Israel Medical Association Journal

Background: Pyoderma gangrenosum is an uncommon ulcerative cutaneous condition associated with inflammatory bowel disease. PG[1] occurs rarely in IBD[2] patients and there are insufficient data on the clinical manifestations of this disease with IBD.

Objective: To determine the incidence, clinical manifestations and treatment of PG in patients with IBD and the connection to IBD, its activity and extent.

Methods: All patients hospitalized with IBD at a university hospital during a 20 year period were evaluated for the occurrence of PG.

Results: Of 986 patients hospitalized for IBD 6 suffered from PG (0.6% incidence). Their average age was 37 with equal sex distribution and equal distribution of Crohn’s disease and ulcerative colitis. PG appeared 6.5 years on average after diagnosis of IBD in all patients. The development of PG correlated with significant clinical exacerbation of IBD, the majority having active colitis at the onset of the PG. Extra-intestinal manifestations of IBD occurred in half the patients (sacroiliitis, peripheral arthritis and erythema nodosum). Pathergy was not elicited in any patients. Four patients had multiple skin lesions, frequently on the lower extremities. Diagnosis was made by skin biopsy in four patients. There was little correlation between amelioration of IBD and the skin lesions. Treatment consisted of high dose steroids and immunomodulatory drugs (cyclosporine, azathioprine and dapsone) in conjunction with topical treatment.

Conclusions: PG is a rare extra-intestinal manifestation of IBD that coincides with the exacerbation of the intestinal disease but does not always respond to treatment of the bowel disease.

Sepsis is an infection-induced inflammatory syndrome that results in a complex network of adaptive and maladaptive alterations in homeostatic mechanisms. Severe sepsis, defined as sepsis associated with acute organ failure, is a serious disease with a mortality rate of 30–50%. The coagulation system, through complex interactions, has an important role in the final outcome of the sepsis-induced inflammatory cascade. A fine and delicate balance that normally exists between anticoagulant mechanisms and the procoagulant response is altered in sepsis. Activated protein C, an endogenous vitamin K-dependent anticoagulant, plays a major role in the down-regulation of the procoagulant arm. It also possesses anti-inflammatory properties. Endothelial damage during sepsis impairs the endothelium-dependent activation of protein C, thus shifting the balance towards thrombosis. This shift may contribute to the development of sepsis-related multi-organ failure. Evidence suggesting that activation of the coagulation system may contribute to sepsis-related morbidity and mortality has led to extensive research attempting to correct the hemostatic defects seen in septic patients. Indeed, a recent randomized controlled trial demonstrated a reduction in overall mortality in patients with severe sepsis treated with APC[1]. In this review we discuss the pathogenesis of the coagulopathy of sepsis, as well as the new therapeutic approaches aimed at correcting the defects in the coagulation system.

Sepsis is an inflammatory syndrome caused by infection. Consequently, anti-inflammatory therapies in sepsis have been a subject of extensive research and corticosteroids have been used for years in the therapy of severe infections. However, studies conducted in the 1980s failed to demonstrate any beneficial effects of high dose, short-term steroid therapy in sepsis and this therapy was therefore abandoned during the last decade. Recently, a new concept has emerged with more promising results - low dose, long-term hydrocortisone therapy – and this approach is now being evaluated in the treatment of septic shock. It is supported by the observation that many sepsis patients have relative adrenal insufficiency. Moreover, the anti-inflammatory effects of steroids and their ability to improve reactivity to catecholamines further contribute to their effects in sepsis. Large randomized clinical trials will be required to determine the exact role of corticosteroids in septic shock.

The etiology of inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, is uncertain. Studies of specific environmental factors and immune dysfunction have provided limited insight into disease pathogenesis. There is ample evidence that these diseases are in part the result of genetic predisposition. The early search for candidate genes focused on genes involved in the regulation of immune function.

Recent genome wide searches reported several susceptibility loci for Crohn’s disease and ulcerative colitis. The recent identification of the IBD1 gene (NOD2) with mutations that are associated with susceptibility to Crohn’s disease will have a major impact on the understanding of the genetics of this disease.
 

Background: Rectal administration of iodoacetamide induces colitis by blocking sulphhydryl groups and generating inflammatory mediators. Thalidomide, a non-barbiturate hyp­notic, also has an anti-inflammatory effect, presumably by suppressing the production of tumor necrosis factor alpha. In patients with Crohn’s disease, neutralization or suppression of TNFá reduces inflammation.

Objectives: To evaluate the effects of thalidomide in a model of experimental colitis.

Methods: Colitis was induced in rats by intracolonic administration of 3% iodoacetamide. In the treatment group, thalidomide 50 mg/kg was given daily by gavage and continued for 7 days until the rats were sacrificed. Their colons were then processed for wet weight, lesion area, weight of mucosal scraping, myeloperoxidase activity and histology. Serum levels of TNF were determined.

Results: Colonic wet weight, lesion area, myeloperoxidase activity and serum levels of TNFá were significantly lower (P<0.05) in the treatment group (iodoacetamide + thalido­mide) than the control group (iodoacetamide only). Histologi­cally, colonic inflammation in the treated group was markedly decreased.

Conclusions: Thalidomide effectively decreases colitis induced by iodoacetamide. The mechanism is probably associated with inhibition of TNFá, and should be further studied.