
Frank Antonicelli, PhD
Philippe Bernard, MD, PhD
Author Affiliations: Department of Dermatology, Reims UniversityHospital,
Reims, France (Sanchez, Bernard); Department of Dermatology, Assistance
Publique des Hôpitaux de Paris, Henri Mondor Hospital, Créteil, France
(Ingen-Housz-Oro, Chosidow); Epidemiology in Dermatology and Evaluation of
Therapeutics, Unit 7379, UniversityParis Est, Créteil, France (Ingen-Housz-Oro,
Chosidow); Laboratory of Dermatology, Unit 7319, University of Reims
Champagne-Ardenne, Reims, France(Antonicelli, Bernard).
Corresponding Author: Philippe Bernard, MD, PhD, Department of
Dermatology, ReimsUniversity Hospital, General Koenig Ave, 51092 Reims,
France (pbernard@chu-reims.fr).
Accepted for Publication: October 20, 2017.
Published Online: January 3, 2018. doi:10.1001/jamadermatol.2017.5176
Author Contributions: Drs Bernard and Sanchez had full access to all of 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: Sanchez, Ingen-Housz-Oro, Bernard.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Sanchez, Ingen-Housz-Oro, Bernard.
Critical revision of the manuscript for important intellectual content:Chosidow,
Antonicelli, Bernard.
Statistical analysis: Sanchez.
Study supervision: Bernard.
Conflict of Interest Disclosures: None reported.
1. Hertl M, Jedlickova H, Karpati S, et al. Pemphigus: S2 guideline for diagnosis
and treatment—guided by the European Dermatology Forum (EDF) in
cooperation with the European Academy of Dermatology and Venereology
(EADV). J Eur Acad Dermatol Venereol. 2015;29(3):405-414.
2. 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.
3. 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.
4. Wang HH, Liu CW,Li YC, Huang YC. Efficacy of rituximab for pemphigus:
a systematic review and meta-analysis of different regimens. Acta Derm Venereol.
2015;95(8):928-932.
5. Joly P, Maho-VaillantM, Prost-Squarcioni C, et al; French Study Group on
Autoimmune Bullous Skin Diseases. First-line rituximab combined with
short-term prednisone versus prednisone alone for the treatment of pemphigus
(Ritux 3): a prospective, multicentre, parallel-group, open-label randomised
trial. Lancet. 2017;389(10083):2031-2040.
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.
Association of Facial Exercise
With the Appearance of Aging
Physical manifestations of facial aging are now understood to
include not only skin laxity and superficial photodamage but
also deeper substructural volume loss of fat and muscle.
1
There has been recent interest in the laycommunity in fac ial
exercises or facial “yoga” that can rejuvenate the agingface, pre-
sumably by inducing underlying muscle growth.
2-4
In this report,
we describe what we believe to be the first clinical trial to assess
facial exercise as a modality for improving skin appearance.
Methods |Healthy participants aged 40 to 65 years with pho-
todamage, associated mild to moderate facial atrophy, and with
an interest in facial exercises were included. Participants received
formal instruction on 32 facial exercises. All participants attended
2 live 90-minute muscle-resistant facial exercise trainingsessions
with a certified facial exercise instructor (G.S.). Neither partici-
pants nor those administering the interventions were blinded.
After the initial training sessions with the instructor, participants
performed daily 30-minute exercises for 8 weeks at home. Dur-
ing weeks 9 to 20, participants continuedprac ticing exercisesev-
ery other day (3-4 times per week).
This study was approved by the Northwestern University
Institutional Review Board and registered at ClinicalTrials
.gov (NCT01689012) prior to participant enrollment. Written
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informed consent was obtained from all participants.
Recruitment and enrollment took place from January to
February 2013. Study procedures were from March to July2013,
and data analyses were performed from April to May 2015.
The primary objective was to determine the association of
a facial muscle exercise program with the appearance of the
face and neck. The secondary objective was to measure par-
ticipant satisfaction with facial appearance before and after
completion of the exercise program.
The primary outcome measure was assessment of stan-
dard photographs rated by 2 blinded physicians (M.A., W.R.)
using the validated Merz-Carruthers Facial Aging Photos-
cales (MCFAP).
5,6
The co-primary outcome measure was
blinded rater estimation of participant age. A secondary out-
come measure was participant satisfaction questionnaire on
an 11-point visual analogue scale (0 = not satisfied at all, 10 = ex-
tremely satisfied).
Scores on the MCFAP were analyzed using the Wilcoxon
signed-rank test as the nonparametric alternative to pairedttests.
Data for predicted age and participant satisfaction were analyzed
with 2-sided paired ttests. Significance level was set at .05.
Results |Twenty-sevenpartic ipantswere enrolled (33 screened,
33 found to be eligible, 6 declined to enroll). Sixteen received
the full 20-week intervention (11 dropped out) and all fol-
low-up visits, and the data from these were analyzed. Demo-
graphic and clinical characteristics of participants are dis-
played in Table 1. Results of the MCFAP are reported in Table2.
Based on the MCFAP scales (Table 2), facial exercise re-
sulted in improved mean (SD) upper cheek fullness (1.1 [0.6]
vs 1.8 [0.7]; P= .003) and lower cheek fullness (0.9[0.7] vs 1.6
[0.9]; P= .003) at 20 weeks vs baseline. Mean (SD) estimated
age decreased significantly when baseline was compared with
study end (50.8 [4.8] y vs 48.1 [5.5] y; P= .002). Participants
were more satisfied with all facial aging outcomes when base-
line was compared with end of study (data not shown).
Table 1. DemographicCharacteristics of 16 Patients
Characteristic Value
a
Age, mean (SD), y 53.7 (5.8)
Female sex, No. (%) 16 (100)
Race, No. (%)
Asian 1 (6)
Black 2 (12)
White 11 (69)
Other 2 (12)
Ethnicity, No. (%)
Hispanic or Latino 2 (12)
Not Hispanic or Latino 11 (69)
Unknown 3 (19)
Skin type, No. (%)
II 6 (38)
III 4 (25)
IV 4 (25)
V 2 (12)
a
Percentages may not total 100 because of rounding.
Table 2. Merz-Carruthers Facial Aging Photoscales
a
Validated Assessment Scale
Mean (SD)
PValue
b
Baseline Week 8 Week 20
Upper face
Forehead lines at rest 0.6 (0.5) 0.7 (0.6) 0.8 (0.7) .38
Forehead lines dynamic 1.7 (1.3) 2.2 (1.0) 2.2 (1.1) .20
Glabellar lines at rest 0.9 (0.7) 0.8 (0.6) 0.8 (0.7) .50
Glabellar lines dynamic 1.9 (1.3) 1.6 (1.3) 1.9 (1.4) >.99
Crow’s feet at rest 1.1 (0.9) 1.1 (0.9) 1.2 (0.8) >.99
Crow’s feet dynamic 2.4 (1.1) 2.3 (1.1) 2.5 (1.2) .78
Female brow at rest 1.9 (1.1) 1.9 (0.9) 1.9 (0.8) >.99
Mid-face
Infraorbital hollow 1.3 (0.8) 1.4 (0.6) 1.7 (0.7) .11
Upper cheek fullness 1.8 (0.7) 1.9 (0.9) 1.1 (0.6) .003
Lower cheek fullness 1.6 (0.9) 1.3 (0.7) 0.9 (0.7) .003
Lower face
Nasolabial folds at rest 1.1 (0.8) 1.6 (0.8) 1.1 (0.8) >.99
Marionette lines at rest 1.4 (0.8) 1.6 (0.6) 1.2 (0.8) .22
Upper lip fullness at rest 2.9 (1.0) 2.9 (0.9) 3.2 (0.8) .29
Lower lip fullness at rest 1.8 (0.8) 2.3 (0.7) 2.3 (0.9) .11
Lip wrinkles at rest 0.9 (0.8) 0.8 (0.8) 0.8 (0.5) .62
Lip wrinkles dynamic 1.4 (1.0) 1.5 (1.2) 1.9 (1.0) .056
Oral commissures at rest 1.2 (0.8) 0.9 (0.8) 1.1 (0.7) .69
Jawline at rest 1.8 (1.2) 1.4 (1.2) 1.4 (1.1) .31
Neck
Neck volume scale 1.9 (1.1) 1.6 (1.0) 1.4 (0.8) .11
a
Five-point scale (0-4) with 0 being
the best outcome and 4 being the
worst outcome.
b
Wilcoxon signed-rank test
performed comparing baseline
(preexercise) with week 20
(postexercise) scores only.
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Discussion |A 30-minute daily or alternate-day facial exercise
program sustained over 20 weeks may modestly improve
the facial appearance of selected middle-aged women.
Blinded ratings of validated photoscales showed significant
improvement in upper and lower cheek fullness. Rater esti-
mates of mean participant age showed a significant mono-
tonic decrease from 50.8 years at baseline to 49.6 years at 8
weeks and 48.1 years at 20 weeks. Participants were highly
satisfied, noting significant improvement in 18 of 20 facial
features.
This study had limitations that may reduce its externalva-
lidity. The sample was small, exclusively of middle-aged
women, there were numerous dropouts, and there was no con-
trol group in the study. Another limitation is that participants
were self-selected and may have been particularly willing to
continue with an exercise regimen.
In conclusion, a regimen of at-home facial exercises main-
tained for 20 weeks seemed to improve mid-face and lowerface
fullness. The mechanism may be exercise-actuated hypertro-
phy of cheek and other muscles. Further research is war-
ranted to isolate the causes and effects of exercise-related
changes and to assess the generalizability of these findings.
Murad Alam, MD, MSCI, MBA
Anne J. Walter, MD, MBA
Amelia Geisler, BS
Wanjarus Roongpisuthipong, MD
Gary Sikorski
Rebecca Tung, MD
Emily Poon, PhD
Author Affiliations: Department of Dermatology, Feinberg School of Medicine,
Northwestern University,Chicago, Illinois (Alam, Walter, Geisler,
Roongpisuthipong, Poon); Department of Otolaryngology,Feinberg School of
Medicine, Northwestern University,Chicago, Illinois (Alam); Department of
Surgery, FeinbergSchool of Medicine, Northwestern University, Chicago, Illinois
(Alam); Division of Dermatology, Department of Medicine, Vajira Hospital,
Navamindrahiraj University, Bangkok, Thailand (Roongpisuthipong); Happy
Face Yoga, Providence, Rhode Island (Sikorski); Division of Dermatology,Loyola
University,Maywood, Illinois (Tung); Dermatology and Skin Surgery Specialists,
Scottsdale, Arizona (Walter).
Accepted for Publication: October 18, 2017.
Corresponding Author: Murad Alam, MD, MSCI, MBA, Department of
Dermatology, 676N St Clair St, Ste 1600, Chicago, IL 60611
(m-alam@northwestern.edu).
Published Online: January 3, 2018. doi:10.1001/jamadermatol.2017.5142
Author Contributions: Dr Alam had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Alam, Walter,Geisler, Sikorski, Tung.
Acquisition, analysis, or interpretation of data: Walter, Geisler,
Roongpisuthipong, Poon.
Drafting of the manuscript: Alam, Geisler,Sikorski, Tung, Poon.
Critical revision of the manuscript for important intellectual content:Walter,
Roongpisuthipong, Tung,Poon.
Statistical analysis: Roongpisuthipong, Poon.
Administrative, technical, or material support: Walter, Geisler,Sikorski, Tung.
Study supervision: Alam, Walter, Geisler, Tung.
Funding/Support: This study was supported by departmental research funds,
Department of Dermatology, Northwestern University.
Role of the Funder/Sponsor:The funding source participated in the design and
conduct of the study; collection, management, analysis, and interpretation of
the data; preparation, review,or approval of the manuscript; and decision to
submit the manuscript for publication.
Conflict of Interest Disclosures: Dr Alam is employed at Northwestern
University.Dr Alam has been a consultant for Amway and Leo Pharma, both
unrelated to this research. Northwestern University has a clinical trials unit that
receives grants from many corporate and governmental entities to perform
clinical research. Dr Alam has been principal investigator on studies funded in
part by Allergan, Medicis, Bioform, and Ulthera. All grants and gifts in kind have
been provided to Northwestern University and not Dr Alam directly,and
Dr Alam has not received any salary support from these grants. Mr Sikorski is
the founder of Happy Face Yoga, which was the exercise regimen used for
training participants.
Additional Contributions: We are indebted to Jason Sloan, MS (Department of
Dermatology, FeinbergSchool of Medicine, Northwestern University) for
helping with initial recruitment; Dennis P. West, PhD (Department of
Dermatology, FeinbergSchool of Medicine, Northwestern University), for
helping with the design and regulatory aspect of the study; Karina Colossi
Furlan, MD (Department of Dermatology,Feinberg School of Medicine,
Northwestern University), for helping edit part of the manuscript; and Emir
Veledar,PhD (Emory University School of Medicine and Baptist Health South
Florida), for insight into statistical considerations. No compensation was
received for such contributions.
1. Wysong A, Joseph T,Kim D, Tang JY, Gladstone HB. Quantifying soft tissue
loss in facial aging: a study in women using magnetic resonance imaging.
Dermatol Surg. 2013;39(12):1895-1902.
2. Nadeau MV.The Yoga Facelift. Boston, MA: Conari Press; 2007.
3. Goroway P. Facial Fitness: Daily Exercises& Massage Techniques for a
Healthier, Younger Looking You.New York, NY: Sterling Publishing; 2011.
4. Goldstein S. Your BestFace Now: Look Younger in 20 Days With the
Do-It-Yourself Acupressure Facelift. New York, NY:Avery, Penguin Group; 2012.
5. Flynn TC, Carruthers A, Carruthers J, et al. Validatedasse ssment scales for
the upper face. Dermatol Surg. 2012;38(2 Spec No.):309-319.
6. Carruthers J, Flynn TC, Geister TL, et al. Validatedassessment scales for the
mid face. Dermatol Surg. 2012;38(2 Spec No.):320-332.
OBSERVATION
Generalized Lichen Nitidus Following Anti–PD-1
Antibody Treatment
Lichen nitidus (LN) is an uncommon skin disease characterized
by minute flesh-colored papules on the abdomen, limbs, and
genitalia.
1
Generalized LN is a rare form of LN that is more often
seen in children and young adults.
1
Anti–programmed cell death
1 (PD-1) antibodies, such as nivolumab, areimmune checkpoint
inhibitors that prevent the bindingof PD-1 to its ligands, thereby
facilitating the activation of T lymphocytes in patients with can-
cers such as melanoma and non–small-cell lung carcinoma.
2
Here,
we report a case of generalized LN following nivolumab treatment
that was highly responsive to topical steroid therapy.
Report of a Case |A man in his 40s presented after developingmul-
tiple skin lesions. He had been diagnosed with metastatic lung
adenocarcinoma the previous year and received 2 courses of ra-
diotherapy to his head and leg and 4 cycles of carboplatin, peme-
trexed, and bevacizumab followed by nivolumab(3 mg /kg) ad-
ministered every 2 weeks. After 8 cycles of nivolumab over 5
months, he developed 1- to 2-mm shinypapules sc atteredon the
upper limbs. Nivolumab therapy was continued, and similar le-
sions spread to the rest of his body over the subsequent3 months
(Figure 1A). Skin biopsy of the papular lesions showed typical his-
tological features of LN: focal lymphohistiocytic infiltrates be-
neath a thinned epidermis circumscribed by elongated rete
ridges, vacuoles in the dermoepidermal junction, and melanin
incontinence (Figure 2). Wetherefore diagnosed the patient with
generalized LN.
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