Lane, T; (2016) The impact of cytokine modulation in acquired and inherited inflammatory disease and AA amyloidosis. Doctoral thesis , UCL (University College London).

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Abstract

Background Inflammatory disorders (IDs) cause significant morbidity. SAA and CRP are acute phase proteins used to diagnose and monitor IDs. SAA is also the precursor to AA amyloidosis (AAA), a serious complication of chronic inflammation, causing renal failure and poor quality of life (QoL). The aim of treatment is thus to prevent AAA or to halt its progression to renal failure, protect renal allografts, and restore QoL. Novel biological therapies have transformed the landscape, but their longer term effects are yet to be elucidated. Aims We set up a nurse-led clinic to explore safety and efficacy of modulation of cytokines IL-1 and IL-6 in patients with IDs and AAA, and studied the changing epidemiology of AAA. We also sought to investigate whether CRP was itself pro-inflammatory. Results Suppressing SAA using anti-IL-1 and anti-IL-6 agents resulted in stabilisation of amyloid deposits and in some, amyloid regression and improved renal function. Treatments were safe and effective in dialysis and renal transplantation, even where the underlying cause of AAA was uncertain. Improvement was seen in almost all anti-IL-1-treated CAPS patients. Common adverse events were infections. QoL improved when treatment was effective. Referral rates of AAA have remained steady whilst other types have increased. The commonest causes of AAA are changing; unknown aetiology has increased. Injection of purified CRP into volunteers did not provoke inflammation.  Conclusions Suppressing SAA by effectively treating the underlying ID can lead to improved renal function and regression of amyloid, even when the cause is uncertain. Anti-cytokine agents offer the possibility of targeted therapies to suppress systemic inflammation. Work reported here shows safety, even in dialysis and transplantation. AAA is becoming less common as some IDs have become easier to control. Single cytokine blockade has proved useful in AAA of unknown aetiology and treatment generally improves symptomatology and inflammation. CRP is itself not pro-inflammatory.

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