Eur J Dermatol 2013; 23(5): 653-7
Therapy Wolfram HOETZENECKER1,a Emmanuella GUENOVA1,a Vanyo MITEV2 Stefan SCHANZ1 Anja ULMER1 Gerhard FIERLBECK1 1 Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, 72076 Tuebingen, Germany 2 Department of Biochemistry, Medical University, Sofia, Bulgaria a These authors contributed equally
Reprints: W. Hoetzenecker Article accepted on 6/2/2013
Treatment of pyoderma gangrenosum with topical factor XIII Pyoderma gangrenosum (PG) is a severe ulcerative skin disease. Despite systemic immunosuppressive therapy, PG ulcers often progress and can develop into life-threatening conditions. In this case series, we treated 6 patients suffering from recalcitrant PG with topical coagulation factor XIII, which has been shown to exert beneficial effects on tissue regeneration and wound healing. All 6 patients showed a positive response to treatment with a marked reduction in wound size that was maintained during a 3-month follow-up period. The treatment was well tolerated with no remarkable adverse effects or complications. Topical factor XIII has potential in combination with standard immunosuppressive therapy for the treatment of PG. Key words: pyoderma gangrenosum, factor FXIII, therapy
yoderma gangrenosum (PG) is a rare, ulcerative, cutaneous disease affecting approximately 3-10 per million individuals per year [1, 2]. The clinical features of PG have been well characterized; however, little is known about its underlying pathogenic and immunologic alterations. Interestingly, 25-50% of PGs are associated with systemic diseases that have a suspected autoimmune or autoinflammatory pathogenesis (e.g., intestinal bowel disease, arthritis, paraproteinemia, and hematological malignancy) . Histologically PG is characterized by a dense neutrophil infiltrate and may be regarded as a paradigm of neutrophil-mediated auto inflammatory disease [3, 4]. At present, there is no gold standard of treatment nor published algorithm for choice of therapy. Because PG is thought to result from a dysregulation/overactivation of the immune system, immunosuppressive and immunomodulating compounds are widely used in the treatment of PG [2, 5]. Occasional case reports and small case-series have demonstrated a role for local and systemic corticosteroids, cyclosporine, mycophenolate mofetil, thalidomide, intravenous immunoglobulin, anti-tumor necrosis factor and anti-IL-12p40/IL-23p40 therapy as treatment modalities for PG [6-9]. However, these treatment regimens are associated with severe side effects and are often ineffective, leading to further progression of the disease. The protransglutaminase factor XIII (FXIII) is a novel and interesting molecule in the field of tissue regeneration. This factor seems to influence wound healing in several ways, including enhancing platelet adhesion to the endothelium, stabilizing the formed fibrin clot, limiting bacterial dissemination from the wound and supporting angiogenesis by forming a complex with the VEGF-receptor 2 and the ␣V␤3 integrin . The importance of FXIII in wound healing is further underlined by the observation of increased wound healing complications in patients with congenital factor XIII deficiency [11, 12]. Similarly, topical therapy with FXIII has shown beneficial effects in chronic leg ulcers, demonstrating enhanced tissue regeneration . Given these reports, we explored the effect of topical FXIII therapy in patients with PG. EJD, vol. 23, n◦ 5, September-October 2013
Methods The study selection criteria included a diagnosis of PG treated with immunosuppressive compounds (e.g., corticosteroids and cyclosporine) and standard wound care for at least one month or more with no improvement. We selected 6 patients for the study as detailed in table 1. The study was conducted in accordance with the Declaration of Helsinki. Compresses (5 × 5 cm) were individually moisturized with two mL of FXIII (Fibrogammin; CSL Behrung AG, Bern, Switzerland, concentration: 62.5 units per mL) and directly applied to the ulcers. After the FXIII application, an occlusive polyurethane adhesive film dressing was used to seal the wound. Wound dressings with FXIII were changed every third day. In that way, patients were treated with FXIII for 2 weeks and then followed up every month with a final follow-up visit 15 weeks after the first treatment (table 2). At every study visit the fibrin layers were carefully removed with wet compresses. The progress of wound healing was monitored at each consultation. Briefly, the wound perimeter was copied onto a sterile plastic sheet (Opsite, Smith & Nephew, USA) with a thin-tipped marker. The sheets were scanned, and the plotted area was analyzed using ImageJ software (ImageJ, NIH, USA). The results were analyzed using a t test.
Cases Case 1 A 62-year-old man with a medical background of hypertension, type II diabetes mellitus and hyperlipidemia presented with a one-year history of skin ulcer on the front aspect of his right lower leg. He was diagnosed with pyoderma gangrenosum (PG); other causes, including infectious disease, malignancy, vasculitis, venous or arterial insufficiency and self-inflicted ulcerations were ruled out. Tissue oxygenation was not significantly reduced in the area of
To cite this article: Hoetzenecker W, Guenova E, Mitev V, Schanz S, Ulmer A, Fierlbeck G. Treatment of pyoderma gangrenosum with topical factor XIII. Eur J Dermatol 2013; 23(5): 653-7 doi:10.1684/ejd.2013.2147
Table 1. Patient characteristics Patient No.
Wound duration [mo]
% of wound area healed at end of study
oral prednisolone (1,000 mg for 5 days followed by 50 mg daily for 8 months), topical tacrolimus (8 months) oral prednisolone (1,000 mg for 5 days followed by 50 mg daily for 12 months), methotrexate (15 mg weekly for 6 months), cyclosporine (300 mg daily for 6 months), topical tacrolimus (12 months), topical corticosteroid (12 months) oral prednisolone (80 mg daily for 1 month), topical corticosteroids (1 month) oral antibiotics (flucloxaciline 2,000 mg daily for 1 week), prednisolone (80 mg daily for 2 weeks), topical corticosteroids (2 weeks) oral prednisolone (60 mg daily for 7 months), azathioprine (150 mg daily for 7 months), topical corticosteroids (7 months) oral prednisolone (50 mg daily for 6 months), cyclosporine (300 mg daily for 6 months), topical gentamycine (1 month), topical corticosteroids (1 month)
96 14 (forefoot) 35 (leg) 76
Table 2. Outline of treatment and follow-up
1 2 3 4 5 6
1 2 3 7 11 15
Physical examination, photographs of ulcer, documentation of wound size, application of FXIIIa Photographs of ulcer, documentation of wound size, application of FXIIIa Follow-up: photographs of ulcer, documentation of wound size Follow-up: photographs of ulcer, documentation of wound size Follow-up: photographs of ulcer, documentation of wound size Follow-up: photographs of ulcer, documentation of wound size
FXIII was applied every third day for two weeks.
the PG, making a diabetic ulcer unlikely. He was treated with high-dose oral corticosteroids (1000 mg) and local therapy with tacrolimus cream. Additionally, he received twice-weekly home dressings by community nurses and attended the Outpatient Wound Foot Clinic at weekly intervals, with no improvement in wound size or the surrounding inflammation. The patient began treatment with FXIII and continued oral corticosteroid therapy (prednisolone, 50 mg). After the first FXIII treatment (week 1), there was a visible reduction in the surrounding inflammation. By the third visit, 2 weeks after the FXIII treatment was initiated, we observed a decrease in wound size by 33%, with the formation of granulation tissue in the wound base. Healing progress slowed over the remaining 3 months with a further reduction in wound size. By visit 6, the patient’s overall wound size had reduced by 48% (ﬁgures 1A-C).
Case 2 A 60-year-old man with a medical background of hypertension, steroid-induced diabetes mellitus and bronchial asthma presented with a 2-year history of pyoderma gangrenosum on the right lateral aspect of the lower leg. Other causes for the chronic ulcer, including infectious
disease, malignancy, vasculitis, venous or arterial insufficiency, self-inflicted ulcerations and diabetic ulcer (normal tissue oxygenation), were ruled out. His treatment in the past year had included high-dose corticosteroids, resulting in a steroid-induced diabetes mellitus in the course of treatment, methotrexate, cyclosporine and local application of tacrolimus and corticosteroid creams. With no clinical wound improvement following high-dose immunosuppressive therapy, the patient began treatment with FXIII. Cyclosporine (300 mg) and prednisolone (50 mg) were continued throughout the study. After topical FXIII for two weeks, we noticed increased granulation tissue at the wound base with small amounts of inflammation at the ulcer margins. At the first follow-up visit, one month after completion of the FXIII treatment, the patient’s wound size had reduced by 21%. The PG continued to decrease in size, and at the end of the study, a total reduction in wound size of 30% was observed (ﬁgure 1A).
Case 3 A 59-year-old woman with a medical background of hypertension, chronic polyarthritis and acrodermatitis chronica athrophicans presented with a 2-month history of PG on EJD, vol. 23, n◦ 5, September-October 2013
Case 1 Case 2 Case 3 Case 4 (leg)
Case 4 (forefoot) Case 5 Case 6
Wound area [cm2]
Wound area [cm2]
10 8 6 4 2 0
located on the forefoot. The PG on the lower leg showed a marked decrease in the surrounding inflammation between week 1 and week 3. After carefully removing the necrotic area from the upper part of the ulcer, granulation tissue was visible. At the last study visit, the patient’s wound size had reduced overall by 35% (ﬁgure 1A).
A 64-year-old woman with a medical background of hypertension and previous myocardial infarction presented with an 8-month history of PG on the left lower leg. Initially, a Bowen carcinoma had been removed on the lower leg with a fast-growing ulcer developing shortly after surgery. Histological analysis of the ulcer excluded remaining Bowen carcinoma and the PG was treated with oral corticosteroids (prednisolone, 60 mg) in combination with azathioprine (150 mg). With no clinical wound improvement, we began treatment with FXIII. Azathioprine (150 mg) and prednisolone (60 mg) were continued throughout the study. After topical FXIII for two weeks, would size had reduced by 27% and beginning granulation tissue was forming at the base of the PG. The PG continued to heal and at the end of the study a total reduction in wound size of 76% was observed (ﬁgure 1A).
Case 6 Figure 1. Reduction in wound area in response to treatment with factor XIII (FXIII). A) Reduction in wound size for each patient for visit 1 through visit 6. B) Percentage of wound area reduction from visit 1 to visit 6 pooled for all 6 patients (mean ± SD, **P