Pyoderma gangrenosum (PG), classified as a neutrophilic dermatosis, is an ulcerative cutaneous condition of unknown origin (1). It predominantly occurs between the second and fifth decades of life. Pyoderma gangrenosum affects both sexes, with a female predominance. The incidence is around 3 to 10 per million per year (2).
The pathogenesis of the disease is still unclear, but a neutrophilic dysfunction was suggested. Some defects in chemotaxis or hyperreactivity in neutrophil trafficking and some aberrant integrin oscillations on neutrophils seem to be implicated (1,3). Moreover, a multifactorial origin is likely with a genetic predisposition, environmental, paraneoplastic, or paraimmune factors, and possible infectious triggers (1).
The diagnosis of PG is proposed in the presence of a necrolytic cutaneous ulcer with an irregular undermined border, painful and progressing rapidly, and by excluding other causes of cutaneous ulcerations (1). Pyoderma gangrenosum is associated with an underlying disease in 50% to 70% of cases (1,3). All patients with PG should undergo extensive evaluation to rule out associated disorders before beginning therapy that may include corticosteroids, antimicrobial agents, steroid-sparing immunosuppressive agents, and immunomodulating drugs (1,3).
In adults, PG is associated with inflammatory bowel diseases (IBDs) in 10% to 15% of cases (4), seronegative rheumatoid arthritis (5), and lymphoproliferative disorders (2,6,7). Exceptionally, cases of PG associated with chronic viral (8) and autoimmune hepatitis (AIH) (9,10) have been reported in the adult population. We describe the case of a young girl with a history of type 2 AIH who developed PG at the age of 14 years. Her PG was refractory to classical immunosupressive therapy, necessitating the introduction of anti-tumor necrosis factor (TNF)-α drugs.
A 14-year-old girl with a previous medical history of AIH developed PG. A type 2 AIH was diagnosed at the age of 3 years (low albumin at 29 g/L, increased IgG at 24 g/L, and positive LKM1 antibodies). At that time, the workup revealed altered liver function tests (ALT 193U/L, AST 322U/L, γGT 55U/L, total and conjugated bilirubin, respectively, 43 and 21 μmol/L, and normal international normalized ratio [INR]). Liver ultrasound revealed heterogeneous hepatomegaly with signs of hyperechogenicity. Liver biopsy showed severe active hepatitis with extensive fibrosis associated to hepatic cell necrosis (Fig. 1A). The patient was treated with oral cyclosporine during 7 months, and then with azathioprine, in combination with prednisone for 6 months, according to a previously established protocol applied in our institution (11). Regular follow-up over a period of 10 years showed normal liver function tests and ultrasound results.
At the age of 14 years, the patient developed quickly profound, painful, bullous, and vesiculous ulcerations on anterior faces of both legs (Fig. 2A). Dermatological evaluation and skin biopsy permitted the confirmation of a diagnosis of PG. At that time, the liver function was strictly normal, and a liver biopsy revealed the absence of inflammatory infiltrate and a major improvement in the liver fibrosis in comparison with the results of the initial biopsy (Fig. 2B). Due to known association of PG and IBD, upper and lower endoscopies were performed but were normal. Complementary investigations excluded other associated diseases, such as lymphoproliferative syndromes.
Treatment with ultrapotent topical steroids (clobetasol propionate), subcutaneous injections of triamcinolone, and topical tacrolimus 0.1%, led to only partial improvement of the skin lesions. Oral immunosuppressive therapy was required. However, the shift from azathioprine to mycophenolate mofetil (MMF), and the transient addition of cyclosporine or intravenous corticosteroids were useless because none of these used drugs permitted the induction of a significant improvement or a maintained remission of PG. At the age of 16 years, after the failure of controlling her PG with classical immunosuppressors, the patient was hospitalized for persistent and painful cutaneous ulcerations of the legs associated with a new ulceration of the left arm. A treatment with infliximab (doses of 5 mg/kg) was started, in addition to continuing the MMF. There was a decrease of the pain over the legs and major improvement after the first dose of infliximab (Fig. 2B). Three doses of the latter (weeks 0, 2, and 6) permitted a complete resolution, allowing stoppage of the medication. However, 5 weeks later, infliximab was started again due to recurrence of skin lesions (Fig. 2C). Eight doses of infliximab were administered, but the last administration provoked mild cutaneous rash and dyspnea. Then, a multidisciplinary team decided to shift the treatment to adalimumab because of the effective initial response to infliximab. To date, this antibody was administered every week subcutaneously at doses of 80 mg for the first 2 injections and of 40 mg for the following 4. This approach resulted in progressive healing of lesions and no recurrence of the hypersensitivity reactions. Liver function remains normal.
Autoimmune hepatitis is an inflammatory disease of unknown but probable multifactorial origin, with a genetic susceptibility, affecting predominantly females (female to male ratio of 4–9:1) (12). There are 2 types of AIH (type 1 and type 2). Forty percent of AIH type 1 are diagnosed <18 years (mean 10 years), and 80% of type 2 AIH are evidenced <18 years (mean 6.5 years) (12). The first type is characterized by the presence of autoantibodies to smooth muscle and/or nucleus. The second type includes the presence of anti-liver kidney microsome (LKM1) and/or anti-cytosol (LC1) autoantibodies. However, 10% of AIH can occur without detectable autoantibodies (12).
Autoimmune hepatitis is known to be associated with several extrahepatic diseases, mainly with autoimmune (AI) conditions (12). The spectrum of diseases associated with AIH type 1 includes ulcerative colitis, Crohn disease, vasculitis, arthritis, thyroiditis, diabetes mellitus, hemolytic anemia, glomerulonephritis, and fibrosant alveolitis. Autoimmune hepatitis type 2 may be associated with AI enteropathy, autoimmune, polyendocrinopathy, candidiasis, ectodermal dystrophy syndrome, thyroiditis, diabetes mellitus, vitiligo, or lymphoproliferative syndromes. The association of AIH type 1 or 2 with celiac disease was also previously described in children (12).
Pyoderma gangrenosum is known to be potentially associated with an AI disease in 50% to 70% of cases (1,3). Some associations were described with IBD (10%–15% of cases) (4), seronegative rheumatoid arthritis (5), viral hepatitis (8), and lymphoproliferative disorders (including monoclonal gammopathies, leukemia, lymphoma, and myelodysplastic syndrome) (2,6,7).
Current knowledge suggests that PG is usually associated with type 1 rather than with type 2 AIH. In recently published literature, there are only 2 case reports relating to the association between AIH and PG (9,10). The first one concerns a 30-year-old woman with a previous medical history of AIH, who developed PG successfully treated with etanercept, oral corticosteroids, and topical creams (including corticosteroids) (9). However, the type of AIH was not mentioned by the authors, and few details about AIH features were described.
The second reported case concerns an 18-year-old male patient presenting a AIH type 1 diagnosed at the age of 15 years (10). After 1 year of treatment with prednisone (20 mg daily) achieving a controlled AIH, severe PG lesions occurred and were successfully treated with cyclosporine. Two years after the diagnosis of PG, a recurrence of the lesions led to further investigations revealing ulcerative colitis and primary sclerosing cholangitis. Despite addition of azathioprine and ursodeoxycholic acid, a liver transplant was necessary and was successfully performed. There are also earlier reported cases in 1970s and 1980s (13,14), in which precisions concerning the type of AIH were, at that time, not described. To our knowledge, there is no published case describing a relation between PG and AIH type 2 in the pediatric population.
Our patient had a good evolution of her AIH for many years and despite the appearance of PG, her liver function and liver ultrasound remained normal. Thus, it is interesting to highlight the absence of parallel evolution of both diseases, suggesting the absence of correlation between their severities. Furthermore, despite its severe form, the PG of our patient was not associated with “classical” AI diseases such as IBD until recently. However, PG increased the morbidity due to severe pain, recurrent infections of cutaneous lesions, and a poor quality of life. The refractory form was difficult to treat despite the addition of conventional immunosuppressive drugs, and required further anti-TNF-α medication.
Treatment of severe forms of PG can be successful with an anti-TNF-α medication (1,3). Because of our experience with infliximab, especially in patients with Crohn disease, we decided to start this treatment to try to control our patient's refractory PG. Infliximab may induce minor side effects including myalgias, rash, asthenia, upper respiratory tract infections, sinusitis, flushing, fever, and headache. More problematic side effects include the reactivation of latent Mycobacterium tuberculosis; reactivation of hepatitis B in chronic carriers; infusion reactions (by induction of anti-chimeric antibodies against infliximab), severe neutropenia and thrombocytopenia, demyelinating disorders, autoimmune antibody formation, and hepatotoxicity (15).
If minor hepatic abnormalities are common with the use of anti-TNF-α agents, severe hepatic side effects are rare (jaundice, hepatitis and cholestasis, AIH, and acute liver failure). However, a few cases of liver failure requiring liver transplantation or resulting in death have now been reported (16,17). Autoimmune hepatitis is one of the rare but increasing complications of treatment with infliximab recently reported in the adult population (15,16). According to Ozorio et al (15), a minimum of 10 cases of AIH had been reported to the manufacturer of infliximab up to 2003, 8 of which were considered either possibly or probably related to the drug. Treatment with prednisone (±azathioprine) showed success in normalizing the liver function tests, except in 1 case in which a liver transplant was required (16). Because the PG in our patient was refractory and difficult to treat despite the use of conventional immunosuppressive drugs, a trial of infliximab was performed, despite the risk of hepatotoxicity. An important concern in our patient was to avoid the occurrence of hepatic complications. Despite previous reports (16) concerning cases of provoked AIH even with concurrent use of an immunomodulator drug, we decided to continue the treatment with MMF.
This case highlights the association between AIH type 2 and PG. The absence of correlation between the clinical severities of both diseases is possible. Because of a certain degree of experience in pediatrics with anti-TNF-α therapy, this option was our first choice in this patient. To avoid potential hepatic side effects of this treatment, based on rare reported experiences, and the absence of data about anti-TNF-α efficacy as an AIH treatment, we combined another immunosuppressive medication (MMF) with the anti-TNF-α drugs. To date, after 8 doses of infliximab and 6 doses of adalimumab, the liver of our patient remains normal, and her PG has remitted.
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