By Abby Van Voorhees, MD, March 01, 2012
In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with Emmanuella Guenova, MD, about her recent Archives of Dermatology article, “Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab.”
Dr. Van Voorhees: What previously has been known about the underlying pathogenetic and immunologic alterations in pyoderma gangrenosum (PG)?
Dr. Guenova: Pyoderma gangrenosum is considered to be an idiopathic disease. In 25-50 percent of the patients, an underlying immunologic abnormality is currently favored given its frequent association with systemic disease with a suspected autoimmune or autoinflammatory pathogenesis.
Unfortunately, there is no currently available specific biomarker for PG, and the diagnosis is predominantly based on the clinical appearance. Pathology results alone are not sufficient but are supportive for the diagnostic process. In a recent issue of the JAAD (64(5):950-954) Hadi and Lebwohl published a very comprehensive review of the literature and proposed strict diagnostic criteria for PG, based on anatomical location, clinical ulcer features, and associated disease.
Dr. Van Voorhees: How frequently is PG associated with other systemic illnesses? Can you remind us of these various autoimmune processes?
Dr. Guenova: Wines et al. (MedGenMed 3(3):6) and Crowson et al (J Cutan Pathol 30(2):97-107) published independently in 2001 and 2003, respectively, large reviews on this topic. According to them, approximately 15 percent of the patients with PG also have inflammatory bowel disease. Around 35 percent will present with arthritis. The percentages are far smaller for paraproteinemia, hematological malignancies, and some seldom-seen humoral and cellular immune abnormalities such as abnormal neutrophil or monocytes function. All of these diseases have been reported as associated conditions, but none of the findings have been demonstrated consistently in larger patient collectives and it is not clear whether there is a causal relation or whether some are detected “just by chance.”[pagebreak]
Dr. Van Voorhees: Are there different types of PG? Are there different associations with each of these various subtypes?
Dr. Guenova: Today, PG can be classified into four main clinical-pathological variants: ulcerative, pustular, bullous and vegetative PG. The first description of the bullous pyoderma dates back to 1972, when Perry and Winkelmann described the case of a painful superficial dermatosis in three patients with leukemia (Arch Dermatol 106(6):901-905). Since then, other cases of pyoderma patients with associated hematological malignancies have been reported in the literature and most of them proved to have bullous type of PG.
Indeed, the more frequently present ulcerative PG is either idiopathic or associated mainly with intestinal bowel disease, while the bullous PG is considered to be the variant of PG that can be associated with hematological malignancies.
Dr. Van Voorhees: Prior to your report, what therapies have been utilized in the treatment of this frustrating disorder?
Dr. Guenova: In the initial stage of the disease, corticosteroids, and calcineurin inhibitors, mostly tacrolimus, are largely used as topical agents. Good results have been achieved in some patients using intravenous immunoglobulins, plasmapheresis, or clofazimine. Additionally, various systemic immunosuppressive regimens have been implemented in the treatment of pyoderma gangrenosum. These often have a serious adverse event profile. For example, high-dose systemic corticosteroids, azathioprine, methotrexate, cyclosporine, mycofenolat mofetil, thalidomide, cyclophosphamide, infliximab, etanercept, etc., are successful in some patients, but not in general.
Dr. Van Voorhees: Tell us a little about your patient. What about her ulcer made you think of using an IL-12/23 compound for treatment? Was it successful? Has it been tried in other patients with other subtypes of PG?
Dr. Guenova: Our patient was a 37-year-old Caucasian woman with recalcitrant PG on the leg. First signs of the disease had started four weeks earlier and systemic treatment with prednisolone has been unsuccessful. Clinical examination revealed a growing skin ulcer with sharply demarcated bluish undermined margins on the left pretibial region. At the time of presentation, there was no sign of associated autoimmune disease, however Crohn’s disease was suspected in early childhood.
As we discussed above, unfortunately there is no predictive factor for personalized medicine, which can help choose the best treatment option with a highest likelihood of success in every individual patient with PG. That means: from all available and previously reported treatment options, we were supposed to pick one out, following the “trial and error” principle.
Indeed, some common clinical and histological clues for PG were the protagonists of our hypothesis of ustekinumab as a possible treatment option for this disease. Namely, a needle prick of the skin can elicit new lesions in PG-prone patients. This so-called “pathergy phenomenon” is regarded to be a clue for neutrophilic dermatoses, one of those being PG. Indeed, histological characteristics of PG are prominent infiltrations of neutrophils followed by hemorrhage and necrosis of the epidermis.
Ustekinumab is a monoclonal antibody, directed against the IL-12/IL-23p40 subunit. IL-23 plays a critical role in driving inflammation associated with IL-17 production and especially neutrophil recruitment. Association of the IL-23-pathway with multiple chronic inflammatory disorders was shown recently. Pyoderma gangrenosum has abundant neutrophilic infiltration, and is sometimes associated with autoinflammatory and autoimmune disorders. Hence our hypothesis, that PG might be driven by a pathogenetic mechanism similar to that of inflammatory bowel diseases or psoriasis.
Having all this in mind, we first performed translational research studies on a skin sample from our patient. Indeed, our first analyses demonstrated IL-23 dominated infiltrate in the lesion. This finding strongly encouraged us to choose ustekinumab as a next treatment option for our patient. After 14 weeks of treatment, the PG lesion had healed completely.
This exciting first data encouraged us to start an investigator-initiated trial on ustekinumab and PG. The study is still in progress, so we do not have more new data yet. As a first step, the objective of our study is to evaluate ustekinumab in the treatment of ulcerative PG. All other forms (pustular, bullous, and vegetative PG) will be excluded from the first pilot study.
We hope after completion, this study might specify a new concept for both the pathophysiology and treatment of PG, and will help us better understand the potential of ustekinumab as a therapeutic agent in human inflammatory and autoimmune disorders.
Dr. Guenova is a dermatologist in the departments of dermatology at Eberhard Karls University in Tbingen, Germany, and Harvard Skin Disease Research Center, department of dermatology, Brigham and Women’s Hospital in Boston. Her article was published in the Archives of Dermatology, 147(10):1203-1205 (October 2011). doi:10.1001/archdermatol.2011.168.