REVIEWS

Pyoderma gangrenosum: A review and updateon new therapies

Jeremiah Miller, MD,a Brad A. Yentzer, MD,a Adele Clark, PA-C,a Joseph L. Jorizzo, MD,a

and Steven R. Feldman, MD, PhDa,b,c

Winston-Salem, North Carolina

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Pyoderma gangrenosum is a rare and often painful skin disease that can be unpredictable in its response totreatment. There is currently no gold standard of treatment or published algorithm for choice of therapy.The majority of data comes from case studies that lack a standard protocol not only for treatmentadministration but also for the objective assessment of lesion response to a specific therapy. This reviewprovides an update to the treatment of pyoderma gangrenosum with a particular focus on new systemictherapies. ( J Am Acad Dermatol 2010;62:646-54.)

Key words: adalimumab; alefacept; clinical trials; efalizumab; etanercept; infliximab.

Pyoderma gangrenosum (PG) is a rare ulcera-tive disorder of the skin that can cause pain,disfigurement, and even death. PG is generally

classified into 4 types: classic (ulcerative), bullous,pustular, and vegetative.1 Diagnosis can be difficult,and the biopsy specimen does not provide anypathognomonic information.2 The key in diagnosingPG is excluding other causes of cutaneous ulcersthrough biopsy, culture, and clinical acumen. Oncediagnosed, treatment should target any underlyingdisease that is present (inflammatory bowel disease,monoclonal gammopathy, hematologic malignancyor paraproteinemia, Behcet disease, Sweet syn-drome, hepatitis, HIV, systemic lupus erythematosus,pregnancy, and Takayasu arteritis).1,3-5

the Departments of Dermatology,a Pathology,b and Public

ealth Sciences,c Center for Dermatology Research, Wake

rest University School of Medicine.

llas Pharma Global Development Inc provided support for the

eparation of this review. The Center for Dermatology Re-

arch is supported by an unrestricted educational grant from

alderma Laboratories LP.

osure: Dr Feldman has received research, speaking, and/or

nsulting support from Abbott Labs, American Society for

ermatologic Surgery, Amgen, Astellas, Aventis Pharmaceuti-

ls, Biogen, Centocor, Connetics, Galderma, Genentech, No-

rtis, and Roche. Dr Jorizzo has received speaking and/or

nsulting support from Amgen. Dr Miller, Dr Yentzer, and Ms

lark have no conflicts of interest to declare.

ints not available from the authors.

spondence to: Steven R. Feldman, MD, PhD, Department of

ermatology, Wake Forest University School of Medicine,

edical Center Blvd, Winston-Salem, NC 27157-1071. E-mail:

eldman@wfubmc.edu.

-9622/$36.00

09 by the American Academy of Dermatology, Inc.

0.1016/j.jaad.2009.05.030

Various drug regimens have been implementedwith success in PG. These often include complicatedcombinations of steroids and other medications thatinhibit some component of the immune system. Thegoal of this review is to provide an update on treatingPG in an effective and safe manner. Information wasgathered from textbooks, a PubMed and Ovid liter-ature search, and expert opinion. The PubMed andOvid searches were performed using a variety ofcombined search terms including ‘‘pyoderma gan-grenosum,’’ ‘‘treatments,’’ ‘‘topical,’’ ‘‘biologics,’’‘‘therapy,’’ ‘‘infliximab,’’ ‘‘etanercept,’’ ‘‘alefacept,’’‘‘efalizumab,’’ and ‘‘adalimumab.’’

LOCAL WOUND MANAGEMENTEffective management of PG ulcers is an objective

evaluation of the ulcers so that wound managementcan be planned. At each visit, objective measure-ments including depth, length, and width of the ulcershould be recorded.6 These measurements incombination with sequential photography can thenserve as a gauge for wound management success.The inflammatory component of PG is assessed bythe border elevation and lesion expansion. When theborder flattens, anti-inflammatory medications canbe slowly tapered.

Once a system for monitoring the lesions is inplace, a decision regarding wound dressing must bemade. Moisture-retentive dressings appear to besuperior to desiccative gauzes in that they providebetter pain control, induce collagen production,facilitate autolytic debridement, and promote angio-genesis.6 Furthermore, these occlusive dressings areless permeable to external infection than gauze.6

Creating a barrier to infection is particularly relevantin PG as many of its systemic treatments (eg, steroids,

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Miller et al 647

biologics) can impair the physiologic immune re-sponse to bacterial invasion. However, in the settingof copious exudate production, alginates are a nec-essary alternative to reduce the risk of macerationthat occlusive dressings may cause.6 The area aroundthe wound must not be neglected as its viability canbe compromised by the increased moisture and

CAPSULE SUMMARY

d There is currently no gold standard oftreatment or published algorithm forchoice of therapy for pyodermagangrenosum.

d Therapy should focus on treating anyunderlying disease.

d Several small trials and case reportsdemonstrate efficacy of the new biologicagents.

d Variability in assessment and outcomesof pyoderma gangrenosum make itdifficult to accurately comparetreatments.

dressing adhesives used intreating the active PG lesion.6

Barrier cream or ointment(eg, zinc oxide paste) shouldbe used to prevent such fur-ther skin breakdown.6

Cultures from a PG lesionoften reveal a complex mix-ture of bacterial and fungalcontaminants that should beirrigated away. Tissue infec-tion is manifested by celluli-tis, lymphangitis, or both andrequires appropriateantibiotics.

PAIN CONTROLWith the exception of the

vegetative variant, patients

with PG almost universally experience debilitatingpain, sometimes described as ‘‘stabbing’’ in quality.The pain can become so severe that amputation hasbeen implemented when systemic therapy is inef-fective.7 Although patients with the vegetative vari-ant of PG may have some tenderness, the pain isgenerally less than that experienced by patients withother types of PG. The source of the pain is multi-factorial, but much of it can be attributed to theinflammatory process of PG in the dermis and theresultant deep ulcer. Repeated manipulation of thewound, inherent with regular dressing changes, is asource of continued discomfort for the patient.8 Justas it is important to quantify the size and progressionof lesions, it is equally important to regularly monitorand document the patient’s level of pain as a markerof treatment efficacy. When lesional inflammation isadequately treated and wound care is appropriatelyaggressive, the pain should subside. Because of theoverall length of disease activity and the need toavoid dependence on narcotics, physicians shouldlimit use of these agents for breakthrough painmanagement. A multispecialty approach is oftenhelpful at addressing the significant chronic painand depression experienced by these patients.

TREATMENTSThere is currently no gold standard of treatment for

PG.9 Choiceof therapywill dependonmultiple factors

including size and depth of the lesion, the rapidity oflesion growth and appearance of new lesions, theassociated disease (eg, inflammatory bowel disease,arthritis), and general medical status of the patient.Other factors in choice of treatment include associatedtoxicities of the medications, as up to 50% of patientswith classic PG require long-term therapy to maintain

remission.9 The patient’s levelof pain and signs of inflam-mation (particularly the ele-vation and redness of thelesion border) help guideresponse to treatment.Treatment discussed here ap-plies to all types of PG.Because PG is very rare, var-iation in the response of dif-ferent forms of PG totreatment has not been as-sessed. The following datafrom studies of PG manage-ment included either classicPG or a mix of classic andatypical PG.

Topical agents

Initial treatment for mild lesions (superficial pus-

tules, papules, or nodules; or shallow, small ulcers)includes local applications such as dressings, topicalagents, or intralesional injections.3 Topical agentscan also be effective adjunctive treatment for moresevere PG.10 Although some topical drugs such astacrolimus, potent corticosteroids, and cyclosporinehave reported efficacy in individual cases or smallcase series,10,11 evidence from large clinical trials islacking. In addition, topical applications are notnecessarily safer, as some drugs have a high rate ofsystemic absorption when applied topically to PGulcers.12 Caution must be taken as a few case reportsof once daily application of topical tacrolimusrevealed immunosuppressant levels in the bloodwithin 12 days.13 Other single case reports exist forusing topical nitrogen mustard, sodium cromogly-cate, and 5-aminosalicylic acid as well.14-18 Althoughthe underlying cause of PG is noninfectious, theulcers can harbor odor-producing bacteria. As such,topical antibiotics such as metronidazole can helpeliminate the odor.

Systemic agentsIn the presence of underlying disease or severe

PG, steroids or other immunomodulators areenlisted (Table I). These very efforts to modulatethe immune system and contain PG have the sec-ondary effect of creating an environment in which

Table I. Potential risks of treatments and level of efficacy evidence

Systemic treatments

Periodic blood

tests required Potential risks Potential benefits

Level of

efficacy

evidence*

Nonbiological treatmentsPrednisone Osteoporosis, cataracts,

increased bloodsugar, psychiatric,adrenal insufficiency,HTN, GI ulcer, vertigo,edema, ecchymosis,glaucoma

Rapid onset(;2-3 d), reliablyeffective

2

Cyclosporine Blood counts,chemistry panelwith creatinine,magnesium,triglycerides

Nephrotoxicity, livertoxicity, HTN,gingival hyperplasia,hypertrichosis,nausea

Rapid action,can initiatetreatmentat full dose

2

Short-term (6-12 mo)use only

Thalidomide Pregnancy, bloodcounts

Cost, neuropathy,teratogen, peripheralneuropathy, bradycardia,anemia, thrombosis,cutaneous eruption

No riskof immunesuppression

2

Highly regulatedby the FDA: Systemfor ThalidomideEducationand PrescribingSafety (STEPS) Program

Methotrexate Blood countsand liverfunction tests

Hepatic, hematologicand pulmonary toxicity

Low cost,once weeklyoral administration

3

Tacrolimus Blood counts,liver and kidneyfunction tests,lipid levels, uricacid levels

Nephrotoxicity, headache,paresthesias, tremor,delirium, coma, HTN,hyperglycemia,diarrhea, infection(respiratory, urinary,HSV), lymphoma,hyperkalemia, drug-druginteractions

Alternative tocyclosporine

3

Azathioprine Blood counts,liver functiontests, amylase level,TPMT level

Pancytopenia, leukopenia,thrombocytopenia,bone-marrowsuppression,hepatotoxicity,nausea, slow onset

Helps reduceexposure tosystemic steroids

3

Mycophenolatemofetil

Blood counts,pregnancy test,electrolytes

Cost, progressivemultifocalleukoencephalopathy,teratogen,constipation, diarrhea,dyspepsia, andnausea/vomiting,renal toxic,infection, neutropenia,

Often well tolerated;can be usedin combinationwith other systemictreatments

3

Continued

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648 Miller et al

Table I. Cont’d

Systemic treatments

Periodic blood

tests required Potential risks Potential benefits

Level of

efficacy

evidence*

Cyclophosphamide Blood counts,pregnancy test,electrolytes

Leukopenia,neutropenia, anemia,thrombocytopenia,pancytopenia,hemorrhagiccystitis, infertility,SIADH, teratogen,alopecia, interstitialpneumonitis

Helps reduceexposure tosystemic steroids

3

Chlorambucil Frequent blood counts Bone-marrowsuppression,neutropenia,nausea/vomiting,nephrotic syndrome

Helps reduceexposure tosystemic steroids

3

IVIG Cost, nausea,headache, asepticmeningitis

No risk ofimmunosuppression

3

Dapsone G6PD levels Anemia, agranulocytosis,exfoliative dermatitis,toxic epidermalnecrolysis,methemoglobinemia,acute tubular necrosis,peripheralneuropathy,hepatotoxicity

Helps reduceexposure tosystemic steroids

3

Granulocyte apheresis Time-consuming, cost Minimal sideeffects relativeto othersystemic therapies35-37

3

Biological treatmentsInfliximab Tuberculosis test Cost, reactivation

of latenttuberculosis,lymphoma,demyelinatingdisease, CHF

Avoids organtoxicity of traditionalsystemic, highlyeffective, rapid action

1

Alefacept CD4 counts Lowers CD4 counts,although thisis generallywell tolerated,slow onset of action

Very safe,appears to haveminimal riskof immunesuppression

2

Adalimumab Tuberculosis test Cost, reactivationof latenttuberculosis,lymphoma,demyelinatingdisease, CHF

Avoids organtoxicity of traditionalsystemic, highlyeffective

3

Efalizumab CBC Cost, reactivationof latenttuberculosis,lymphoma,demyelinatingdisease, CHF, PML

Avoids organtoxicity oftraditional systemic

3

Continued

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Miller et al 649

Table I. Cont’d

Systemic treatments

Periodic blood

tests required Potential risks Potential benefits

Level of

efficacy

evidence*

Etanercept Tuberculosis test Cost, reactivationof latenttuberculosis,lymphoma,demyelinatingdisease, CHF

Avoids organtoxicity of traditionalsystemic

3

CBC, Complete blood cell count; CHF, congestive heart failure; FDA, Food and Drug Administration; G6PD, glucose-6-phosphate

dehydrogenase; GI, gastrointestinal; HSV, herpes simplex virus, HTN, hypertension; IVIG, intravenous immunoglobulin; PML, progressive

multifocal leukoencephalopathy; SIADH, syndrome of inappropriate antidiuretic hormone hypersecretion; TPMT, thiopurine

methyltransferase.

None of these medications are currently FDA approved for use in treatment of pyoderma gangrenosum.

*Adapted with permission from Bolognia et al38 and Chow and Ho.63 1 = Prospective placebo-controlled trial; 2 = retrospective study, large

case series, or small uncontrolled trials; 3 = small case series or case reports.

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bacteria may thrive. Moreover, continued use ofimmunosuppressants can lead to an array of well-documented side effects.4,19 Table II provides aranking of systemic therapy based on available safetyand efficacy and authors’ opinions.

Classic ulcerative PG is often treated initially withhigh-dose corticosteroids (prednisone 1-2 mg/kg/d),because of the rapidity of response (;2-3 days).However, because some ulcers may require monthsto years to fully resolve and/or are unresponsive tocorticosteroids, other immunomodulators have beenused. The next most commonly used agent, cyclo-sporine, can help act as a corticosteroid-sparingtherapy. However, cyclosporine has its own side-effect profile that includes renal toxicity with pro-longed use. Cyclosporine should be restricted topatients with idiopathic disease because it is not anappropriate long-term treatment, as is needed forpatients with underlying disease such as inflamma-tory bowel disease. Methotrexate and thalidomidehave also been used in the treatment of PG, but aregenerally more effective as adjunctive therapy ratherthan as first-line, monotherapy agents. Dapsone, incombination with prednisone or alone as a mainte-nance therapy, is sometimes used to treat PG inpatients with normal levels of glucose-6-phosphatedehydrogenase.

Given the risks of immunosuppressants, intrave-nous immunoglobulin (IVIG) has recently shownpromise in severe cases. In one retrospective study of10 patients with classic PG, 7 demonstrated clearanceof PG lesions with adjuvant IVIG at a dosage of 2g/kg divided into 3 doses given over 3 consecutivedays on a monthly basis. Side effects of IVIGreported include nausea and headache and onereport of aseptic meningitis.4 A drawback of IVIG isthe associated high cost of ongoing therapy.

Biologic agentsMore recently, tumor necrosis factor-alfa blockers

and other injectable biologics have been used withsome success (Table III). Tumor necrosis factor-alfablockers are frequently chosen to treat patients withcoexisting Crohn disease or rheumatoid arthritis.Infliximab is the only biologic demonstrated to beefficacious in classic PG in a randomized, double-blind, placebo-controlled trial. Thirty patients in thestudy were exposed to either 5 mg/kg of infliximabor placebo. Those receiving placebo continued onvarious regimens they had previously been pre-scribed. Six (46%) of the 13 patients in the infliximabgroup demonstrated improvement in the severityand/or size of the ulcers (as determined by theclinician and patient global assessments) versus onlyone (6%) in the placebo group at week 2. After 2weeks, the 16 nonresponders from the placebogroup were also given infliximab. By week 6, 69%(20 of 29) of all patients who received infliximabdemonstrated a beneficial clinical response, 6 ofwhom achieved complete resolution of lesions.20

Etanercept has also been used with success inseveral case series. In one series, 6 patients, mostlywith lower extremity lesions, achieved significant ifnot complete resolution of their ulcers on etaner-cept.21 The most common dosing was 50 mg weekly,either given in one dose or divided into two doses of25 mg each.21 Another series on the use of etanerceptfor PG documented improvement within the firstmonth,with complete resolutionoccurringbetween2and 5 months in all 5 cases.22-25 Charles et al26 report aretrospective analysis of 7 cases of PG which demon-strated an average time to complete healing of 12.5weeks when given between 25 and 50 mg twice perweek. Although one patient stopped therapy becauseof the side effect of cacogeusia, all 7 cases of PG

Table II. Safety, efficacy, and overall rank of treatments for idiopathic pyoderma gangrenosum

Rank Safety Efficacy Cost (less expensive) Overall rank

1 Granulocyte apheresis Prednisone Prednisone Prednisone2 IVIG Infliximab Methotrexate Cyclosporine3 Alefacept Cyclosporine Dapsone Methotrexate*4 Etanercept Mycophenolate mofetil Azathioprine Mycophenolate mofetil5 Dapsone Adalimumab Mycophenolate mofetil Dapsone6 Adalimumab Etanercept Cyclosporine Adalimumab7 Infliximab Cyclophosphamide Cyclophosphamide Infliximab8 Methotrexate Tacrolimus Tacrolimus Etanercept9 Thalidomide Alefacept Chlorambucil Thalidomide

10 Mycophenolate mofetil Chlorambucil Etanercept IVIG11 Azathioprine IVIG Adalimumab Alefacept12 Prednisone Granulocyte apheresis IVIG Granulocyte apheresis13 Cyclosporine Thalidomide Infliximab Tacrolimus14 Tacrolimus Dapsone Thalidomide Cyclophosphamide15 Cyclophosphamide Methotrexate Granulocyte apheresis Chlorambucil16 Chlorambucil Azathioprine Alefacept Azathioprine

IVIG, Intravenous immunoglobulin.

Based on efficacy, safety, cost, and experience. There are no rigorous head-to-head trials comparing these treatments. Order of medications

is based on available data and authors’ opinions. In addition, it should be noted that this ranking is for idiopathic disease, as treatment of

underlying disease will guide choice of therapy (ie, using infliximab in patient with Crohn disease). In addition, some of these drugs may be

used in combination.

*Best as adjunctive therapy.

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responded favorably to the treatment (4 with com-plete clearance, 3 with reduction of ulcer size).26

Adalimumab, another tumor necrosis factor-alfainhibitor, has been used with success in for ulcerativePG in 8 reported cases.27-32 The drug has beenadministered in various patterns of 40 mg perweek, 40 mg bimonthly, or 80 mg bimonthly.Regardless of dosing schedule, the majority of recip-ients have achieved some measure of improvementor success on adalimumab within 2 weeks to 2months. Most cases did not specify an end point,but rather implied that the patients were kept ondrug as maintenance.

Reports of the use of efalizumab in PG are limited,but Woodson et al33 report a recalcitrant case thatcompletely resolved after 6 months of therapy.

A recent study using alefacept, an immunomod-ulator that decreases T-cell activation, demonstratedimprovement when used in patients with PG.34 After4 patients received 15 mg of alefacept intramuscu-larly for 20 weeks, one achieved remission, two hadmarked improvement, and the fourth only had slightimprovement using criteria set forth by the physicianglobal assessment.34 By week 32, 12 weeks afterconclusion of treatment, a total of two patientsachieved remission.

CLINICAL TRIALSSeveral studies have emerged showing the benefit

of using biologics (infliximab, etanercept,

efalizumab, adalimumab, and alefacept) for thetreatment of PG. Most of the studies used an endpoint of complete resolution of lesions (Table III).However, this is not the most sensitive method fordetecting efficacy, as many biologics may yieldsignificant clinical improvement without completeresolution of lesions or lesions may require moretime for complete healing than the constraints of thestudy permit. Other studies have used variousmarkers (lesion size, inflammatory markers, orpain) as measurements of clinical improvement.However, although this may be sensitive for detect-ing any clinical improvement, there is no standardoutcome to easily compare across studies.

With the exception of the study by Brooklyn etal,20 clinical trials of PG have not been randomized,placebo-controlled studies. This is likely secondaryto the ethics of giving a placebo to a patient with PG.Although the article by Brooklyn et al20 does notspecify the ethical considerations of having a pla-cebo group, patients who did not improve were keptin the placebo group for only the first 2 weeks.

Because of the rarity of PG in the general popula-tion, large studies are not feasible.1 Furthermore, itmay not be practical in a clinical trial to segregatepatients with underlying disease from those without.However, clinical trials of PG can be improved toprovide a clearer picture about efficacy and treatmentduration for a given medication. Some areas in whichprevious trials were inadequate include definitions of

Table III. Reported use of biologics for treatment of pyoderma gangrenosum

Infliximab Etanercept Efalizumab Adalimumab Alefacept

No. of case reports orretrospective studies

20 13 1 8 0

Total No. of clinical trials 7 0 0 0 1Placebo-controlled trials 1 0 0 0 0Total No. of patients

exposed92 13 1 8 4

OutcomesFailures 17 Patients5,20,32,39,40 1 Patient26 0 0 0

NI-16 SE-1SE-1

Clinical improvement(decrease in lesionsize, inflammatorymarkers, or patient’spain)

29 Patients20,39-45 7 Patients22,26 0 4 Patients27,32 3 Patients34

‘‘Almost’’ completeresolution

2 Patients46,47 0 0 0 0

Complete resolutionof lesions

44 Patients5,20,40,48-62 5 Patients22-25 1 Patient33 4 Patients28-31 1 Patient34

Total No. of patientswith success

75 12 1 8 4

NI, No improvement; SE, intolerable side effect.

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the type of PG, regular measurements of size andprogression of lesions, standardized wound care,standardized outcome (definition for complete reso-lutionof lesions), and time required to reachoutcome.Furthermore, it may be useful to assess time to initialresponse (as defined by a reduction of inflammation)and the rate of wound closure. Only when these areasare adequately addressed can we begin to adequatelyquantify response to particular drugs.

ConclusionsThe use of biologics for treating PG seems prom-

ising. However, PG can be unpredictable in itsresponse to treatment and there is currently nogold standard of treatment. There is simply a lackof systematic data on therapies. The final, overallranking (Table II) is based on the authors’ opinionswhen weighing safety, efficacy, cost, and experi-ence. Of the biologics, there has only been aplacebo-controlled study of infliximab. Data onlong-term outcomes are unavailable. The majorityof data come from case studies that lack a standardprotocol for either treatment administration or theobjective assessment of lesion response to a specifictherapy. Objective and carefully constructed assess-ment criteria are necessary to define efficacy in ameaningful and comparable way. Through consis-tent measurement, it may be possible to identify bestpractices. Given the debilitating nature of the dis-ease, and the side effects such as liver, kidney, and

bone toxicity of older treatments (Table I), furtherstudies are necessary to identify specific therapiescapable of successfully treating PG without causingunintended harm to the patient.

The authors would like to extend a special thanks to DrsAlex Michaels, Barbara Mathes, and Jeffrey P. Callen fortheir contributions to the preparation of this manuscript.

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