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Poor Prognosis of Arthritis-Associated Pyoderma Gangrenosum FREE

Carlos A. Charles, MD; Tracy L. Bialy, MD, MPH; Anna F. Falabella, MD; William H. Eaglstein, MD; Francisco A. Kerdel, MD; Robert S. Kirsner, MD
Arch Dermatol. 2004;140(7):861-864. doi:10.1001/archderm.140.7.861.
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Published online

ABSTRACT

Background  The association between pyoderma gangrenosum (PG) and arthritis is well established. We have observed a refractory population of patients with arthritis-associatedPG (PGA). We, therefore, tested the hypothesis that differences exist in response to treatment in patients with PGA compared with patients with PG without arthritis.

Observations  We performed a review of patients with PG during a 2-year period. Patients had noninfectious chronic ulcerations clinically typical for PG, exclusionof relevant differential diagnoses, and consistent histopathological features. Outcomes compared between patients with arthritis (PGA) and without arthritis(PG) included complete healing, percentage change in wound size, and duration of therapy. Of 10 PG ulcers, 7 healed, compared with 2 of 8 PGA ulcers. Therewas a greater mean percentage decrease in wound size in the PG vs the PGA ulcers (78.9% vs 23.4%; P = .10) and a shorter meanduration of treatment (8.7 vs 14.8 months; P = .18).

Conclusions  The ulcers of patients with PGA seem more refractory to treatment than the ulcers of patients with PG alone. Those with PGA ulcers represent a refractorysubset of patients, and the ulcers are possibly secondary to unique pathophysiological features.

Figures in this Article

PYODERMA GANGRENOSUM (PG) is a rare ulcerating inflammatory skin disease of unknown cause.1 Lesions may be solitaryor multiple, with the most common site involving the lower extremity.2 This destructive disease of the skin most commonly affects young to middle-aged adults, and women are more frequently affectedthan men. The diagnosis of PG is based on clinicopathological findings consistent with the condition and the exclusion of other disorders that mimic the clinicaldisease, such as bacterial, fungal, and mycobacterial infections, collagen vascular diseases, and various vasculitides.3

Pyoderma gangrenosum may occur as an idiopathic disease confined to the skin in 40% to 50% of patients. Approximately 50% of patients with PGhave an associated systemic disease.4 In the 60 years since PG was first defined as a clinical entity, many associatedconditions have been described, including inflammatory bowel disease,5 neoplastic disease,6 and arthritis.7 The association between PG andarthritis has been well established by reports8 showing up to 37% of PG patients with arthritis-associated PG (PGA). The arthritisassociated with PG has been seropositive and seronegative. The details regarding the clinical pattern of joint inflammation are variable, but the most commonpresentation is large-joint seronegative monoarticular arthritis.

We have observed that patients with PGA seemed to respond poorly to treatment when compared with patients with PG alone. Accordingly, we performeda retrospective review to compare a series of patients with PG alone with those with PGA. We compared the response to treatment in patients with PGand PGA. We tested the hypothesis that a difference exists in the response time to heal or in the ability to significantly reduce the size of the PGulcers between patients with PG and those with PGA.

METHODS

After institutional review board approval, a review was performed of the records of all patients examined and treated at the University of MiamiWound Clinic, Miami, during a 2-year period (December 1, 1998–December 1, 2000). All patients included met the clinicopathological criteria for lowerextremity PG. These include clinical criteria (painful ulceration, an undermined border, surrounding erythema, a purulent base, and rapid onset and enlargement)and histologic criteria (epidermal necrosis/ulceration, superficial dermal edema, and a dense, neutrophilic, and mixed dermal/subcutaneous infiltrate).Patients had noninfectious chronic ulcerations clinically typical for PG and the exclusion of relevant differential diagnoses through biopsy, tissue culture,and appropriate laboratory studies. If a patient had multiple ulcers, the target lesion was defined as the largest ulcer. Treatment measures other thanprednisone included cyclosporine, intralesional triamcinolone acetonide, minocycline, doxycycline, granulocyte-macrophage colony-stimulating factor, oral tacrolimus,and colchicine (Table 1). Outcomes compared between patients with PG and those with PGA included complete healing,percentage change in wound size, and duration of therapy. Arthritis was defined as one or more of the following findings: rheumatoid factor positive, physicalfindings of arthritis, or arthritis by medical history. Percentage change in wound size was defined as follows: (ulcer sizeb − ulcer sizef)/(sizeb × 100). In the equation, b is baseline; and f, final. Statistical methodsincluded paired t tests and the signed rank test.

Table Graphic Jump LocationTable 1. Number of Patients Treated With a Specified Modality

RESULTS

Eighteen patients met the inclusion criteria for PG and were included in our study. Of the 18 patients, 8 had PGA and the other 10 had PG not associatedwith arthritis. Patients were seen and followed up for a mean of 12.1 months (SD, 9.6 months), with a range of 1 to 24 months. For consistency of comparison,only patients treated for ulcers located on their lower extremities were enrolled. Patients with PGA were similar to patients with PG alone with regard to age,race, sex, size of the ulcer pretreatment, and histologic features (Table 2).

Table Graphic Jump LocationTable 2. Demographic Characteristics and Ulcer Sizes of the 2 Groups*

We found differences between the treatment response of the 2 groups.Of the 10 PG ulcers, 7 healed, compared with 2 of the 8 PGA ulcers (Figure 1). While the ulcer size between groupswas similar before treatment, the PG ulcers were significantly smaller than the PGA ulcers after treatment. In addition, the mean ulcer size after treatmentwas significantly smaller in the PG patients (P = .01), while PGA ulcers did not demonstrate a significant (P = .54) response (Figure 2).The mean duration of treatment was shorter in the PG group compared with the PGA group, but this did not reach statistical significance (P = .18) (Figure 3). Becausea reduction in wound size represents a good prognostic factor for other long-term wounds, such as venous ulcers,9 we comparedulcers that decreased by greater than 50% during the treatment period. We found that 8 of the 10 PG ulcers decreased by greater than 50%, compared with3 of the 8 PGA ulcers (Figure 4).

Place holder to copy figure label and caption
Figure 1.

Response to treatment: 7 of 10 pyoderma gangrenosum (PG) ulcers healed compared with 2 of 8 arthritis-associatedPG (PGA) ulcers.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Mean difference in ulcer size before and after treatment: ulcer size after treatment was smaller in thepatients with pyoderma gangrenosum (PG) (P = .01), while the arthritis-associated PG (PGA) ulcers did not demonstrate a significant (P = .54) response.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Mean treatment duration for groups: although not statistically significant (P = .18), the mean durationof treatment was shorter in the pyoderma gangrenosum (PG) group compared withthe arthritis-associated PG (PGA) group.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Decrease in wound size by 50% or less or greater than 50%: 8 of 10 pyoderma gangrenosum (PG) ulcers decreasedby greater than 50% compared with 3 of 8 arthritis-associated PG (PGA) ulcers.

Graphic Jump Location

COMMENT

We describe a refractory subset of patients with PGA. The association between PG and arthritis is well established, and has included various typesof arthritis. Classic seropositive rheumatoid arthritis (RA); an unusual, progressive, erosive, seronegative arthritis that is not associated with HLA-B27,psoriasis, or Reiter syndrome; and a seronegative arthritis associated with inflammatory bowel disease have all been associated with PG.7 Also,seronegative HLA-B27–positive spondyloarthropathies have been reported in association with PG.10 In the 18 patientsstudied retrospectively in this report, 10 had PG alone while 8 presented with PGA. Although other series8 have describedup to 37% of patients with PG being associated with arthritis, the large percentage of PGA patients in the present series may be because of a referral bias inherentto our university-based clinic, due to either a more difficult to diagnose or a more refractory subset of patients.

To better compare outcomes, we compared ulcers in patients with PG andPGA that occurred on the lower extremities. Pyoderma gangrenosum commonlypresents on the lower extremities,4 and patients with RA are also predisposed to developing leg ulcerations.11 Severalpossible explanations may account for why patients with PGA represent a more refractory subset. Concomitant disease present in patients with PGA may bepartially to blame. The presence of decreased ankle range of motion in patients with arthritis, in general, is associated with venous insufficiency,12 the most common cause of chronic leg ulcers. Alternatively,patients with PGA may have distinct pathophysiological features. The basis of the lower leg predilection for ulceration of PG- and RA-associated ulcershas not been completely elucidated; however, there are several identifiable factors present in patients with RA that may lead to this phenomenon. Factorssuch as skin fragility, arterial disease, peripheral edema, nutritional status, and, most important, venous insufficiency may all predispose patients withRA to leg ulcerations.

Patients with arthritis are at an increased risk for developing venous insufficiency because of their immobility, impaired fibrinolysis,13 and poor calf muscle pump function due to ankle arthritisand muscle atrophy.12 In fact, a study by McRorie et al14 assessed the venous function, arterialpressures, and range of ankle movement in 23 patients with RA with a leg ulcer, and compared the results with those in the nonulcerated contralateral limband in 25 patients with RA matched for age and duration of arthritis. They found evidence of venous insufficiency in the patients with RA and ulcer comparedwith control subjects. In addition, ankle movement was more restricted in the ulcerated limb compared with the nonulcerated contralateral limb. Therewas no difference in large-vessel arterial function between groups. These findings suggest that venous insufficiency may play a fundamental role inthe development and progression of leg ulcers for patients with RA, and may play a critical role in the refractory nature of leg ulcers for PGA patients.

Because the differential diagnosis of PG is expansive, it remains possible that in the setting of concomitant seronegative or seropositive arthritis,the inflammatory process associated with arthritis may be causal in these patients' ulcers, representing a unique entity. In addition, a combinationof factors, including PG and arthritis, may also be at play. Interestingly, cutaneous ulcerations secondary to arthritis are known to be particularlyresistant to treatment and associated with a great deal of morbidity.15

While this report demonstrates the refractory nature of PGA ulcers, there are inherent limitations to this case study. First, only 18 patientsmet the inclusion criteria and were studied. Second, as previously stated, the patients studied in this report were all taken from a referral-based universitywound care center.

In conclusion, we describe a refractory subset of patients with PGA.This may be either related to concomitant disease or possibly secondary tounique pathophysiological features.

ARTICLE INFORMATION

Correspondence: Robert S. Kirsner, MD, Department of Dermatologyand Cutaneous Surgery, University of Miami School of Medicine/Veterans AdministrationMedical Center, 1201 NW 16th St, Miami, FL 33125 (Rkirsner@med.miami.edu).

Accepted for publication August 29, 2003.

This study was partially supported by the Dermatology Foundation of South Florida, Miami.

REFERENCES

Callen  JP Pyoderma gangrenosum and related disorders Med Clin North Am. 1989;731247- 1261
PubMed
Bennett  MLJackson  JMJorizzo  JLFleischer Jr  ABWhite  WLCallen  JP Pyoderma gangrenosum: a comparison of typical and atypical forms with an emphasis on time to remission: case review of 86 patients from 2 institutions Medicine (Baltimore). 2000;7937- 46
PubMed Link to Article
Trent  JTKirsner  RS Diagnosing pyoderma gangrenosum Adv Skin Wound Care. 2001;14151- 153
PubMed Link to Article
von den Driesch  P Pyoderma gangrenosum: a report of 44 cases with follow-up Br J Dermatol. 1997;1371000- 1005
PubMed Link to Article
Ljung  TStaun  MGrove  OFausa  OVatn  MHHellstrom  PM Pyoderma gangrenosum associated with Crohn disease: effect of TNF-α blockade with infliximab Scand J Gastroenterol. 2002;371108- 1110
PubMed Link to Article
Rogalski  CPaasch  UGlander  HJHaustein  UF Bullous pyoderma gangrenosum complicated by disseminated intravascular coagulation with subsequent myelodysplastic syndrome (chronic myelomonocyticleukemia) J Dermatol. 2003;3059- 63
PubMed
Holt  PJDavies  MGSaunders  KCNuki  G Pyoderma gangrenosum: clinical and laboratory findings in 15 patients with special reference to polyarthritis Medicine (Baltimore). 1980;59114- 133
PubMed Link to Article
Powell  FCSchroeter  ALSu  WPPerry  HO Pyoderma gangrenosum: a review of 86 patients Q J Med. 1985;55173- 186
PubMed
Tallman  PMuscare  ECarson  PEaglstein  WHFalanga  V Initial rate of healing predicts complete healing of venous ulcers Arch Dermatol. 1997;1331231- 1234
PubMed Link to Article
Oliveria  ICosta  AMCantini  F  et al.  Pyoderma gangrenosum in association with undifferentiated seronegative spondyloarthropathy Arthritis Rheum. 1996;391062- 1065
PubMed Link to Article
Thurtle  OACawley  MI The frequency of leg ulceration in rheumatoid arthritis: a survey J Rheumatol. 1983;10507- 509
PubMed
Gaylarde  PMDodd  HJSarkany  I Venous leg ulcers and arthropathy Br J Rheumatol. 1990;29142- 144
PubMed Link to Article
Belch  JJMcArdle  BMadhok  R  et al.  Decreased plasma fibrinolysis in patients with rheumatoid arthritis Ann Rheum Dis. 1984;43774- 777
PubMed Link to Article
McRorie  ERRuckley  CVNuki  G The relevance of large-vessel vascular disease and restricted ankle movement to the aetiology of leg ulceration in rheumatoid arthritis Br J Rheumatol. 1998;371295- 1298
PubMed Link to Article
Negus  DFriedgood  A The effective management of venous ulceration Br J Surg. 1983;70623- 627
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Response to treatment: 7 of 10 pyoderma gangrenosum (PG) ulcers healed compared with 2 of 8 arthritis-associatedPG (PGA) ulcers.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Mean difference in ulcer size before and after treatment: ulcer size after treatment was smaller in thepatients with pyoderma gangrenosum (PG) (P = .01), while the arthritis-associated PG (PGA) ulcers did not demonstrate a significant (P = .54) response.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Mean treatment duration for groups: although not statistically significant (P = .18), the mean durationof treatment was shorter in the pyoderma gangrenosum (PG) group compared withthe arthritis-associated PG (PGA) group.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Decrease in wound size by 50% or less or greater than 50%: 8 of 10 pyoderma gangrenosum (PG) ulcers decreasedby greater than 50% compared with 3 of 8 arthritis-associated PG (PGA) ulcers.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Number of Patients Treated With a Specified Modality
Table Graphic Jump LocationTable 2. Demographic Characteristics and Ulcer Sizes of the 2 Groups*

References

Callen  JP Pyoderma gangrenosum and related disorders Med Clin North Am. 1989;731247- 1261
PubMed
Bennett  MLJackson  JMJorizzo  JLFleischer Jr  ABWhite  WLCallen  JP Pyoderma gangrenosum: a comparison of typical and atypical forms with an emphasis on time to remission: case review of 86 patients from 2 institutions Medicine (Baltimore). 2000;7937- 46
PubMed Link to Article
Trent  JTKirsner  RS Diagnosing pyoderma gangrenosum Adv Skin Wound Care. 2001;14151- 153
PubMed Link to Article
von den Driesch  P Pyoderma gangrenosum: a report of 44 cases with follow-up Br J Dermatol. 1997;1371000- 1005
PubMed Link to Article
Ljung  TStaun  MGrove  OFausa  OVatn  MHHellstrom  PM Pyoderma gangrenosum associated with Crohn disease: effect of TNF-α blockade with infliximab Scand J Gastroenterol. 2002;371108- 1110
PubMed Link to Article
Rogalski  CPaasch  UGlander  HJHaustein  UF Bullous pyoderma gangrenosum complicated by disseminated intravascular coagulation with subsequent myelodysplastic syndrome (chronic myelomonocyticleukemia) J Dermatol. 2003;3059- 63
PubMed
Holt  PJDavies  MGSaunders  KCNuki  G Pyoderma gangrenosum: clinical and laboratory findings in 15 patients with special reference to polyarthritis Medicine (Baltimore). 1980;59114- 133
PubMed Link to Article
Powell  FCSchroeter  ALSu  WPPerry  HO Pyoderma gangrenosum: a review of 86 patients Q J Med. 1985;55173- 186
PubMed
Tallman  PMuscare  ECarson  PEaglstein  WHFalanga  V Initial rate of healing predicts complete healing of venous ulcers Arch Dermatol. 1997;1331231- 1234
PubMed Link to Article
Oliveria  ICosta  AMCantini  F  et al.  Pyoderma gangrenosum in association with undifferentiated seronegative spondyloarthropathy Arthritis Rheum. 1996;391062- 1065
PubMed Link to Article
Thurtle  OACawley  MI The frequency of leg ulceration in rheumatoid arthritis: a survey J Rheumatol. 1983;10507- 509
PubMed
Gaylarde  PMDodd  HJSarkany  I Venous leg ulcers and arthropathy Br J Rheumatol. 1990;29142- 144
PubMed Link to Article
Belch  JJMcArdle  BMadhok  R  et al.  Decreased plasma fibrinolysis in patients with rheumatoid arthritis Ann Rheum Dis. 1984;43774- 777
PubMed Link to Article
McRorie  ERRuckley  CVNuki  G The relevance of large-vessel vascular disease and restricted ankle movement to the aetiology of leg ulceration in rheumatoid arthritis Br J Rheumatol. 1998;371295- 1298
PubMed Link to Article
Negus  DFriedgood  A The effective management of venous ulceration Br J Surg. 1983;70623- 627
PubMed Link to Article

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