Importance Pyoderma gangrenosum is a rare inflammatory skin condition that is difficult to diagnose. Currently, it is a “diagnosis of exclusion,” a definition not compatible with clinical decision making or inclusion for clinical trials. Objective To propose and validate diagnostic criteria for ulcerative pyoderma gangrenosum. Evidence Review Diagnostic criteria were created following a Delphi consensus exercise using the RAND/UCLA Appropriateness Method. The criteria were validated against peer-reviewed established cases of pyoderma gangrenosum and mimickers using k-fold cross-validation with methods of multiple imputation. Findings Delphi exercise yielded 1 major criterion—biopsy of ulcer edge demonstrating neutrophilic infiltrate—and 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations, at least 1 on an anterior lower leg; (7) cribriform or “wrinkled paper” scar(s) at healed ulcer sites; and (8) decreased ulcer size within 1 month of initiating immunosuppressive medication(s). Receiver operating characteristic analysis revealed that 4 of 8 minor criteria maximized discrimination, yielding sensitivity and specificity of 86% and 90%, respectively. Conclusions and Relevance This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum. The criteria may serve as a guideline for clinicians, allowing for fewer misdiagnoses and improved patient selection for clinical trials.

To the Editor: We would like to thank Maverakis et al for expressing interest in our article and for raising important discussion points.1Ashchyan H.J. Nelson C.A. Stephen S. James W.D. Micheletti R.G. Rosenbach M. Neutrophilic dermatoses: pyoderma gangrenosum and other bowel- and arthritis-associated neutrophilic dermatoses.J Am Acad Dermatol. 2018; 79: 1009-1022Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar In particular, we applaud them for drawing attention to the new diagnostic criteria for pyoderma gangrenosum (PG) that were published this year.2Maverakis E. Ma C. Shinkai K. et al.Diagnostic criteria of ulcerative pyoderma gangrenosum: a delphi consensus of international experts.JAMA Dermatol. 2018; 154: 461-466Crossref PubMed Scopus (211) Google Scholar, 3Jockenhofer F, Wollina U, Salva KA, Benson S, Dissemond J. The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum. Br J Dermatol. doi: 10.1111/bjd.16401, Accessed December 8, 2018.Google Scholar These criteria represent an important step forward in the diagnosis of PG. Maverakis et al contend that PG should no longer be labeled a diagnosis of exclusion, as it is impractical to have a medical diagnosis that requires one to rule out all other possible diagnoses.2Maverakis E. Ma C. Shinkai K. et al.Diagnostic criteria of ulcerative pyoderma gangrenosum: a delphi consensus of international experts.JAMA Dermatol. 2018; 154: 461-466Crossref PubMed Scopus (211) Google Scholar We respectfully disagree. From a semantic standpoint, we believe that the label “diagnosis of exclusion” is crucial to remind physicians to exclude mimickers, such as ulceration of vascular, infectious, inflammatory, and neoplastic etiologies, before rendering a diagnosis of PG.3Jockenhofer F, Wollina U, Salva KA, Benson S, Dissemond J. The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum. Br J Dermatol. doi: 10.1111/bjd.16401, Accessed December 8, 2018.Google Scholar For example, failing to exclude infection before initiating immunosuppressive therapy could have dire consequences for the patient and medicolegal ramifications for the physician. Indeed, in their article, Weenig et al demonstrated that PG is commonly misdiagnosed and concluded that a thorough evaluation is required in all patients suspected of having PG to rule out alternative diagnoses.4Weenig R.H. Davis M.D. Dahl P.R. Su W.P. Skin ulcers misdiagnosed as pyoderma gangrenosum.N Engl J Med. 2002; 347: 1412-1418Crossref PubMed Scopus (301) Google Scholar The sole major diagnostic criterion for ulcerative PG yielded by the Delphi exercise was biopsy of ulcer edge demonstrating a neutrophilic infiltrate.2Maverakis E. Ma C. Shinkai K. et al.Diagnostic criteria of ulcerative pyoderma gangrenosum: a delphi consensus of international experts.JAMA Dermatol. 2018; 154: 461-466Crossref PubMed Scopus (211) Google Scholar Biopsy is also valuable to evaluate for PG mimickers. Although we acknowledge that excluding every alternative diagnosis in every patient may not be practical, at a minimum we recommend that patients with a suspected diagnosis of ulcerative PG undergo a thorough history and physical examination, a skin biopsy with tissue culture, a complete blood count with differential, and age-appropriate malignancy screening, with further evaluation guided by the patient's age, comorbidities, and symptoms according to the clinical judgment of the treating physician.5Ashchyan H.J. Butler D.C. Nelson C.A. et al.The association of age with clinical presentation and comorbidities of pyoderma gangrenosum.JAMA Dermatol. 2018; 154: 409-413Crossref PubMed Scopus (71) Google Scholar Maverakis et al appropriately question our “key point” that systemic corticosteroids are the therapeutic criterion standard for PG. This key point glosses over the nuance that we presented in the body of our article, and we appreciate the opportunity for clarification. The original diagnostic criteria for PG proposed by Su et al listed rapid response to systemic steroid treatment as the fourth minor criterion.6Su W.P. Davis M.D. Weenig R.H. Powell F.C. Perry H.O. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria.Int J Dermatol. 2004; 43: 790-800Crossref PubMed Scopus (411) Google Scholar From a historical perspective, systemic corticosteroids have been used as the therapeutic criterion standard against which novel steroid-sparing therapies have been measured. In our discussion regarding the management of PG, we noted that cyclosporine and tumor necrosis factor-α inhibitors are now considered first-line therapies for PG along with systemic corticosteroids. We emphasized that individual patient characteristics should guide the physician in selecting first-line therapy.3Jockenhofer F, Wollina U, Salva KA, Benson S, Dissemond J. The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum. Br J Dermatol. doi: 10.1111/bjd.16401, Accessed December 8, 2018.Google Scholar In conclusion, we thank Maverakis et al2Maverakis E. Ma C. Shinkai K. et al.Diagnostic criteria of ulcerative pyoderma gangrenosum: a delphi consensus of international experts.JAMA Dermatol. 2018; 154: 461-466Crossref PubMed Scopus (211) Google Scholar for their letter and their contributions to the literature on PG. We look forward to reading more of their work and, we hope, collaborating to shed light on this challenging disease. New validated diagnostic criteria for pyoderma gangrenosumJournal of the American Academy of DermatologyVol. 80Issue 4PreviewTo the Editor: We read with interest the review on neutrophilic dermatoses by Ashchyan et al1 and believe that it will be of significant value to the dermatologic community. To supplement their review, there are 2 additional viewpoints that we would like to highlight, specifically, regarding the diagnosis and treatment of pyoderma gangrenosum (PG). Full-Text PDF

Neutrophilic dermatoses are a group of conditions characterized by the accumulation of neutrophils in the skin and clinically presenting with polymorphic cutaneous lesions, including pustules, bullae, abscesses, papules, nodules, plaques and ulcers. In these disorders, the possible involvement of almost any organ system has lead to coin the term ‘neutrophilic diseases’. Neutrophilic diseases have close clinicopathological similarities with the autoinflammatory diseases, which present with recurrent episodes of inflammation in the affected organs in the absence of infection, allergy and frank autoimmunity. Neutrophilic diseases may be subdivided into three main groups: (1) deep or hypodermal forms whose paradigm is pyoderma gangrenosum, (2) plaque-type or dermal forms whose prototype is Sweet’s syndrome and (3) superficial or epidermal forms among which amicrobial pustulosis of the folds may be considered the model. A forth subset of epidermal/dermal/hypodermal forms has been recently added to the classification of neutrophilic diseases due to the emerging role of the syndromic pyoderma gangrenosum variants, whose pathogenesis has shown a relevant autoinflammatory component. An increasing body of evidence supports the role of pro-inflammatory cytokines like interleukin (IL)-1-beta, IL-17 and tumour necrosis factor (TNF)-alpha in the pathophysiology of neutrophilic diseases similarly to classic monogenic autoinflammatory diseases, suggesting common physiopathological mechanisms. Moreover, mutations of several genes involved in autoinflammatory diseases are likely to play a role in the pathogenesis of neutrophilic diseases, giving rise to regarding them as a spectrum of polygenic autoinflammatory conditions. In this review, we focus on clinical aspects, histopathological features and pathophysiological mechanisms of the paradigmatic forms of neutrophilic diseases, including pyoderma gangrenosum, Sweet’s syndrome, amicrobial pustulosis of the folds and the main syndromic presentations of pyoderma gangrenosum. A simple approach for diagnosis and management of these disorders has also been provided.

Atopic dermatitis is one of the most prevalent and one of the most studied skin diseases. Despite extensive investigations, it is however still poorly understood. Its denomination is questionable, its definition is imprecise and controversial, and its pathophysiology remains obscure. The onset and the course of atopic dermatitis imply many factors which belong to the skin itself, to internal systems and to the environment. It can be concluded that atopic dermatitis does not represent a disease in the usual sense, but the common cutaneous denominator of skin abnormalities, internal dysfunctions and external influences. The term “Skin-Disease”, modelled on the psychoanalytic concept of “Skin-Ego”, could be proposed to express this novel conception of atopic dermatitis

Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal polymorphonuclear leukocytes. The main clinical forms of ND include Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and their atypical or transitional forms. ND are often idiopathic, but they may be associated with myeloid hematologic malignancies (Sweet syndrome), inflammatory bowel disease or rheumatoid arthritis (pyoderma gangrenosum), and monoclonal gammopathies (erythema elevatum diutinum, subcorneal pustular dermatosis). The possible infiltration of internal organs with neutrophils during the setting of ND underlies the concept of a neutrophilic systemic disease. ND may be seen as a polygenic autoinflammatory syndrome due to their frequent association with other autoinflammatory disorders (monogenic or polygenic) and the recent published efficacy of interleukin-1 blocking therapies in their management.

Congenital erosive and vesicular dermatosis is a rare syndrome first described by Cohen et al in 1985. Most of the 18 cases published have been reported in premature newborns. Affected babies typically present with erosions and vesicles that tend to heal shortly after birth with reticulated scaring. We report an additional case, followed up for 5 years, in which we excluded a pathogenic mutation in the TP63 gene.

The prevalence of metastatic basal cell carcinoma (MBCC) varies between 0.0028% and 0.55% of all cases. In total, more than 300 MBCC have been reported in the literature. We report the case of a 72 year old lady, who presented in September 2009 with a 10-year history of a progressively growing, giant, facial basal cell carcinoma (BCC). Clinical and imaging evaluations identified large local invasion with bone and meningeal involvement. Treatment consisted of an extensive surgery including left eye exenteration and meningeal resection followed by radiotherapy. A solitary lung metastasis was identified five months after the primary tumor resection. As the lesion remained solitary but had increased in size five months later, the patient finally accepted a surgical resection. A right upper-lobe pneumonectomy was performed and pathologic examination confirmed the metastasis as a MBCC.

Prurigo nodularis is a pruritic dermatosis of unknown origin. Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukaemia/lymphoma. HTLV-1 is not considered to be a cause of prurigo nodularis. A 52-year-old black man, from the French West Indies, who had had prurigo nodularis for 12 years, presented with a distinct micropapular eruption with the typical pathological picture of epidermotropic T-cell lymphoma. Based on HTLV-1-positive serology and monoclonal integration of HTLV-1 we diagnosed smouldering adult T-cell leukaemia/lymphoma. Re-examination of previous skin biopsies revealed that the disease had been evolving for 12 years. Treatment with alpha-interferon, 3 x 106 units three times a week, associated with zidovudine, 1 g daily, resulted in complete remission within 4 months. When investigating a prurigo nodularis, we therefore recommend: (i) performing HTLV-1 serology if the patient comes from an endemic area; (ii) if positive, performing CD25 staining and looking for a HTLV-1 clonal integration; and (iii) if positive, using a treatment targeting HTLV-1.

The quest for clarifying the pathophysiology of atopic dermatitis (eczema) has lasted for 25 centuries. Yearning to discern the primum movens of atopic dermatitis, physicians aimed to identify the curative therapy. Recent scientific efforts has brought to the light an ever-growing amount of interplaying pathophysiologic factors, including the epidermal barrier, the digestive flora, food, early infections and antigenic stimulations, and innate and adaptive immune response; however, overfocusing on some of these factors, along with misconceptions about the benefit/risk balance of topical therapies, has sometimes led topical therapies being disregarded. Reviewing the history of pathophysiologic concepts, we aim to return topical therapies to the center of the clinical management of atopic dermatitis.

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