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\begin{document}

\title{Simultaneous occurrence of Pyoderma Gangrenosum and Palmoplantar
Pustular Psoriasis: Is it an association or coincidental findings?}



\author[1]{Pukar Chapagain}%
\author[2]{Sudha Agrawal}%
\author[2]{Punam Poudyal}%
\affil[1]{Affiliation not available}%
\affil[2]{BP Koirala Institute of Health Sciences}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
A female presented with Palmoplantar Pustular psoriasis (PPP) followed
by Pyoderma gangrenosum (PG) on bilateral legs. Complete remission was
achieved with methotrexate and prednisolone. Both dermatoses have female
preponderance, similar immuno-pathologic mechanisms and rapid treatment
response, suggests a possible etiological relation between the two and
not a coincidental finding.%
\end{abstract}%



\sloppy


\textbf{Simultaneous occurrence of Pyoderma Gangrenosum and Palmoplantar
Pustular Psoriasis: Is it an association or coincidental findings?}

A female presented with Palmoplantar Pustular psoriasis (PPP) followed
by Pyoderma gangrenosum (PG) on bilateral legs. Complete remission was
achieved with methotrexate and prednisolone. Both dermatoses have female
preponderance, similar immuno-pathologic mechanisms and rapid treatment
response, suggests a possible etiological relation between the two and
not a coincidental finding.

Keywords: Dermatology, Pyoderma gangrenosum, Plantar Pustular Psoriasis,
neutrophilic dermatosis

\textbf{INTROUCTION}

Pyoderma gangrenosum (PG) is a rare non-infectious neutrophilic
dermatosis of unknown etiology, characterized clinically by chronic and
recurrent cutaneous ulcers with a necrolytic border and is commonly
associated with underlying systemic disease. About 33-50\% of the
patients are known to have various underlying diseases such as
inflammatory bowel disease (IBD), hematological malignancies and
rheumatoid arthritis.\textsuperscript{1,2} Whereas palmoplantar
pustulosis (PPP) presents with erythematous and scaly plaques studded
with sterile pustules localized on the palms and/or soles and has a
chronic and relapsing course. It is commonly associated with psoriasis
vulgaris and or psoriatic arthritis.\textsuperscript{3}

Although the pathogenesis of PG and PPP is poorly understood, recent
studies have suggested that dysregulation of the innate immunity
involving several common cytokines such as tumor necrosis factor-a
(TNF-\selectlanguage{greek}α\selectlanguage{english}), interleukin (IL)-17 and (IL)-23 may play important role in the
development of both PG and PPP and share a common characteristic
histological feature of neutrophilic infiltration in
skin.\textsuperscript{4,5,6} Psoriasis and psoriatic arthritis have been
found to be associated in up to 10\% of PG
patients\textsuperscript{7}but the coexistence of PG and PPP in the same
patient has been reported only in 5 cases in the literature till
date\textsuperscript{8,9,10} and all were reported from Japan\textbf{.}
We report herein a female patient with PPP who developed PG on her lower
leg as a first case report other than in Japanese population and tried
to justify the coexistence of both the conditions based on the review of
the literature.

\textbf{CASE REPORT:}

A 45-year-old Nepalese female presented with 4 months history of
moderately itchy erythematous plaque on bilateral soles with few
discrete pustules and yellow brown crust. Three months after onset of
lesions, she developed multiple pustules on erythematous base over the
extensor aspect of left leg associated with moderate pain. These
pustules ruptured to form ulcers over 3-4 days and coalesced rapidly
over 1-2 weeks to forma a large ulcer of irregularly shape, undermined
edge, measuring 10\selectlanguage{ngerman}×8 cm2 and non-foul smelling scanty serous discharge
on floor and hyperpigmented surrounding skin. There was no history of
trauma prior to the onset of lesion, significant weight loss, fever,
arthralgia or gastrointestinal symptoms and was nonsmoker.

The biopsy specimen from the edge of the leg ulcer showed a hemorrhagic
ulcer adjoining an intact epidermis with large necrotizing suppurative
dermal inflammation, leukocytoclastic vasculitis within central
suppurative zone, angiocentric and intraneural lymphocyte infiltration
and uninvolved zones showed normal hair follicles and adnexal structures
surrounded by lymphocytes (Fig 1 a, b and c). Special stains were
negative for organism, tuberculous bacilli, mucin or fibrin.

Other laboratory tests, including complete blood count, liver and renal
functions, erythrocyte sedimentation rate and chest X-ray were
unremarkable. A culture from the ulcer did not demonstrates any
pathogenic organisms. A diagnosis of classical ulcerative type of
pyoderma gangrenosum with palmoplantar pustulosis was made. She was
treated with a tapering dose of oral prednisolone (50 mg/ day), and the
ulcer healed within 1 and 1/2 months to leave an atrophic scar. Then the
patient was lost to follow up.

Four months later, she developed again multiple pustules over previously
healed atrophic scar with similar progression as in the previous episode
to form a larger ulcer. On examination, an irregular shaped ulcer
approximately 7×4 cm2 was present over lower 1/3rd of dorsum of left leg
with undermined edge and hyperpigmented border with scanty serous
discharge, granulation tissue and adherent yellowish crust on the floor.
Similar smaller ulcers approximately 1-2 cm2 were present on the
periphery of larger ulcer. The ulcer was tender with mild induration of
the borders. An atrophic plaque with hyperpigmented margin was present
on the dorso-lateral aspect of leg surrounding the ulcer (Fig. 2 a and
b). Similarly, on bilateral soles, well defined erythematous plaque with
semi adherent whitish scales with multiple adherent yellow brown crust
and few pustules was present (Fig.2 c and d). Nail examination revealed
yellowish discoloration, distal onycholysis, few pits on almost all nail
plates of bilateral hands and feet with subungual hyperkeratosis of
great toes (Fig 2 e and f).

Biopsy of the erythematous plaque on right sole showed hyperkeratosis
with parakeratosis with munro's micro-abscess and psoriasiform
hyperplasia of epidermis (Fig 3 a, b and c).

laboratory tests including complete blood count, liver and renal
functions, erythrocyte sedimentation rate and chest X-ray were
unremarkable. The culture of wound swab was sterile. The patient was
admitted in the dermatology ward and was given 8 mg dexamethasone
intravenously for 5 days, which was later changed to oral prednisolone
80 mg per day along with wound care. The patient was also started on
tablet methotrexate 15mg per week. The ulcer showed rapid improvement
over 1 week with 30-40\% improvement in pain and discharge and 15 \%
improvement in the size of the ulcer (Fig. 2 g and h). The ulcer of PG
and lesions of PPP showed about 90\% improvement after 4 weeks of
treatment (Fig. 2 i and j). The dose of prednisolone was tapered weekly
10mg for 4 weeks and then every 2 weeks till 10 mg. The dose of
methotrexate was increased to 20 mg per week after 6 weeks and then
tapered to 17.5 mg/week dose which she continued for 4 weeks. The
patient was unable to come for follow up and she stopped all medicines
after 20 weeks of initiating treatment. However, she visited OPD after 9
months and was on complete remission with healed scar on the site of
previous ulcer (Fig 2 k, l m and n) with significant improvement on
nails (Fig 2 o and p).

\textbf{DISCUSSION}

Pyoderma gangrenosum is a rare inflammatory skin disorder occurring most
commonly between 20-50 years of age\textsuperscript{11} with females
comprising of 59--76\% of cases.\textsuperscript{12} PG is clinically
classified into 4 types, \emph{i.e.,} ulcerative, bullous, pustular and
vegetative types. Ulcerative PG is the most common type that is
characterized by appearance of small follicular pustules appear
initially that rapidly forms abscess and ulcerates. These ulcers enlarge
rapidly to form irregular ulcers undermined edge, raised edematous and
violaceous borders with necrotic tissues and scanty discharge on floor.
The most frequently involved site of PG is the lower legs; however, any
other sites can also be involved. \textsuperscript{11}

PG is associated with other diseases in 33--50\% of
cases.\textsuperscript{1,2} The most frequent disease associations
include Inflammatory Bowel Disease (IBD) present in 20--30\% of cases.
Rheumatoid arthritis and other seronegative arthritis's occur in about
10\% of cases, hematological malignancy or monoclonal gammopathy in
approximately 5\% and other visceral malignancies in
5\%.\textsuperscript{7,11} The association of pyoderma gangrenosum with
psoriasis and psoriatic arthritis has been found to be approximately
10\%.\textsuperscript{7}

Palmoplantar pustulosis is a chronic inflammatory dermatosis
characterized by erythematous and scaly plaques studded with sterile
pustules on the palms and/or soles. It occurs most commonly between the
ages of 30 and 50 years \textsuperscript{12}with a female predominance
ratio of 5:1.13 The associated nail changes are seen in 30-76\% of cases
of PPP. The most common finding are onycholysis, followed by pitting and
destruction of the nail. The other nail changes include scale, subungual
hyperkeratosis, subungual pustulation, indention, transverse and
longitudinal ridging, curvature abnormalities, discoloration, splinter
hemorrhage, and thickening of the nail.\textsuperscript{14} In our
patient yellowish discoloration, distal onycholysis and a few pits were
found in all most all nail plates of bilateral hands and feet and
subungual hyperkeratosis in the great toes.

Palmoplantar pustulosis is most commonly associated with psoriasis and
or psoriatic arthritis in 24-84.21\% of cases followed by autoimmune
thyroid disease in 20-40\% of cases and it is the commonest cutaneous
manifestation of SAPHO syndrome (synovitis, acne, pustulosis,
hyperostosis and osteitis).\textsuperscript{3,15} Approximately 10\% of
patients with palmoplantar pustulosis suffer from osteoarticular
symptoms, termed pustulotic arthro-osteitis (PAO), which most commonly
affects the stern costoclavicular joints, followed by the spine and
sacroiliac joints.\textsuperscript{10}

The pathogenesis of both palmoplantar pustulosis remains unclear but
they are considered as a spectrum of common disorder involving several
common cytokines such as tumor necrosis factor-a (TNF-\selectlanguage{greek}α\selectlanguage{english}), interleukin
(IL)-17 and (IL)-23 and share a common histological feature of
neutrophilic infiltration.\textsuperscript{3,4,5} Recent studies have
demonstrated that TNF-a, IL-17 and IL-23 are increased in lesional skin
of PG.4,5,6 Upregulation of TNF-a, IL-17 and IL-23 also have been
observed in PPP skin samples. In 2014, Ohtsuka and Yamamoto observed
IL-17-positive lymphocytes in both of the biopsy samples obtained from a
leg ulcer and plantar pustule.\textsuperscript{10} These findings
suggest that the T-helper (Th) 17-associated cytokines may play crucial
roles in both PG and PPP. Many patients with PG as well as PPP responded
well to biologic agents such as anti-TNF-a and anti-IL-12/23p40
antibodies.\textsuperscript{16,17}

Although association between plaque psoriasis and psoriatic arthritis is
observed, co-existence of PG and Palmoplantar pustular psoriasis (PPP)
is rarely reported in literature. Occurrence of multiple
autoinflammatory diseases simultaneously in one patient has been the
subject of several reports. This phenomenon may result from similar
etiologic pathways involved in the development of the autoinflammatory
conditions. Similarly, coexistence of PG and PPP may be implicated by
similar etiopathogenesis of both conditions. Only five cases have been
reported till date in Japanese population and our is the 6th case in the
literature and first case report from Nepal. The genetic predisposition
may influence the susceptibility of PG and PPP; however, the genetic
background of PPP is complex. There may be some ethnic association and
may be similarities between Japanese and ours case, but we were not able
to do the genetic study. Certain stimuli are required to provoke PG. In
all 5 reported cases, PPP was preceded 1month to 30 years to give rise
to the onset of PG lesion.10 In our case also, the lesions of PPP
developed 4months prior to the development of PG lesion. PPP may be a
triggering factor for PG and active lesions of PPP is needed for the
occurrence of PG. Like in our case, PPP and PG recurred after the
stopping of the oral prednisolone.

The first line of treatment of PG is systemic corticosteroids. However,
for the refractory cases, other immunosuppressive and immunomodulatory
drugs, such as cyclosporine, azathioprine, methotrexate, thalidomide,
tacrolimus, mycophenolate mofetil, and recently biologics are also used.
Methotrexate has been found to reduce the neutrophil chemotaxis,
suggesting a role for its use in pyoderma gangrenosum. However no
therapeutic standards have been established for controlling PPP. Various
treatments including methotrexate have been used to treat. The patient's
condition may be well controlled with low-dose regimen of methotrexate.
It may be effective in the treatment of nail complications, reduce the
serious adverse effects of corticosteroid, cheaper than retinoid and
azathioprine. Therefore, we gave in our patient a short duration of oral
prednisolone and maintained with the low dose of methotrexate with good
response to prevent the recurrence of the conditions and hoping to get a
good response in nail changes of PPP.

In conclusion, PG and PPP share the common pathogenesis with
histological features, common age group and female preponderance suggest
a common etiological link. Further research is required to ensure the
etiological relationship between PG and PPP.

\textbf{Acknowledgments} :

The authors would like to acknowledge Dr. Muna Bista who reviewed
manuscript for intellectual content and aided in submission of Journal.

\textbf{Conflict of interest} : none

\textbf{Funding Source} : none

\textbf{Consent statement}

Patient provided written consent for publication of this case report. It
is available upon request.

\textbf{Ethical approval} :

This case report was ethically approved by Institutional Review
Committee (IRC) of BP Koirala Institute of Health Sciences (BPKIHS).

Author's contribution:

Author 1: preparation and literature review

Author 2: Idea, concept and editing

Author 3: Histopathology reporting

\textbf{Reference:}

1. Vidal D, Puig L, Gilaberte M, Alomar A. Review of 26 cases of
classical pyoderma gangrenosum: clinical and therapeutic features. J
Dermatol Treat 2004;15(3):146--152

2. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma
gangrenosum: a comprehensive review. Am J Clin Dermatol 2012; 13:
191--211.

3. Misiak-Galazka M, Wolska H, Galazka A, Kwiek B, Rudnicka L. General
characteristics and comorbidities in patients with palmoplantar
pustulosis. Acta Dermatovenerol Croat. 2018;26(2):109--18

4. Marzano AV, Cugno M, Trevisan V et al. Role of inflammatory cells,
cytokines and matrix metalloproteinases in neutrophil-mediated skin
diseases. Clin Exp Immunol 2010; 162: 100--107.

5. Guenova E, Teske A, Fehrenbacher B et al. Interleukin 23 expression
in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch
Dermatol 2011; 147: 1203--1205.

6. Murakami M, Hagforsen E, Morhenn V, Ishida-Yamamoto A, Iizuka H.
Patients with palmoplantar pustulosis have increased IL-17 and IL-22
levels both in the lesion and serum. Exp Dermatol 2011; 20: 845--847.

7. Binus AM, Qureshi AA, Li VW, Winterfield LS. Pyoderma gangrenosum: a
retrospective review of patient characteristics, comorbidities and
therapy in 103 patients. Br J Dermatol 2011; 165:1244--1250.

8. Kameyama H, Akagane Y, Kawada A, Tezuka T. A case of palmoplantar
pustulosis associated with pyoderma gangrenosum. Hifunokagaku 2003; 2:
526--531.

9. Ogasawara K. Pyoderma gangrenosum associated with palmoplantar
pustulosis (original title in Japanese). Nihon Rinsho Hifuka Ikai Zasshi
2006; 23: 136--138

10. Ohtsuka M and Yamamoto T. Association of pyoderma gangrenosum and
palmoplantar pustulosis: A case report and review of the previous works.
Journal of Dermatology 2014; 41: 732--735

11. Langan SM, Groves RW, Card TR, Gulliford MC. Incidence, mortality,
and disease associations of pyoderma gangrenosum in the United Kingdom:
a retrospective cohort study. J Invest Dermatol 2012; 132:2166--70

12. Eriksson MO, Hagforsen E, Lundin IP, Michaelsson G. Palmoplantar
pustulosis: a clinical and immunohistological study. Br J Dermatol 1998;
138:390--8.

13. Burden AD, Kemmett D. The spectrum of nail involvement in
palmoplantar pustulosis. Br J Dermatol 1996;134;1079--82.

14. Hiraiwa T, Yamamoto T. Nail involvement associated with palmoplantar
pustulosis. Int J Dermatol. 2017;56(2): e28--9

15. Nguyen MT, Borchers A, Selmi C, et al. The SAPHO syndrome. Semin
Arthritis Rheum 2012; 42:254--65

16. Miller J, Yentzer BA, Clark A, Jorizzo JL, Feldman SR. Pyoderma
gangrenosum: a review and update on new therapies. J Am Acad Dermatol
2010; 62: 646--654.

17. Gerdes S, Franke J, Domm S, Mrowietz U. Ustekinumab in the treatment
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Figures:

Figure 1(a) (10X) H \& E stain showing hemorrhagic ulcer (black arrows)
adjoining an intact epidermis with large necrotizing suppurative dermal
inflammation (white arrows) (b) (40X) H \& E stain showing dense
neutrophilic infiltrate in the dermis with extravasation of Red blood
cells (c) (40X) H \& E stain (red arrows) showing endothelial swelling
with neutrophilic infiltration of blood vessel wall

Figure 2 (a and b) showing irregular undermined ulcer with atrophic
plaque on dorsum of left foot, (c and d) erythematous plaque with yellow
brown crust, (e and f) onycholysis and subungual hyperkeratosis, (g and
h) 1 week after starting treatment, (I and j) 4 weeks after starting
treatment and (m, n, o and p) 9 months after stopping the treatment

Figure 3(a) (10X) H \& E stain showing hyperkeratosis with parakeratosis
with munro's micro abscess (black arrows) with hypogranular layer (white
arrow) with psoriasiform hyperplasia of epidermis (red arrow) (b) (10X)
H \& E stain showing munro microabscess with underlying hypogranular
layer (c) 100X magnification showing neutrophil and neutrophilic dusts
in stratum corneum (munro microabsess)\selectlanguage{english}
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