Pyoderma Gangrenosum A Systematic Review of The Molecular Characteristics of

Received: 21 August 2021 | Revised: 18 January 2022 | Accepted: 30 January 2022
DOI: 10.1111/exd.14534
REVIEW ARTICLE
Pyoderma gangrenosum: A systematic review of the molecular

characteristics of disease
Akshay Flora1,2,3 | Emily Kozera1,2 | John W. Frew1,2,3
1
Ingham Institute for Applied Medical
Research, Liverpool, NSW, Australia Abstract
2
Department of Dermatology, Liverpool Pyoderma gangrenosum is a painful recurrent ulcerative neutrophilic dermatosis in
Hospital, Liverpool, NSW, Australia
3
which the pathogenesis is incompletely defined. Current evidence suggests that PG is
University of New South Wales, Sydney,
NSW, Australia associated with dysregulation of components of both the innate and adaptive immune
system with dysregulation of neutrophil function and contribution of the Th17 im-
Correspondence
John W. Frew, Department of mune axis. PG can be present in numerous heterogeneous clinical presentations and
Dermatology, Liverpool Hospital, Suite be associated with multiple inflammatory conditions including rheumatoid arthritis,
7, Level 1 45-47 Goulburn St, Liverpool,
NSW, Australia. inflammatory bowel disease and hidradenitis suppurativa. However, no critical evalu-
Email: john.frew@unsw.edu.au ation of the observed molecular characteristics in PG studies in association with their
Funding information clinical findings has been assessed. Additionally, emerging evidence suggests a po-
Australian Government Research Training tential role for other cell types and immune pathways including B cells, macrophages,
Program Scholarship
autoantibodies and the complement system in PG, although these have not yet been
integrated into the pathogenesis of disease. This systematic review aims to critically
evaluate the current molecular observations regarding the pathogenesis of PG and
discuss associations with clinical characteristics as well as the evidence supporting
novel cell types and immune pathways in PG.
KEYWORDS
autoantibodies, inflammasome, neutrophil extracellular traps, neutrophilic dermatosis,
pathophysiology, pyoderma gangrenosum, Th17
1 | I NTRO D U C TI O N been described.4 Some patients present with multiple ulcers, or ulcer
recurrence with sparing of previously scarred sites. PG subtypes in-
Pyoderma gangrenosum (PG) is a chronic, recurrent, recalcitrant clude classic, peristomal, pustular, bullous and superficial granulo-
neutrophilic dermatosis manifesting with painful, rapidly expanding matous. Approximately 30 to 50% of cases demonstrate pathergy in
cutaneous ulceration, often in association with systemic inflamma- response to localised trauma.5,6
tory conditions or underlying malignancies. It was first described in The worldwide incidence of PG is estimated to be 3–10 cases per
1908 by Brocq as “phagedenisma geometrique” with the term pyo- million people, per year, and it most commonly occurs in those aged
derma gangrenosum later coined by Brunsting in 1931.1 PG typically 25–45 years.3 Approximately half of the patients diagnosed with
begins as sterile pustules, rapidly expanding to erythematous to vi- PG will have an underlying systemic disease such as inflammatory
olaceus ulcerating plaques with an irregular and undermined edge, bowel disease, inflammatory arthropathies, vasculitis or haemato-
violaceous border and central purulent or haemorrhagic exudate. 2,3 logical conditions.7
The ulcers are most commonly located on the lower legs, although PG has also been described within certain syndromes such as
locations such as the head and other extracutaneous sites have also PAPA (pyogenic arthritis, PG and acne) which arises from mutations
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
498 |
wileyonlinelibrary.com/journal/exd Experimental Dermatology. 2022;31:498–515.
|
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FLORA et al. 499
in the proline/serine/threonine phosphatase-

interacting protein 2.2 | Appraisal and synthesis methods
8
1 (PSTPIP1), and PASH (PG, acne and suppurative hidradenitis),
which may be associated with increased CCTG microsatellite repeats Data were collected independently by 2 authors (AF and JWF), with
in the promoter region of the PTSPIP1 gene. any disagreements about the inclusion of a study being referred to
To date, the pathogenic mechanisms underlying PG remain in- a third author (EK) for further evaluation. The principal outcome of
completely understood. Evidence suggests that it is likely due to a interests was gene expression or immunohistochemical changes
complex interplay of dysregulated components of both the innate present within lesional PG tissue compared with unaffected tissue,
and adaptive immune system upon a background of genetic predis- or clinical changes in response to the administration of biological
position.9 More recent hypothesis states that PG is primarily a T- agents for PG.
10
cell-mediated disease, which targets follicular adnexal structures, Bias for observational studies was assessed using the NIH qual-
or a complement pathway-mediated condition with hyperactivation ity assessment tool (Table S1). Potential sources of bias include the
of C5a,11 which would explain its correlation with other conditions small number of PG patients within studies, the variability in biopsy
including hidradenitis suppurativa. Whilst it is classified as a neu- sampling, the laboratory techniques used for staining and serum cy-
trophilic dermatosis and neutrophils predominate in the established tokine studies, and the variability in measuring the clinical response
histopathology of the disease, it is unclear whether neutrophils are of PG to biological agents. These variables were used to assess the
the primary causative cell type in the development of the disease, heterogeneity of the studies.
or otherwise a bystander in established immunological dysfunction,
which precipitates the development of PG lesions.
It has been previously documented that dysregulated neutrophil 3 | R E S U LT S
responses, Th17 immune axis activation and inflammasome activity
all contribute to the immunological dysregulation observed in PG le- The article selection process is illustrated in the PRISMA diagram
12,13
sions. However, a critical evaluation of the extant literature with presented in Figure 1. A total of 3252 nonduplicated citations were
regards to the sites of lesional biopsies, included patient variables identified from the three databases; 3193 of these citations were re-
(such as age, gender and comorbidities associated with PG) and clin- moved after reviewing their titles and abstracts, as they offered no
ical subtype is pertinent in order to dissect the potential pathways, new data or were not related to pyoderma gangrenosum. A full-text
which may be involved in the pathogenesis of PG. Additionally, more review of the 59 remaining articles was performed, and a further 20
recent insights into the complex interplay of neutrophils and TH17 articles were removed, as they provided insufficient data. The re-
immune axis with B-cell-and fibroblast/monocyte-associated path- maining 39 results were used for the basis of this systematic review.
ways may give further insight into the role of dysregulated epidermal
maintenance in the development of rapid ulceration in this disease.14
3.1 | Patients with ulcerative PG with inflammatory
bowel disease comprise the majority of participants in
2 | M E TH O D S identified studies
This systematic review is registered with PROSPERO and was con- A total of 236 patients with PG were identified, with 107 of these
ducted using the PRISMA guidelines. Information sources were re- being females (45.33%), 100 males (42.37%) and 29 with no gen-
trieved from MEDLINE (1957—14 March 2021), Embase (1957—14 der specified. The mean age of patients from the studies ranged
March 2021) and Web of Science (1957—14 March 2021). from 3.75 to 73. A total of 88 biopsies were recorded, with 64 of
these being on the legs (including the thighs, lower leg, ankle and
foot), 7 on the trunk, 5 on the abdomen, 4 on the head and neck
2.1 | Study eligibility criteria region, 3 on the back, 3 in the mouth, 1 in the perineum and 1 on
the scrotum. The clinical characteristics of the patients included in
Randomised control trials, observational studies such as cohort the analysis are presented in Table 1. The subtype of PG present
studies and case-control studies, and case studies were deemed was recorded in 177 patients, with 139 of these being the ulcera-
eligible. There were no restrictions on sex, age or ethnicity of the tive subtype (78.53%), 15 vegetative (8.47%), 7 bullous (3.95%), 7
participants included in the studies, nor was there a restriction on pustular (3.95%), 3 pyostomatitis vegetans (1.69%), 3 peristomal
language of the publication. Eligible studies were those that per- (1.69%) and 3 undetermined (1.69%). Of the 236 patients, 59 had
formed serum quantification of cytokines, gene expression studies a recorded associated underlying inflammatory disease, with 30 of
or immunohistochemistry studies on the lesional tissue of patients these being inflammatory bowel disease (50.85%), 7 rheumatoid
with diagnosed PG, or those that administered biological agents for arthritis (11.86%), 4 cystic fibrosis (6.78%), 10 with haematological
PG with an assessment of clinical response. Ineligible studies in- abnormalities (16.9%), 2 hidradenitis suppurativa, 1 SLE, 1 autoim-
cluded articles involving animals only, or those that were a review of mune enteropathy, 1 IgA nephropathy, 1 autoimmune cholangiopa-
previously published data with no new additional information. thy, 1 vasculitis and 1 with a lung carcinoid tumour. Twenty-seven
|
500 FLORA et al.
F I G U R E 1 PRISMA diagram outlining the search strategy employed in this review
patients were recorded to have PG in association with a known syn- PG, 24 with C5a in particular being purported to function through
drome; 16 of these were PASH syndrome, 5 PAPA syndrome, 3 with self-amplification of neutrophil activity. 25
Kleinfelter's syndrome, 2 Type 1 leucocyte adhesion deficiency and G-C SF has also been identified to be elevated in the serum of a
1 with PAPASH. patient with PG, which could explain increased activation and pro-
longed survival of neutrophils seen in this condition, 26 although fur-
ther mechanistic data are required. Interestingly, there have been
4 | DISCUSSION reports of patients who have developed PG after receiving G-C SF
as part of their chemotherapy treatment for malignancies, thus sup-
4.1 | Tissue transcriptomics identify porting the role of G-C SF in the pathogenesis of PG. 27,28
proneutrophilic markers including IL-8 , CXCL CXCL 1/2/3, CXCL16 and RANTES were also found to be over-
chemokines and G-C SF as major dysregulated expressed,13,15,16 enabling for neutrophil trans-endothelial migration
markers in PG. into the tissue (Table 2).
IL-8 (also known as CXCL8)13,15–19 and TNF-a13,15,16,18–23 were con-

sistently found to be overexpressed in the wound bed of PG le- 4.2 | Neutrophil extracellular traps are
sions, with the latter also being elevated in the serum of PG patients prominent in PG and may have interactions with B
(Table 2). IL-8 is a potent chemoattractant for neutrophils and, along cells and monocytes
with inflammatory effects of TNF-a, may contribute to an ongoing
neutrophil presence in PG tissue. One study identified that IL-8 Neutrophil extracellular trap (NET) formation has been demon-
was released by multiple different cell types in PG, including der- strated to be elevated in PG lesions, including those with PAPA syn-
mal fibroblasts, endothelial cells, T lymphocytes and macrophages.18 drome. 20,29 NET consists of a meshwork of chromatin fibres that are
The release of these cytokines may be mediated by overactivation embedded with various proteins and enzymes. 20 They function to
of the Fas/FasL and CD40/CD40L systems,15 which are known to trap and destroy microbes, as well as stimulating the release of other
promote apoptosis and inflammation respectively. Furthermore, an proinflammatory cytokines and causing vascular damage. 20 Patients
increased expression of genes involved in the complement pathway who had PG as part of PAPA syndrome were also found to have en-
has been identified within the perilesional dermis of patient with hanced spontaneous NET formation and reduced NET degradation
TA B L E 1 Baseline characteristics and clinical subtypes of pyoderma gangrenosum within studies
Number of PG Mean age Associated inflammatory disease, malignancy or Study

patients Male Female (years) Clinical subtype of PG Biopsy site syndrome reference
FLORA et al.
10 NR NR NR Ulcerative NR NR 10
15 7 8 48.6 NR NR Inflammatory bowel disease (2 patients) 12
Cystic fibrosis (1 patient)
Klinefelter (1 patient)
20 11 9 42 Ulcerative NR Inflammatory bowel disease (2 patients) 13
PASH syndrome (7 patients)
14 4 10 55.57 Ulcerative (11 patients) Legs (11 patients—all ulcerative) Ulcerative colitis (2 patient) 50
Peristomal (1 patient) Abdomen (2 patients—one abdominal Rheumatoid arthritis (1 patient)
Vegetative (1 patient) and one vegetative) Hepatitis C and rheumatoid arthritis (1 patient)
Atypical (1 patient) Chest/back/scalp (1 patient—atypical) Autoimmune cholangiopathy (1 patient)
Monoclonal gammopathy (1 patient)
4 3 1 21.25 NR Arm (1 patient) PAPA syndrome (all four patients) 51
Sites for other patients not recorded
16 9 7 48 Ulcerative Lower leg (11 patients) Inflammatory bowel disease (2 patients) 15
Trunk (2 patients) Cystic fibrosis (1 patient)
Scalp (1 patient) Klinefelter (1 patient)
Legs and arm (1 patient)
Legs and trunk (1 patient)
5 3 2 32.2 Ulcerative NR PASH (4 patients) 16
PAPASH (1 patient)
3 2 1 38.67 Pyostomatitis vegetans Mouth Inflammatory bowel disease (3 patients) 17
21 12 9 48 Ulcerative (11 patients) Inflammatory bowel disease (4 patients with 18
Vegetative (5 patients) ulcerative PG and 1 patient with vegetative
Bullous (5 patients) PG)
IgA myeloma (1 patient with bullous PG)
IgA monoclonal gammopathy (1 patient with
ulcerative PG)
Klinefelter syndrome (1 patient with bullous PG)
Cystic fibrosis (1 patient with vegetative PG)
13 6 7 61 NR NR Inflammatory bowel disease 21
5 1 4 44 Ulcerative (3 patients) Lower leg (2 patients) Inflammatory bowel disease (3 patients—1 patient 22
Peristomal (2 patients) Perineum (1 patient) with ulcerative PG, 2 with peristomal PG)
Peristomal (2 patients)
1 1 0 51 Ulcerative Lower legs None 23
1 0 1 66 Ulcerative Scalp Nil 26
4 NR NR NR NR NR NR 29
15 7 8 NR Ulcerative NR Nil 32
| 501
502
TA B L E 1 (Continued)
|
Number of PG Mean age Associated inflammatory disease, malignancy or Study

patients Male Female (years) Clinical subtype of PG Biopsy site syndrome reference
10 4 6 49 Ulcerative Lower leg (9 patients) Inflammatory bowel disease (3 patients) 33

Trunk (1 patient) Cystic fibrosis (1 patient)
1 0 1 37 Ulcerative Right lower leg None 40
1 0 1 73 Ulcerative Left lower leg Lung carcinoid tumour 52
2 0 2 3.75 Ulcerative NR Type 1 leucocyte adhesion deficiency 53
1 0 1 37 NR Left lower leg PASH syndrome 54
1 1 0 25 Ulcerative Lower leg PAPA syndrome 57
3 NR NR NR NR NR PASH 58
1 0 1 63 Ulcerative Lower leg Polycythaemia rubra vera 59
4 3 1 NR NR NR None 60
24 10 12 52 Ulcerative (5 patients) Thigh (14 patients) Inflammatory bowel disease (5 patients—3 61
Vegetative (9 patients) Foot/ankle (3 patients) patients with vegetative PG, 2 with pustular
Pustular (7 patients) Scalp (1 patient) PG)
Bullous (2 patients) Neck (1 patient) Essential thrombocytopaenia, monoclonal IgA (2
Undetermined (1 patient) Sternum (1 patient) patients—both with vegetative PG)
Breast (1 patient) Vasculitis (1 patient—with undetermined PG type)
Back (1 patient) IgA nephropathy (1 patient—ulcerative PG)
Hip (1 patient) Autoimmune haemolytic anaemia (1
Scrotum (1 patient) patient—vegetative)
Rheumatoid arthritis (2 patients—one ulcerative
PG, one bullous PG)
Systemic lupus erythematosus (1 patient with
ulcerative PG)
Autoimmune enteropathy (1 patient with
ulcerative PG)
Chronic lymphocytic leukaemia (1 patient)
22 10 12 56.4 Ulcerative or peristomal NR Inflammatory bowel disease (4 patients) 62
PG (PG subtype Rheumatoid arthritis (3 patients)
numbers not recorded)
5 4 1 52.2 Subtype not recorded Left breast (1 patient) None 19
Right abdomen (1 patient)
Left inguinal region (1 patient)
Right leg (1 patient)
1 1 0 56 Ulcerative Left foot None 63
FLORA et al.
TA B L E 2 Cytokine and molecular characteristics identified within PG lesional tissue or serum of PG patients
Number of PG Cytokines or
Study reference Method of assessment patients Tissue analysed Measurement method molecule analysed Fold change or score compared to healthy controls
FLORA et al.
10 Immunohistochemistry 10 Lesion scar tissue Cell counts (400× CD3 −3.03

magnification) CD4 −2.63
CD34 −2.78
CD45RO −1.78
Desmin −19.96
10 Gene expression 1 Lesional tissue Real-time PCR CXCL-9 41.6
CXCL-10 27.8
CXCL-11 59.8
IL-36G 34.3
CCL-3 7
CCL-5 3.6
GATA-3 −3.8
STAT1 9.1
STAT4 4.4
12 Immunohistochemistry 15 Lesional tissue Cell count CD4 21.89
CD25 11.33
FOXP3 10
IL-10 15
TGF-B1 8.33
CD161 31
IL-18 19.5
RORyt 14
| 503
| 504
13 Gene expression 20 Lesional tissue Next-generation IL-1B 3.64

sequencing IL-1R-1 0.57
IL-1R-2 1.56
TNF-a 0.31
sTNF-R 1.59
sTNF-R-II 1.35
IL-17 0.48
IL-17R 0.5
E-selectin 0.75
L-selectin 2.81
CXCL 1/2/3 6.32
CXCL 16 0.70
RANTES 5.76
MMP-2 1.03
MMP-9 18.34
TIMP-1 22.88
TIMP-2 2.2
IL-8 5.43
FLORA et al.
(Continues)
FLORA et al.
15 Cytokine array 16 Lesional tissue Biottin–streptavidin–Cy3 IL-1B 9.16

complex, with IL-1R1 0.84
detection through
microarray laser IL-R 2 1.45
scanner TNF-a 0.25
TNF-R1 1.13
TNF-R 2 1.17
IL-17 1.67
IL-17R 0.37
IL-8 4.14
CXCL1/2/3 3.82
CXCL16 0.96
RANTES 1.986
MMP-2 1.29
MMP-9 8.35
TIMP-1 16.9
TIMP-2 3.28
Siglec-5 11.91
Siglec-9 5.58
Fas 0.88
FasL 0.91
CD40 0.67
CD40L 1.49
| 505
TABLE 2 (Continued)
| 506
16 Homogenisation of 5 Lesional tissue Cytokine antibody array IL-1B 14.07

lesional skin with IL-1R1 1.41
addition of protease
IL-1R3 2.51
TNF-a 0.7
TNF-R1 2.1
TNF-R 2 10.94
IL-17 0.74
IL-17R 0.98
L-selectin 3.26
E-selectin 1.22
IL-8 8.27
CXCL1/2/3 10.62
CXCL16 1.7
RANTES 3.5
MMP-2 1.9
MMP-9 6.56
TIMP-1 36.50
TIMP-2 3.40
Siglec-5 24.2
Siglec-9 6.54
Fas 1.07
FasL 1.17
CD40 0.73
CD40L 2.50
FLORA et al.
(Continues)
FLORA et al.
17 Immunohistochemistry 3 Lesional tissue Cell counts (×400) CD3 2

CD4 −1
CD8 1.33
CD20 Nil
CD79A Nil
IL-6 1.33
IL-8 1.67
TNF-a Nil
18 Immunohistochemistry 21 Lesional tissue Cell counts (×400) CD3 1.29
performed, with CD163 1.57
immunoreactivity
score assigned Myeloperoxidase 2.48
TNF-a 1.81
IL-17 1.57
IL-8 2.38
MMP-2 1.90
MMP-9 2.48
VEGF 1.57
19 Gene expression 5 Lesional tissue Real-time PCR IL-1a 25
IL-1B 180
IL-6 30
IL-8 6000
IL-12 1.5
IL-36a 80
IL-36y 1
TNF-a 10
IFN-y 13
20 Fluorescence-activated 5 Serum % of low-density Low density FC: 4.67
cell sorting for granulocytes granulocytes
CD10−/+/CD14lo/ (LDG's)
CD15 cells in the
peripheral blood
mononuclear cell
fraction
| 507
TABLE 2 (Continued)
| 508
20 MPO staining and DNA 5 Serum DNA-cit-H3 levels NETs (through NET FC: 0.8
labelled with Hoechst remnants)
33342
20 N/A 9 Serum Serum concentration IL-1B 80
TNF-a 10
IFN-y 400
IL-6 40
IL-17A 10
21 Immunohistochemistry 13 Lesional tissue Skin tissue microarrays TNF-a 10.78
for cytokine NF-KB 3.24
expression
CD-68 28.4
STAT1 1.4
STAT3 1.71
Caspase-3 18.67
Caspase-9 3.74
22 Immunohistochemistry 24 Lesional tissue (nil Cell count (×100 Cytokines Number of patients (out of 20 or 24) with positive
healthy controls) magnification) –semi staining in each zone (E1, E2, E3)
quantitative E1 (Border E2 (Proliferative E3 (Stroma)
epithelium) epithelium)
MMP-1 6/24 20/24 20/24
MMP-7 0/20 4/20 4/20
MMP-8 0/24 0/24 12/24
MMP-9 7/24 2/24 23/24
MMP-10 11/24 20/24 18/24
MMP-26 10/24 0/24 0/24
TIMP-1 0/24 0/24 19/24
TIMP-3 18/20 19/20 20/20
TNF-a 3/24 2/24 23/24
23 N/A 1 Serum Serum cytokine TNF-a 1.92
concentration IL-6 62.41
26 N/A 1 Serum Serum concentration G-C SF 6.15
IL-6 128
FLORA et al.
(Continues)
FLORA et al.
29 Immunofluorescence 4 Lesional tissue % of neutrophils NETosis Score: 65.28%

for subnucleosomal undergoing NETosis
complex staining (400× magnification)
32 Immunohistochemistry 15 Lesional tissue Cell counts (400× IFN-y 29
magnification) IL-12 11.67
CXCR3 8.33
CCR5 26
IL-4 2.75
IL-5 5
IL-13 17
CCR3 32
CD40 3.8
CD40L 32
IL-15 14.33
CD56 46
33 N/A 10 Serum Flow cytometry CCR4 −0.89
CCR5 1
CCR6 1.18
25hiFoxP3 −1.9
33 N/A 10 Serum Flow cytometry Myeloid derived 7
dendritic cells
33 N/A 10 Serum Flow cytometry Myeloid:Lymphoid/ 4.69
plasmacytoid
ratio
| 509
| 510
TABLE 2 (Continued)
55 Gene expression 5 Lesional tissue Real-time PCR STAT1 2.8

changes compared to IL-1R1 2.2
nonlesional tissue
MAPK-8 2.4
IRF-3 2.3
NF-KB1 2.3
MX-1 2.3
HLA-A 2
TLR-4 2
TLR-6 1.7
CD40 1.7
CD40LG 1.2
ITGAM 1.4
IRF-7 1.2
57 N/A 1 Serum Serum concentration IL-18 415.59
64 Immunohistochemistry 4 Lesional tissue Qualitative—intensity HIF-2a N/A
of staining on VEGF N/A
microscopy
Ang-2 N/A
FLORA et al.
|
FLORA et al. 511
due to a lack of DNAse activity. 20 Interestingly, IL-1B was found to Alongside the well-established Th17 activation, this indicates the
be a cause-enhanced NET formation in PAPA patients, as blockade complex inflammatory mileu of PG and complex interactions be-
through anakinra in the serum led to reduced NET formation. 20 tween cell types, which may be at play.
Enhanced NET formation has been identified in other autoin- A study examining the T-
cell receptor repertoire within the
flammatory diseases such as hidradenitis suppurativa and rheu- serum and lesional edge of early PG in 5 patients identified oligoclo-
matoid arthritis.14 In these conditions, autoantibodies against NET nal expansion of the TCRβV receptor. Four of the 5 patients demon-
components and citrullinated proteins have been found in the strated the same TCRβV clones in both the serum and skin lesions,
sera, as well as an increase in circulating plasma cells and an ac- indicating that there is T-cell trafficking from the blood to the skin
tivation of type 1 IFN.14 It is possible that a similar B-cell inflam- in PG. 22 It should be noted that whilst a particular type of receptor,
matory response may be occurring in PG tissue, although further TCRβV20, may be present in normal skin, these four patients had
studies of NET activity within PG lesional tissue and associated oligoclonity of other TCRβV receptors such as TCRβV4.2, TCRβV27
autoantibodies are required. IL-1B was consistently elevated in and TCRβV28. 22 This suggests that the T-cell oligoclonality may be a
several studies, including in PG patients who did not present with response to some form of autoantigens within the skin that is being
13,15,16,19,20
a syndrome. This suggests that there may be overactiva- presented to the T cells by the dendritic cells. 22
tion of inflammasome complexes leading to the production IL-1B. Regulatory T cells have also been found to be reduced in PG
However, further in vitro serological studies are required to deter- when compared to T-helper 17 cells.12 This was demonstrated within
mine whether IL-1B causes enhanced NET formation in PG patients 15 PG patients, where there was a reduced IL-10/CD4 + ratio, TBF-β/
who do not have PAPA syndrome. CD4 + ratio and FOXP3/RORyT ratio within the dermis of lesions
when compared to healthy controls.12 These findings signify a de-
creased ability of the adaptive immune system in regulating the del-
4.3 | The role of fibroblasts and monocytes/ eterious T-cell inflammatory response seen in PG.
macrophages is implied through MMP and IL-15 IL-17, a key cytokine released by Th17 cells, and its receptor
upregulation, but further investigations are needed IL-17R, is also overexpressed in the lesions of PG.13,18,20 IL-17 can
induce the production of multiple proinflammatory cytokines, fur-
Metalloproteinases (MMPs) such as MMP-9 and to a lesser extent ther exacerbating the innate immune response seen in PG. It is pos-
13,15,16,18,22
MMP-2 have been found in the stroma of PG lesions. sible that IL-23 may be driving the Th17 response, although there
MMPs are synthesised by inflammatory cells such as neutrophils and are a lack of studies measuring IL-23 in PG. Another possibility is
normally function to break down the extracellular matrix to enable through local Th9 cells initially producing IL-9 in PG lesions, which
for tissue remodelling and wound repair. The ongoing overexpres- has been found to be elevated in other inflammatory skin diseases
sion of MMPs by neutrophils within PG lesions, however, is likely such as psoriasis.34 Once the Th17 response is well-established,
responsible for the prolonged ulceration that is commonly observed. Th9-mediated release of IL-9 may be downregulated through local
IL-15 has been identified as a key cytokine in enabling for wound dendritic cells producing IFN-y.35
30
repair and regeneration through the proliferation of keratinocytes.
Nonhealing chronic wounds have also been identified as having in-
creased levels of IL-15Ra levels when compared to healing chronic 4.5 | Increased activation of the complement
wounds, suggesting that the production of IL-15 may play a role in pathway identified in PG tissue represents
initiating repair.31 IL-15 and CD56 were also overexpressed in PG a novel therapeutic target
tissue compared with healthy controls.32 IL-15+ cells were found to
be particularly concentrated around the perivascular regions of the The complement pathway, particularly C5a, can activate multiple
dermis.32 IL-15 is known to cause NK cell activation and prolifera- inflammatory cells when released, including neutrophils.11 The com-
tion, which explains why CD56, a molecule located on NK cells, is plement pathway has been identified to have an increased expres-
32
also highly expressed in PG tissue. sion in inflammatory disorders such as hidradenitis suppurativa,
where it has been implicated in the formation of dermal tunnels,36
and elevated in serum proteomics.37 In PG, the complement system
4.4 | Th1, Th2 and Th17 polarisation is observed has recently been identified to have an increased expression within
in PG lesional tissue, suggesting a complex the dermis of perilesional PG when compared to healthy controls,
inflammatory mileu strongly suggesting its role in the pathophysiology of this disease. 24
Blockade of C5a through therapeutic agents such as IFX-1 could
Th1 inflammatory markers such as IL-12, IFN-y, CXCR3 and CCR4 was therefore theoretically reduce neutrophilic inflammation in PG
found to be markedly overexpressed in PG tissue,19,32,33 with Th2 and promote ulcer healing. A current phase IIa open-label study of
markers including IL-4, IL-5, IL-13 and CCR3 also overexpressed.32 Vilobelimab, 800 mg twice weekly for 12 weeks (NCT03971643),
The Th2 signals may be indicative of B-cell involvement alongside has so far showed promising results, with 6 out of 7 patients having
T-cell activation and is supported by immunohistochemical markers. clinical remission and target ulcer closure.38
|
512 FLORA et al.
F I G U R E 2 Pyoderma gangrenosum is a complex inflammatory skin disease where the follicular unit is the proposed initial target of
subclinical inflammation (Panel A). Initial inflammatory priming from underlying genetic polymorphisms, dendritic cell activation from
unknown triggers and systemic inflammation all lead to T-cell polarisation with a skew toward follicular-associated Th17 (and possibly Th9)
activity. Interactions between the follicular epithelium, infiltrating T cell, neutrophils, monocytes and the interfollicular epithelium likely
mediate proneutrophilic cytokines including CXCL1,2,3,8,16 as well as TNF-a and IL-1 production. The subsequent activation of monocyte/
macrophages to produce IL-15 result in NK-T-cell activation leading to the possibility of further inflammatory recruitment and development
of the classic undermined PG ulcer (Panel B). Established lesions demonstrate high transcriptomic levels of IL-1, CXCL1/8 IL-36 and IL-17
isoforms with NETosis, B-cell infiltrates and the presence of activated fibroblasts and monocyte/macrophages. Self-amplifying mechanisms
involving neutrophils, macrophages and B cells, common to rheumatoid arthritis and hidradenitis suppurativa are likely implicated in this
process, although direct observational evidence in PG remains to be established. Resolution of PG lesions (Panel C) results in complete
destruction of the follicular unit with activated myofibroblasts and angiogenesis producing the classic cribriform scarring seen in the disease
4.6 | The follicular unit has been hypothesised as a 4.7 | Gene expression studies confirm the
possible target for PG inflammation involvement of multiple molecular and inflammatory
pathways within PG tissue
Ulcerative PG has been hypothesised to be a T-
cell-and Th17-
mediated disease, which targets the follicular adnexal structures10 A recent study by Ortega-Loayza et al. analysed the expression of
(Figure 2). One study examining 10 patients found statistically sig- multiples genes in perilesional PG tissue compared with nonlesional
nificantly fewer CD4+ and CD34 + (fibroblast) cells within PG scars PG tissue and healthy controls using RNA sequencing.24 The study
10
compared with active PG lesions and normal skin. The complete identified a total of 5763 significantly differentially expressed genes
lack of adnexal structures, lack of undifferentiated fibroblasts on within the dermal perilesional PG tissue compared with healthy con-
histology of PG scars, along with a statistically significant decrease trols.24 It found that there was an increased expression of genes in-
in desmin when compared to normal skin and control scars found in volved in neutrophil degranulation, complement cascade molecules,
this study10 potentially explains why recurrence of PG in previous cytokine–cytokine receptor interactions and cell adhesion molecules
sites with scarring is uncommon, and in regions that lack adnexal within the dermis of PG tissue.24 There was also an increased expres-
structures, such as the palmo-plantar region.10 This also suggests sion of genes associated with myeloid cells, and in particular dendritic
that inflammatory fibroblasts may have a potential role in the patho- cells, within PG tissue, 24 suggesting that they may be a dominant im-
physiology of active PG. munological cell type involved in driving or sustaining PG lesions.
|
FLORA et al. 513
4.8 | Successful monoclonal antibody therapies in other, at a dose of 4 mg a day.46 JAK inhibitors may be effective as
PG suggest clinically relevant inflammatory targets a treatment for PG given that they target multiple cytokine recep-
in PG tors involved in PG pathogenesis such as IL-23R, IL-12R and IL-10R.
JAK-STAT inhibitors are currently being used and trialled for other
A comparison of the efficacy of various biological therapies in the autoinflammatory conditions such as psoriasis, rheumatoid arthritis
treatment of PG is difficult to perform due to a lack of a consistent and hidradenitis suppurativa, although their long-term safety is still
scoring or severity assessment tools. Many of the studies and case re- being investigated.47
ports assessed the response of PG through clinical appearance alone. A limitation of reviewing the effects of biological agents for PG,
IL-23 inhibition through guselkumab (100 mg monthly), and IL- however, is that only those studies with a positive response tend to
12/IL-23p40 inhibition through ustekinumab (45 mg, at week 0 and be published and made available, especially because many of them
4) has been demonstrated to produce complete or near-complete are case reports or case series, given the rarity of PG. The role of
healing of PG ulcers within approximately 3 months, although these JAK inhibitors as a treatment for PG is yet to be assessed, although
were both examined in only one patient each.39,40 Risankizumab, their use has theoretical benefit given that they can target cytokine
an IL-23p19 antagonist, has been shown to induce significant ulcer receptors such as IL-23R, IL-12R and IL-10R.
healing within a patient who had large ulcerative PG of the leg and
received four doses of this agent (150 mg at week 0, 4, 16 and 28).41
It also has demonstrated a moderate improvement of surrounding 4.9 | Limitations to data in this review
erythema and size of a peristomal PG in another patient who re-
ceived a single dose of risankizumab (150 mg).42 Most individuals involved in the collated studies involved “classic”
IL-17R inhibition through brodalumab (210 mg/1.5 ml either ulcerative PG of the lower limbs. This limits the external validity of
weekly or second weekly) has also demonstrated rapid resolution the discussed findings to other forms of PG including peristomal PG,
of PG ulcers in two patients, with complete healing achieved in pyodermatitis vegetans etc. until larger more comprehensive mo-
3 months by one patient, and 6 months in the other.43 The rapid and lecular characterisation of these PG subtypes can confirm or refute
sustained resolution of PG in these six cases strongly suggests that the underlying assumptions of disease homogeneity. The volume of
the Th17 axis plays a central role in the pathophysiology of PG, and studies is insufficient for exploratory analysis of whether associated
that biological agents blocking the Th17 axis represents a suitable diseases influence the inflammatory profile of PG or dysregulation of
therapeutic option. associated inflammatory molecules.
Given that IL-1B is produced by the inflammasome, and that IL-1B is Another limitation of this review is that studies using different
associated with the downstream expression of multiple inflammatory molecular platforms have been cited. Direct comparisons of cyto-
mediators such as IL-17, IL-21 and IL-22, as well as possibly inducing kine expression within PG tissue between studies may therefore not
NETosis, blockade of this cytokine may represent a suitable therapeu- be possible.
tic option. One study examining IL-1B inhibition through canakinumab
in 5 patients has demonstrated modest efficacy for PG healing, with a
mean surface area change of −8.8 cm2 over 16 weeks, and with 60% of 4.10 | Major open questions
patients having complete resolution by week 16 in one study.19
TNF-a antagonism through infliximab or etanercept has also Whilst most research has focussed upon the Th17 pathway and the
proven effective, although the time to complete resolution appears contribution of neutrophils to disease activity, ongoing questions re-
longer when compared to IL-23 or IL-17R inhibition, with complete garding the role of other cell types including B cells, macrophages
healing occurring by 12 months. 23,44 A larger study examining adali- and fibroblasts require further investigation. Tantalising hints at
mumab in 22 patients with PG demonstrated an average change of novel pathology and potential therapeutic targets exist given the
ulcer size of −63.8% from baseline to week 26, and a mean target upregulation of IL-18 in lesion tissue likely secondary to inflamma-
healing time of 114.9 days. some overactivation, as well as the involvement of components of
Apremilast, a phosphodiesterase-4 inhibitor, has demonstrated the aryl hydrocarbon receptor-mediated pathway.48,49
rapid and sustained resolution of vegetative PG lesions in a single Recent evidence in hidradenitis suppurativa and rheumatoid ar-
patient over the course of 4 months at a dose of 30 mg twice daily.45 thritis has identified cross talk between B cells, neutrophils and mac-
The inhibition of TNF-a and IL-8 through apremilast may explain why rophages through antibodies to citrullinated peptides,14 and given the
45
such a large improvement was seen, and further studies are re- relationship between these conditions and PG, investigation into the
quired to determine if it is an effective treatment option for other role of such antibodies in PG is an important area of future enquiry.
patients with PG.
The role of JAK inhibitors as a treatment option for PG is yet AC K N OW L E D G E M E N T S
to be thoroughly assessed. Baricitinib has been trialled for two pa- We acknowledge the support given by the Australian Government
tients with ulcerative PG involving the scalp and the legs, with com- Research Training Program Scholarship in the production of this sys-
plete regression seen in 5 weeks in one patient and 3 months in the tematic review.
|
514 FLORA et al.
C O N FL I C T O F I N T E R E S T immune dysregulation in hidradenitis suppurativa. Sci Transl Med.

JWF has conducted advisory work for Janssen, Boehringer-Ingelheim, 2019;11(508):eaav5908.
15. Marzano AV, Fanoni D, Antiga E, et al. Expression of cytokines,
Pfizer, Kyowa Kirin, LEO Pharma, Regeneron, Chemocentryx,
chemokines and other effector molecules in two prototypic auto-
Abbvie and UCB, participated in trials for Pfizer, UCB, Boehringer- inflammatory skin diseases, pyoderma gangrenosum and Sweet's
Ingelheim, Eli Lilly, CSL and received research support from Ortho syndrome. Clin Exp Immunol. 2014;178(1):48-56.
Dermatologics and Sun Pharma. AF and EK declare no conflicts of 16. Marzano AV, Ceccherini I, Gattorno M, et al. Association of pyo-
derma gangrenosum, acne, and suppurative hidradenitis (PASH)
interest.
shares genetic and cytokine profiles with other autoinflammatory
diseases. Medicine (Baltimore). 2014;93(27):e187.
AU T H O R C O N T R I B U T I O N S 17. Ficarra G, Baroni G, Massi D. Pyostomatitis vegetans: cellular im-
Conceptualization: JWF. Data Curation: AF JWF. Formal Analysis: mune profile and expression of IL-6, IL-8 and TNF-alpha. Head Neck
Pathol. 2010;4(1):1-9.
AF JWF. Funding Acquisition: AF JWF. Methodology: AF EKK JWF.
18. Marzano AV, Cugno M, Trevisan V, et al. Role of inflammatory cells,
Project Administration: JWF. Resources: JWF. Supervision: JWF. cytokines and matrix metalloproteinases in neutrophil-mediated
Validation: JWF AF EKK. Visualisation: JWF AF EKK. Writing- skin diseases. Clin Exp Immunol. 2010;162(1):100-107.
Original Draft: AF. Writing Review and Editing: AF EKK JWF. 19. Kolios AG, Maul JT, Meier B, et al. Canakinumab in adults with
steroid-refractory pyoderma gangrenosum. Br J Dermatol.
2015;173(5):1216-1223.
DATA AVA I L A B I L I T Y S TAT E M E N T 20. Mistry P, Carmona- Rivera C, Ombrello AK, et al. Dysregulated
Data sharing is not applicable to this article as no new data were cre- neutrophil responses and neutrophil extracellular trap for-
ated or analyzed in this study. mation and degradation in PAPA syndrome. Ann Rheum Dis.
2018;77(12):1825-1833.
21. Vavricka SR, Galvan JA, Dawson H, et al. Expression patterns of
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Pyoderma Gangrenosum A Systematic Review of The Molecular Characteristics of

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Received: 21 August 2021 | Revised: 18 January 2022 | Accepted: 30 January 2022