Accepted Article

PROF. BRIGITTE DRENO (Orcid ID : 0000-0001-5574-5825)

Article type : Original Article

ARTICLE
Acne fulminans and Cutibacterium acnes phylotypes

S. Bocquet-Trémoureux1, S. Corvec2,3, A. Khammari1,2 , M-A Dagnelie2, A. Boisrobert1, and B. Dreno1,2

Affiliations:
1. Department of Dermatology, CHU Nantes, France
2. CIC 1413, CRCINA Inserm U 1232, University Nantes, Nantes, France
3. Department of Bacteriology, CHU Nantes, CRCINA Inserm U1232, University Nantes, Nantes, France

Corresponding author:
Professor Brigitte Dreno
CHU Nantes - Place Alexis Ricordeau
44093 Cedex 01 - FRANCE
Tel.: +33 2 40 08 31 18
Fax: +33 2 40 08 31 17
E-mail: brigitte.dreno@atlanmed.fr

Number of words: 3006

Number of figures: 3
Number of tables: 5
Number of references: 30

Funding source: Authors have no funding source to declare.

Conflict of interest: Authors have no conflict of interest to disclose.

This article has been accepted for publication and undergone full peer review but has not been through the
copyediting, typesetting, pagination and proofreading process, which may lead to differences between this
version and the Version of Record. Please cite this article as doi: 10.1111/JDV.16064

This article is protected by copyright. All rights reserved

Accepted Article
Abstract

Background

Acne fulminans (AF) is a rare and severe form of inflammatory acne. It is characterized by a
sudden worsening of acne with appearance of ulcero-necrotic lesions, which can be associated
with systemic signs. Its pathophysiology and the best therapeutic strategy are only partially
known.

Objective

Our main objectives were to describe the clinical and biological profile of AF patients and to
determine whether there was a difference in C. acnes phylotype in AF compared to acne vulgaris.
The secondary objective was to assess the efficacy of different therapies.

Methods

A retrospective observational study was conducted in all patients followed for AF in our
department between 2008 and 2018. Bacteriological samples were taken from each patient to
analyze C. acnes phylotype distribution. The therapeutic response was assessed using the ECLA
and GEA scales.

Results

Fifteen patients with a median age of 15 years were included (12 men, 80%). A family history of
acne was found in 86.7% of patients. Nine patients (60%) had isotretinoin-induced AF. Only one
patient (6.7%) showed systemic signs. The bacteriological culture was positive for C. acnes in
80% of patients. The predominant phylotype was IA1 in 60% of patients, corresponding to the
predominant phylotype in acne vulgaris. Only 33.3% of patients were in remission after a first-line

This article is protected by copyright. All rights reserved

 treatment with systemic corticosteroids, alone or in combination. Seven patients were treated with
Accepted Article
biotherapy, including 5 successfully with secukinumab.

Conclusion

Our results suggest that there is no specific C. acnes phylotype associated with AF, raising the
hypothesis that acute inflammation associated with AF may be more related to an abnormal
cutaneous innate immunity activation. The use of preventive strategies, the impact of combined
treatments and an assessment of the role of biotherapies, especially anti-IL-17, in AF treatment
remain to be more investigated.

This article is protected by copyright. All rights reserved

Accepted Article
INTRODUCTION

Acne fulminans (AF) is an extremely rare variant of severe inflammatory acne, the
pathophysiology and treatment of which have not yet been fully determined. Classically, AF
occurs in adolescents aged 13 to 22, more than 75% of whom are male, and is more common in
Caucasians (1–4). Acne fulminans can be associated with systemic signs (4): fever, asthenia,
weight loss, diffuse myalgia, arthralgia or even arthritis of the large joints. More rarely, other
symptoms may be associated, including weight loss, erythema nodosum, hepatosplenomegaly (5)
or even aseptic osteomyelitis (6). Biologically, inconstant abnormalities may be observed such as
hyperleukocytosis, neutrophil polynucleosis, increased C-reactive protein (CRP), thrombocytosis
and increased liver enzymes.
AF may be induced by isotretinoin prescribed in patients with severe acne. In this form,
there is usually no systemic involvement but the lesions are often severe (4).
Although acne vulgaris is a ubiquitous disease, AF is rarely reported, with about 200 cases
documented in the literature (1–3,7–9). The incidence of publications has gradually decreased
between its first description and the 2010s, which may reflect a lower occurrence of severe forms
with systemic signs or suggest an absence of progression in the knowledge of the pathophysiology
of this disease and its treatment.
Indeed, AF pathophysiology remains unknown. The bacterium Cutibacterium acnes (C.
acnes), plays a major and unavoidable role in acne. A theory for AF development would involve
an exaggerated immunological reaction against C. acnes, in particular at the innate immunity on a
genetically predisposed background (3). Several recent studies have suggested that specific
subtypes of C. acnes could play a key role in the severity of inflammatory acne (10–12). A recent
study has shown a greater proinflammatory activity in acne with phylotype III (10). However, no
study has specifically focused on C. acnes isolates in AF.
The primary objectives of this study were to describe the clinical and biological profile of
AF patients followed in our department and to determine whether there is a difference in C. acnes
phylotype and lineage between AF and acne vulgaris strains using molecular typing according to

This article is protected by copyright. All rights reserved

 the three currently known levels (phylotype, clonal complex and single locus sequence typing
Accepted Article
[SLST]). The secondary objective was to assess the efficacy of different therapies.

MATERIALS AND METHODS

Patients and collected data

In this retrospective study, all patients treated for AF in our Dermatology department
between 2008 and 2018 were included.
The following epidemiological data were recorded: age, body mass index, age at acne
onset, acne type according to the evolution (persistent or late onset acne), presence of prepubertal
lesions, family history of acne, factors triggering acne, presence of a hormonal disease associated
with acne (obesity, hyperpilosity, irregular menstruation, amenorrhea), sport practice (competition
level or not and 3 or more times per week), smoking status, use of cosmetics and previous
systemic acne treatments.
Acne severity was assessed at each consultation using the ECLA scale (23), combined with
a global assessment using the GEA grading (24). Seborrhea intensity was determined using a
semi-quantitative grading (0 = no seborrhea, 1 = mild, 2 = moderate and 3 = severe).

Bacteriological samples

Bacteriological swab samples were collected from papules, pustules and nodules on the
face and/or trunk and provided to the Bacteriology department in less than 30 minutes. Each
sample was cultured anaerobically at 37°C for 7-10 days. The Bacteriological samples were
collected as standard care investigations.

Microbiological analysis

This article is protected by copyright. All rights reserved

Accepted Article All isolates were identified by matrix-assisted laser desorption/ionization time-of-flight
mass spectrometry with a VitekMS® mass spectrometer (MALDI-TOF MS) (bioMérieux SA,
Marcy-l'Etoile, France). All strains were identified with an accuracy >99.9%.

Molecular techniques

DNA extraction and phylotype determination

Total DNA from C. acnes isolates was extracted using the InstaGene Matrix method (Bio-
Rad Laboratories, Hercules, CA, USA) according to the manufacturer's instructions. After
centrifugation, the supernatant was used as a DNA template for phylotype multiplex PCR analysis
as previously described (15).
Multi- and single locus sequence typing and sequencing protocol

MLST is a method to determine to which clonal complex a C. acnes strain belongs. It was
carried out on all isolates as described by Kilian et al. (20). This typing is based on partial
sequencing of nine housekeeping genes comprising a total of 4,287 nucleotides and is available at
http://pacnes.mlst.net/.

SLST is a molecular typing method based on the analysis of a single locus of C. acnes
genome. The portion of amplified DNA allows identifying C. acnes SLST type. SLST was carried
out on all isolates, as described by Scholz et al (19). Reference sequences for alignment and
trimming may be found in the web-interface typing tool available at http://medbac.dk/slst/pacnes.

Study endpoints

Regarding therapeutic assessment, a complete remission (CR) was defined as the absence
of nodule (Ip = 0), a maximum score of 1 in each other ECLA subcategory and a GEA score of 0-
1 for the face. A partial remission (PR) was defined as an improvement greater than 50% in the
ECLA score and a GEA score of 1 or 2.

This article is protected by copyright. All rights reserved

Accepted Article
RESULTS

Patients

A total of 15 patients were followed for AF between 2008 and 2018 and were included.
Patient characteristics are summarized in Table 1. Twelve patients (80%) were male. Patient
median age was 15 years. All patients had pre-existing acne vulgaris for a median time of 1.5
years (0-4 years) before AF onset. No patient was overweight or obese. Among the factors of poor
prognosis identified in the literature, six patients (40%) had prepubertal acne and 13 patients
(86.7%) had a family history of acne (father, mother or siblings), including 2 patients whose father
had AF. No patient reported taking anabolic steroids. Fourteen patients (93.3%) had received at
least one previous systemic treatment line, including 11 patients (73.3%) with systemic antibiotics
with a median number of 1.2 treatments. The median follow-up duration at the time of analysis
was 38 months (range: 2-75 months).

Clinical presentation

The clinical presentation on the day of the consultation assessment is reported in Table 2.
Nine patients (60%) had isotretinoin-induced AF without systemic signs (IIAF-WOSS). Among
the other 6 patients, 5 (33.3%) had non-isotretinoin-induced AF without associated systemic signs
(AF-WOSS), and only 1 (6.7%) had AF with systemic signs (AF-SS), including fever and
arthralgia. It should be noted that one patient experienced AF 9 months after receiving injectable
testosterone treatment for Kallman syndrome.
The median ECLA score was 16,5 (range: 7-25). All patients had facial involvement, but
only 11 (73.3%) had associated trunk involvement.
Among patients with IIAF (isotretinoin-induced AF), the median duration of treatment
prior to AF was 30 days (7-117 days). The median initial dose of isotretinoin was 0.3 mg/kg/day
(range: 0.16-0.5 mg/kg/day).

This article is protected by copyright. All rights reserved

 Biological assessment
Accepted Article
The results of the biological analysis performed in some patients at the first visit are
summarized in Table 3. Seven patients had hyperleukocytosis with a median level of 11.93 g/L
(range: 10.42-17.39 g/L). Increased CRP was noted in 5 out of the 7 patients with a median level
of 15.35 mg/L (range: 12.2-35.9 mg/L). Two out of the 8 patients showed increased liver
enzymes. Total testosterone was increased in one out of seven men and delta 4 androstenedione in
one woman with clinical signs of hyperandrogenism. 25-OH-vitamin D deficiency was observed
in 5 out of 7 patients. No patient showed an increase in IgF1 or a decrease in zinc levels.

Cultivable skin microbia

The bacteriological culture was positive for all patients included (100%), and C. acnes was
identified in most cases (12/15, 80%).
The Cutibacterium species alone was identified in 10 patients (10/15, 66.7%): C. acnes in
9 patients and Cutibacterium avidum (C. avidum) in one patient.
In 2 patients (2/15, 13.3%), Staphylococcus aureus (S. aureus) was identified in
association with C. acnes, and in 2 other patients (2/15, 13.3%) S. aureus was identified alone.
The last patient (1/15, 6.7%) had a positive culture for both C. acnes and Cutibacterium
granulosum (C. granulosum).

Phylotype of Cutibacterium

Four different C. acnes phylotypes were identified (fig. 1), both on the back and face.
Phylotype IA1 was predominant (9/15, 60%) in all samples as well as in the 2 subgroups;
then phylotype II (3/15, 20%), phylotype IB (2/15, 13.3%) and phylotype IA2 (1/15, 6.7%) were
found.
C. granulosum was identified in the back sample of a 17-year old patient who previously
had acne conglobata followed by IIAF.
C. avidum was identified in the back sample of a 13-year old patient with a family history
of severe acne and a personal history of prepubertal acne, who practiced sport more than 3 times a

This article is protected by copyright. All rights reserved

 week. His biological assessment revealed high levels of total testosterone. He experienced severe
Accepted Article
non-isotretinoin-induced AF requiring treatment with biotherapy.

C. acnes phylotype diversity on the face vs. the back

Results are shown in figure 2.

On the face, phylotype IA1 was largely predominant (7/9, 77.8%) compared to phylotypes
IB (1/9, 11.1%) and II (1/9, 11.1%).
On the back, the phylotypes were more diversified: IA1 (2/6, 33.3%), II (2/6, 33.3%), IA2
(1/6, 16.7%) and IB (1/6, 16.7%).
Three patients had positive culture for C. acnes on samples collected on both the face and
back: 2 patients showed two different phylotypes of C. acnes on the two samples, and one patient
had phylotype IA1 on both the face and back.

SLST and MLST

Results are shown in Table 4. The A1 SLST subtype was predominant (8/15, 53.3%) and
the clonal complex (CC) distribution analysis revealed a predominance of CC18 (8/15, 53.3%)
with no difference between isotretinoin-induced or spontaneous AF.

C. acnes resistance

The resistance to erythromycin, clindamycin and tetracyclines was studied for all strains of
C. acnes.
Four out of 12 strains were resistant to erythromycin in facial samples only, one of which
was resistant to both erythromycin and clindamycin. Among these 4 patients, 3 had received a
prior treatment with topical antibiotic.
No strain was resistant to tetracyclines.

Other species

This article is protected by copyright. All rights reserved

Accepted Article S. aureus was identified on the face in 4 patients, none on the back. Three of these patients
(75%) had IIAF. One patient progressed to Verneuil’s disease thereafter.

Treatment

Non-isotretinoin-induced AF

Regarding the 6 patients with non-isotretinoin-induced AF, they were all treated with
systemic corticosteroids as a first-line therapy. The median initial dose was 0.5 mg/kg/day (range:
0.45-0.8 mg/kg/day). The dose was tapered until treatment discontinuation over a median time of
5 months (range: 2-17 months).
In two patients, low-dose isotretinoin (0.1 mg/kg) was immediately combined with
systemic corticosteroids, in two other patients, it was first used as a monotherapy for one month
and then combined. The median initial dose was 5 mg/day, i.e. 0.07 mg/kg/day (range: 0.06-0.22
mg/kg/day). The median treatment duration was 12 months (range: 11-29 months).
The last two patients were treated with oral antibiotics in combination with oral
corticosteroids (one with minocycline, one with doxycycline).
Among these 6 patients, only 2 achieved a PR or CR within a median time of 4.5 months
(systemic corticosteroids and minocycline, corticosteroids and isotretinoin).
One patient experienced a relapse of necrotic lesions upon corticosteroid tapering to 10
mg/day (0.17 mg/kg/day).

Isotretinoin-induced AF

The 9 patients were treated with systemic corticosteroids as a first-line treatment. The
median initial dose was 0.47 mg/kg/day (range: 0.21-1.00 mg/kg/day). The median total treatment
duration was 12.75 months (range: 5-26 months).
Isotretinoin was discontinued in all patients, except one for whom the dose was decreased,
without achieving remission.
Isotretinoin was reintroduced after 1 month on oral corticosteroids in 2 patients: one patient
experienced a new inflammatory flare-up and the second remained stable.

This article is protected by copyright. All rights reserved

Accepted Article Two patients were directly treated with therapy combining systemic corticosteroids,
spironolactone and zinc: a CR of lesions was achieved within 3 months in the first patient while
the other one did not respond to treatment.
In 2 patients, dual therapy with systemic corticosteroids and minocycline was introduced,
and a CR was achieved within 5 months in one patient while the other one did not respond to
treatment.
In the last 2 patients, treatment with spironolactone was combined with systemic
corticosteroids and no effect was observed.

Overall, 3 patients were in CR after a median time of 5 months, with no recurrence of AF

thereafter.

Biologics

Seven patients resistant to several therapeutic lines were treated with biotherapy (Table 5):
2 patients with anakinra, an anti-IL-1, administered subcutaneously at a dose of 100 mg/day; 5
patients with secukinumab, an anti-IL-17, including one after failure of anakinra, administered
subcutaneously at a dose of 300 mg/month; and the last patient with ustekinumab, and anti-IL-
12/23.

Of the 5 patients treated with secukinumab: 1 CR and 1 PR were achieved in 2 and 3

patients, respectively, with a response time ranging from 3 to 7 months. Two patients experienced
an "end-of-dose" effect, which required a closer injection interval (every 3 weeks). In one patient
in CR after 16 months on secukinumab, the injections were spaced every 6 weeks. Figure 3
illustrates treatment response in a patient after 12 months of secukinumab.
The patient treated with ustekinumab was in PR from the third month, which was
maintained after one year of treatment, without however achieving a CR.
In contrast, in 2 patients treated with anakinra, no treatment response was observed.

This article is protected by copyright. All rights reserved

 DISCUSSION
Accepted Article
Our case report confirmed a high male predominance in AF (80%), with a significantly
lower rate of systemic signs than previously reported (2,3,8). Only one patient experienced fever
and arthralgia. Some authors have assumed that the condition and its treatment were recognized
earlier, limiting the appearance of systemic signs (1). In Karvonen case series (3), 30.4% of
patients developed AF under isotretinoin treatment versus 60% in our case series. In the study by
Thomson and Cunliffe reporting a case series of 15 patients with sudden onset of ulcerative
lesions without systemic signs referred to as "acne fulminans sine fulminans", 93.3% of patients
were treated with isotretinoin (16).
In our study, most patients (86.7%) had a family history of acne, including two patients
with a family history of AF. This finding suggests the role of a possible genetic susceptibility in
AF. A large study conducted in monozygotic or dizygotic twins has shown that 81% of acne
variations were attributable to cumulative genetic factors (17). In particular, 4 cases of AF in twins
are reported in the literature (18–21).
Biologically, when the assay was performed, no zinc deficiency, no increase in IGF1, and
no 25-OH-vitamin D deficiency were found compared to the general population, unlike in
Verneuil's disease (22).
To our knowledge, this is the first study to investigate C. acnes phylotype in a population
with AF. The culture identified 4 out of the 6 main known phylotypes of C. acnes, showing a
significant diversity, with however a predominance of phylotype IA1 as in acne vulgaris (23,24).
The results of the study conducted by Kwon et al. in 2013 (25) have shown that about 40% of
patients with acne vulgaris and healthy subjects had phylotype IA1. This percentage was higher in
inflammatory skin, reaching 75%.
In our study, 60% of patients had C. acnes phylotype IA1. Thus, these results suggest
that there is no specific C. acnes phylotype associated with AF. This raises the hypothesis that the
mechanism involved in AF could be more related to an abnormal activation of the cutaneous
innate immunity.
It has recently been shown that severe inflammatory acne was associated with a loss of C.
acnes diversity, with a high prevalence of phylotype IA1 (15). This loss of microbiota diversity
may activate the cutaneous innate immunity with development of inflammatory lesions. β-

This article is protected by copyright. All rights reserved

 defensin 2 and TLR-2 have been shown to be overexpressed in the non-lesional skin of patients
Accepted Article
with nodular acne on the back compared to the healthy skin of healthy subjects (15). The innate
immune system thus appears to be overactive in patients with nodular acne on the back compared
to healthy subjects.
C. acnes could thus play a key role in the activation of the cutaneous innate immunity by
inducing the production of proinflammatory cytokines by keratinocytes, monocytes and
macrophages: IL-8, IL-17 and IL-1 (26–28), as well as the expression of TLRs, mainly TLR-2 by
keratinocytes (29).
In our patients, we did not find any loss of diversity similar to that reported in nodular
acne. In contrast, we identified S. aureus in 4 out of 15 patients, 3 of whom had IIAF. A recent
study has investigated the cutaneous microbiota response to isotretinoin treatment (30). After
treatment, a change in skin microenvironment was observed with increased  and  diversity,
decrease in C. acnes, but also an initial increase in Staphylococcus species during treatment, as
found in our patients.

The therapeutic strategy currently recommended in AF is now codified since Greywal et al.
recommendations in 2017 (4). Systemic corticosteroids are recommended from the onset of AF to
rapidly control inflammation. A low dose of isotretinoin may then be combined (0.1 mg/kg/day),
while continuing oral corticosteroids for at least 4 weeks. Isotretinoin doses may then be
progressively increased concomitantly with the decrease in oral corticosteroids.
In our study, 5 patients (33.3%) were in PR or CR after a first treatment line with systemic
corticosteroids, alone or in combination. Corticosteroid duration was significantly longer in
patients with IIAF with a median duration of 12.75 months versus 5 months, respectively.
No specific data are available in the literature regarding the use of biotherapies in AF. In
our two cases treated with anakinra (anti-IL1), treatment was not effective. However, treatment
with secukinumab (anti-IL-17) appeared to be an interesting therapeutic option with achievement
a PR or CR in our five cases. The rational for this therapeutic choice is based on the stimulation by
C. acnes of the production of proinflammatory cytokines, in particular IL-17 by TH17 cells (27).

AF is therefore a very rare condition, affecting mainly men, and a family history is
common. Our study raises the hypothesis that AF is not associated with a specific phylotype of C.
acnes, nor with a loss of phylotypic diversity. S. aureus could play a role in the development of

This article is protected by copyright. All rights reserved

 the acute inflammatory response in association with C. acnes but this remains to be confirmed.
Accepted Article
Larger prospective studies are needed to assess the use of preventive strategies, the impact of
combined treatments and specific data regarding the use of biologics in AF.

This article is protected by copyright. All rights reserved

Accepted Article
References

1. Zaba R, Schwartz RA, Jarmuda S, Czarnecka–Operacz M, Silny W. Acne fulminans:

explosive systemic form of acne. J Eur Acad Dermatol Venereol. 2010; 25(5):501‑7.

2. Seukeran, Cunliffe. The treatment of acne fulminans: a review of 25 cases. Br J Dermatol.

2001;141(2):307‑9.

3. Karvonen S-L. Acne fulminans: Report of clinical findings and treatment of twenty-four
patients. J Am Acad Dermatol. 1 avr 1993;28(4):572‑9.

4. Greywal T, Zaenglein AL, Baldwin HE, Bhatia N, Chernoff KA, Rosso JQD, et al.
Evidence-based recommendations for the management of acne fulminans and its variants. J Am
Acad Dermatol. 1 juill 2017;77(1):109‑17.

5. Cordoliani F. Acne fulminans therapy. Ann Dermatol Venereol. janv 2002;129(1 Pt

1):89‑92.

6. Pauli SL, Valkeakari T, Räsänen L, Tuomi ML, Reunala T. Osteomyelitis-like bone lesions
in acne fulminans. Eur J Pediatr. nov 1989;149(2):110‑3.

7. Schram A, Rosenbach M. Acne Fulminans. In: Acneiform Eruptions in Dermatology: A

Differential Diagnosis. New-York : Springer-Verlag; 2014; p. 117‑23.

8. Massa AF, Burmeister L, Bass D, Zouboulis CC. Acne Fulminans: Treatment Experience
from 26 Patients. Dermatol Basel Switz. 2017;233(2‑3):136‑40.

9. Alakeel A, Ferneiny M, Auffret N, Bodemer C. Acne Fulminans: Case Series and Review
of the Literature. Pediatr Dermatol. 4 oct 2016;33(6):e388‑92.

This article is protected by copyright. All rights reserved

Accepted Article
10. Jasson F, Nagy I, Knol AC, Zuliani T, Khammari A, Dréno B. Different strains of
Propionibacterium acnes modulate differently the cutaneous innate immunity. Exp Dermatol. sept
2013;22(9):587‑92.

11. Nakase K, Hayashi N, Akiyama Y, Aoki S, Noguchi N. Antimicrobial susceptibility and

phylogenetic analysis of Propionibacterium acnes isolated from acne patients in Japan between
2013 and 2015. J Dermatol. nov 2017;44(11):1248‑54.

12. Scholz CFP, Jensen A, Lomholt HB, Brüggemann H, Kilian M. A novel high-resolution
single locus sequence typing scheme for mixed populations of Propionibacterium acnes in vivo.
PloS One. 2014;9(8):e104199.

13. Dreno B, Bodokh I, Chivot M, Daniel F, Humbert P, Poli F, et al. ECLA grading: a system
of acne classification for every day dermatological practice. Ann Dermatol Venereol. févr
1999;126(2):136‑41.

14. Dréno B, Poli F, Pawin H, Beylot C, Faure M, Chivot M, et al. Development and
evaluation of a Global Acne Severity Scale (GEA Scale) suitable for France and Europe. J Eur
Acad Dermatol Venereol JEADV. janv 2011;25(1):43‑8.
15. Dagnelie M-A, Corvec S, Saint-Jean M, Bourdès V, Nguyen J-M, Khammari A, et al.
Decrease in Diversity of Propionibacterium acnes Phylotypes in Patients with Severe Acne on the
Back. Acta Derm Venereol. 7 févr 2018;98(2):262‑7.

16. Thomson KF, Cunliffe WJ. Acne fulminans « sine fulminans ». Clin Exp Dermatol. juin
2000;25(4):299‑301.

17. Bataille V, Snieder H, MacGregor AJ, Sasieni P, Spector TD. The influence of genetics
and environmental factors in the pathogenesis of acne: a twin study of acne in women. J Invest
Dermatol. déc 2002;119(6):1317‑22.

18. Darley CR, Currey HL, Baker H. Acne fulminans with arthritis in identical twins treated

This article is protected by copyright. All rights reserved

 with isotretinoin. J R Soc Med. avr 1984;77(4):328‑30.
Accepted Article
19. Gonzalez T, Gantes M, Bustabad S, Diaz-Flores L. Acne fulminans associated with
arthritis in monozygotic twins. J Rheumatol. avr 1985;12(2):389‑91.

20. Saint-Jean M, Frenard C, Le Bras M, Aubin GG, Corvec S, Dréno B. Testosterone-induced

acne fulminans in twins with Kallmann’s syndrome. JAAD Case Rep. 18 oct.

21. Wong SS, Pritchard MH, Holt PJ. Familial acne fulminans. Clin Exp Dermatol. sept
1992;17(5):351‑3.

22. Guillet A, Brocard A, Bach Ngohou K, Graveline N, Leloup A-G, Ali D, et al. Verneuil’s
disease, innate immunity and vitamin D: a pilot study. J Eur Acad Dermatol Venereol JEADV.
juill 2015;29(7):1347‑53.

23. Lomholt HB, Kilian M. Population genetic analysis of Propionibacterium acnes identifies
a subpopulation and epidemic clones associated with acne. PloS One. 19 août 2010;5(8):e12277.

24. McDowell A, Patrick S, Eishi Y, Lambert P, Eady A. Propionibacterium acnes in human

health and disease. BioMed Res Int. 2013;493564.

25. Kwon HH, Yoon JY, Park SY, Suh DH. Analysis of distribution patterns of
Propionibacterium acnes phylotypes and Peptostreptococcus species from acne lesions. Br J
Dermatol. nov 2013;169(5):1152‑5.

26. Nagy I, Pivarcsi A, Koreck A, Széll M, Urbán E, Kemény L. Distinct strains of

Propionibacterium acnes induce selective human beta-defensin-2 and interleukin-8 expression in
human keratinocytes through toll-like receptors. J Invest Dermatol. mai 2005;124(5):931‑8.

27. Agak GW, Qin M, Nobe J, Kim M-H, Krutzik SR, Tristan GR, et al. Propionibacterium
acnes Induces an IL-17 Response in Acne Vulgaris that Is Regulated by Vitamin A and Vitamin
D. J Invest Dermatol. févr 2014;134(2):366‑73.

This article is protected by copyright. All rights reserved

Accepted Article
28. Kistowska M, Gehrke S, Jankovic D, Kerl K, Fettelschoss A, Feldmeyer L, et al. IL-1β
drives inflammatory responses to Propionibacterium acnes in vitro and in vivo. J Invest Dermatol.
mars 2014;134(3):677‑85.

29. Jugeau S, Tenaud I, Knol AC, Jarrousse V, Quereux G, Khammari A, et al. Induction of
toll-like receptors by Propionibacterium acnes. Br J Dermatol. déc 2005;153(6):1105‑13.

30. McCoy WH, Otchere E, Rosa BA, Martin J, Mann CM, Mitreva M. Skin Ecology during
Sebaceous Drought-How Skin Microbes Respond to Isotretinoin. J Invest Dermatol. mars
2019;139(3):732‑5.

This article is protected by copyright. All rights reserved

Accepted Article
Tables

Table 1. Patient characteristics (n=15)

Characteristics Value
Age, years, median (range) 15 (11-19)
Gender, n (%)
Male 12 (80)
Female 3 (20)
BMI, kg/m2, median (range) 20.3 (16.4-22.9)
Age at acne onset, years, median (range) 13 (8-18)
Time to acne and AF onset, years, 1.5 (0-4)
median (range)
Prepubertal acne, n (%) 6 (40)
Family history of acne, n (%) 13 (86.7)
Father 8 (61.5)
Mother 6 (46.2)
Siblings 6 (46.2)
Triggering factors for acne flare-up 8 (53.3)
identified, n (%)*
Stress 2 (25)
Sun 2 (25)
Periods (in female patients) 1 (33.3)
Sweating 1 (0.13)
Diet 4 (50)
Sport practice  3 times/week, n (%) 4 (26.7)
Indoor 4 (100)
Outdoor 0
Swimming pool 0
Competition 2 (50)
Anabolic steroid intake 0
Active smoking, n (%) 1 (6.7)

This article is protected by copyright. All rights reserved

 Cosmetic care, n (%) 3 (20)
Accepted Article
Women, n (%) 2 (66.7)
Men, n (%) 1 (6.3)
Cosmetician 2 (66.7)
Exfoliation 3 (100)
Face masks 1 (33.3)
Prior systemic treatment, n (%) 14 (93.3)
Number of lines, median 1.5
Antibiotics 11 (78.6)
Number of antibiotics treatments, median 1.2
Zinc 2 (14.3)

* Several triggering factors could be reported for a given patient

This article is protected by copyright. All rights reserved

Accepted Article
Table 2. Clinical presentation on the assessment day

Total Isotretinoin-Induced Non induced AF

AF
n 15 9 6
Systemic signs, n (%) 1 (6.7) 0 1 (16.7)
Trunk involvement, n (%) 11 (73.3) 6 (66.7) 5 (83.3)
Seborrhea (0-3), median 2 3 2
Face severity score (F1) 8 (4-15) 8 (5-15) 8 (4-11)
median (range)
Trunk severity score (F2) 8 (0-14) 6 (0-14) 9 (2-14)
median (range)
Extra-facial nodules 5 (0-29) 7 (0-29) 7.5 (0-20)
median (range)
ECLA score 16.5 (7-25) 16 (7-24) 16.5 (11-25)
median (range)

This article is protected by copyright. All rights reserved

Accepted Article
Table 3. Biological results on the assessment day (T0)

Number of Yes No
patients
Hyperleukocytosis 9 7 2
Thrombocytosis 9 2 7
Increased CRP 7 5 2
Impaired liver function 8 2 6
Decreased 25-OH-vitamin D 7 5 2
Increased total testosterone (men) 7 1 6
Increased delta 4 androstenedione (women) 1 1 0
Decreased zinc levels 4 0 4
Decreased IgF1 6 0 6

This article is protected by copyright. All rights reserved

Accepted Article
Table 4. Distribution of C. acnes (SLST, MLST)

TYPE SUBTYPE TOTAL Non-induced AF Isotretinoin-Induced

(n=4) AF
(n=11)
n % n % n %

A1 8 53.3% 3 75 5 45.5

A2 1 6.7% 0 0 1 9.1

D1 1 6.7% 0 0 1 9.1

E3 1 6.7% 0 0 1 9.1
SLST H1 1 6.7% 0 0 1 9.1

K15 1 6.7% 1 25 0 0

K2 1 6.7% 0 0 1 9.1

K7 1 6.7% 0 0 1 9.1

CC18 8 53.3% 3 75 5 35.5

CC19 1 6.7% 0 0 1 9.1

CC28 1 6.7% 0 0 1 9.1

CC31 1 6.7% 0 0 1 9.1

MLST CC36 1 6.7% 0 0 1 9.1

This article is protected by copyright. All rights reserved

Accepted Article
Table 5. Therapeutic response on biotherapy

Number of
prior
Treatment Response Response
AF Biotherapy treatment lines Response
Patients duration at 3 at 6
type type (monotherapy at 1 year
(months) months months
or dual
therapy)
1 IIAF secukinumab 4 6 PR CR on the -
(ongoing) face/PR on
the back
2 IIAF secukinumab 2 12 0 PR CR
(ongoing)
3 IIAF anakinra 5 5 0 - -
secukinumab 6 16 PR CR on the CR
(ongoing) face/PR on
the back
4 IIAF ustekinumab 1 39 PR PR PR
5 AF secukinumab 1 9 PR PR -
(ongoing)
6 IIAF secukinumab 4 12 PR CR PR on the
(ongoing) face/
CR on the
back
7 AF anakinra 4 3 0 - -

PR = partial response, CR = complete response

This article is protected by copyright. All rights reserved

Accepted Article

jdv_16064_f1.jpg

This article is protected by copyright. All rights reserved

Accepted Article

jdv_16064_f2.jpg

This article is protected by copyright. All rights reserved

Accepted Article

jdv_16064_f3.jpg

This article is protected by copyright. All rights reserved