1. Association of Pyrin mutations and Autoinflammation with Complex Phenotype Hidradenitis Suppurativa: A Case Control Study
S. Vural,1,2 M. Gündoğdu,1 E. Gökpınar,3 C.D. Durmaz,3 A. Vural,4 L. Steinmüller-Magin,5 A. Kleinhempel,6 L.M. Holdt,6 T. Ruzicka,7 K.A. Giehl,7 H.I. Ruhi,3 A. Boyvat1
1 Ankara University, Department of Dermatology and Venereology, Ankara, Turkey
2 Koç University, Department of Dermatology, İstanbul, Turkey
3 Ankara University, Department of Medical Genetics, Ankara Turkey
4 Koç University, Department of Neurology, İstanbul, Turkey
5 Institute of Laboratory Medicine and Human Genetics, Singen, Germany
6 Ludwig Maximilian University of Munich, Institute of Laboratory Medicine, Munich, Germany
7 Ludwig Maximilian University of Munich, Department of Dermatology and Allergy, Munich, Germany
British Journal of Dermatology. DOI: /bjd.17466

2. Dr Seçil Vural

3. Introduction What’s already known?
Hidradenitis suppurativa (HS) is a neutrophilic dermatosis with unclear pathogenesis, but immune dysregulation is implicated.
MEFV mutations are reported in several patients with PASH (pyogenic arthritis, acne, hidradenitis suppurativa) syndrome.
MEFV mutations are the pathogenic variation in familial Mediterranean fever (FMF).
FMF is an autoinflammatory disease characterized by serositis attacks accompanied with high fever.

4. MEFV Gene
Composed of 10 exons and encodes a 781-amino acid protein (pyrin).
Pyrin plays a crucial role in innate immunity and is a critical component of inflammasomes.
Mutated pyrin represents a gain-of-function mutation that leads to spontaneous inflammasome formation.

5. Objective
We aimed to investigate the association of pathogenic MEFV variants with severe and complex HS .
We evaluated the frequency of clinical FMF disease among patients with HS.

6. Methods Case control study.
Hidradenitis suppurativa patients from a single tertiary reference centre in Turkey ( ).
119 patient with HS were included.
Patients were then catagorised into two subgroups:
1. Complex HS
2. Non-complex HS
Complex HS patients were defined as: Hurley stage III disease and/or Hurley stage II disease with at least one inflammatory disorder including pyoderma gangrenosum, arthritis, dissecting cellulitis of scalp, inflammatory bowel disease, and acne conglobata.

7. Methods
Whole-gene analysis of MEFV from patients with complex HS and PSTPIP1 from patients with accompanying pyoderma gangrenosum were performed.
Allele frequency and prevalence of mutations in the MEFV gene from the HS group were compared with MEFV variants extracted from the in-house database of 192 healthy unrelated controls.

8. Methods
Patients with clinical and genetic diagnosis of familial Mediterranean fever were also detected.
Genetic testing was conducted to confirm the presence of the MEFV gene in all FMF patients.
The prevalence of FMF in the HS population was calculated on the basis of these data.

9. Results
Among 119 patients, 38 were classified as complex HS (31.9%) Within this group, 21 patients gave consent for further genetic analysis.
The mean age at onset of HS was significantly earlier in patients with complex HS (24 versus 30 years of age in non-complex HS patients, p=0.002).
Male patients made up a significantly higher percentage of the complex HS group (68.4%, p=0.022).

10. Results
OR evaluations for specific alleles revealed three risk factors in complex HS patients:
(1) the presence of one or more pathogenic variant (2.80 (CI: , p<0.001)
(2) the presence of the M680I allele [19.05 (CI: ), p=0.001]
(3) the presence of the M694V allele [4.19 (CI: ), p=0.006]
On the other hand when E148Q variant (the pathogenicity of this variant is a matter of debate for FMF) was excluded from the analysis, the OR increased from 2.80 to 4.88, indicating a low pathogenicity for HS.

11. Odds ratio for additional clinical features in complex HS group versus normal population, and SMR calculation for clinical FMF disease
Definitions
Number of Patients
Allele Frequency
Of MEFV variants
Odds
Ratio*
95% Confidence intervals
P Value
Clinical FMF disease*
5/119 NA
45**
<0.001
Hurley Stage III
13/21
34.6%
4.17
0.001
Arthritis
8/21
31.3%
3.58
0.023
Acne
15/21
26.6%
2.87
0.018
Pyoderma gangrenosum
4/21
50%
7.88
0.004
Dissecting cellulitis of the Scalp
5/21
30%
3.38
0.09
An OR with a lower boundary of the 95% confidence interval above one is equivalent to a significance level of <0.05.
*Odds ratio is calculated using allele frequency of 11.2 in the healthy population.
**Standardized morbidity ratio is calculated using population data. Clinical prevalence of familial Mediterranean
fever in Turkey is 1/1075.
NA: Not applicable

12. Discussion
In our current understanding, HS is one of the disorders in a spectrum of a heterogeneous group of diseases associated with autoinflammation.
The co-occurrence and severity of these symptoms may indicate a more specific association with autoinflammation.
Pathogenic MEFV mutations have been previously reported in patients with PASH syndrome.
However, the association of MEFV mutations with pathogenicity in non-PASH patients was not investigated
In the present study, we pursued a strategy of selecting patients based on their medical records to assemble a cohort of HS patients with significant autoinflammation.

13. Discussion
Comparison on the basis of this grouping strategy showed that the complex HS group represented a distinct population characterized by early onset of HS.
We found that pathogenic MEFV variants were increased not only in PASH patients but also among patients fulfilling the criteria of ‘complex HS’ when compared to the healthy Turkish population.
The pro-inflammatory status in carriers of MEFV in complex HS group may contribute to pathogenicity.

14. Discussion
Previously Hodak et al. reported a 0.7% prevalence of FMF in a cross-sectional study of 4,417 Israeli HS patients, suggesting an association.
This study also confirmed the association of FMF and HS.
In our study, 80% of HS patients with accompanying FMF exhibited a complex phenotype, further suggesting a role for MEFV mutations as risk factors.
MEFV mutations may cause a proinflammatory state in FMF patients, causing aggravation of inflammation which results in a severe phenotype of HS.

15. Conclusions What does this study add?
Pathogenic MEFV variants are more frequent in complex HS patients than healthy controls.
Not only HS in syndromic forms (PASH, PAPASH) but also severe HS and HS with additional inflammatory symptoms, belong to autoinflammatory spectrum neutrophilic skin diseases.
Complex HS patients, especially with susceptible racial background, may benefit from genetic screening for MEFV gene mutations. In HS patients with MEFV mutations, the conventional FMF drug colchicine and the IL-1β inhibitors anakinra and canakinumab may have favourable effects.

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