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LETTER TO THE EDITOR

On the basis of the literature review and personal experience,

Systematic review of surgical we developed a surgical treatment algorithm with proposed
treatment of pyoderma immunosuppressive and adjuvant measures shown in Fig. 1.
The basic immunosuppression consists of CS. As a second step,
gangrenosum with negative
we prefer dapsone as anti-inflammatory steroid sparing agent
pressure wound therapy or skin over cyclosporine, as it does not affect renal function or blood
pressure and for its well-known additional antimicrobial proper-
grafting
ties.6 Indeed, mortality rates from 11% to 17% have been
Editor reported for PG and were mostly related to sepsis3,7 and septical
Pyoderma gangrenosum (PG) is a rare autoinflammatory complications were the cause of death in the two deceased
ulcerative skin disease.1 Fewer than 50% of the patients patients from the literature review.3,8 As a third step, if neces-
achieve wound healing after 6 months of immunosuppressive sary, the anti-TNF-alpha antibody infliximab is used as the sole
therapy and relapses occur in 30% to 60% of the cases.2,3 biologic with a positive randomized, double-blinded, placebo-
Progression of existing lesions or development of new controlled trial for PG. We further suggest the use of pentoxy-
lesions after surgery or minor trauma is reported in up to phylline as adjuvant treatment for its known rheologic,
30% of PG patients (pathergy phenomenon).3,4 Therefore, immunomodulatory and anti-TNF-alpha activities. Indeed, it is
the role of surgical interventions such as split thickness skin advised by a Cochrane review for leg ulcers and also successfully
grafting (STSG) and negative pressure wound therapy used in other diseases with neutrophil dysfunction like oral aph-
(NPWT) is controversially discussed, as these procedures thous ulcers or Behcßet’s disease.9 Another drug with anti-inflam-
might pose a trigger and further aggravate the condition, matory activity and positive effects on wound healing
especially if performed without immunosuppression.5 A demonstrated recently in a blinded, randomized clinical trial is
broad search of the PubMed, Medline, EBSCO Biomedical simvastatin.10 The adjuvant use of prostaglandins (iloprost) is
Reference Collection and Cochrane databases was performed suggested to facilitate skin grafting.11 Its positive effects on
and a total of 61 relevant articles describing 94 patients inflammation, ischaemic, but also venous leg ulcers are well
could be retrieved and complemented with our personal known.12
multicentre experience of 21 patients (see Table 1). A total This first comprehensive review of surgical treatment for PG
of 115 patients with PG (69% females, median age 53) were confirms that NPWT and STSG comprises a valuable and safe
identified. Ulcers were mainly situated on the lower extremi- treatment option for PG if performed under adequate immuno-
ties (n = 90; 78%), followed by breasts (n = 11; 10%), abdo- suppressive therapy. A paradigm change in the treatment of PG
men (n = 7; 6%) and other localizations (12; 10%). Surgical towards surgical approaches with STSG is suggested as this
treatment consisted of split thickness skin grafts (STSG) approach significantly accelerates healing time. A sustained
alone (n = 53; 46%), STSG together with NPWT (n = 35; immunosuppressive treatment with slow tapering and follow-up
30%), NPWT alone (12; 10%) or other forms of skin graft- is suggested to avoid or manage recurrences as fast as possible.
ing (cultured cells, suction blisters, full thickness skin grafts,
pinch grafts n = 15, 13%). Systemic immunosuppression M. Pichler,1 T. Thuile,1 B. Gatscher,1 L. Tappeiner,1
consisted mainly of systemic corticosteroids (n = 107; 93%), J. Deluca,1 L. Larcher,2 M. Holzer,3 V.A. Nguyen,3 G. Exler,4
supplemented with cyclosporine (21; 19%), dapsone (12; M. Schmuth,3 G.F. Klein,4 K. Eisendle1,5,*
1
9%), TNF-alpha antibodies (11; 9%), mycophenolate mofetil Department of Dermatology, Venereology and Allergology, Academic
Teaching Department of Medical University Innsbruck, Central Teaching
(9; 8%), azathioprine (7, 6%) and others used in less than
Hospital Bolzano/Bozen, Bolzano/Bozen, Italy, 2Department of Plastic,
five patients. Treatment was successful in 84 cases (73%), 18
Aesthetic and Reconstructive Surgery, Hospital of St. John of God
patients healed but had a recurrence (16%), eight improved
Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria,
(7%), treatment failed in three patients and two patients 3
University Department of Dermatology and Venereology, Medical
died due to sepsis. The lower relapse rates observed in this University Innsbruck, Innsbruck, Austria, 4Department of Dermatology,
review is probably due to the short follow-up in the many Hospital of Elisabethinen, Linz, Austria, 5College of Health Care
single patients reported. No case of pathergy was observed, Professions, Bolzano/Bozen, Italy
neither at the side of PG nor at the skin graft donor sites. *Correspondence: K. Eisendle. E-mail: [email protected]

JEADV 2016 © 2016 European Academy of Dermatology and Venereology

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Table 1 All reports published in the literature so far of surgical treatment of pyoderma gangrenosum (PG) with skin graft or negative wound pressure therapy. Author, publication
year, number of patients treated with NPWT or skin grafting, age, gender, localization of PG, procedures performed, systemic treatment and outcome are reported

Author, year P Age, sex Localization Procedural Systemic treatment Outcome

JEADV 2016
interventions
Ridenhour G et al., Ann Surg 1968 1 62 M Left elbow, both lower legs STSG CS, topical aqueous silver nitrate Successful graft, healed without
recurrence
McGarity WC et al., Dis Colon 1 53 F Abdominal wall STSG CS Successful graft, healed without
Rectum 1977 recurrence
Davis JC et al., Plast Reconstr Surg 4 64 M Legs (lower) 4, elbow 1 STSG (4), HBO CS (4), in 3 CS were tapered under Successful graft, healed without
1987 62 F (4) HBO and inactive PG grafted without recurrence
17 F
22 F
Gerard A et al., Ann Med Interne 1 41 M Left hand STSG CS, plasma exchange Successful graft, healed without
(Paris) 1988 recurrence
Dean SJ et al., Ann Plast Surg 1991 1 71 F Leg (ankle) Cultured CS Successful, healed without
epithelial recurrence
autografts
 M et al., J Dermatol Surg
Lımova 1 44 F Leg (dorsal food) Cultured CS systemic + intralesional 95% graft take, healed without
Oncol 1994 keratinocyte recurrence
autografts
Maier H et al., Hautarzt 1995 1 34 F Leg STSG CS, CyA Successful graft, healed without
recurrence
Vereecken P et al., Dermatology 1 87 F Leg (right tibia): STSG Lymecycline, topical benzoyl Successful graft, healed without
1997 peroxide recurrence
Michel S et al., Hautarzt 1998 1 68 F Leg (calves): STSG CS, CyA, MMF Successful graft, healed without
recurrence
Havlik RJ et al., Plast Reconstr Surg 1 15 F Breast STSG CS Successful graft, healed without
1998 recurrence
Cliff S et al., Dermatol Surg 1999 4 66 M Legs (lower) 2, left tight 1, STSG (4) 1 without immunosuppression One failed with exacerbation (Patient
36 F abdomen 1 (unknown PG), CS (3) without immunosuppression), three
28 F healed with no recurrence
68 F
Rozen SM et al., Ann Plast Surg 3 61 F Legs (all lower) STSG (3), rectus CS (3) + AZA/Daps/Mesalamine 1; Successful graft in all, one minor
2001 73 F abdominis flap (1) +AZA/MMF/Tacrolimus 1 recurrence after 3 months managed
46 M conservatively
Kaddoura IL et al., Ann Plast Surg 3 13 F 15M 56 M Legs (right lower leg 4 ulcers, STSG (3) CS (3) Successful in all, one small
2001 left lower leg 2 ulcers) recurrence managed conservatively
with systemic corticosteroids
de Imus G et al., J Am Acad 1 26 F Leg Allogeneic CS, CyA Successful, healed without
Dermatol 2001 cultured human recurrence
skin equivalent
(Graftiskin)
Letter to the Editor

© 2016 European Academy of Dermatology and Venereology

 Table 1 Continued

Author, year P Age, sex Localization Procedural Systemic treatment Outcome

interventions

JEADV 2016
Gilmour E et al., Br J Dermatol 2001 1 16 M Leg Cultured CS, CyA, MMF Healed after 7 months, no
epidermis recurrence after 10 months
unsuccessful
Letter to the Editor

followed by
NPWT and
delayed STSG
Lifchez et al., Ann Plast Surg 2002 1 40 F Breasts STSG CS Successful graft, healed without
recurrence
Zakhireh M et al., Plast and Reconstr 3 64 F, 60 F, 30 F Legs (lower) STSG (3) CS (3) with CyA (2) one with Successful graft take, healed without
Surg 2004 additional MTX recurrence
Geller SM et al. 2005 1 82 F Leg (lower) NPWT CS Halted the inflammatory process,
healing after 7 months
Niezgoda et al., J Am Podiatr Med 1 46 M Leg (left, tibia) NPWT, STSG, CS Successful graft, healed without
Assoc 2006 HBO recurrence
Keskin M et al., Ann Plast Surg 2006 1 9M Legs (lower) STSG CS Successful graft, healed without
recurrence
Ghersi MM et al., Arch Dermatol 1 57 F Leg (lower left) controlled NPWT None, previous CS, IVIG, MMF, Healed without recurrence after
2007 and slow-healing PG cyclophosphamide 6 weeks
Zutt M et al., Dermatology 2007 1 50 F Legs (right: lower leg and NPWT and CS, AZA, CyA, Daps, MMF, Iloprost Successful graft, healed without
dorsal foot) STSG recurrence
Hoff NP et al., Hautarzt 2008 1 53 M Both lower legs STSG CS, topical tacrolimus Successful graft, healed without
recurrence
Kim DW et al., Ann Plast Surg 2008 1 47 F Legs (left calf) STSG CS, CyA Successful graft, healed without
recurrence
Toyozawa S et al., Dermatol Online 1 69 F Legs STSG CS Successful graft, healed without
J 2008 recurrence
Descheemaeker V et al., J Gynecol 1 31 F Breast NPWT and STSG CS Successful graft, healed without
Obstet Biol Reprod (Paris) 2008 recurrence
Procianoy F et al., Arg Bras Oftalmol 1 19 F Eyelid FTSG CS, Daps Successful graft, healed without
2009 recurrence
Rajapakse Y et al., J Plast Reconstr 1 50 F Breasts NPWT CS Successful graft, healed without
Aesthet Surg 2010 recurrence
Wollina U et al., J Eur Acad Dermatol 1 50 F Both lower legs Hyaluronic acid CS, MMF One ulcer healed, second ulcer 60%;
Venereol 2010 derivate recurred shortly thereafter
(Hyalogran)
followed by
grafting of
autologous
cultured
keratinocytes
Schintler MV et al., Plast Reconstr 1 45 F Breasts NPWT (instil) and CS, CyA, IGIV Successful graft, healed without
Aesthetic Surg 2010 free flap recurrence
3

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Table 1 Continued

Author, year P Age, sex Localization Procedural Systemic treatment Outcome

interventions

JEADV 2016
Lamet S et al., Acta Clin Belg 2010 1 44 F Legs STSG CS Graft at first successful, then
relapsed
Schoemann MB et al., Ann Plast 1 50 F Abdomen STSG CS Successful graft, healed without
Surg 2010 recurrence
Melson MR et al., Ophtal Plast 1 41 F Eyelids FTSG CS Successful, recurred after 6 months
Reconstr Surg 2010
Kikuchi N et al., Int J Dermatol 2010 1 28 F Abdomen STSG CS Successful graft, healed without
recurrence
Goshtasby PG et al., Aesthet Surg J 1 49 F Breasts Integra, STSG CS, Infxmb, MTX Successful graft, healed without
2010 recurrence
Andreev Dlu, Vestn Khir Im I I Grek 1 30 F Legs STSG CS Successful graft, healed without
2011 recurrence
Hafner J et al., Dermatology 2006 1 64 F Lower Leg Cultured CS, CyA, AZA Successful but recurred within
autologous 6 weeks
epidermis
Mandal A et al., Eur J Plast Surg 3 72 F Leg (right knee) 2, thighs and NPWT (3) and CS (3), and CyA (1) Successful flap (1), partial rejection
2006 17 M groin 1 STSG (2) and at the STSG borders healed
45 F gastrocnemius conservatively (1), improvement with
muscle flap (1) NPWT healed within 6 months; no
recurrences
Lambropoulos V et al., Int J Surg 1 13 F Leg (left ankle) and left arm NPWT, cultured CS, CyA 90% graft take, no complete healing
Case Rep 2011 autologous after 6 months
keratinocytes
(Epicelâ)
Hill DS et al., Plast Reconstr 1 63 F Leg (after knee arthroplasty) NPWT, muscle First none, CS after diagnosis NPWT ineffective without
Aesthetic Surg 2011 flap with STSG, immunosuppression, flap and graft
HBO failure secondary to sepsis,
prolonged course healed eventually
with HBO, no recurrence
Ga
miz RC et al., Ugeskr Laeger 1 58 F Both legs NPWT and CS Successful graft, healed without
2011 STSG recurrence
Saracino A et al., Australas J 2 Not specified Legs Pinch graft (1), CS (2) Successful graft, no recurrence
Dermatol. 2011 (series of 26 STSG (1)
mean age
61.5, 65%F)
Fraccalvieri M et al., Int Wound J 4 53 M Legs (lower) 3, Breasts 1 NPWT (4) CS (4), CyA (4), Daps (1), IGIV (1), Marked pain reduction, good
2012 59 F cyclophosphamide (1) granulation tissue, no healing
72 F reported
45 F
Sick I et al., Hautarzt 2012 3 62 F Legs STSG (3) and CS/AZA (1), CS/CyA (1), MMF/IVIG Successful/one recurrence at a
70 F NPWT (1) (1), topical tacrolimus and clobetasol different location
44 M (3)
Letter to the Editor

© 2016 European Academy of Dermatology and Venereology

 Table 1 Continued

Author, year P Age, sex Localization Procedural Systemic treatment Outcome

interventions

JEADV 2016
Neiderer K et al., Ostomy Wound 1 76 M Leg (anterior left) NPWT, CS Healed within 6 weeks
Manage 2012 bioengineered
skin substitute
Letter to the Editor

generated from
neonatal foreskin
(Apligraf)
Kolios L et al., Handchir Mikrochir 1 47 F Breasts STSG CS Successful graft, healed without
Plast Chir 2012 recurrence
Cubero CC et al., Reumatol Clin 1 33 M Leg (right ankle) STSG CS, Infxmb Successful graft, healed without
2012 recurrence
Das SK et al., JNMA J Nepal Med 1 53 F Legs, right groin STSG CS Successful graft, healed without
Assoc 2012 recurrence
Andrisani G et al., J Crohns Colitis 1 76 M Left Breast STSG CS, Infxmb Successful graft, healed without
2013 recurrence
Arau
jo FM et al., Ann Bras Dermatol 1 50 M Leg (left) STSG, HBO CS, AZA Over 90% graft take, healed without
2013 recurrence
Cabalag MS et al., Ann Plast Surg. 3 Not specified Legs STSG (3) with CS (3), CyA (1) Successful graft (3), healed (1),
2013 (series of 29, HBO (2) improved (2), died due to sepsis:
59%F, mean perforated sigmoid diverticular
age 71) abscess (1)
Mowlds DS et al., Can J Plast Surg 1 61 F Right Hand STSG and Local acetic acid, no Healed, second PG at the left hand
2013 NPWT and HBO immunosuppression (PG diagnosed
later)
Lee HS et al., J Foot Ankle Surg 1 47 F Legs (left foot) STSG CS Successful graft, healed without
2013 recurrence
Mooij JE et al., Int J of Dermatol 2 Not specified Legs STSG (2) CS (2), Infxmb (2) Successful graft, healed without
2013 (series of 6 recurrence
mean age
49, 83%F)
Fakhar F et al., BMJ Case Rep 2013 1 41 F Breasts (PG after III° burn) STSG, NPWT CS Not successful, eventually healed
after breast under prednisolone, mycophenolate
amputation mofetil and adalimumab
Aydin S et al., J Obstet Gynaecol 1 32 F Abdomen (after caesarian NPWT and CS, AZA Successful graft, healed without
Res 2014 delivery) STSG recurrence
Ye MJ et al., Dermatol Res Pract 2 51 F, 89 F Lower leg (1); abdomen, left STSG (2), CS (2), MMF (1) >90% graft take, healed without
2014 tights, sacral (1) primary closure recurrence
sacral
Stair-Buchmann ME et al., J burn 6 Not specified Legs (lower) NPWT and CS (6), plus Daps (1), Infxmb (1) Three closed (NPWT&STSG 1,
Care Res 2014 (series of 7: STSG (4), STSG STSG 1), one died due to sepsis
29%F, mean (1), NPWT (1) (NPWT&STSG), two lost to follow-up
age 65)
5

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JEADV 2016
Table 1 Continued

Author, year P Age, sex Localization Procedural Systemic treatment Outcome

interventions
Richmond N et al., JAMA Dermatol. 5 40 F, 50 M, Legs (lower 4, upper 1) Epidermal CS (3) with CyA (1); CyA (2) with All successful, three healed within
2014 50 F, 30 F, Grafting with MMF (1) 3 months, two marked ulcer size
80 M suction blister– reduction
harvesting
system 5
(Cellutome)
Tay DZ et al., J Family Med Prim 1 58 F Legs (lower) STSG Sulfasalazine, topical Successful, healed within 3 months
Care. 2014 betamethasone
Ishikawa K et al., J Wound Ostomy 1 69 M Abdomen (peristomal) NPWT and None Successful graft, healed without
Continence Nurs 2015 STSG recurrence
Personal experience Deluca J et al. 21 Mean age 62, Legs (19), Breast (1), Occipital (1) NPWT and CS (21), Daps (10), Infxmb (4), Completely healed: 16 (76%), with
J Eur Acad Dermatol Venereol 2015, 67%F STSG (17), Adalimumab (1), MTX (2), IVIG (2), primary healing without recurrence
Larcher L et al., Aesthetic Plast (14F, 7M) STSG (1), NPWT MMF (1), HQ (1), Ptxph (5), Iloprost after first treatment cycle in 14 (67%),
Surg. 2015, Pichler M et al., J Am (2) (4), Simvastatin (4) two patients healed after recurrences
Acad Dermatol, 2016 treated with a second cycle. Over
90% improvement: 3 (14%). Two
patients still with larger ulcers (10%):
one had healed but recurred two
times, one never improved more than
30%. Recurrences observed: 7
(33%),four single, three with two or
more.
Total 115 69%F, mean Legs (90; 78%) STSG (53; 46%), CS (107; 93%), CyA (21; 18%), Daps Healed without recurrence (84; 73%);
age 53 (median Breast (11; 10%) NPWT alone (12; (12; 9%), Infxmb (10; 9%), MMF (9; improved (8, 7%); healed but
53, range 9-89, Abdomen (7; 6%) 10%). 8%), AZA (7; 6%), others used <5 recurred (18; 16%, three of them at a
SD 19)* Other localizations (12; 10%) STSG+NPWT patients different localization); failed (3; 3%
(35; 30%), Other including two without
(cultured cells, immunosuppression), died due to
suction blister, sepsis (2; 2%)
FTSG, pinch
graft 15; 13%)

*In the case of series, where exact data on age and gender were missing (Nr. 42, 51, 54, 58) given mean age was utilized and the corresponding sex percentage.
AZA, azathioprine; CS, corticosteroids; CyA, cyclosporine; Daps, dapsone; FTSG, full thickness skin graft; HBO, hyperbaric oxygen; Infxmb, infliximab; IVIG, intravenous immunoglobulins; MMF,
mycophenolate mofetil; MTX, methotrexate; NPWT, negative pressure wound therapy; P, Patients; PG, pyoderma gangrenosum; Ptxph, pentoxyphylline; SD, standard deviation; STSG, split thickness
skin graft.
Letter to the Editor

© 2016 European Academy of Dermatology and Venereology

Letter to the Editor 7

step 4 Add or change to others3

Immuno- step 3 Add infliximab 5 mg/kg at week 0 / 2 / 8

suppressive
step 2 Add dapsone 50-200 mg/day 4
ladder

step 1 Systemic corticosteroids (methylprednisolone 0.5-1 mg/kg/day)

NPWT1 followed by STSG2 secured by NPWT

Surgery
Antibiotic prophylaxis - to prevent graft infection/rejection and
thrombosis prophylaxis with low molecular weight heparin

Pentoxyphylline 400 mg bid

Adjuvant
Simvastatin 40 mg/day
treatment
Iloprost after STSG2 to improve graft take

Basic High caloric and protein rich diet

exclude other diagnoses / seek and treat underlying disease
measures

(1) NPWT: negative pressure wound therapy

Figure 1 Proposed treatment algorithm for (2) STSG: split thickness skin graft
PG with basic measures, surgical (3) Cyclosporine, mycophenolate mofetil, methotrexate, intravenous immunoglobulins, other TNF
procedures, possible adjuvant treatment alpha blockers, IL 12/23 blockers, IL-17 blockers or combinations eg: cyclosporine +
and a proposed immunosuppressive mycophenolate mofetil
(4) Check for glucose-6-phosphate dehydrogenase deficiency before commencing, combination
treatment ladder. with 500mg ascorbic acid (vitamin C) bid. reduces methemoglobinemia.

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Immunol 2014; 178: 48–56. managed in a burn treatment center. J burn Care Res 2015; 36: e190-3.
2 Ormerod AD, Thomas KS, Craig FE et al. Comparison of the two most 9 Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg
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JEADV 2016 © 2016 European Academy of Dermatology and Venereology