Pyoderma gangrenosum

0 downloads 0 Views 426KB Size Report
2004;5:1333–45. 69. Fujimoto E, Fujimoto N, Kuroda K, Tajima S. Leukocy- tapheresis treatment for pyoderma gangrenosum. Br J Der- matol. 2004;151:1090–2.
review Wien Med Wochenschr DOI 10.1007/s10354-014-0285-x

Pyoderma gangrenosum: pathogenetic oriented treatment approaches Uwe Wollina · Georgi Tchernev

Received: 5 January 2014 / Accepted: 1 May 2014 © Springer-Verlag Wien 2014

Summary  Pyoderma gangrenosum (PG) shows features of autoimmune and autoinflammatory disorders. Genetic defects which affect the inflammasome, and in particular the NLRP3 zone, can cause an abnormal secretion of interleukin 1 (IL-1). IL-1 may be involved in clinical manifestation of certain (genetic) forms of PG. IL-1 receptor antagonists reduce the activity of IL-1α and IL-1β. Mutations in the PSTPIP1 gene have been identified in patients with pyogenic arthritis, pyoderma gangrenosum and acne syndrome. In patients with a pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome these mutations cannot be found and the effect of IL-1 inhibition is questionable. Another upcoming opportunity is targeted therapy by tumor necrosis factor-alfa inhibitors in steroid-resistant patients. This review has been focused on (1) the modern pathogenetic concepts, (2) the currently accepted criteria for differentiating the disease, (3) the target therapy and (4) valuable advice to the clinicians regarding a number of medicaments capable of aggravating or inducing the PG. Keywords  Pyoderma gangrenosum  · Neutrophilic disorders  · IL-1 inhibitors  · TNF-a inhibitors  · Inflammasome

Prof. Dr. U. Wollina, MD () Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany e-mail: [email protected] Ass.-Prof. Dr. G. Tchernev, MD, PhD Policlinic for Dermatology and Venerology, University Hospital Lozenetz, Academic Educational Hospital of the Saint Kliment Ohridski University, Koiak street 1, 1407 Sofia, Bulgaria

13

Pyoderma gangraenosum – pathogenetisch orientierte Behandlungsoptionen Zusammenfassung  Das Pyoderma gangraenosum (PG) weist Symptome der autoimmunen und autoinflammatorischen Erkrankungen auf. Genetische Defekte, die das Inflammasom beeinflussen, insbesondere die NLRP3Zone, können zur abnormen Sekretion von Interleukin 1 (IL-1) führen. IL-1 scheint bei der klinischen Manifestation bestimmter (genetischer) Typen des PG beteiligt zu sein. IL-1-Rezeptorantagonisten reduzieren die Aktivität von IL-1a und IL-1β. Mutationen im PSTPIP1-Gen sind bei Patienten mit dem PAPA-Syndrom beobachtet worden. Bei Patienten mit einem PASH-Syndrom ließen sich derartige Mutationen nicht nachweisen. Hier ist der Einsatz von IL-1-Antagonisten fragwürdig. Eine weitere Option für steroid-resistente PG-Patienten stellt die zielgerichtete Behandlung mit Tumornekrosefaktora-Inhibitoren dar. In dieser Übersicht widmen wir uns folgenden Themen: 1) den modernen pathogenetischen Konzepten, 2) den aktuellen diagnostischen Kriterien, 3) der targeted therapy und 4) Hinweisen zur Induktion oder Aggravation des PG durch Medikamente. Schlüsselwörter  Pyoderma gangraenosum  · Neutrophile Erkrankungen  · IL-1-Inhibitoren  · TNF-a-Inhibitoren · Inflammasom List of abbreviations ANA Antinuclear antibodies ASC Apoptosis-associated speck-like protein possessing a caspase-recruiting domain (identical to TMS1) CAMPS CARD 14 mediated psoriasis CAPS Cryopyrin-associated periodic syndrome CARD14 Caspase recruitment domain-coding protein 14 CINCA Chronic infantile neurologic cutaneous and articular syndrome

Pyoderma gangrenosum: pathogenetic oriented treatment approaches  

1

review

DIRA Deficiency of interleukin-1 receptor antagonist ECMPS Enteric-coated mycophenolate mofetil EO-IBD Early-onset inflammatory bowel diseases FACS Familial cold autoinflammatory syndrome FMF Familial Mediterranean fever HIDS Hyperimmunoglobulin D syndrome IL Interleukin IL-1Ra Interleukin-1 receptor antagonist mg Milligram MWS Muckle-Wells syndrome NLRP3 Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3 NOMID Neonatal-onset multisystem inflammatory disease PAPA Pyogenic arthritis, pyoderma gangrenosum and acne PASH Pyoderma gangrenosum, acne suppurative hidradenitis PEST (proline-, glutamic acid-, serine-, and threonine-rich) family of protein tyrosine phosphatases PGA Pediatric granulomatous arthritis PG Pyoderma gangrenosum PRAAS Proteasome associated autoinflammatory syndromes PSTIP1 Proline-serine-threonine phosphatase-interacting protein-1 TMS1 Target of methylation-induced silencing-1 (identical to ASC) TNF-a Tumor necrosis factor alpha TRAPS Tumor necrosis factor receptor associated periodic syndrome TRECID Tumor necrosis factor-related chronic inflammatory diseases

Introduction Pyoderma gangrenosum (PG) has been initially described in 1930 by Brunsting et al. [1]. It is a rare non-infectious disease that belongs to the spectrum of neutrophilic dermatoses [2, 3]. Although the PG itself does not belong to the autoimmune dermatoses, the association of PG with such disorders has repeatedly been observed [2, 3]. PG is a disease which is often associated with other severe pathologies such as ulcerative colitis, Crohn’s disease, rheumatoid arthritis, seronegative arthritis, myelocytic leukemia, hairy cell leukemia, myelofibrosis, myeloid metaplasia, and monoclonal gammopathy among others [2]. Diagnosis of PG is based on the exclusion of other disorders mimicking some of its clinical features, typical clinical presentation, and histopathological verification [3]. Contemporary scientific research, performed on a cytokine and molecular level, has given a considerable thrust to the optimization of the therapeutic schemes and has created serious preconditions for the prompt control of the clinical symptoms in a part of the affected

patients. The new targeted drugs may offer fewer side effects combined with high efficacy [4, 5]. IL-1 antagonists are the first-line treatment in patients with Schnitzler syndrome and cryopyrinopathies [5]. They could also become an important alternative in patients with acute and febrile neutrophilic dermatoses (including PG) either unresponsive to or with contraindications to conventional treatments [5]. On the other hand, targeted drugs may exert unexpected induction or aggravation of PG as it was reported for TNF-a inhibitors adalimumab or etanercept [6, 7, 8, 9]. The article focuses on the new and modern pathogenetic aspects (on a molecular and genetic level), as well as on the selection of the respective therapeutic scheme depending on the individual’s clinical status and the capacities of the medical institution performing the treatment.

Epidemiology Epidemiological data is hard to come by and differs according to the different populations in the respective geographical regions [10]. The epidemiology of PG has never been formally assessed in a population-based study [11]. The epidemiology of this disorder seems to be based on case reports, case series, and cohort studies of individuals with inflammatory bowel disease [12, 13]. As a result, the incidence of, PG has been estimated as 3–10 per million population per year [14]. In most cases the disease manifests itself between the second and fifth decade of life (Figs. 1, 2, 3 and 4) [10, 14]. About 4 % of the affected patients are children [15].

Pathogenesis of pyoderma gangrenosum The etiopathogenesis of PG is incompletely understood [2, 10]. In spite of the fact that a significant amount of cases may be associated with some of the autoimmune

Fig. 1  Postoperative form of pyoderma gangrenosum, treated successfully with cyclosporin A and topical tacrolimus 0.1 %-ointment

2   Pyoderma gangrenosum: pathogenetic oriented treatment approaches

13

review

Fig. 2 50-year-old female patient with multifocal form of pyoderma gangrenosum treated successfully with initially infliximab 3x i.v. (induction), followed by adalimumab for maintenance

Fig. 4 Uncommon clinical presentation of superficial PG in the submammary area

Fig. 3  50-year-old patient with pyoderma gangrenosum since 10 years. No clinical improvement after the systemic administration with prednisolone/azathioprine, followed by combination therapy with corticosteroids and cyclosporin A. The treatment scheme has been changed because of the development of serious side effects. High dose therapy with corticosteroids and mycophenolat mofetil (Myfortic®) 3 × 720 mg/d resulted

in a limited control of the disease (a). Topical treatment with tacrolimus 0.1 % ointment caused temporary renal failure. TNF-a inbitors were contraindicated due to bone tuberculosis (TB). After TB eradication therapy for 2 years, i.v. therapy with high-dose gammaglobulin was initiated without success (b, c). The patient died due to sepsis with multiorgan failure

diseases, the commonly accepted assumption that PG is a kind of autoimmune disease is gradually losing popularity [16, 17]. In fact there are a number of different views regarding its immunopathogenesis [2]. Until recently, one of the oversimplified concepts was based on the scant data indicating, that the damages to the T-cell immunity and the phagocytosis may be one of the factors leading to the hyperactivation of

the immunological cascade in PG [2, 18]. Aberrant integrin oscillations on neutrophils and subsequent aberrant neutrophil tracking has also been observed in PG [19, 20]. Unspecific factors may initiate the inflammatory cascade leading to PG such as trauma or infections with Chlamydia pneumonia [2, 21]. There is a touch of skepticism regarding the factors for the above-mentioned

13

Pyoderma gangrenosum: pathogenetic oriented treatment approaches  

3

review

phenomena because these cannot be observed in all patients. A number of authors summarize PG to the group of autoinflammatory diseases, within which one may also find erysipelas-like erythema in FMF; urticaria-like rashes in tumor necrosis factor receptor 1- or cryopyrinassociated periodic syndromes (TRAPS, CAPS), hyperimmunoglobulin D syndrome (HIDS), Schnitzler syndrome, PG and acne in PAPA syndrome, behçetoid aphthous ulcerations in HIDS, and PFAPA syndrome [22, 23]. Familial periodic fever syndromes, of which FMF is the most common and best known, belong to this group as well—although PG is not associated with FMF [22]. The common background for the clinical manifestation of these diseases is alterations of so-called inflammasome, which leads to the uncontrollable and increased activation of interleukins including IL-1 [22, 23, 24]. The inflammasomes, recently identified innate immune complexes that sense intracellular danger- or pathogen-associated molecular patterns, are now known to be responsible for triggering inflammation in response to several molecular patterns [24]. Dysregulation of inflammasome function is however also the cause of a family of genetic autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS) characterized by recurrent episodes of fever, urticarial-like cutaneous lesions, systemic inflammation and arthritis [24]. The autoinflammatory diseases can be grouped based on clinical findings into: 1. The three classic hereditary “periodic fever syndromes”, familial Mediterranean fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. The cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA. 3. Pediatric granulomatous arthritis (PGA); 4. Disorders presenting with skin pustules, including deficiency of IL-1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, PG and acne (PAPA) syndrome; deficiency of IL-36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. Inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. Very rare conditions presenting with autoinflammation and immunodeficiency [25]. Objects of mutations in patients with PG may be genes of various kinds. The (PEST) family of protein tyrosine phosphatases is a critical regulator of adhesion and migration. PSTPIP1 is a cytoskeleton-associated adaptor protein that links PEST-type phosphatases to their substrates [26, 27]. PSTIP1 creates a filamentous network

that can be modified by pyrin. Pyrin can recruit PSTIP1 into adapter protein apoptosis associated speck-like protein containing a CARD (ASC) [28, 29]. ASC has a central importance for activation of all inflammasomes and subsequent activation of caspase-1 [29]. There is abundant literature on ASC/TMS1 in the epigenetic regulation of apoptosis and carcinogenesis, and on the assembly of inflammasomes and stimulation of inflammation [30]. There is substantial evidence on common aspects in the regulation of apoptosis and inflammation, which may be related to the function of ASC/ TMS1 [30]. Mutations of CD2BP1/PSTPIP1 gene produce ASC specks with high efficacy [28, 29].This pathway seems to be involved in diseases related to PG such as chronic inflammatory bowel disease and aseptic abscesses syndrome [26, 27]. Several familial cases have been reported, suggesting the involvement of genetic factors in the etiology of PG. Two mutations (A230T and E250Q) in the PSTPIP1 gene, encoding proline-serine-threonine phosphatase-interacting protein (PSTPIP)1 have been identified in patients with PAPA syndrome, a rare autoinflammatory disorder with autosomal dominant inheritance [27]. The pro-inflammatory cytokine TNF alpha (TNFa) is another key factor in the pathogenesis of several infectious and inflammatory diseases [31]. Clarification of its role in the pathogenesis of rheumatoid arthritis, spondyloarthritis, uveitis, psoriasis, and inflammatory bowel disease has resulted in the successful development of TNF-a inhibitory therapy. The acronym TRECID describes this concept of “TNF RElated Chronic Inflammatory Diseases” [31]. Thus the concept of TRECID can be regarded as a role model for a dynamic, interdisciplinary cooperation based on shared pathophysiological aspects. So far, PG can be described as a neutrophilic disorder of innate immunity and a member of TRECID (TNF-a related chronic inflammatory diseases) [31]. In spite of this, the data on TNF-a inhibitors in PG remain heterogeneous. A number of questions are raised. What role does inflammation play in PG associated malignancies? Does PG bear an increased risk for skin cancer or lymphomas which have been associated to TNF-a inhibitors in general [32]? Case reports suggested a possible induction or aggravation of PG by TNF-a inhibitors [6–9]—a phenomenon that has been observed as a paradoxical reaction in psoriasis [33]. On the other hand, PG may be a life-threatening disease not responding to classical treatment with immunosuppression and even IL-1 inhibitors.

Clinical presentation, and diagnosis of PG The primary lesion is a sterile pustule often missed because of its unspectacular and temporary nature. These lesions rapidly enlarge and produce purulent erosions, ulcers, and sometimes bullae. Any immunosuppressive treatment will modify the typical clinical fea-

4   Pyoderma gangrenosum: pathogenetic oriented treatment approaches

13

review

tures (Figs. 1–4). From a clinical point of view four major types have been differentiated [10, 11]:

Autoimmune phenomena in pyoderma gangraenosum

●● ●● ●● ●●

PG is not an antibody mediated disease. Nevertheless, serologic investigations revealed the presence of autoantibodies in 24.9 % cases with antinuclear antibodies (ANA) in 16.5 %. PG patients often suffer from anemia (65.2 %). Only a minority is due to iron deficiency [9]. In a retrospective evaluation of 86 patients, PG associated autoimmune disorders were diagnosed in 32.5 % [36].

Ulcerative PG Pustular PG Bullous PG Vegetative PG.

A rare variant of PG is superficial granulomatous pyoderma. Ulcerative PG is the most common type. These ulcers are characterized by violaceous undermined borders, rapidly growing and painful ulcers. The most common sites are the legs (pretibial) but any part of the body including mucous membranes can be involved. Microbiological swabs from fresh lesions are sterile. Later on, a secondary colonization may lead to false diagnosis. Diagnosis is mainly clinical. Histology and microbiology help eliminate differential diagnoses. There is no laboratory test that is diagnostic [34]. Recently modified diagnostic criteria have been defined (Table 1). Since PG is associated with underlying pathologies in up to 75 % cases, a complete diagnostic panel should search for the most important ones like endocrine disorders, chronic inflammatory bowel disease, lymphomas, and blood dyscrasia. In some cases PG develops after surgery (hip replacement, knee total endoprosthesis, breast surgery). It seems that surgery with significant trauma to adipose tissue is predominant (Table 2) [35]. Table 1 Diagnostic criteria for pyoderma gangraenosum [35]. Diagnosis needs two major and at least two additional criteria I. Main criteria Primary sterile pustule or ulcer with livid, undermined wound-border AND: Exclusion of other relevant differential diagnoses like chronic venous/arterial leg ulcer, pyodermatitis, vasculitis II. Additional criteria Histology of the wound-border: neutrophilic infiltration of the dermis with signs of vasculitis and accumulation of immunoglobulins and/or complement factors beside the vessels Existence of relevant, associated concomitant diseases (Table 2) Response to a systemic immunosuppressive therapy or no response to a conventional ulcer-therapy Triggering of a PG by pathergy-phenomenon Extremely painful ulcer (VAS > 4 points)

Table 2  Comorbidities in pyoderma gangraenosum [35] Comorbidity

Frequency (%)

Endocrine disorders incl. diabetes mellitus

36.7

Gastrointestinal disorders

25.5

Arthropathy/Arthritis

18.5

Cancer

8.5

Hematologic disorders

3.5

13

Autoimmune disorders associated with pyoderma gangraenosum A wide spectrum of autoimmune diseases has been observed in patients with PG. The most common is rheumatoid arthritis with a clear dominance of female PG patients. Large trials suggested a frequency of about 10–12 % [14, 35, 36]. Painful and recalcitrant leg ulcers in rheumatoid arthritis are suggestive of PG [37, 38]. It is noteworthy, that TNF-a inhibitors used in rheumatoid arthritis may aggravate PG [6–9]. Painful leg ulcers in lupus erythematosus are suggestive for PG [39, 40]. They occur in about 1 % of patients referred to a medical center. Lupus vasculitis is a major differential diagnosis in these cases. Histology is helpful to exclude primary vasculitis [40, 41]. In scleroderma, PG is very rare [42]. Peristomal PG has been seen in a patient with systemic scleroderma [43]. PG in dermatomyositis is extremely rare; a case of scrotal ulcerative PG has been published [44]. The same is true for Wegener’s granulomatosis where PG may occur in the first place [45]. Other unusual associations of PG are autoimmune hepatitis [46], juvenile idiopathic arthritis [47], Sjögren’s syndrome [48], Takayasu’s arthritis [49], Churg-Strauss syndrome [50], autoimmune neutropenia of infancy [51], autoimmune hemolytic anemia [52], and autoimmune thyreopathies [53, 54].

Treatment The therapy of PG usually is systemic but may include topical drugs as well (Table 3). Some drugs are used preferentially for induction therapy while others for maintenance therapy [2, 3, 10]. Since randomized controlled trials have never been performed in this orphan disease treatment is empirical. The standard systemic therapy includes immunosuppressive drugs which unfortunately do not have a strictly specific effect causing unwanted adverse effects [2, 3]. The most widely propagated scheme is either monotherapy with corticosteroids or corticosteroids in combination with azathioprine for induction [3]. The systemic application of corticosteroids in doses between 1 and 2  mg/kg body weight is consensus [10]. For rapidly progressing cases pulse or suprapharmaco-

Pyoderma gangrenosum: pathogenetic oriented treatment approaches  

5

review

Table 3  Treatment algorithm for pyoderma gangrenosum Dosage Induction therapy 1st line

Systemic corticosteroids

Uncomplicated cases

1–2 mg/kg body weight

Rapidly progressing cases

1 g/d for several days (4–6)

Cyclosporine A

With corticosteroids

2–3(-5) mg/kg body weight

2nd line

Dapsone

Milder cases

200 mg/day

3rd line

Thalidomide

+/- Corticosteroids

100–200 mg/day

Tacrolimus Cyclophosphamide

0.1 g/kg body weight In steroid-refractory Crohn’s

1000 mg/day once a months

Infliximab

5 mg/kg body weight

Adalimumab

80 mg week 0, 40 mg week 1, followed by 40 mg every other week

Etanercept

Less effective than antibodies to TNF-a

50 mg twice a week

Azathioprine

+ Corticosteroids

100–150 mg/day

Cyclosporine A

+/- Corticosteroids

2–3 mg/kg body weight

Dapsone

+/- Corticosteroids

100–200 mg/day

Mycophenolate mofetil

+ Corticosteroids

2 × 500 mg/day

Enteric-coated mycophenolat mofetil

+ Corticosteroids

2 × 360 mg/day

Clofazimine

+/- Corticosteroids

300–400 mg/day

Maintenance therapy 1st line

2nd line 3rd line

TNF-a inhibitors

logical therapy with corticosteroids in dosages of 1 g/day was introduced which brings to fast clinical results but conceals risks for a number of side effects and this necessitates the daily monitoring of the patients [10]. Pulse therapy may be combined with azathioprine [3]. Cyclosporine A is the second widely used monotherapy [55]. It has been employed mainly for maintenance but sometimes in combination with corticosteroids as induction therapy [54]. Dosages vary between 2 and 3 mg/kg body weight depending on the individual’s tolerance and the side effects. The risk of relapse remains comparatively high after dose reduction or abrogation [55–57]. Azathioprine is applied in combination with corticosteroids, the objective being a gradual reduction of the corticosteroids [3]. Azathioprine alone is not effective in PG. Prior to setting the treatment dose it is also highly desirable to define the activity of the thiopurine methyltransferase (due to existing genetic polymorphisms), because it metabolizes the azathioprine and may show substantial differences in its activity [58, 59]. Dapsone is a second-line drug used in daily doses of 200  mg in patients with normal glucose-6-phosphate dehydrogenase levels [10]. Dapsone can be used as a monotherapy for mild and superficial PG, or as a combined therapy with corticosteroids, the objective being to subsequently switch to dapsone monotherapy. Monthly methemoglobin control and blood tests are obligatory. Clofazimine and thalidomide have been described in literature as possible therapeutic options but have failed to find a wider application [10, 60]. Clofazimine stimu-

lates phagocytosis and possesses an additional, direct antibacterial effect which is of importance in relation to accompanying bacterial infections [60]. The dosage varies between 300–400 mg daily [10, 60]. Common side effects are hyperpigmentations. Thalidomide has a blocking effect on TNF-a. It also blocks chemotaxis of neutrophils in the acute phase of the disease [61]. Monotherapy and a combined therapy with corticosteroids is possible [10]. It is absolutely contraindicated in females during childbearing age due to its teratogenic potency. Thalidomide can induce persistent neuropathies. In doses of 2  g daily, mycophenolate mofetil also appears to be a good alternative to azathioprine with comparatively low side effects [62–64]. The selective calcineurin inhibitor tacrolimus has been used in PG at a daily dosage of 0.1  mg/kg body weight [10, 64]. Preferably the treatment needs laboratory monitoring. The serum level of the drug should be between 4 and 6 ng/L [65]. With its ability to block or inhibit the function of the neutrophils, colchicine is another therapeutic option but common gastrointestinal adverse effects limit its use in maintenance therapy [66]. Cyclophosphamide pulse therapy followed by either azathioprine or methotrexate is an effective treatment option in steroid-refractory Crohn’s disease. In cases of Crohn’s associated PG one may achieve remissions with this regimen lasting for up to 30 months [67]. Another interesting treatment option seems to be the application of enteric-coated mycophenolate sodium

6   Pyoderma gangrenosum: pathogenetic oriented treatment approaches

13

review

[ECMPS] which is an advanced formulation delivering mycophenolic acid. At a dosage of 720 mg ECMPS exhibits equivalent mycophenolate acid exposure to mycophenolate mofetil 1000 mg [68]. Leukocytapheresis and granulocyte adsorptive apheresis, a more selective procedure, have been used in single cases with success in patients with PG [69, 70]. TNF-a inhibitor infliximab appears to be effective in patients with PG and inflammatory bowel disease [10, 71, 72]. The dosage is 5 mg/kg body weight. Infliximab is given intravenously at week 0, 2, and 6 followed by application every other month [10, 73]. Case reports and case series have also been published on the use of etanercept and adalimumab [74, 75]. These drugs are applied subcutaneously. The dose for etanercept is 50 mg twice a week, adalimumab is given at 80 mg week 0 and 40 mg week 1 followed by 40 mg every other week. Due to the increased risk of TB reactivation by TNF-a inhibitors, patients need to be screened for TB prior to as well as during the therapy, although the risk of activation of TB is higher with antibodies to TNF-a than with TNF-a receptor antagonist [70, 74, 75]. The paradoxical induction or worsening of PG by TNF-a inhibitors is not well understood. In psoriasis, where the phenomenon has longer been observed a switch from one TNF-a inhibitor to another may result in prompt response again [33] (Table 4). TNF-a inhibitors may be considered third-line treatments in steroid refractory cases with the need of systemic treatment. New hopes have appeared with the blocking of one of the most powerful mediators of inflammation—IL-1a [24, 77]. IL-1a inhibitors are directed to blocking the inflammation within the framework of generalized processes like sepsis and general febrile conditions of various causes [24, 77]. IL-1a connects to the interleukin-1 receptor and thus activates TNF-a. IL-1α and TNF are both acute-phase cytokines that act to promote fever and inflammation [77]. IL-1a is constitutively produced by epithelial cells also. It is found in substantial amounts in normal human epidermis and is distributed in a 1:1 ratio between living epidermal cells and stratum corneum [77].

Table 4  Induction or worsening of pyoderma gangrenosum by drugs Tumor necrosis factor alpha-inhibitors  Etanercept (receptor antagonist)

[6]

 Adalimumab (monoclonal antibody)

[7], [8]

Interferon alpha (probably due to pathergy)

[92]

Sunitinib (multi-kinase inhibitor)

[93], [94]

Gefitinib (epidermal growth factor-receptor antagonist)

[95]

(Pegylated) filgrastim (granulocyte colony-stimulating factor)

[96]

Oral isotretinoin for acne

[97], [98]

Propylthiouracil for Grave’s disease

[99]

Sulpiride (antipsychotic drug)

[100]

13

The generation of an immunological cascade is an extremely complicated, multifactor-based process. The process relates to the so-called inflammasome. Various genetic mutations of the different components of the inflammasome, like NLRP3 (NBD-, LRR- and PYDcontaining protein 3) and in some of its other zones are capable of causing the respective clinical symptoms and/ or diseases. The mutations in the NLRP3 zone lead to the hyperactivation or the secretion of certain genetic products which support the inflammatory process. Treatment with IL-1 inhibitors, such as anakinra (Kineret®; Swedish Orphan Biovitrum), canakinumab (Ilaris®; Novartis) or rilonacept (Arcalyst®; Regeneron), ameliorates the disease [77]. Contradicting data, however, can also be found. Activation of the inflammasome, which is practically a multi-protein complex, is the result of factors and actions differing in their nature and genesis. Among them one finds contact allergens, bacteria, fungous elements, products from dying cells, crystals from uric acid, etc. [77–83]. The activation of the inflammasome leads to the subsequent activation of caspase 1 and from there of interleukin-1β (IL-1β) and IL-18. Whether the inflammasome will be activated once within the framework of contact dermatitis or an acute form of gout, certain bacteria, fungous elements, or it will be permanently activated as result of a genetic defect, is also of significant importance for the treatment choice. In the first case the inflammation will self-regulate after the removal of the risk or provoking factor. And this may even be desirable. In the case of bacterial pathogens, pyroptosis is a mechanism that effectively contributes to infection control [81–83]. According to the presented data, the indication for the respective therapy should be strictly defined in relation to the initial diagnose, the possible accompanying infections and the co-morbidity of the patients. In cases of genetic defects, however, the major objective should be a long-term effect achieved via a strictly specified targeted therapy [77]. In other words, it must be pathogenetically substantiated. In patients with dermatological problems, it is of interest that the various mutations directly, or not, affect the secretion of IL-1 and are able to cause the clinical expression of one or another disease depending on their localization in the chain. The available data on the rapid and lasting response of PG to targeted treatment with the recombinant human IL-1 receptor antagonist (rHuIL1Ra) anakinra in a patient with PAPA syndrome is also of interest [84]. The same group described a partial improvement of the clinical symptoms in a patient with a clinical trial of PG, acne, and suppurative hidradenitis (PASH syndrome) due to IL-1Ra anakinra [85]. None of the respective mutations have been identified in this particular case, but in spite of this a highly selective target therapy was started [85]. Is a targeted therapy substantiated when underlying mutations are absent? There is a growing necessity of strictly defining the indications for a target therapy, especially when the

Pyoderma gangrenosum: pathogenetic oriented treatment approaches  

7

review

object is a disease of unclear molecular genesis. Given the absence of respective mutation or genetic defect we should rather stick to the classical immunosuppressive therapeutic schemes. Topical therapy is a useful adjunct to systemic treatment. It should be applied depending on the clinical condition [3, 10]. In the case of exudative ulcers without secondary infection one may use foam or gel dressings or laminate dressings composed of different layers [3, 10]. In cases of suppurative wounds semi-occlusive bandages cannot be recommended [3]. Compresses, soaked with potassium permanganate or Ringer-lactate solution, as well as octenisept, lavasept solutions, are an option to reduce bacterial load and malodor [3]. For small flat lesions without secondary infection high potency corticosteroids or calcineurin inhibitors like tacrolimus or pimecrolimus may be used [86, 87]. In case of larger lesions, however, systemic absorption needs consideration. We observed a patient who developed a temporary renal failure due to topical tacrolimus 0.1 % [88]. Surgery has to be used with caution because of its potential to aggravate PG. Any surgical procedure has to be done as an adjunct to immunosuppression only in patients with stable disease [10, 62]. Vacuum-assisted closure has been used successfully to induce granulation tissue in large ulcerated PG—as long as immunosuppression is effective [89].

Conclusions Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of autoinflammatory diseases and especially of PG. Both TNF-a inhibitors as well as IL-1Ra are promising new biologic agents for the treatment of autoinflammatory diseases and especially some variants of PG. Despite advances in pathogenesis and management, the long term outcome of PG remains unpredictable. We recommend the following algorithm of treatment: When there are no mutations capable of affecting certain zones of the so-called inflammasome, it is recommended to start with the commonly accepted therapeutic schemes of immunosuppression. The new attempts of treatment with biologics needs careful investigation since this could provide a new understanding of the disease. Today these options are considered as treatments of 2nd or 3rd choice for PG. The implementation of multicenter trials in PG would be most helpful to identify those patients who would benefit most from emerging treatments. Conflict of interest The authors declare that there are no actual or potential conflicts of interest in relation to this article.

References  1. Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma [ecthyma] gangrenosum: Clinical and experimental observations in five cases occurring in adults. Arch Dermatol Syph. 1930;22:655–80.   2. Tchernev G, Trebing D, Göring H-D, Steinhoff M, Zouboulis CC, Orfanos C. Pyoderma gangrenosum in Crohn’s disease—the role of immunologic parameters and histological data in diagnosis and differential diagnosis. Bulg J Hepatogastroenterol. 2005;7:56–60.   3. Wollina U. Clinical management of pyoderma gangrenosum. Am J Clin Dermatol. 2002;3:149–58.  4. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25:469–84. doi: 10.1016/j.smim.2013.10.008.   5. Lipsker D, Lenormand C. Indications and modes of use for interleukin (IL)-1 antagonists in inflammatory dermatosis: a new therapeutic approach to immune-mediated inflammatory diseases. Ann Dermatol Venereol. 2012;139:459–67.   6. Kowalzick L, Bertolini J, Baumann C, Walther B, Truhm B, Eickenscheidt L. Paradoxical reaction to etanercept: development of pyoderma gangraenosum during therapy of psoriasis arthritis. J Dtsch Dermatol Ges. 2013;11:447–9.   7. Kikuchi N, Hiraiwa T, Ohashi T, Hanami Y, Satoh M, Takenoshita H, et al. Pyoderma gangrenosum possibly triggered by adalimumab. Eur J Dermatol. 2012;22:804–5.  8. Stichenwirth M, Riedl E, Pehamberger H, Tappeiner G. Pyoderma gangrenosum in a patient with seronegative rheumatoid arthritis during therapy with adalimumab: toxic effects of adalimumab or failure of adalimumab to prevent the onset of this phenomenon? Arch Dermatol. 2008;144:817–8.  9. Kleinpenning MM, Langewouters AM, Van De Kerkhof PC, Greebe RJ. Severe pyoderma gangrenosum unresponsive to etanercept and adalimumab. J Dermatolog Treat. 2011;22:261–5. 10. Wollina U. Pyoderma gangrenosum—a review. Orphanet J Rare Dis. 2007;2:19. 11. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol. 1996;34:395–409. 12. Farhi D, Cosnes J, Zizi N, Chosidow O, Seksik P, Beaugerie L, et al. Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2,402 patients. Medicine (Baltimore). 2008;87:281–93. 13. Vavricka SR, Brun L, Ballabeni P, Pittet V, Prinz Vavricka BM, Zeitz J, et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol. 2011;106:110–9. 14. 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. 15. Graham JA, Hansen KK, Rabinowitz LG, Esterly NB. Pyoderma gangrenosum in infants and children. Pediatr Dermatol. 1994;11:10–7. 16. Callen JP. Pyoderma gangrenosum and related disorders. Adv Dermatol. 1989;4:51–69. 17. Wolff K, Stingl G. Pyoderma gangrenosum. In: Freedberg IM, Eisen AZ, Wolff K, Austen FK, Goldsmith LA, Katz SI, et al., editors. Dermatology in general medicine. New York: McGraw Hill; 1999. pp. 1140–8. 18. Powell FC, Schroeter AL, Perry HO, Su WP. Direct immunofluorescence in pyoderma gangrenosum. Br J Dermatol. 1983;108:287–93.

8   Pyoderma gangrenosum: pathogenetic oriented treatment approaches

13

review

19. Shaya S, Kindzelskii AL, Minor J, Moore EC, Todd RF 3rd, Petty HR. Aberrant integrin [CR4; αxβ2; CD11c/CD18] oscillation on neutrophils in a mild form of pyoderma gangrenosum. J Invest Dermatol. 1998;111:154–8. 20. Adachi Y, Kindzelskii AL, Cookingham G, Shaya S, Moore EC, Todd RF 3rd. Aberrant neutrophil trafficking and metabolic oscillations in severe pyoderma gangrenosum. J Invest Dermatol. 1998;111:259–68. 21. Sams HH, Mitchell MM, Stratton CW, King LE Jr. Culture and immunohistochemical evidence of chlamydia infection in ulcerative pyoderma gangrenosum. J Am Acad Dermatol. 2003;48:966–9. 22. Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9:232–46. 23. Lamprecht P, Gross WL. Autoinflammatory syndromes. Internist (Berl). 2009;50:676–84. 24. Contassot E, Beer HD, French LE. Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly. 2012;142:w13590. 25. Almeida de jA, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147:155–74. 26. Wollina U, Haroske G. Pyoderma gangraenosum. Curr Opin Rheumatol. 2011;23:50–6. 27. Nesterovitch AB, Hoffman MD, Simon M, Petukhov PA, Tharp MD, Glant TT. Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with pyoderma gangrenosum. Clin Exp Dermatol. 2011;36:889–95. 28. Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100:13501–6. 29. Hara H, Tsuchiya K, Kawamura I, Fang R, Hernandez-Cuellar E, Shen Y, et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of specklike aggregates and inflammasome activity. Nat Immunol. 2013;14:1247–55. 30. Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K. Epigenetic regulation of ASC/TMS1 expression: potential role in apoptosis and inflammasome function. Cell Mol Life Sci. 2014;71:1855–64. 31. Müller-Ladner U, Alten R, Heiligenhaus A, Kekow J, Koletzko S, Mrowietz U, et al. “TRECID”, TNFalpha related chronic inflammatory diseases—a new multiple diseases bridging concept. Dtsch Med Wochenschr. 2009;134:2132–6. 32. Fellermann K. Adverse events of tumor necrosis factor inhibitors. Dig Dis. 2013;31:374–8. 33. Wollina U, Hansel G, Koch A, Schönlebe J, Köstler E, Haroske G. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am J Clin Dermatol. 2008;9:1–14. 34. Schadt CR, Callen JP. Management of neutrophilic dermatoses. Dermatol Ther. 2012;25:158–72. 35. Al Ghazal PH, Herberger K, Schaller J, Strölin A, Hoff NP, Goerge T, et al. Associated factors and comorbidities in patients with pyoderma gangrenosum in Germany: a retrospective multicentric analysis in 259 patients. Orphanet J Rare Dis. 2013;8:136. 36. Powell F, Schroeter A, Su W, Perry H. Pyoderma gangrenosum: a review of 86 patients. Q J Med. 1985;55:173–86. 37. Seitz CS, Berens N, Bröcker EB, Trautmann A. Leg ulceration in rheumatoid arthritis—an underreported multicausal complication with considerable morbidity: analysis of thirty-six patients and review of the literature. Dermatology. 2010;220:268–73.

13

38. Hasegawa M, Nagai Y, Sogabe Y, Hattori T, Inoue C, Okada E, et al. Clinical analysis of leg ulcers and gangrene in rheumatoid arthritis. J Dermatol. 2013;40:949–54. 39. Chia HY, Tang MB. Chronic leg ulcers in adult patients with rheumatological diseases—a 7-year retrospective review. Int Wound J. 2012;doi: 10.1111/iwj.12012. [Epub ahead of print] 40. Wollina U, Hein G. Lupus erythematosus: uncommon presentations. Clin Dermatol. 2005;23:470–9. 41. Reddy V, Dziadzio M, Hamdulay S, Boyce S, Prasad N, Keat A. Lupus and leg ulcers–a diagnostic quandary. Clin Rheumatol. 2007;26:1173–5. 42. Feld J, Bergman R, Weltfriend S, Zisman D. Pyoderma gangrenosum in a patient with systemic sclerosis. J Rheumatol. 2012;39:197. 43. Fujikura M, Ohtsuka T, Oyamada Y. Systemic sclerosis in association with peristomal pyoderma gangrenosum. Br J Dermatol. 2007;157:618–9. 44. Shah M, Lewis FM, Harrington CI. Scrotal pyoderma gangrenosum associated with dermatomyositis. Clin Exp Dermatol. 1996;21:151–3. 45. Zycinska K, Wardyn K, Zielonka TM, Nitsch-Osuch A, Smolarczyk R. Cutaneous changes: an initial manifestation of pulmonary Wegener’s granulomatosis. Adv Exp Med Biol. 2013;755:307–10. 46. Halac U, Al Dhaybi R, Powell J, Bouron-Dal Soglio D, Alvarez F. Unusual association between autoimmune hepatitis and severe pyoderma gangrenosum. J Pediatr Gastroenterol Nutr. 2010;50:219–21. 47. Chandrasekhara PK, Jayachandran NV, Thomas J, Agrawal S, Narsimulu G. Successful treatment of pyoderma gangrenosum associated with juvenile idiopathic arthritis with a combination of topical tacrolimus and oral prednisolone. Clin Rheumatol. 2009;28:489–90. 48. Ravic-Nikolic A, Milicic V, Ristic G, Jovovic-Dagovic B. Pyoderma gangrenosum associated with Sjögren syndrome. Eur J Dermatol. 2009;19:392–3. 49. Richetta AG, D’Epiro S, Mattozzi C, Giancristoforo S, Calvieri S. Folgoration as an example of pathergy in a patient affected by pyoderma gangrenosum and Takayasu’s arteritis. Dermatol Res Pract. 2009;2009:393452. 50. Dejardin Botelho A, Delesalle F, Delaporte E, Wallaert B. Pyoderma gangrenosum and Churg-Strauss syndrome. Rev Med Interne. 2007;28:564–5. 51. Mehta AJ, Charman CR. Pyoderma gangrenosum in association with autoimmune neutropenia of infancy. Pediatr Dermatol. 2008;25:620–2. 52. Coors EA, von den Driesch P. Pyoderma gangrenosum in a patient with autoimmune haemolytic anaemia and complement deficiency. Br J Dermatol. 2000;143:154–6. 53. Necas M, Semrádova V, Vaskù V. Pyoderma gangraenosum associated with autoimmune thyreopathy and hyperandrogenic syndrome. Acta Dermatovenerol Alp Panonica Adriat. 2005;14:57–60. 54. Livideanu C, Lipsker D, Paul C, Juillard J, Schubert B. Pyoderma gangrenosum as initial manifestation of Graves’ disease. Clin Exp Dermatol. 2006;31:659–61. 55. Matis WL, Ellis CN, Griffiths CEM, Lazarus GS. Treatment of pyoderma gangrenosum with cyclosporin. Arch Dermatol. 1992;128:1060–4. 56. O’Donnell B, Powell FC. Cyclosporin treatment of pyoderma gangrenosum. J Am Acad Dermatol. 1991;24:141–3. 57. Zumdick M, Goerz G, Schuppe HC, Milde P, Ruzicka T. Niedrig dosierte Cyclosporin-A-Therapie bei Pyoderma gangraenosum. Erfahrungen bei 6 Patienten. Hautarzt. 1995;46:697–701.

Pyoderma gangrenosum: pathogenetic oriented treatment approaches  

9

review

58. Van den Driesch P. Pyoderma gangrenosum: a report of 44 cases with follow-up. Br J Dermatol. 1997;137:1000–5. 59. Prystowsky JH, Kahn SN, Lazarus GS. Present status of pyoderma gangrenosum. Arch Dermatol. 1989;125:57–64. 60. Arbiser JL, Moschella SL. Clofazimine: a review of its medical uses and mechanisms of action. J Am Acad Dermatol. 1995;32:241–7. 61. Peuckmann V, Fisch M, Bruera E. Potential novel uses of thalidomide: focus on palliative care. Drugs. 2000;60:273–92. 62. Wollina U, Karamfilov T. Treatment of recalcitrant ulcers in pyoderma gangrenosum with mycophenolate mofetil and autologous keratinocyte transplantation on a hyaluronic acid matrix. J Eur Acad Dermatol Venereol. 2000;14:187–90. 63. Daniels NH, Callen JP. Mycophenolate mofetil is an effective treatment for peristomal pyoderma gangrenosum. Arch Dermatol. 2004;140:1427–9. 64. Lee MR, Cooper AJ. Mycophenolate mofetil in pyoderma ganrenosum. J Dermatolog Treat. 2004;15:303–7. 65. Baumgart DC, Wiedenmann B, Dignass AU. Successful therapy of refractory pyoderma gangrenosum and periorbital phlegmona with tacrolimus [FK506] in ulcerative colitis. Inflamm Bowel Dis. 2004;10:421–4. 66. Kontochristopoulos GJ, Stavropoulos PG, Gregoriou S, Zakopoulou N. Treatment of pyoderma gangrenosum with low-dose colchicine. Dermatology. 2004;209:233–6. 67. Schmidt C, Wittig BM, Moser C, Zeitz M, Stallmach A. Cyclophosphamide pulse therapy followed by azathioprine or methotrexate induces long-term remission in patients with steroid-refractory Crohn’s disease. Aliment Pharmacol Ther. 2006;24:343–50. 68. Budde K, Glander P, Diekmann F, Waiser J, Fritsche L, Dragun D, et al. Review of the immunosuppressant enteric-coated mycophenolate sodium. Expert Opin Pharmacother. 2004;5:1333–45. 69. Fujimoto E, Fujimoto N, Kuroda K, Tajima S. Leukocytapheresis treatment for pyoderma gangrenosum. Br J Dermatol. 2004;151:1090–2. 70. Mori S, Nagashima M, Yoshida K, Yoshino K, Aoki M, Kawana S, et al. Granulocyte adsorptive apheresis for leg ulcers complicated by rheumatoid arthritis: a report on three successfully treated cases. Int J Dermatol. 2004;43:732–5. 71. Girolomoni G, Pastore S, Albanesi C, Cavani A. Targeting tumor necrosis factor-alpha as a potential therapy in inflammatory skin diseases. Curr Opin Investig Drugs. 2002;3:1590–5. 72. Mimouni D, Anhalt GJ, Kouba DJ, Nousari HC. Infliximab for peristomal pyoderma gangrenosum. Br J Dermatol. 2003;148:813–6. 73. Sapienza MS, Cohen S, Dimarino AJ. Treatment of pyoderma gangrenosum with infliximab in Crohn’s disease. Dig Dis Sci. 2004;49:1454–7. 74. Kaufman I, Caspi D, Yeshurun D, Dotan I, Yaron M, Elkayam O. The effect of infliximab on extraintestinal manifestations of Crohn’s disease. Rheumatol Int. 2005;25:406–10. 75. Roy DB, Conte ET, Cohen DJ. The treatment of pyoderma gangrenosum using etanercept. J Am Acad Dermatol. 2006;54(Suppl 2):128–34. 76. Hinterberger L, Müller CS, Vogt T, Pföhler C. Adalimumab: a treatment option for pyoderma gangrenosum after failure of systemic standard therapies. Dermatol Ther (Heidelb). 2012;2(1):6. 77. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010;10:89–102. 78. Steiger S, Harper JL. Mechanisms of spontaneous resolution of acute gouty inflammation. Curr Rheumatol Rep. 2014;16:392.

79. Tavares AH, Magalhães KG, Almeida RD, Correa R, Burgel PH, Bocca AL. NLRP3 Inflammasome activation by Paracoccidioides brasiliensis. PLoS Negl Trop Dis. 2013;7:e2595. 80. Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013;39:1003–18. 81. Cunha LD, Zamboni DS. Subversion of inflammasome activation and pyroptosis by pathogenic bacteria. Front Cell Infect Microbiol. 2013;3:76. 82. Mao L, Zhang L, Li H, Chen W, Wang H, Wu S, et al. Pathogenic fungus Microsporum canis activates the NLRP3 inflammasome. Infect Immun. 2014;82:882–92. 83. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol. 2010;11:1136–42. 84. Brenner M, Ruzicka T, Plewig G, Thomas P, Herzer P. Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol. 2009;161:1199–201. 85. Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)–a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409–15. 86. Baumgart DC, Wiedenmann B, Dignass AU. Successful therapy of refractory pyoderma gangrenosum and periorbital phlegmona with tacrolimus [FK506] in ulcerative colitis. Inflamm Bowel Dis. 2004;10:421–4. 87. Khurrum Baig M, Marquez H, Nogueras JJ, Weiss EG, Wexner SD. Topical tracrolimus [FK506] in the treatment of recalcitrant parastomal pyoderma gangrenosum associated with Crohn’s disease: report of two cases. Colorectal Dis. 2004;6:250–3. 88. Wollina U. Letter to the editor: Temporary renal insufficiency associated with topical tacrolimus treatment of multilocal pyoderma gangrenosum. J Dermatol Case Rep. 2013;7:106–7. 89. Neiderer K, Martin B, Hoffman S, Jolley D, Dancho J. A mechanically powered negative pressure device used in conjunction with a bioengineered cell-based product for the treatment of pyoderma gangrenosum: a case report. Ostomy Wound Manage. 2012;58:44–8. 90. Hill DS, O’Neill JK, Toms A, Watts AM. Pyoderma gangrenosum: a report of a rare complication after knee arthroplasty requiring muscle flap cover supplemented by negative pressure therapy and hyperbaric oxygen. J Plast Reconstr Aesthet Surg. 2011;64:1528–32. 91. Ghersi MM, Ricotti C, Nousari CH, Newman MI. Negative pressure dressing in the management of pyoderma gangrenosum ulcer. Arch Dermatol. 2007;143:1249–51. 92. Mir-Bonafé JM, Blanco-Barrios S, Romo-Melgar A, SantosBriz A, Fernández-López E. Photoletter to the editor: Localized pyoderma gangrenosum after interferon-alpha2b injections. J Dermatol Case Rep. 2012;6:98–9. 93. ten Freyhaus K, Homey B, Bieber T, Wilsmann-Theis D. Pyoderma gangrenosum: another cutaneous side-effect of sunitinib? Br J Dermatol. 2008;159:242–3. 94. Nadauld LD, Miller MB, Srinivas S. Pyoderma gangrenosum with the use of sunitinib. J Clin Oncol. 2011;29:e266–7. 95. Sagara R, Kitami A, Nakada T, Iijima M. Adverse reactions to gefitinib (Iressa): revealing sycosis- and pyoderma gangrenosum-like lesions. Int J Dermatol. 2006;45:1002–3. 96. Bustillo I, Kaley K, Saif MW. Rash associated with the use of pegylated filgrastim in a patient with advanced pancreatic cancer. Cutan Ocul Toxicol. 2009;28:181–4.

10   Pyoderma gangrenosum: pathogenetic oriented treatment approaches

13

review

97. Tinoco MP, Tamler C, Maciel G, Soares D, Avelleira JC, Azulay D. Pyoderma gangrenosum following isotretinoin therapy for acne nodulocystic. Int J Dermatol. 2008;47:953–6. 98. Freiman A, Brassard A. Pyoderma gangrenosum associated with isotretinoin therapy. J Am Acad Dermatol. 2006;55:107–8.

13

99. Hong SB, Lee MH. A case of propylthiouracil-induced pyoderma gangrenosum associated with antineutrophil cytoplasmic antibody. Dermatology. 2004;208:339–41. 100. Srebrnik A, Shachar E, Brenner S. Suspected induction of a pyoderma gangrenosum-like eruption due to sulpiride treatment. Cutis. 2001;67:253–6.

Pyoderma gangrenosum: pathogenetic oriented treatment approaches  

11