Off-label use of rituximab in autoimmune disease in the Top End of the Northern Territory, 2008-2016.

BACKGROUND: Rituximab, an anti-CD20 B-cell depleting monoclonal antibody, is increasingly prescribed off-label for a range of autoimmune diseases. There has not previously been an audit of off-label rituximab use in the Northern Territory, where the majority of patients are Aboriginal. AIMS: To evaluate retrospectively off-label rituximab use in autoimmune diseases in the Top End of the Northern Territory. METHODS: We performed a retrospective audit of 8 years of off-label rituximab use at the Royal Darwin Hospital, the sole tertiary referral centre for the Darwin, Katherine and East Arnhem regions. Electronic and paper records were reviewed for demographic information, diagnosis/indication for rituximab, doses, previous/concomitant immunosuppression, clinical outcomes and specific adverse events. RESULTS: Rituximab was prescribed off-label to 66 patients for 24 autoimmune diseases. The majority of patients (62.1%) were Aboriginal and 60.6% female. The most common indications were refractory/relapsing disease despite standard therapies (68.7%) or severe disease with rituximab incorporated into an induction immunosuppressive regimen (19.4%). Systemic lupus erythematosus was the underlying diagnosis in 28.8% of cases. A clinically significant response was demonstrated in 74.2% of cases overall. There were 18 clinically significant infections; however, 13 were in patients receiving concurrent immunosuppressive therapy. There was a total of nine deaths from any cause. CONCLUSION: Rituximab has been used off-label for a range of autoimmune diseases in this population with a high proportion of Aboriginal patients successfully and safely in the majority of cases.

Effects of antibiotics on expression and function of Toll-like receptors 2 and 4 on mononuclear cells in patients with advanced cirrhosis.

BACKGROUND & AIMS: Toll-like receptors (TLRs) are critical to innate immune responses. TLR4 recognises Gram-negative bacteria, whilst TLR2 recognises Gram-positive. We examined TLR expression and function in cirrhosis, and whether this is affected by antibiotic therapy. METHODS: Sixty-four subjects were included (23 controls and 41 Child-Pugh C cirrhotic patients). Thirty patients were taking norfloxacin or trimethoprim-sulfamethoxazole as prophylaxis against bacterial peritonitis and 11 were not. In a second study, 8 patients were examined before and after commencement of antibiotics. Monocyte expression of TLR2 and 4 was determined by flow cytometry. Monocytes from the patients with paired samples were stimulated using TLR ligands and TNF-alpha production measured. RESULTS: Patients not taking antibiotics had significantly decreased TLR4 expression compared with controls (0.74 vs. 1.0, p=0.009) and patients receiving antibiotics (0.74 vs. 0.98, p=0.02). There were no differences with regard to TLR2. In the patients with paired samples, TLR4 expression increased (0.74-1.49, p=0.002) following antibiotic use, whilst again, there was no change in TLR2 expression (0.99 vs. 0.92, p=0.20). TLR4-dependent TNF-alpha production increased following antibiotic use (1077 vs. 3620pg/mL, p<0.05), whilst TLR2-dependent production was unchanged. CONCLUSIONS: TLR4 expression is decreased in patients with Child-Pugh C cirrhosis, but is restored by antibiotics targeting enteric Gram-negative bacteria. TLR4-dependent cytokine production also increases significantly following antibiotic therapy. This suggests that the high incidence of Gram-negative infection in cirrhotic patients is in part due to down-regulation of the TLR4-dependant immune response and that the efficacy of antibiotic prophylaxis is contributed to by modulation of innate immunity.

Long-term outcome of patients treated with terlipressin for types 1 and 2 hepatorenal syndrome.

BACKGROUND: Studies suggest that terlipressin is effective in the treatment of hepatorenal syndrome (HRS). However, factors predicting response to therapy and the long-term outcome of patients have not been defined. METHODS: We reviewed all patients from our institution treated with terlipressin between July 1, 2001 and December 31, 2005 for HRS. Follow up continued until June 30, 2006. HRS was defined according to the International Ascites Club. The following data were retrieved: age, gender, etiology of liver disease, Child-Pugh score, HRS precipitant, therapy duration, creatinine at day 0 and end of treatment, adverse events, and patient outcome. RESULTS: Sixty-nine patients were included. Forty-nine episodes (71%) of HRS were type 1, and 20 episodes (29%) type 2. Forty-one (59.4%) patients responded to terlipressin. Two variables predicted renal function improvement: type 1 HRS and age. Twenty-one (30.4%) patients survived; 17 (81%) had type 1 HRS while four (19%) had type 2 HRS (P = 0.27). The only factor predicting transplant-free survival was type 1 HRS. No patients with type 2 HRS survived without transplantation (P = 0.02). CONCLUSIONS: The only factor predicting transplant-free survival following terlipressin therapy is the presence of type 1 HRS. Therefore, it is difficult to justify the use of this drug in patients with type 2 HRS who are not liver transplant candidates.