Pyoderma gangraenosum L88

Brocq, 1916; Brunsting & Goeckermann, 1930

Rare, solitary or multiple, chronic progressive, painful, often crossing the borders of the skin organ to the deep, polycyclic, destructive, sterile neutrophilic autoinflammatory dermatitis/panniculitis of unexplained etiology and pathogenesis. The disease is characterized by marked resistance to therapy.

A distinction is made according to clinic and histology (var. n. Powell 1996):

• Ulcerative form (classic and most common type): rapidly deep - or area-progressive, purulent-serous ulceration with undermined, livid-red margins. Associated arthritides, inflammatory bowel disease, monoclonal gammopathies.
• Pustular form: 0.2-0.8 cm pustules initially sieve through a larger inflammatory plaque. By confluence, the pus foci join to form a smeary purulent ulcerative conglomerate(this constellation is largely identical to the finding described as vegetating pyoderma). Commonly associated inflammatory bowel disease.
• Bullous form: Subepidermal blistering with inflammatory rim that erodes or ulcerates.
• Vegetating superficial granulomatous form: superficial usually solitary ulcer without undermined rim, often in surgical scars.
• Peristomal form: ulcerating, painful papules or plaques around stomas. Evolving to the typical ulcerative form with undermined margins.
• Mucosal type = pyostomatitis vegetans: this very rare, chronic ulcerative clinical picture of the oral mucosa is considered by some authors to be a (mucosal) variant of pyoderma gangraenosum.

The disease is observed worldwide. The incidence is not precisely determined. Estimates are 0.3-1.0/100,000 inhabitants/year.

Occurs in ulcerative colitis (in approx. 5% of cases), Crohn's disease (in approx. 1% of cases), rheumatoid arthritis and in the context of injuries.

The etiology is not known for certain. Some patients cite minor trauma, insect bites or surgical procedures as triggering events.

A malfunction of the neutrophil granulocytes is discussed. More recent findings point to a causal relationship between an abnormal T-cell response with consecutive increased release of TNF-alpha. This could explain the therapeutic effect of TNF-alpha inhibitors. Associated in varying prevalence are various systemic diseases (Jockenhöfer 2016) such as: chronic inflammatory bowel disease (8.7%), rheumatoid arthritis (5.7%), hematological diseases (4.0%) such as: multiple myeloma, lymphoma, plasmocytic, IgA deficiency, congenital, myeloproliferative diseases(myeloid leukemia, hairy cell leukemia, myelofibrosis, Hodgkin, M., polycythemia vera , monoclonal gammopathies). In almost all patients, partial aspects of the metabolic syndrome can be detected: arterial hypertension (50.3%), diabetes mellitus (25.1%), lipid metabolism disorders (10.8%).

The association with ulcerative colitis has decreased in frequency over the years(1957: 60%; 1981: 17%); reports of associations with hematologic diseases are increasing.

Rarer associations are: HIV infection, chronic active hepatitis, primary biliary cirrhosis, Behçet's disease, SLE, Wegener's granulomatosis, hidradenitis suppurativa.

Pyoderma gangraenosum in association with monogenic autoinflammatory syndromes:

• PAPASH (mutations in the PSTPIP1 gene)(psoriatic arthritis-pyoderma gangraenosusm-acne-hidradenitis suppurativa): aberrant splice variants of the PSTPIP1 transcript with deletions of exons 9, 11 and 12 as well as exons 9-12 have been demonstrated (Nesterovitch AB et al. 2011). The disease-causing mutations are thought to impair the physiological signaling required to maintain an adequate inflammatory response.
• NFKB1-associated familial autoinflammatory pyoderma gangraenosum (see below NFKB1-associated sterile familial autoinflammatory necrotizing fasciitis), which is associated with an LOF mutation R157X in the NFKB1 gene, is known from a few casuistic reports (Bergbreiter A et al.2021).
• PASH synd rome: Pyoderma gangraenosum, acne, hidradenitis suppurativa (PSTIP1 gene, IL1RN, NOD2, NLRP3)
• PAS syndrome: Pyoderma gangraenosum, acne, hidradenitis suppurativa, seropositive spondyloarthropathy/genetic defect as yet unknown)

In summary, pyoderma gangraenosum presents with a complex reaction pattern that is characterized by a clinically typical symptomatology due to dysregulation of different metabolic and signalling pathways. It is therefore an indicative, ulcerative disease that should give rise to a subtle internal examination of the affected person.

Mainly located on the lower extremities, less frequently on the trunk, neck and head.

Single or multiple highly inflammatory skin lesions consisting primarily of blisters, pustules, papules, flat nodules or plaques, which are already initially very painful. These often occur after minor traumas (insect bites, minor injuries). Within a few days, flat ulcerations develop, initially flat, but over the course of a few weeks deep-reaching ulcerations that extend beyond the skin organ (subcutis, possibly affecting muscles and tendon beds). Apposition and progression along the edges leads to permanent enlargement. Characteristic and thus of diagnostic importance is an extremely painful marginal zone with a wavy, dark red or even grey, undermined hem. Special form: Postoperative progressive gangrene. A pathergy phenomenon is detectable after trauma.

Initially the picture of a superficial and deep neutrophilic follicular or perifollicular dermatitis is shown. Leukocytoclasia may occur. In a later stage, superficial dermal neutrophil abscesses with ulceration appear. In the ulcer area the epidermis is laterally elevated. Dense infiltrate at the base of the ulcer, consisting of neutrophils, lymphocytes, plasma cells, histiocytes and giant foreign body cells. Hyperergic vasculitis may be present.

The diagnosis is considered confirmed when both major criteria and at least 2 minor criteria are met.

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The Paracelsus score described by Jockenhöfer et al in 2019 is intended to facilitate diagnosis. This score includes 10 features

Two major criteria represent the rapid disease process present in 98% of pyoderma gangraenosum patients, as well as the red-purple wound margin. Secondary criteria include response to immunosuppressants in 61-95% of patients, extreme painfulness, irregular ulceration shape, localization after trauma, additional criteria include purulent inflammation seen histopathologically in 61% of patients, undermined wound edges, and concomitant systemic diseases. The major criteria are each scored with 3 points, the minor criteria with 2 points, and the additional criteria with 1 point. A score of 10 or more indicates a high probability of pyoderma gangraenosum.

• A diagnosis of pyoderma gangraenosum is particularly likely if the ulcers worsen after debridement.

• Clinical:
  • Ecthyma: Ulcers of varying depth, usually max.1 cm in diameter, with sharply cut edges and smeary purulent coatings (as if punched out). Possible lymphangitis and -adenitis. No concomitant systemic disease.
  • Erysipelas (necrotizing): Acute onset with fever, painful swelling and redness, and extensive ulceration. ASL is markedly elevated.
  • Necrotizing vasculitis: Acute onset. Clinical picture of "palpable purpura" is usually detectable. Histological picture of leukocytoclastic vasculitis is regularly detectable. Furthermore formation of hemorrhagic plaques, erosions or extensive painful ulcers.
  • Livedovasculopathy: Always a livedo picture with stabbing permanent pain is detectable (it is not the livedo picture but the stabbing permanent pain that leads to the doctor!), usually localized in the ankle region.
  • Ulcus cruris arteriosum: V.a. localized at toes, foot edge, heels or extensor sides of the lower leg. Almost always an arterial occlusive disease is detectable. The ulcers are painful and sharply demarcated. Serological signs of inflammation are absent. Ulcer pain is improved with lowering of the extremity.
  • Ulcus cruris venosum: Mostly chronic ulcer localized in loco typico (splitter area of the ankles), of variable size and depth in inflamed, often indurated and hyperpigmented skin as a sign of chronic venous insufficiency. Pain in the ulcer may be persistently severe; it diminishes after elevation.
  • Necrobiosis lipoidica (necrotizing form): Chronic stationary disease, usually lasting for years. Frequently diabetes mellitus. Localization: extensor side of lower legs. Usually solitary, irregularly configured, sharply demarcated, platelike, rather coarse plaque, with 1 or more interspersed, poorly healing, nonpainful or only slightly painful ulcers.

Histologic:

• Sweet syndrome: diffuse neutrophilic dermatitis, no ulceration.
• Rheumatoid neutrophilic dermatitis: diffuse neutrophilic dermatitis with variable leukocytoclasia, no ulceration, no signs of vasculitis.
• Behçet's syndrome: diffuse neutrophilic dermatitis with variable leukocytoclasia, signs of leukocytoclastic vasculitis

• first-line therapy:
  • Immunosuppressive with Ciclosporin A (e.g. immunosporin) 5 mg/day/kg bw in combination with glucocorticoids such as prednisone 100-150 mg/day. The effect is usually noticeable within a few days (level of evidence III). In 15-20% of the patients the lesions healed completely within 6 weeks, after 6 months in 47% of the patients (Partridge ACR et al. 2018).
  • Alternatively, glucocorticoids as pulse therapy (1 g/day i.v. day 1-5; if necessary repeat after 4 weeks) (level of evidence III).
• Experimental therapy approaches (level of evidence IV)
  • In case of resistance to therapy intravenous immunoglobulin administration (IVIG). This therapeutic approach has been reported in several larger monocentric studies (level of evidence III-IV).
  • Successful in individual case reports:
    • Etanercept: 25-50 mg 2 times/week s.c.
    • Mycophenolate mofetil: 2.0-2.5 g/day p.o. as monotherapy or in combination with Ciclosporin A 50 mg/day p.o. and/or prednisolone.
    • In a retrospective multicenter study 13 subjects were treated with Infliximab 5 mg/day/kg bw i.v. All 13 volunteers were completely healed. The first clinical improvement was seen after an average of 11 days. Infliximab will mainly be used in association with Crohn's disease (Partridge ACR et al. 2018).
    • Canakinumab: The data situation corresponds to that of Infliximab (Partridge ACR et al. 2018).
    • Azathioprine (e.g. Imurek) 50-150 mg/day in combination with prednisolone (0.3-1.0 mg/kg bw/day).
• In case of superinfection, antibiotics after antibioogram.

Cave! Surgical intervention in the acute stage is contraindicated.

Medical history: The 68-year-old patient with a history of untreated hepatitis C presented with an approximately 3.0 x 4.0 cm large, purulent, painful and therapy-resistant ulcer of the left lower leg. The ulcer had formed 4 weeks earlier after a banal trauma and deteriorated rapidly in the meantime.

Clin: The circine, blurred, almost lobed border with a marginal livid erythema strip about 1.0 cm in size was conspicuous.

Laboratory: Genotypic virus determination revealed the detection of HCV, genotype 1A, with a high viral load. Furthermore a cryoglobulinemia was detected.
Detection of an IL26B receptor polymorphism; GOT: 120U/l, GPT: 90U/l, gamma GT: 160U/l
Histopathology (ulcer margin): non-specific neutrophil dermatitis, no evidence of vasculitis.
Therapy: antiviral combination therapy with Ledipasvir/Sofosbuvir and prednisolon course
: complete (!) healing of the ulcer within 6 weeks. The viral load was no longer detectable at this time.

1. Ahn C et al (2018) Pyoderma gangrenosum: a review of pathogenesis and treatment. Expert Rev Clin Immunol 14:225-233.
2. Antonelli E et al (2021) Dermatological manifestations in inflammatory bowel diseases. J Clin Med 10:364.
3. Alexis A et al (2005) Off-label dermatologic uses of anti-TNF-a therapies. J Cutan Med Surg 9: 296-302.
4. Barrick CJ et al (2019) Necrobiosis lipoidica with superimposed pyoderma vegetans. Cutis 103:44-45.
5. Bianchi L et al (2001) Pyoderma vegetans and ulcerative colitis. Br J Dermatol 144:1224-1247.
6. Al Ghazal P et al (2010) Cofactors in the pathogenesis of pyoderma gangraenosum: preliminary results of a clinical investigation. JDDG 8: 958
7. Brocq LAJ (1916) Nouvelle contribution à l'étude du phagédénisme gémoetrique. Annales de dermatologie et de syphilographie, 5th sr, Paris, 6: 1-39.
8. Brunsting L, Goeckerman W, O'Leary P (1930) Pyoderma (ecthyma) gangrenosum: clinical and experimental observations in five cases occurring in adults. Arch Dermatol 22: 655-680
9. Callen JP et al (2002) Neutrophilic dermatoses. Dermatol Clin 20: 409-419
10. Chiba T et al (2005) Topical tacrolimus therapy for pyoderma gangrenosum. J Dermatol 32: 199-203
11. Coady K (2000) The diagnosis and treatment of pyoderma gangraenosum. J Wound Care 9: 282-285.
12. Heermann R et al (2002) Pyoderma gangraenosum. Case report and comparison with necrotizing fasciitis. HNO 50: 244-247
13. Herberger K (2016) Pyoderma gangraenosum. Dermatologist 67: 753-763
14. Hubbard VG et al (2005) Systemic pyoderma gangrenosum responding to infliximab and adalimumab. Br J Dermatol 152: 1059-1061.
15. Jockenhöfer F et al. (2016) Patients with pyoderma gangrenosum - analyses of the German DRG data from 2012. Int Wound J 13:951-956.
16. Keltz M et al (1992) Peristomal pyoderma gangrenosum. J Am Acad Dermatol 27: 360-364.
17. Meier F et al (2003) An unusual case of pyoderma gangraenosum with necrotizing granulomatous dermatitis. JDDG 1: 302-305
18. Nesterovitch AB et al (2011) Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with pyoderma gangrenosum. Clin Exp Dermatol 36:889-895.
19. Partridge ACR et al. (2018) Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic
20. review of observational studies and clinical trials. Br J Dermatol 179:290-295.
21. Pourmorteza M et al (2016) Successful treatment of pyoderma gangrenosum with cryoglobulinemia and hepatitis C. Am J Case Rep 17:434-438.
22. Shanavas S et al (2019) Pyoderma vegetans of the perineum in the setting of ulcerative colitis. ACG Case Rep J 6:e00170.
23. Su WPD et al (2004) PG:clinicopathologic correlation and proposed diagnostic criteria. J Clin Gastrenterol 23: 29-34.
24. Swale VJ et al (2005) Pyoderma gangrenosum outside the context of inflammatory bowel disease treated successfully with infliximab. Clin Exp Dermatol 30: 134-136
25. Trémezaygues L et al (2010) Management of pyoderma gangrenosum. Dermatologist 61: 345-355
26. Yu SX et al (2020) Nasal mucosa pyoderma vegetans associated with ulcerative colitis: A case report. World J Clin Cases 8:4953-4957.
27. Wenzel J et al (2002) Topical treatment of pyoderma gangraenosum. Dermatology 205: 221-223
28. Jockenhöfer F et al (2019) The PARACELSUS score: a diagnostic tool for pyoderma gangrenosum. Br J Dermatol 180: 615-620