Introduction

Macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymfohistiocytosis (HLH) is poorly described life-threatening condition. It is caused by excessive activation of immune system with subsequent proinflammatory state resulting in multiorgan involvement. Clinically, MAS is characterized by fever, cytopenia, hepatosplenomegaly and elevated circulating ferritin. MAS can develop into acute liver failure (ALF) with poor prognosis.

Aims & Methods

We retrospectively analysed patients referred to our transplantation centre for ALF in whom the diagnosis of MAS was confirmed by histology. We focused on diagnosis leading to MAS, survival, transplantation outcome and clinical, laboratory and histological findings.

Results

From January 2005 to November 2022, we found eight patients with MAS referred to our centre for ALF. The underlying condition was EBV infection in five cases and adult Still disease in three cases. All eight patients had strongly elevated circulating ferritin (in average 19321 μg/l), leukocytosis and thrombocytopenia. All patients except one had at least one negative bone marrow or lymph node examination prior to definitive diagnosis of MAS. Seven patients were treated with high-dose corticosteroids. Four patients met King's College criteria for urgent liver transplantation. Two of them were transplanted. Despite intensive therapy based on mechanical ventilation, continuous renal replacement therapy and circulation support, their clinical condition further deteriorated and all four patients died on average 34 days after symptom onset of multiorgan failure. At the autopsy, hemophagocytic macrophages have been described in multiple organs. Four patients who responded to corticosteroid therapy are in long-term remission after specialized haematological treatment with etoposide.

Conclusion

Macrophage activation syndrome represents rare cause of acute liver failure with high mortality, it is difficult to diagnose and even harder to treat. Our case series suggests that when the patients meet King's College criteria, they die despite the successful liver transplant. Therefore, it is important to carefully consider liver transplantation in these patients.

Introduction

Combination with an advanced therapy (AT) and immunomodulator (IMM) is commonly used to optimise outcomes in Crohn’s disease (CD) and ulcerative colitis (UC). However, the comparative benefit of IMM co-therapy with different ATs and optimal duration of IMM co-therapy are unclear.

Aims & Methods

We aimed to determine the impact of IMM co-therapy on AT persistence.
We interrogated the Persistence Australian National IBD Cohort (PANIC5) registry of CD and UC patients from 2007-2021. The PANIC registry includes 100% of AT prescribing data in Australia. Non-persistence was defined as failure to dispense prescriptions for over six months. Co-therapy with IMM was defined as concurrent dispensing of a thiopurine (azathioprine or mercaptopurine) or methotrexate during AT use. Kaplan-Meier survival curves were generated and compared using the log-rank test. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).

Results

31,967 CD patients and 13,492 UC patients were included. 44.2% of CD and 37.9% of UC patients had received co-therapy with IMM. IMM co-therapy increased persistence of infliximab in both CD (median Kaplan Meier survival time 50.0 [95% CI 47.3-52.7] vs 27.0 months [95% CI 24.5-29.5], HR=0.68, p<0.001) and UC (35.0 [95% CI 31.4-38.6] vs 18.0 [95% CI 16.2-19.8], HR=0.71, p<0.001). Similarly, IMM co-therapy increased persistence of adalimumab in both CD (48.0 [95% CI 45.6-50.4] vs 25.0 [95% CI 23.3-26.7], HR=0.67, p<0.001) and UC (25.0 [95% CI 19.2-30.8] vs 17.0 [95% CI 14.2-19.8], HR=0.77, p<0.001). IMM co-therapy did not significantly affect persistence of vedolizumab in CD (33.0 [95% CI 27.0-39.0] vs 36.0 [95% CI 31.1-40.9], p=0.43), vedolizumab in UC (45.0 [95% CI 38.7-51.3] vs 48.0 [95% CI 41.8-54.2], p=0.11) or ustekinumab in CD (median survival and 95% CI unable to be calculated as event rate >50%; p=0.13). Ustekinumab was not approved for UC in Australia before 2021; thus no UC data were available.
Subgroup analysis showed a significant difference in anti-tumour necrosis factor inhibitor (TNFi) persistence across CD patients based on IMM timing during TNFi therapy (Table 1; p<0.001). CD patients who had at least three months of IMM before de-escalation had better persistence compared to those who stopped IMM within the first three months of TNFi (96.0 vs 19.0 months, p<0.001). Continuous IMM use during TNFi therapy had intermediate persistence (37.0 months, 95%CI 33.1-40.8). Patients who were not treated with IMM initially but started IMM in the last three months of therapy had the worst persistence (4.0 months, 95%CI 2.7-5.3). A similar pattern was seen in UC (Table 1). There was no difference between thiopurine and methotrexate co-therapy in either CD (p=0.41) or UC (p=0.45).

Table 1 – Median Kaplan Meyer persistence, stratified by timing of immunomodulator usage during anti-tumour necrosis alpha inhibitor (TNFi) therapy

Conclusion

IMM co-therapy significantly improved persistence of TNFi, but not vedolizumab or ustekinumab in both CD and UC. Discontinuing IMM within three months of commencing TNFi was associated with reduced persistence compared to continuing initial co-therapy for longer before de-escalation.

Disclosure

RWL has served as an advisory board member for AbbVie, Aspen, BMS, Celgene, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences and Takeda, and has received research funding from Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer and MRFF.