A Case of Colchicine-refractory Familial Mediterranean Fever and Lessons for IBD

Abstract

Purpose: A 22-year-old woman with familial Mediterranean fever (FMF) treated with colchicine and a strong family history of Crohn's disease presented with severe lower abdominal pain, nausea, vomiting and fevers up to 104 F. The differential diagnosis for her symptoms included Crohn's, ulcerative colitis, appendicitis, intussusception, cholecystitis, pelvic inflammatory disease, peptic ulcer and colchicinerefractory FMF flare. Physical exam was unremarkable, except for abdominal tenderness predominantly in the RLQ with modest guarding. Laboratory evaluation showed normal electrolytes, CBC, amylase/lipase, TFTs, PTH and vitamin levels. Stool and urine cultures were negative. Gynecologic evaluation, including transvaginal ultrasound, was normal. MRE showed no evidence of bowel wall inflammation or obstruction. Upper endoscopy biopsies showed a chronic chemical gastropathy with no Barrett's, no H. pylori, and normal jejunal villous architecture. Colonoscopy was normal, with normal terminal ileum and colonic mucosal biopsies. Given the recurrence of symptoms and greater than one febrile attack per month, the patient was deemed to have colchicine-resistant FMF and was referred to rheumatology for initiation of anti-IL1β biologic therapy. Discussion: FMF is a hereditary auto-inflammatory disease characterized by periodic fevers and serositis triggered by deregulated inflammasome production of IL-1β. With peritonitis, abdominal pain and fever being the most common manifestations, gastroenterologists need to consider FMF in the DDX of IBD-associated inflammatory symptoms. FMF is caused by mutations in the MEFV gene encoding pyrin. Mutant pyrin fails to regulate caspase-1 activity and additionally activates NFκB. Careful follow-up of FMF patients is critical as they are at increased risk of developing late-onset IBD. This increased risk for IBD may be related to the close association of the CD-susceptibility gene NOD2 with the MEFV gene on chromosome 16. Pyrin also interacts with the innate immune intracellular NOD-like receptor Nlrp3, which has been shown to contribute to Crohn's susceptibility. Nlrp3 is a crucial regulator of intestinal homeostasis, mediating assembly of the inflammasome complex in the presence of microbial ligands, triggering caspase-1 activation and secretion of IL-1β and IL-18. Although colchicine is the first line of treatment for FMF, case reports have shown some efficacy with anti-TNF biologics. However, IL-1β biologics are emerging as the best second-line therapy for colchicine-resistant FMF patients. Despite the FMF and IBD overlap in inflammasome deregulation of the IL-1β pathway, studies are lacking on the effectiveness of colchicine or anti-IL-1β therapy for IBD.