Systemic therapy
For patients with a more widespread disease or rapidly progressive course, systemic treatment is mandatory. Corticosteroids, like prednisolone, 1 to 2 mg per kg per day, are widely used for initial therapy [
2,
4,
25]. Trying an initial high-dose therapy aims to prevent progression and rapidly stop inflammation. Action of pulse therapy with suprapharmacological doses of corticosteroids [1 g of methylprednisolone] is faster [
40]. Since this treatment may cause fatal side effects in patients with cardiovascular disease on diuretics, patients have to be carefully selected.
Ciclosporin A is an inhibitor of T-lymphocyte activation. Immunosuppressive therapy with ciclosporin A has become an accepted treatment for widespread PG after initial steroids or in combination with steroids. In many cases, steroids can be completely be replaced by ciclosporin A [
41,
42]. Doses of 2 to 3 mg ciclosporin A/kg body weight and day show efficacy in PG [
43]. During therapy with ciclosporin A it is necessary to control blood pressure and creatinine. The drug induces an early response but has no impact on the incidence of recurrences [
44]. Therefore, combination with other drugs can become necessary even after initial response to ciclosporine A monotherapy.
Sulfa drugs are useful in milder cases of PG. The combination of steroids with diaminodiphenylsulfone [dapsone] up to 200 mg daily [only for patients with a normal glucose-6-phosphate dehydrogenase level] is the most popular. Dapsone inhibits neutrophil migration and production of reactive oxygen species and exerts a variety of other anti-inflammatory activities [
4,
45]. Formation of met-hemoglobin needs regular monitoring during this treatment.
Clofazimine is a scavenger of hypochlorus acid, thus reducing the chlorination of proteins by neutrophils. It stimulates phagocytosis and superoxide production and has a direct antibacterial activity as well. In my opinion the efficacy of clofazimine 300 to 400 mg/day is comparable to that of sulfa drugs as dapsone. A common side effect is hyperpigmentation [
46].
Thalidomide shows immunomodulatory activity such as suppression of tumour necrosis factor-alpha, basic fibroblast growth factor and neutrophil chemotaxis. It was used in combination with steroids [
47]. Thalidomide is teratogenic and therefore absolutely contraindicated in fertile women.
Colchicine, an inhibitor of the spindle-apparatus with anti-inflammatory properties, was employed in two patients with PG from Greece [
48]. It may be used as a single agent or in combination with prednisolone depending on the severity of disease. Gastrointestinal adverse effects may limit its use.
Azathioprine [100–150 mg/day] is a cytotoxic drug usually administered for its steroid-sparing effects. Its action is delayed of at least about 2 to 4 weeks. Blood counts and transaminases should be monitored [
2,
4,
45]. There is a wide inter-individual variability in azathioprine metabolism due to a common genetic polymorphism of thiopurine methyltransferase, a major metabolizing enzyme of azathioprine. Azathioprine and sulfasalazine are a good choice when the underlying disease is ulcerative colitis or Crohn's disease.
Another cytotoxic drug that has been used in PG is cylophosphamide. Cyclophosphamide pulse therapy followed by either azathioprine or methotrexate is an effective treatment in steroid-refractory Crohn's disease. In cases of Crohn's associated PG may achieve long term remissions with this regimen lasting for up to 30 months [
49].
Mycophenolate mofetil is an inhibitor of the purin synthesis selectively reducing the proliferation of T- and B-lymphocytes. With the dosage of 2 g/day there is a very low risk of renal and hepatic side effects. Mycophenalate mofetil was used in peristomal PG and other refractory cases [
50,
51]. Recently, a case of staphylococcal and pseudomonal sepsis has been reported in a mycophenolate mofetil treated PG-patient [
52].
Enteric-coated mycophenolate sodium [ECMPS] is an advanced formulation delivering mycophenolic acid. At a dosage of 720 mg ECMPS exhibits equivalent mycophenolate acid exposure to mycophenolate mofetil 1000 mg. Recent trials demonstrated that ECMPS has a similar safety profile than mycoephenolate mofetil [
53].
Tumour necrosis alpha inhibitor infliximab was reported to be effective in PG associated with inflammatory bowel disease at a dosage of 5 mg/kg body weight. Infliximab is given by infusion at weeks 0, 2 and 6, and every 8 weeks thereafter. The chimeric antibody is usually combined with low-dose methotrexate for Crohn's disease [
54,
55]. In a small series including 4 patients with fistulating Crohn's disease and PG infliximab was given either as a single infusion or a series of three infusions at a dosage of 5 mg per kg body weight/day. All patients demonstrated a rapid healing of PG within 4 weeks after starting the treatment. Healing was complete and relapses were not observed [
56]. In another study four patients with PG-ulcers and Crohn's disease showed a marked improvement after a single infusion of infliximab [
57]. Since infusion reactions can occur in 3% to 17% of patients with Crohn's disease that are antibody associated the concurrent administration of steroids and the use of immunosuppressant like methotrexate or azathioprine has been recommended [
58].
The positive effect on PG has also seen with another tumour-necrosis factor alpha antagonist etanercept, a fusion protein [
59]. Etanercept is applied by subcutaneous injections of 50 mg twice weekly. Because there is a risk of reactivation of tuberculosis during anti-tumour necrosis alpha therapy patients have to be screened for tuberculosis before and during treatment [
58].
Tacrolimus, a selective calcineurin inhibitor, was used at low dosages of 0.1 mg per kg body weight/day. The treatment was monitored to maintain a serum level of between 4 and 6 ng/L. Complete clearance of skin lesions was observed in two patients with underlying ulcerative colitis [
60].
Since PG is a neutrophilic disease, removal of activated neutrophiles should improve the symptoms. Leukocytapheresis, where white blood cells are removed extracorporeal, and granulocyte adsorptive apheresis, a more selective procedure, have been used in single cases with success. These methods have been used in single cases unresponsive to systemic standard therapy with success [
61,
62].