Clinical variations in pyoderma gangrenosum

An age-specific evaluation of patients with pyoderma gangrenosum (PG) may allow for the development of focused algorithms for prioritizing assessment based on age, according to a cohort study of 356 cases of PG in JAMA Dermatology.

The study found that while clinical features of the rare inflammatory skin condition were comparable between younger and older patients, associated medical comorbidities varied by age. For instance, there were higher rates of inflammatory bowel disease (IBD) in patients younger than 65, while patients 65 and older had higher rates of solid organ and hematologic malignant neoplasms, hematologic disorders, and inflammatory arthritis.
"When handling very rare entities, often our understanding is based on a
single institution, sometimes even a single-provider, retrospective series," says co-author Misha Rosenbach, M.D., an associate professor of dermatology and internal medicine at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

The current study pooled data from two large tertiary care academic centers: University of Pennsylvania and Harvard Medical School. "We gathered three times as many cases as the largest previous study," Dr. Rosenbach tells Dermatology Times. "This allowed us to confirm some previously held beliefs about systemic disease associations in general, and also to identify a clear split in the age-groups and their systemic disease associations."

Overall, 66.3% of patients had associated medical comorbidities. "This is a larger number than previously reported," Dr. Rosenbach says. "Perhaps this is because we are tertiary care referral centers, or perhaps because we do a more thorough workup looking for these entities."

In addition, "perhaps not surprisingly, the older age group was more likely to have malignancies and hematological disorders than the younger group, although importantly some young patients did have cancer/hematologic abnormalities," Dr. Rosenbach says.

Dr. Rosenbach points out that the high numbers of younger patients with PG-associated IBD -- 47.7% versus 26.6% of older patients -- "really strengthens the need for clinicians to carefully screen for IBD with directed questions, and have a very low threshold to refer patients for
gastrointestinal (GI) evaluation."

Neutrophilic dermatoses, including PG, Sweet's syndrome (SS) and other entities in general, are fairly understudied and poorly understood, according to Dr. Rosenbach director of inpatient dermatology at the University of Pennsylvania. "Patients with these diagnoses often are quite uncomfortable, and there can be a long delay in diagnosis because it often requires an experienced medical dermatologist to recognize these entities," he says. "We would really like to move the field forward and gain a better understanding for how and why these diseases occur: Why are they associated with different underlying systemic diseases? How do they impact patients? And how can we best treat them?"

Dr. Rosenbach says he and his colleagues are in the midst of some translational studies looking further into the etiopathogenesis of these disorders.  "As part of that, we wanted to identify pure, proven cases of neutrophilic dermatoses to use," he says. "In doing so, we carefully catalogued the cases we had at Penn and presented our findings at a national meeting."

Collaborating with Arash Mostaghimi, M.D., and his Harvard group "really expanded the numbers, impact, and scope of the study," Dr. Rosenbach says. "We hope that cooperative, multidisciplinary research like this will help expand our understanding of these types of rare diseases."

However, in this era of cost-conscious care, "it is important not to perform every test on every patient, and to carefully consider the costs, pretest likelihood of a result, and how a test will impact medical decision-making," Dr. Rosenbach says.

While traditionally IgA paraproteinemia has been reported as a rare association with PG, "our study makes it pretty clear that while paraproteins in general are more common as you age, in PG in particular
those types of disorders truly are much more important to consider in older patients, and really should not be the first priority in younger patients. Age-stratified initial workup for PG should make things easier on clinicians and on the patients."

Going forward, translational studies are needed "to demonstrate the key, critical cytokines involved in these diseases, validated diagnostic tools and severity-assessment scores, and then clinical trials using targeted therapies to mitigate the inflammation," Dr. Rosenbach says.

Because there are currently no uniformly accepted diagnostic criteria for PG, a Delphi consensus exercise comprised of 12 international expert physicians proposed and validated criteria for ulcerative PG in JAMA Dermatology.

However, the consensus statement yielded only one major criterion: biopsy of ulcer edge demonstrating neutrophilic infiltrate.

But there were eight minor criteria: exclusion of infection; pathergy; history of IBD or inflammatory arthritis; history of papule, pustule or vesicle ulcerating within 4 days of appearing; peripheral erythema, undermining border and tenderness at ulceration site; multiple ulcerations, with at least one on an anterior lower leg; cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and decreased ulcer size within 1 month of initiating immunosuppressive medication(s).

Approved diagnostic criteria were tested and validated using 113 case reports (65 pertaining to PG and 48 related to PG mimickers).

“Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively,” wrote the authors, led by Emanual Maverakis, M.D., of the Department of Dermatology at the University of California, Davis.

The authors hope that the combined major and minor criteria might serve as a guideline for clinicians, resulting in fewer misdiagnoses and better patient selection for clinical trials.
The authors also note that the proposed diagnostic criteria will no longer be a diagnosis based on exclusion.

But the consensus statement acknowledges that atypical ulcerative PG cases may be missed, especially when the biopsy was obtained after starting immunosuppressive therapy or during spontaneous resolution.

In an editorial about the two papers in JAMA Dermatology, Benjamin Kaffenberger, M.D., an assistant professor of dermatology at Ohio State University, said the Rosenbach/Mostaghimi study is the largest cohort of PG patients to date and supports that an underlying disease like Crohn’s, ulcerative colitis, cancer and blood disorders “can be detected in greater than the conventionally cited 50% of patients. The study also shows that younger patients are far more likely to have IBD, whereas cancer is much more likely in the elderly.”

On the other hand, the Delphi consensus paper presents a new method for confirming the diagnosis of PG. “This is a substantial step forward for confirming disease, provided it holds up in clinical practice,” Dr. Kaffenberger, director of Inpatient Consult Service at the university, tells Dermatology Times. “The paper used case reports, which typically represent either the most classic of diseases or most severe/extreme cases to validate the criteria. We just need to be certain that the method for confirmation performs just as well in clinical practices. I would be hesitant to use it without another validation step.”

REFERENCES
Hovik J. Ashchyan, BA; Daniel C. Butler, MD; Caroline A. Nelson, MD; et al. "The Association of Age With Clinical Presentation and Comorbidities of Pyoderma Gangrenosum," JAMA Dermatology. Feb 14, 2018. DOI:10.1001/jamadermatol.2017.5978

Emanual Maverakis, MD; Chelsea Ma, MD; Kanade Shinkai, MD, PhD; et al. "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum," JAMA Dermatology. Feb. 14, 2018. DOI:10.1001/jamadermatol.2017.5980

Benjamin H. Kaffenberger, MD; John Trinidad, MD, MPH "Diagnosis uPGrade-Advances in Pyoderma Gangrenosum," JAMA Dermatology. Published online February 14, 2018. DOI:10.1001/jamadermatol2017.5979